Professional Documents
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Primer On Nephrology
Primer On Nephrology
Editor
Primer
on Nephrology
Second Edition
123
Primer on Nephrology
Mark Harber
Editor
Primer on
Nephrology
Second Edition
Editor
Mark Harber
Department of Renal Medicine
UCL
London, UK
This Springer imprint is published by the registered company Springer Nature Switzerland AG
The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland
V
Preface
of global warming without seeming to resort to hyperbole. But the bottom line from
the 6th International Panel on Climate Change was that “climate change is real, man
made, rapid and unprecedented. That temperatures will continue to rise in all scenar-
ios. Species extinction, widespread disease, unlivable heat, ecosystem collapse and cities
menaced by rising seas will become painfully obvious before a child born today turns
30.” Or put it another way, approximately 1 billion, nearly half the world’s population
of children, currently live in regions at extreme risk of environmental stresses from
flooding to drought, extreme heat, ecosystem collapse, and famine. Low-income coun-
tries will bear the brunt initially, but high-income countries are already seeing extreme
weather events and a dawning of the disorder this will cause. The multitude of ways
climate change will affect patients with kidney conditions are not difficult to imagine,
but supply-chain disruption including energy, food, and water will occur. In 2019, there
were estimated to be approximately 80 million refugees or internally displace individu-
als. Extremes of heat, flooding, and famine will inevitably contribute to a huge increase
in this number. Optimizing the care of patients with lifelong CKD or those receiving
renal replacement therapy as the consequences of climate change or war, will become
increasingly demanding, especially for those who are displaced or in high-risk regions.
We face the most serious practical, ethical, and financial issues, many of which are not
difficult to predict, and yet our collective response has thus far been grossly inadequate.
The healthcare sector is responsible for roughly 5% of CO2 emissions, and nephrol-
ogy has a disproportionately large carbon footprint, so we have a particular obligation
to address this and start thinking sustainably. The good news is that, as recently dem-
onstrated, we are at our best when free to innovate and invent. In this context, there are
huge changes afoot in healthcare with rapidly developing alliances of like-minded peo-
ple and green nephrology networks aimed at sustainable change and using the financial
clout of the healthcare sector to catalyze change in providers. And then there is us,
healthcare professionals who have had a crash course in supporting each other and
remodeling, who like science, evidence, and facts, the wealth of which mean it is not
difficult to predict the challenges ahead. As a profession, we are well regarded and have
a responsibility to influence change and change the ethos of the institutions we work in
with vigor and urgency.
I hope that this edition not only serves as a useful and engaging text on nephrology
but also invites us all to ambitiously reassess practice with the aim of achieving the best
possible experience and outcomes for our patients.
Mark Harber
Hampstead
London, UK
VII
Acknowledgments
As with the previous edition, Practical Nephrology, I would like to thank again the
generosity of the numerous authors who have contributed to this book. For most, clin-
ical practice over the last 2 years has been particularly punishing and all consuming, so
I remain especially indebted to all those authors have over the years taught me much of
the nephrology I know and who contributed so generously and with such tolerance.
I am also particularly grateful to those who have very generously contributed to the
additional material used in the book, especially Sue Car and Peter Topham, Steve Holt
and Michael Ci, Mr. Peter Veitch, Arundi Mahendran, Justin Harris, Dominic Yu,
Shella Sandoval, Ramesh Batra, Hannah Deltrey-King, Amanda Rea, and David
Bishop who have produced videos that demonstrate procedures with much greater clar-
ity than I could have achieved in prose and that I hope will assist doctors in carrying
out these procedures with safety and confidence. I would particularly like to thank Paul
Sweny for his mentorship and for the gift of his collection of clinical images accumu-
lated over the years of frontline service. Histological images were generously provided
by Lauren Heptinstall, Paul Bass, Alec Howie, Catherine Horsfield, and Mared Casey-
Owen.
Once again, my heartfelt thanks to our patients who have contributed to this book
in so many ways and who remain the key motivation behind this book.
IX
Contents
2 Urine Analysis....................................................................................................................................... 29
Scott R. Henderson and Mark Harber
V Glomerular Diseases
18 Management of the Nephrotic Patient: The Overall Approach
to the Patient with Nephrotic Syndrome ........................................................................... 379
Gabrielle Goldet and Ruth J. Pepper
VI Tubulointerstitial Disease
32 Acute Tubulointerstitial Nephritis .......................................................................................... 585
Vasantha Muthu Muthuppalaniappan and Simon Ball
46 The Renal Patient in Critical Care - The ICU: Renal Interface ................................. 799
Katie Lane, Zudin Puthucheary, and Nasirul Jabir Ekbal
X Dialysis
76 Prevention of Infection in Kidney Patients ....................................................................... 1275
Caroline Tulley, Gerlineke Hawkins- van der Cingel, and Mark Harber
XIV Contents
XI Transplantation
85 Setting-Up and Running a Renal Transplant Unit ........................................................ 1445
Andrew Ready and Jennie Jewitt-Harris
Supplementary Information
Index ............................................................................................................................................................. 1717
XVII
Contributors
Shahid Abdullah, MBBS, MRCP Salford Royal NHS Foundation Trust, Salford, UK
Manchester Royal Infirmary, Manchester, UK
Asmat Abro, MBBS, MRCP UCL Centre for Nephrology, Royal Free Hospital, London, UK
Department of Renal Medicine and Transplantation, Royal Free Hospital, London, UK
a.abro@nhs.net
Sarah Afuwape Department of Nephrology and Transplantation, Royal Free London NHS
Foundation Trust, London, UK
sarah.afuwape@nhs.net
John Agar University Hospital Geelong and Deakin University School of Medicine, Barwon
Health, Geelong, VIC, Australia
geerenal@ncable.net.au
Yogita Aggarwal University Hospitals of Coventry and Warwickshire NHS Trust, London, UK
Yogita.Aggarwal@uhb.nhs.uk
Ammar Al Midani Department of Nephrology & Transplantation, Royal Free London NHS
Foundation Trust, London, UK
ammar.almidani@nhs.net
Rakesh Anand, BSc, MSc, MBBS, MRCP Royal Free London NHS Foundation Trust, London,
UK
rakesh.anand1@nhs.net
Marilina Antonelou Department of Renal Medicine, University College London and Royal
Free London NHS Foundation Trust, London, UK
Department of Renal Medicine, University College London, London, UK
Marilina.antonelou@nhs.net
Caroline Ashley, BPharm (Hons), FFRPS, FRPharmS Department of Pharmacy, Royal Free
London NHS Foundation Trust, London, UK
carolineashley@nhs.net
Richard J. Baker, MBBChir, MA, FRCP, PhD Renal Medicine, St James’s University Hospital,
Leeds, UK
Richard-j.baker@nhs.net
XVIII Contributors
Jonathan Barratt The John Walls Renal Unit, Leicester General Hospital, University
Hospitals of Leicester, Leicester, UK
jb81@le.ac.uk
Hannah Blakey Renal Department, Queen Elizabeth Hospital NHS Trust, Birmingham, UK
hannah.blakey2@uhb.nhs.uk
Sarah Blakey Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK
sarahblakey@nhs.net
Detlef Bockenhauer University College London, Great Ormond Street Hospital, London,
UK
d.bockenhauer@ucl.ac.uk
James Brown Department of Respiratory Medicine, Royal Free London NHS Foundation
Trust, London, UK
james.brown13@nhs.net
Ben Caplin, BSc (Hons), MBChB, PhD UCL Medical School, Royal Free Campus, London, UK
Department of Renal Medicine, UCL Medical School, Royal Free Campus, London, UK
Department of Renal Medicine, University College London, London, UK
b.caplin@ucl.ac.uk
Paul J. Champion de Crespigny The Royal Melbourne Hospital, Melbourne, VIC, Australia
Paul.ChampiondeCrespigny@mh.org.au
Melanie M. Y. Chan, MRCP UCL Department of Renal Medicine, Royal Free Hospital, Lon-
don, UK
melanie.chan@nhs.net
Rawya Charif, MRCP, MD (Res) Imperial College Kidney and Transplant Centre, Imperial
College Healthcare NHS Trust, Hammersmith Hospital, London, UK
Rawya.Charif@nhs.net
Lindsay Chesterton, FRCP, DM Department of Renal Medicine, Royal Derby Hospital, Derby,
UK
lindsay.chesterton@nhs.net
Pratima Chowdary, MBBS, MRCP, FRCPath Katharine Dormandy Haemophilia and Thrombosis
Centre, Royal Free London NHS Foundation Trust, London, UK
Department of Haematology, University College London, London, UK
P.chowdary@ucl.ac.uk
John O. Connolly, PhD, FRCP UCL Department of Renal Medicine, Royal Free Hospital,
London, UK
johnconnolly@nhs.net
A. E. Courtney Regional Nephrology & Transplant Unit, Belfast City Hospital, Belfast, UK
aisling.courtney@belfasttrust.hscni.net
XX Contributors
Jeff Cove Renal Psychology Service, Royal Free London NHS Foundation Trust, London, UK
j.cove@nhs.net
John Cunningham UCL Centre for Nephrology, The Royal Free Hospital, London, UK
Sunil K. Daga, MBBS, MRCP (Nephrology), PhD Renal Medicine, St James’s University Hospital,
Leeds, UK
Sunildaga@nhs.net
Andrew Davenport UCL Centre for Nephrology, Royal Free Hospital, University College
London Medical School, London, UK
University College London, London, UK
Andrewdavenport@nhs.net
Neeraj Dhaun, MD Centre for Cardiovascular Science, University of Edinburgh, The Queen’s
Medical Research Institute, Edinburgh, UK
bean.dhaun@ed.ac.uk
Peter J. Dupont, PhD, FRCPI Department of Renal Medicine, University College London,
Royal Free Hospital, London, UK
pdupont@nhs.net
Nasirul Jabir Ekbal Royal Free London NHS Foundation Trust, London, UK
Nasirul.Ekbal@nhs.net
Timothy John Ellam Renal Services, The Newcastle upon Tyne Hospitals NHS Foundation
Trust, Newcastle upon Tyne, UK
timothy.ellam@nuth.nhs.uk
Stanley Fan Consultant Nephrologists, The Royal London Hospital, Barts Health NHS Trust,
London, UK
fan.stanley@bartshealth.nhs.uk
Raymond Fernando, BSc, PhD Department of Renal Medicine, University College London &
The Anthony Nolan Laboratory, Royal Free Hospital, London, UK
raymond.fernando@nhs.net
Richard J. Fluck, FRCP, MA (Cantab), MBBS Department of Renal Medicine, Royal Derby
Hospital, Derby, UK
richard.fluck@nhs.net
Daniel Gale, MA, MB, BChir, PhD, FRCP Department of Renal Medicine, University College
London, Royal Free Hospital, London, UK
d.gale@ucl.ac.uk
Jack Galliford, MBBS, FRCP Richard Bright Renal Unit, Southmead Hospital, Bristol, UK
Jack.Galliford@nbt.nhs.uk
David Game, MA, PhD, FRCP Department of Nephrology and Transplantation, Guy’s
Hospital, London, UK
David.Game@gstt.nhs.uk
Julian D. Gillmore UK National Amyloidosis Centre, University College London and Royal
Free Hospital London NHS Foundation Trust, London, UK
j.gillmore@ucl.ac.uk
Darren Green Vascular Research Group, Manchester Academic Health Sciences Center,
University of Manchester, Salford Royal NHS Foundation Trust, Stott Lane, Salford, UK
Unkn524@meteor.com
Pooja Mehta Gudka Renal Services, Department of Pharmacy, Royal Free London NHS
Foundation Trust, London, UK
Poojamehta.gudka@nhs.net
Angela D. Gupta, MD Texas Childrens Pediatric Urology Clinic, Houston, TX, USA
agupta45@jhmi.edu
Sanjana Gupta, MBBS, MSc, MRCP, DPMSA Royal Free and Royal London Hospital, London,
UK
University College London, London, UK
sanjana.gupta@ucl.ac.uk
Zoya Hameed, BSc, MBBS, MSc, FRCOphth Royal Free London NHS Foundation Trust,
London, UK
Zoya.hameed@nhs.net
Sally Hamour Department of Renal Medicine, University College London and Royal Free
London NHS Foundation Trust, London, UK
sallyhamour@nhs.net
Mark Harber, MBBS, PhD, FRCP Department of Renal Medicine UCL, London, UK
mark.harber@nhs.net
Gerlineke Hawkins-van der Cingel Royal Free London NHS Foundation Trust, London, UK
gerlineke.hawkins-vandercingel@nhs.net
Scott R. Henderson UCL Centre for Nephrology, Royal Free Hospital, London, UK
scotthenderson@nhs.net
Heidy Hendra Department of Nephrology & Transplantation, Royal Free London NHS
Foundation Trust, London, UK
Royal Free London NHS Foundation Trust, London, UK
heidy.hendra1@nhs.net
Joanne Henry Department of Nephrology and Transplantation, Royal Free London NHS
Foundation Trust, London, UK
joannehenry@nhs.net
XXIII
Contributors
Peter Hill West London Renal and Transplant Centre, Hammersmith Hospital, Imperial
College Health Trust, London, UK
peter.hill4@nhs.net
Stephen G. Holt, BSc, MBBS, PhD, FRCP, FRACP The University of Melbourne, School of
Medicine, Melbourne, VIC, Australia
steve.holt@mh.org.au
Ferina Ismail, BSc, MBBS, MRCP, PhD Department of Dermatology, Royal Free London NHS
Foundation Trust, London, UK
ferina.ismail@nhs.net
Aneesa Jaffer Department of Nephrology & Transplantation, Royal Free London NHS Foun-
dation Trust, London, UK
aneesa.jaffer@nhs.net
Paramjit Jeetley Department of Cardiology, Royal Free London NHS Foundation Trust,
London, UK
paramjit.jeetley@nhs.net
Philip A. Kalra, MA, MB, BChir, FRCP, MD Vascular Research Group, Manchester Academic
Health Sciences Center, University of Manchester, Salford Royal NHS Foundation Trust, Stott
Lane, Salford, UK
XXIV Contributors
Department of Renal Medicine, Salford Royal NHS Foundation Trust, Stott Lane, Salford, UK
philip.kalra@srft.nhs.uk
Nigel Suren Kanagasundaram The Newcastle upon Tyne Hospitals NHS Foundation Trust,
Newcastle upon Tyne, UK
suren.kanagasundaram@newcastle.ac.uk
Helen J. Lachmann UK National Amyloidosis Centre, University College London and Royal
Free Hospital London NHS Foundation Trust, London, UK
h.lachmann@ucl.ac.uk
Steven Law UCL Department of Renal Medicine, Royal Free Hospital, London, UK
stevenlaw@nhs.net
Ben Lindsey, FRCS Department of Vascular Surgery and Department of Renal Surgery, The
Royal Free London NHS Foundation Trust, Hampstead, UK
ben.lindsey@nhs.net
Ciara N. Magee UCL Centre for Nephrology, Royal Free Hospital, London, UK
Ciara.magee@nhs.net
Hannah Maple, FRCS, PhD Department of Nephrology and Transplantation, Guy’s Hospital,
London, UK
Hannah.Maple@gstt.nhs.uk
Stephen D. Marks, MD, MSc, MRCP, DCH, FRCPCH Professor of Paediatric Nephrology and
Transplantation, University College London Great Ormond Street Institute of Child Health and
Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
stephen.marks@gosh.nhs.uk
Philip David Mason, BSc, PhD, MBBS, FRCP Oxford Kidney Unit, The Churchill Hospital,
Headington, Oxford, UK
Phil.Mason@ouh.nhs.uk
David Mathew Department of Nephrology & Transplantation, Royal Free London NHS
Foundation Trust, London, UK
david.mathew2@nhs.net
Alexander P. Maxwell, MD, PhD, FRCP Regional Nephrology Unit, Belfast City Hospital,
Belfast, Antrim, UK
Centre for Public Health, Queens University Belfast, Institute of Clinical Sciences, Block B,
Royal Victoria Hospital, Belfast, Antrim, Ireland
a.p.maxwell@qub.ac.uk
Adam McLean, MA, MBBS, FRCP, DPhil Imperial College Kidney and Transplant Centre,
Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK
AdamMclean@nhs.net
Clare Melikian Department of Anaesthesia, Royal Free London NHS Foundation Trust,
London, UK
c.melikian@nhs.net
Shona Methven, BSc, MBChB, MD, MRCP, FRCP(Edin) Aberdeen Royal Infirmary, Aberdeen,
UK
shona.methven@nhs.net
Shabbir H. Moochhala UCL Department of Renal Medicine, Royal Free Hospital, Royal Free
Hospital, London, UK
Royal Free Hospital, London, UK
smoochhala@nhs.net
David Nicol Department of Urology, Royal Marsden Hospital & Institute of Cancer Research,
London, UK
davidnicol@nhs.net
Katharine Pates, MBBS, MBiochem Department of Renal Medicine, UCL Medical School,
Royal Free Campus, London, UK
Unknown_54098@Meteor.com
Benedict L. Phillips, BSc (Hons), MSc, MRCS Renal and Transplant Surgery, Guy’s Hospital,
London, UK
benedict.phillips@nhs.uk
Liam Plant Department of Renal Medicine, Cork University Hospital & University College
Cork, Cork, Ireland
william.plant@ucc.ie
Madhu Potluri, MBCHB, MRCP UK, MRCP Gloucestershire Hospitals NHS Foundation Trust,
Cheltenham, UK
madhupotluri@nhs.net
Nithya Prasannan, MBBS, MRCP, FRCPath Katharine Dormandy Haemophilia and Thrombosis
Centre, Royal Free London NHS Foundation Trust, London, UK
Department of Haematology, University College London, London, UK
XXVIII Contributors
Maria Prendecki Centre for Inflammatory Disease, Department of Immunology and Inflam-
mation, Imperial College London, London, UK
m.prendecki@imperial.ac.uk
Zudin Puthucheary William Harvey Research Institute, Barts and The London School of
Medicine and Dentistry, Queen Mary University of London, Royal London Hospital, Barts
Health NHS Trust, London, UK
z.puthucheary@nhs.net
James Ritchie Vascular Research Group, Manchester Academic Health Sciences Center,
University of Manchester, Salford Royal NHS Foundation Trust, Stott Lane, Salford, UK
james.ritchie@nca.nhs.uk
Adam Rumjon, MBBS, PhD, MRCP North Middlesex University Hospital, Sterling Way,
London, UK
adamrumjon@nhs.net
Alan D. Salama, MBBS, MA, PhD, FRCP University College London, London, UK
Royal Free Hospital, London, UK
UCL Department of Renal Medicine Royal Free Hospital, London, UK
a.salama@ucl.ac.uk
Nasreen Samad Consultant Nephrologists, The Royal London Hospital, Barts Health NHS
Trust, London, UK
nareen.samad@bartshealth.nhs.uk
Haresh Selvaskandan The John Walls Renal Unit, Leicester General Hospital, University
Hospitals of Leicester, Leicester, UK
haresh.selvaskandan@nhs.net
XXIX
Contributors
Claire C. Sharpe Department of Inflammation Biology, Faculty of Life Sciences and Medicine,
King’s College London, London, UK
Claire.sharpe@kcl.ac.uk
Neil S. Sheerin National Renal Complement Therapeutic Centre, Translational and Clinical
Research Institute, Newcastle University, Newcastle upon Tyne, UK
neil.sheerin@ncl.ac.uk
Kin Yee Shiu, MBBS, PhD, FRCP Department of Renal Medicine, University College London,
Royal Free Hospital, London, UK
kinyee.shiu@nhs.net
James Smith, BSc, MBChB, PhD, MRCP Abderdeen Royal Infirmary, Foresterhill, Aberdeen,
UK
jsmith82@nhs.net
Henry Stephens, BSc, PhD Department of Renal Medicine, University College London & The
Anthony Nolan Laboratory, Royal Free Hospital, London, UK
h.stephens@ucl.ac.uk
Charles R. V. Tomson, MA, BMBCh, FRCP, DM (Oxon) Newcastle upon Tyne Hospitals NHS
Foundation Trust, Newcastle upon Tyne, UK
Freeman Hospital, Newcastle upon Tyne, UK
charles.tomson1@nhs.net
A. Neil Turner, PhD, FRCP Centre for Inflammation, University of Edinburgh, QMRI,
Edinburgh, UK
neil.turner@ed.ac.uk
XXX Contributors
Robert Unwin UCL Department of Renal Medicine, Royal Free Hospital, Royal Free Hospi-
tal, London, UK
robert.unwin@ucl.ac.uk
Diana Vassallo Vascular Research Group, Manchester Academic Health Sciences Center,
University of Manchester, Salford Royal NHS Foundation Trust, Stott Lane, Salford, UK
Unk534@meteor.com
David C. Wheeler, MD, FRCP Department of Renal Medicine, UCL Medical School, Royal
Free Campus, London, UK
d.wheeler@ucl.ac.uk
William White Departments of Acute Medicine & Nephrology, Royal London Hospital,
London, UK
william.white9@nhs.net
Eleri Williams, MB, BChir, MRCP Centre for Inflammation, University of Edinburgh, QMRI,
Edinburgh, UK
eleri.williams@doctors.org.uk
Jo Wilson Royal Free Hospitals London NHS Foundation Trust and University of Bath,
London, UK
jo.wilson8@nhs.net
XXXI
Contributors
Dan Wood, PhD, FRCS (Urol) Adolescent Urology, University College London Hospitals NHS
Foundation Trust, London, UK
dan.wood1@nhs.net
Nick Woodward, MBBS, MRCP, FRCR Department of Radiology, Royal Free London NHS
Foundation Trust, London, UK
nick.woodward@nhs.net
Contents
1.1 Introduction – 4
1.4 Assessment of the Patient When the Renal Disorder Has Yet
to Be Identified and/or Characterised – 8
1.4.1 Presentation with Renal Impairment – 8
1.4.2 Presentations Other Than with Biochemical Evidence of Change
in Renal Function – 9
1.4.3 Clinical History Relevant to Establishing a Renal Diagnosis – 12
1.4.4 Aspects of the Clinical Examination to Help Establish the Cause
of a Renal Disorder – 22
n Learning Objectives The first priority is to ask if the patient is safe. This
1 1. To safely assess the unwell patient with renal dis- question provides the starting point of this chapter.
ease and develop suitable assessments of patients Since an assessment of fluid balance is integral to the
for varying stages of their illness, in order to inform patient’s clinical safety, as well as many aspects of subse-
diagnosis and treatment. quent diagnosis or management, this is the next focus.
Subsequently, it is usually important to clarify whether
the patient is already being managed for an underlying
Key Points kidney condition. The approach to the patient with
1. The first question before performing an assessment established kidney disease, for example, a patient receiv-
must be: Is the patient safe? Are they in the appro- ing dialysis or with inflammatory glomerulonephritis,
priate environment? Is there an indication for emer- will be completely different from the approach to the
gency medical therapy? Do they require urgent patient who presents with a renal disorder for the first
renal replacement therapy? time. In first presentations, the priority will be to estab-
2. Assessment of fluid balance requires integration of lish the underlying cause of the renal disorder. This is
multiple sources of clinical, biochemical and radio- the clinical scenario where there is often significant diag-
logical information. nostic uncertainty, representing some of the most inter-
3. Taking different approaches to patients who are esting and challenging areas of nephrology practice.
presenting for the first time versus those well- Patients with established disease often require equally
known to renal services facilitates more organised challenging, focused and specific assessment to optimise
clinical thinking and better management of time their management, and this is addressed in the last sec-
and resource. tion of this chapter.
4. When assessing the first presentation of a case of
renal dysfunction, determining the chronicity is a
key factor for deciding on the next steps of man-
agement. 1.2 Urgent Assessment for Renal
5. Attention to the extra-renal sequela of systemic Emergencies
disease can often hint at the diagnosis prior to renal
deterioration. As with all acutely unwell patients, the priority is assess-
ing and correcting potentially life-threatening physio-
logical dysfunction. For the maintenance of an adequate
1.1 Introduction airway, ventilation and circulation (ABC), urgent renal-
specific contributors are likely to relate to intravascular
Patients may present to nephrology services with a spec- volume depletion or fluid overload (see next section)
trum of renal disease, from asymptomatic incidental alongside metabolic disturbance, most usually hyperka-
findings to severe renal impairment or electrolyte distur- laemia or acidaemia. These latter scenarios may be an
bance in a critically ill patient. Others will have significant indication for urgent renal replacement therapy (RRT)
comorbidity perhaps alongside previously diagnosed and if not responsive to medical treatment. When there is an
complex chronic renal disease. These factors mean the indication for urgent RRT, attention must be given to
assessment of the ‘renal patient’ can be a challenging the most appropriate mode of delivery and the correct
proposition to the less (and on occasion the more) expe- clinical environment in which to deliver it. Requirements
rienced physician. There are numerous approaches to the will depend on the need for other organ support, and
assessment of patients with kidney disease, and practitio- local policies will vary, but the use of any extracorporeal
ners will develop their own style with time. However, a circuit (even with the low blood flows used in continuous
common pitfall for the new nephrologist is the failure to therapies such as haemofiltration) risks haemodynamic
recognise that although attention to detail is essential, the instability. Adequate (usually invasive) monitoring and
potential to lose the critical aspects of history and exami- access to vasopressors or inotropes are mandatory in
nation in a mass of less relevant information is high. One those receiving RRT who are cardiovascularly unstable
strategy to avoid this is to frame the assessment as a series (see 7 Chap. 12). Critically, the immediate management
of questions by asking oneself ‘what is the next thing I may depend on whether the acidaemic or hyperkalaemic
need to know to guide my management?’ The ‘practical’ patient has an immediately remediable medical condi-
approach we outline here is only one of many but one tion; a patient with urinary retention and potassium of
that we find successful in day-to-day practice. We 7.2 mmol/L may be easy to manage medically (following
approach the assessment of the renal patient with a series relief of obstruction), whereas a septic oliguric hypoten-
of questions, as illustrated in the flow-diagram sive patient with a potassium of 5.8 mmol/L is much
(. Fig. 1.1) below. more likely to need renal replacement imminently.
Assessment of the Renal Patient
5 1
. Fig. 1.1 Practical approach No
Is the patient safe? Assess and treat:
to the assessment of a renal
- Hyperkalaemia
patient
- Acidosis
Yes
- Fluid overload
No Yes
Yes
Gather further information to aid diagnosis :
- Age
- Gender
- Ethnicity/country of origin
- Family history
- Childhood history
- Occupation
- Travel and hobbies
- Psychosocial
- Medication and allergy
- Clinical examination
History Paroxysmal nocturnal dyspnoea, orthopnoea, increased weight and worsening oedema are relatively
sensitive and fairly specific symptoms of fluid overload
Thirst is a relatively sensitive marker of dehydration or salt overload. A history of significant fluid loss or
reduced fluid intake contributes to assessment of fluid balance
Examination
Pulse Tachycardia is a non-specific marker of intravascular volume depletion and may be associated with
excessive intravascular volume in the context of heart failure
Blood pressure Relative hypotension (comparison with historical blood pressure) and episodes of documented hypotension
(intraoperative, hospital or community based) are always a significant finding in patients with renal
dysfunction. Although trends may inform assessment, hypotension is a non-specific marker of intravascular
volume depletion
Orthostatic changes Reflex tachycardia (increase in 30 beats per minute or more) is sensitive for acute large blood loss but
insensitive for smaller bleeds or other causes of hypovolaemia and non-specific
Changes in blood pressure with changes in posture are a useful finding that can be delegated to ward staff.
Changes of 20 mmHg in systolic and 10 mmHg in diastolic blood pressure upon change in posture are
widely used as significant thresholds
Peripheral tempera- Cool nose, hands or feet at room temperature imply either decreased intravascular volume (low JVP) or
ture cardiac failure (raised JVP). These are not sensitive but easy and reproducible. Unhelpful in patients with
peripheral vascular disease or vasodilated patients (sepsis, cirrhosis, thyrotoxicosis)
Jugular venous Operator dependent and highly dependent on body habitus. Raised JVP may represent either increased
pressure (JVP) intravascular volume or high right ventricular filling pressure (cardiac failure, pulmonary hypertension,
tricuspid regurgitation or stenosis, restrictive defects, tamponade). Common for ESRD patients with
previous access to have internal jugular stenosis or occlusion (including secondary to current line) or SVC
obstruction
Oedema Diurnal variation (feet swollen in the evening, face in the morning) usually rules out any anatomical cause.
A bed-bound patient may have normal ankles but several litres in sacral or flank oedema. Oedema will also
be influenced by drugs and plasma oncotic pressure
Third heart sound (S3 Indicative of ventricular failure/overload, insensitive
gallop rhythm)
Ascites and pleural Non-specific and poorly sensitive
effusions
Bedside measurements:
Weight Extremely useful serial measurement for general nephrology patients as well as those on dialysis with a ‘dry
weight’. Serial measurements for inpatients extremely valuable measure of total body water (but not
intravascular volume)
Urine output Non-specific but important part of AKI classification and relatively sensitive marker of intravascular
volume. Unhelpful as a marker of intravascular volume if AKI from whatever cause or concentrating
defect, e.g. post-obstructive diuresis
Documentation of Anaesthetic charts, ward charts including drain losses and stool charts can be invaluable if accurate but do
inputs and outputs not equate to current fluid status
Bedside ultrasound Inferior vena cava compressibility
Laboratory measurements:
Urine specific gravity High or low SG suggests intravascular depletion or a positive fluid balance; however, acute or chronically
(SG) injured kidneys lose the ability to concentrate and therefore has limited value
Urinary sodium A low spot urinary sodium or fractional excretion of sodium is indicative of reduced renal perfusion and
can be helpful in differentiating pre-renal (including hepatorenal) from replete intravascular volume but
invalid in the face of acute tubular injury, diuretics or dopamine
N-terminal probrain- Some evidence of correlation with fluid status, particularly in the dialysis population
type natriuretic peptide
Assessment of the Renal Patient
7 1
useful, whereas skin turgor and dryness of mucous of the technique and requires direct measurement of
membranes are insensitive and non-specific signs. cardiac output in real time [3].
Bedside ultrasound is increasingly available and nec-
essary in the acute assessment of unwell patients in the
1.3.2 Bedside Tests hospital setting. With the necessary training, ultrasound
can be a useful tool in fluid assessment since there is
At the bedside, it is important to recognise that dynamic good evidence for correlation of inferior vena cava
markers of intravascular volume are usually the most diameter and collapsibility in assessing fluid responsive-
informative. In particular, the critical care field has pro- ness [4–6].
vided some reliable indices for assessment of volume
status, since dynamic changes of arterial waveform- 1.3.2.1 Investigations
derived variables in mechanically ventilated patients Chest X-ray can be invaluable in diagnosing or confirm-
have good evidence for accurately predicting volume ing gross fluid overload, but it is not particularly sensi-
responsiveness [1]. Furthermore, there is some evidence tive for mild/moderate overload, and acute lung injury/
of a relationship between the amplitude of the arterial leaky lungs can occur with no increase in right-sided fill-
pressure wave correlates with pulse oximetry waveform ing pressure (see . Fig. 1.2a and b).
(again in ventilated patients [2]), suggesting this Bioimpedance is an inexpensive and non-invasive
approach might be useful in the assessment of a renal technique to estimate body water. Given the difficulties
patient managed outside of critical care environment. with clinical assessment of fluid status, the possibility of
However, evidence to assess the utility of this approach an easily usable objective measure is attractive. However,
is lacking. as with many of the clinical parameters guiding assess-
An alternative method in the spontaneously breath- ment of fluid balance, a single measurement in an indi-
ing patient is to use the passive leg raise. By raising the vidual patient does not appear to add significant value
patient’s legs from the recumbent position, and back to clinical assessment. Serial measures may be more
again, the passive leg raise delivers a venous return of valuable, so this technique may be most useful in patients
approximately 300 ml from the lower body to the right attending chronic dialysis or the outpatient department
heart of the patient. This test relies on precise execution rather than in the acute situation [7].
a b
. Fig. 1.2 a CXR of a patient with raised left ventricular end- same patient within 24 h in the absence of any filling or cardiac event
diastolic pressure (LVEDP) showing upper lobe blood diversion, but in the presence of sepsis. This demonstrates that pulmonary
fluid in the fissure and Kerley B lines. This approximately equates to oedema on a CXR is not necessarily indicative of excessive filling
an LVEDP of 18 mmHg or above. b Frank pulmonary oedema in the pressures per se
8 M. Khosravi et al.
Biochemical measures that have been advocated as renal dysfunction where a baseline creatinine that would
1 indices of fluid status such as a ‘disproportionately’ high uncover the time course of the disease is not available.
urea, raised serum urate or elevated serum lactate also The duration of symptoms can be a useful indicator of
lack sensitivity or specificity. Natriuretic peptides have chronicity; however, advanced renal impairment can be
been shown to be a useful biomarker of volume status in present for some time before the patient reports the
dialysis patients, but in the general adult population, stud- onset of illness. Furthermore, the presence of risk fac-
ies are inconclusive and clouded by confounding data [8]. tors or a systemic disorder known to put the patient at
risk of kidney disease does not provide definite evidence
for the time of onset of any pre-existing renal dysfunc-
1.4 Assessment of the Patient When tion.
the Renal Disorder Has Yet The best markers of long-standing (and conse-
to Be Identified and/or Characterised quently irreversible) renal impairment are radiological
appearances. Bipolar renal diameter <10 cm in combi-
1.4.1 Presentation with Renal Impairment nation with increased cortical echogenicity (defined as a
higher pixel density in the renal cortex than the liver) is
a strong indicator of advanced chronic kidney disease
Impaired kidney function is the commonest reason for
[9]. Exceptions to this rule occur, where the size of
referral to a nephrologist. Patients may present with
chronically diseased kidneys is preserved, most typically
symptoms directly related to renal dysfunction
in diabetes, but also cystic diseases (such as ADPKD),
(. Table 1.2), but these symptoms usually herald
protein deposition diseases (amyloid), chronic obstruc-
advanced renal impairment. More often, referrals follow
the incidental finding of renal impairment in blood tests tion, xanthogranulomatous pyelonephritis and HIV
performed following a clinical presentation unrelated to nephropathy.
the kidney. Biochemical markers such as potassium, calcium,
phosphate, parathyroid hormone and haemoglobin are
1.4.1.1 Does the Patient Have Acute or often described as indicators of chronic renal dysfunc-
Chronic Renal Impairment? tion. However, these parameters have limited utility in
practice since all can also change rapidly in the context
The urgency of further investigation in a patient with
of AKI.
impaired kidney function is critically dependent on
whether the onset is acute (occurring over days to weeks) 1.4.1.2 Diagnostic Breakdown of Acute or
or chronic (occurring over months to years).
Chronic Renal Dysfunction
Differentiation of these clinical scenarios is straightfor-
ward if previous blood tests are available. The distinc- Assessment of a patient with AKI is described in detail
tion can be more difficult in cases of acute on chronic in 7 Chap. 5. However, the classical subdivision into
pre-, post- and intrinsic causes of renal impairment is a
useful approach in any patient presenting with either
acute or chronic renal impairment.
. Table 1.2 Symptoms attributable to renal impairment
Pre-renal Causes
Uraemia Anorexia, nausea, pruritis, malaise and
sleep disturbance are all common symptoms
A ‘pre-renal’ aetiology implies hypoperfusion of the
in ESRD. Patients may also complain of kidney. This is a critical component of the assessment of
headaches, reduced mental agility, chest patients with AKI as this form of insult is usually asso-
pain (pericarditis), prolonged bleeding or ciated with an acute presentation. However, renal artery
bruising
stenosis and chronic hypovolaemia (e.g. in patients with
Anaemia Lethargy, palpitations, shortness of breath high output stomas) may develop more insidiously and
(particularly exertional) present with CKD. Therefore, potential precipitants of
Electrolyte Palpitations, musculoskeletal pain, cramps, pre-renal injury should be sought in all patients with
disturbance restless limbs, seizures, confusion renal dysfunction. Circulatory shock, whether vasodila-
Fluid Facial or peripheral swelling, shortness of tory, cardiogenic or hypovolaemic will invariably lead to
maldistribution breath or reduced exercise tolerance, an acute injury. These and other potential precipitants
or excess orthopnoea, paroxysmal nocturnal of pre-renal impairment are outlined in . Table 1.3.
dyspnoea
Urinary Oliguria, dysuria, nocturia (a common Post-renal Causes
symptoms symptom in CKD), alterations in appear- Post-renal causes of renal impairment are often straight-
ance (colour/froth)
forward to treat which in turn can lead to the full or
partial recovery of the associated renal injury.
Assessment of the Renal Patient
9 1
Furthermore, obstruction is a common and often abnormalities are also often sent for expert review. The
asymptomatic cause for unexpected deterioration in assessment of isolated haematuria and proteinuria is
patients with established medical renal disease. discussed in the following chapter. In addition to urinary
Although the clinical history or examination abnormalities, nephrologists will find themselves faced
(. Table 1.4) may suggest an obstructive cause of kid- with diverse clinical syndromes. These syndromes and
ney injury, exclusion of a post-renal cause of renal the logical diagnostic approaches are discussed further
impairment cannot be made without radiological inves- in the chapters devoted to these subjects, but some of
tigation. A renal ultrasound is the first line of investiga- the more common presentations are discussed briefly
tion, but there are limitations which should be considered below.
when interpreting the results:
5 ‘False positives’ can occur in cases of chronic dila- 1.4.2.1 Haematuria
tion of the pelvicalyceal system. Functional imaging Haematuria can originate from anywhere along the uri-
(renograms) can be helpful for establishing the sig- nary tract, so it is important to identify coexistent lower
nificance of anatomical abnormality (but kidney urinary tract symptoms in any patient with visible blood
function must be adequate for these to be useful). in the urine. Intermittent visible haematuria can be tem-
Renograms with the addition of diuretics using porally associated with an upper respiratory tract infec-
nuclear medicine tracers can be helpful in this con- tion which is suggestive of IgA nephropathy or related
text (see 7 Chap. 5) to exercise. Haematuria associated with menses can be
5 ‘False negatives’ can occur in anuric patients, who seen in patients with endometriosis. Finally, myoglobin-
may not have pelvicalyceal dilatation. If the history uria and haemoglobinuria (both important non-
is suggestive, more detailed anatomical imaging such glomerular precipitants of AKI) will often lead to a
as MRI or CT may be helpful. However, a trial of false-positive dipstick urinalysis for haematuria.
relief of the potential obstruction can be the only
way to definitively make a diagnosis in some cases. 1.4.2.2 Proteinuria
Proteinuria is usually identified on dipstick testing dur-
Symptomatic changes in urine volume are not usu- ing routine medical examinations or surveillance (e.g.
ally diagnostically helpful other than abrupt anuria for diabetes) or in the investigation of associated
which may point to a bilateral obstruction but can also oedema, but patients with nephrotic range proteinuria
reflect medical renal disease (see below). Clinical history can on occasion present symptomatically with frothy
that might suggest a post-renal causes of kidney dys- urine. History of past episodes of dipstick positive pro-
function is shown in . Table 1.4. teinuria is helpful but is rarely recalled by patients.
Relative hypotension A drop in BP, for whatever reason, in a normally hypertensive patient
Cardiogenic shock Risk factors for cardiovascular disease, suggestive of cardiological investigations
Intravascular volume depletion
Blood loss
Poor oral intake In the confused or immobile patient
Fever, sweating, burns
Vomiting, diarrhoea Patients with short bowel or high output stomas are at particular risk of volume
depletion
Polyuria Prescribed or non-prescribed diuretics, mannitol
Central polyuria (intracranial causes) – cerebral salt wasting, diabetes insipidus
(DI)
Tubular dysfunction – Addison’s, nephrogenic DI (lithium toxicity), salt-losing
nephropathies, hyperglycaemia, diuresis associated with recovery of kidney
function
Fluid redistribution with reduced arterial perfusion
Ascites Liver disease
Fluid accumulation in the GI tract Bowel obstruction, post-operative ileus
Oedema secondary to nephrotic syndrome
Septic/anaphylactic shock
Drugs Calcium channel blockers, minoxidil, thiazolidinediones, docetaxel, pramipexole
Adrenal Hypoadrenalism – primary or secondary
Local hypoperfusion
Arterial occlusion Emboli, most commonly following endovascular intervention; arterial dissection;
malignant infiltration
Renal artery stenosis ‘Crash’ pulmonary oedema caused by sudden reduction of GFR post renin-angio-
tensin blockade
Venous obstruction Renal vein thrombosis (consider in association with pro-coagulant states, e.g.
nephrotic syndrome), page kidney (subscapular haematoma causing compression)
following kidney biopsy
NB patient notes (including anaesthetic records) are invaluable for identifying episodes of relative hypotension, poor IV or oral intake,
excessive losses or weight changes
identified and treated (. Table 1.6). Such an underlying can occur in numerous conditions. The differential diag-
cause is more likely if hypertension occurs before the age nosis of causes of loin pain is listed in . Table 1.7.
of 40 years (the younger the patient, the greater the like- Nephrolithiasis is usually accompanied by severe
lihood of a secondary cause) or if there is severe end symptoms although it may only be on direct questioning
organ damage, accelerated hypertension, sudden wors- that patients mention passing ‘gravel’ (small sand-like
ening or a family history of early hypertension/stroke. material). Working or living in hot, dehydrating environ-
However, it is important to recognise that the majority ments, with limited access or possibility for adequate
of secondary hypertension relates to underlying renal hydration, multiple long flights and high salt intake, as
disease. well as any dietary precipitants such as betel nut, are
associated with stones in epidemiological studies. Any
1.4.2.5 Loin Pain history of obstruction, lithotripsy or stone removal is
Although kidney stones are a common and potentially also clearly important. Identifying if and where any
serious cause of loin pain, pain arising from the kidneys stones have been analysed is very helpful and can expe-
dite appropriate preventative therapy.
Assessment of the Renal Patient
11 1
. Table 1.4 Clinical history suggestive of urinary tract . Table 1.5 Approach to intrinsic renal causes of renal
obstruction dysfunction
Visible haematuria Nephrolithiasis, malignancy, papillary Tubulointerstitial Autoimmune, infiltrative, e.g. lymphoma,
necrosis inflammatory or inflammatory, e.g. TB or sarcoid
Further information on renal involvement in mito- opment and future risk of CKD. A baby born from a
chondrial cytopathies is available elsewhere [11]. mother with medical, behavioural (e.g. smoking),
social or environmental comorbidity is more likely to
1.4.3.5 Childhood History be have a low birth weight and consequently a smaller
Any evidence of childhood kidney or urological issues number of nephrons and be at higher risk for develop-
(congenital anomalies of the kidney and urinary tract, mental programming of hypertension and renal dis-
pyelonephritis, glomerular disease) even if renal func- ease [13].
tion is normal is associated with a significant increased
risk of developing ESRF in later life [12]. 1.4.3.6 Obstetric History
An antenatal history may also be important with An abnormal obstetric history can suggest chronic
evidence now highlighting the importance of the underlying renal disease. Moreover, dipstick urinalysis
intra-uterine environment on consequent renal devel- and blood pressure measurement at booking (usually
Assessment of the Renal Patient
15 1
. Table 1.11 Populations at increased risk of ESRD compared with native population and geography-prevalent nephropathy
12 weeks) and throughout pregnancy may unveil both of both occupation and hobbies is important to avoid
pregnancy-associated and pre-existing renal condi- continued risk of deterioration.
tions. If the patient is not clear about the details, it is
worthwhile pursuing via her family practitioner or 1.4.3.8 Travel and Hobbies
obstetric unit. In addition to considering the patient’s geographical
The number of pregnancies, including miscarriages, origins, a travel history should be completed. This is
stage of pregnancy reached and any reason for early particularly important history in the context of AKI,
delivery can be highly relevant as outlined in and important questions are shown in 7 Box 1.1.
. Table 1.14. Relevant hobbies include water sports (leptospirosis),
pets (hantavirus) and endurance sports (haematuria,
1.4.3.7 Occupation rhabdomyolysis).
Occupation may be a factor in risk of developing some
renal conditions (. Table 1.15). Sometimes, the expo-
sure is not immediately apparent, and a detailed history
16 M. Khosravi et al.
Male
1 Female Sex unknown
Mating Siblings
For each person record:
- Age
- Known disease
Consanguinity - Known symptoms
- Age of onset
- Age at death
Separated
No offspring Infertility
. Fig. 1.3 Symbols used for documenting family history. This should be in the family history bit of the chapter see below
. Table 1.12 Family history in renal disease Deafness Female family members may have history
of isolated haematuria suggesting
X-linked Alport’s, Fabry’s, autosomal
CKD or ESRD Cause as identified by renal unit, age of
dominant history suggestive of
(dialysis or onset or pattern of inheritance
branchio-oto-renal syndromes, MYH9
transplantation
mutations, mitochondrial disorders,
Hypertension Polygenic influence, renal cysts and ciliopathies
and diabetes diabetes (RCAD) syndrome
Microscopic X-linked or autosomal recessive Alport’s
Stones Calcium nephrolithiasis haematuria syndrome; thin basement membrane
nephropathy; CFHR5 nephropathy;
Reflux nephrop- Dysplastic kidneys, posterior urethral HANAC syndrome; MYH9-associated
athy valves (PUV) or any other congenital nephropathies (Epstein/Fechtners
abnormality of the urogenital tract syndromes)
Renal tumours Age of onset, numbers, other malignan- Retinitis Bardet-Biedl syndrome and other
cies, non-renal malignancies (including pigmentosa ciliopathies; m-mitochondrial disorders
pheochromocytoma), epilepsy, learning
disabilities, pneumothorax, fibroids, skin Liver fibrosis Autosomal recessive polycystic kidney
lesions – may indicate Von Hippel-Lindau and cysts disease
disease (VHL), Birt-Hogg-Dube (BHD),
Heart disease Fabry’s disease; hereditary amyloidosis
Hereditary leiomyomatosis and renal cell
cancer (HLRCC) or tuberous sclerosis Gout Uromodulin-associated disease
complex (TSC) (MCKD2)
Sub-arachnoid May indicate PKD or need for screening
haemorrhage if known PKD
Assessment of the Renal Patient
17 1
. Table 1.14 Obstetric history and renal disease . Table 1.15 Occupations associated with renal diagnoses
Pre-eclampsia Early (<20/40) pre-eclampsia is suggestive Metal workers Heavy metal nephropathy
of underlying renal disease (20% have [15]
underlying CKD). An underlying renal
cause is more likely if hypertension
worsens in second pregnancy (with the
same partner). A history of maternal – Rural vs. urban destinations
jaundice suggests haemolysis, elevated liver – Unwell contacts
enzymes and low platelet count (HELLP) – Time period between return and onset of
or haemolytic uremic syndrome (HUS) symptoms
UTIs (lower or Pyelonephritis is more common in – Accommodation and food/drink exposures
pyelonephritis) pregnancy and may result in renal scarring – Fresh water swimming
Obstetric sepsis/ AKI following either may rarely result in – Animal contacts or bites: tick, animal, bird or
severe haemor- cortical necrosis bat bites and scratches
rhage – Occupation and hobbies – e.g. water sports or
agricultural employment
– Recent dental work, surgical procedures
– Sexual history
Box 1.1 Key Travel Questions
5 Details of travel, particularly in the previous
12 months
5 Particular attention should be paid to the
1.4.3.9 Psychosocial History
following: There are several aspects of the psychosocial history rel-
– Pre-travel vaccinations and malaria prophy- evant to the care of the renal patient. There remains a
laxis significant excess of CKD in those from socioeconomi-
cally disadvantaged groups as well as those with a his-
Assessment of the Renal Patient
21 1
potential toxins in use at the onset of renal dysfunction.
. Table 1.16 Substance misuse
Accurately identifying a complete drug history may be
Smoking Hastens the progression of renal
time-consuming, but confirming prior use of aminogly-
disease associated with both diabetes cosides, exposure to a common cause of tubulointersti-
and hypertension tial nephritis or that a patient is taking a product
Increased microalbuminuria containing aristolochic acid may be critically important.
Increased likelihood of pulmonary Key elements of the drug history are shown in 7 Box
haemorrhage in anti-GBM disease
1.2.
Alcohol IgA nephropathy in alcoholic liver
cirrhosis, rhabdomyolysis
Cirrhosis and hepatorenal syndrome
Solvent Toluene in ‘glue sniffing’ has been Box 1.2 Key Elements of Medication History
associated with numerous tubular 5 Prescribed medication
and glomerular lesions – Start and stop dates
Cocaine Renal ischaemia, vasculitis or – Route of administration including prepara-
rhabdomyolysis tions such as PR
Heroin FSGS – Previous exposures on timeline
5 Non-prescribed, over the counter or commercially
Intravenous drug Blood borne viruses
injection Infective endocarditis
purchased medication
AA Amyloid – Particularly analgesic and NSAID use which
may not be volunteered
Ketamine Inflammatory cystitis and obstruc-
tive uropathy
– Include use of creams and gels with consider-
ation to systemic absorption
Ecstasy/MDMA Increased risk of rhabdomyolysis 5 Drug interactions
Anabolic steroids FSGS – Anticipated/dose adjustment/drug level moni-
Synthetic cannabi- AKI secondary to acute tubular
toring
noids (“spice”) necrosis and tubulointerstitial 5 Drug reactions
nephritis – Fever, rash, arthralgia in suspected AIN
3-fluorophenmetrazine Renal ischaemia
– Defining accuracy of interaction with precipi-
tating drug
– Reversibility of effect
– Concomitant administration of prophylaxis
for side effects
tory of mental illness or substance misuse. Educational – Including IV contrast reaction
level, mental health issues, non-prescribed drug use and 5 Dietary supplements
home circumstances can pose barriers to engagement – Creatine-based sports supplements
with medical professionals and delay recognition of ill – Dieting supplements
health, delay initial diagnosis, limit adherence and influ- – Nutritional additives
ence suitability for home therapies. Getting a clear – Laxatives and diuretics
understanding of a patient’s psychosocial history is 5 Herbal preparations
therefore fundamental to the delivery of full and effec- – Whenever possible, ascertain the origin, and
tive care. In addition, there are certain abused substances obtain a sample for analysis since it may con-
that have associations with renal disease shown in tain heavy metals or NSAIDS
. Table 1.16. – Consider interactions with prescription medi-
cation, for example, via cytochrome P450
1.4.3.10 Medication and Allergy 5 Illicit drug abuse
The kidneys are susceptible to a wide range of adverse – Modality – frequency of needle use and shar-
effects from medications and their active metabolites. ing between individuals or participation in
Different medications may cause toxicity in a variety of needle exchange
sites within the kidney. It is essential to obtain a history – Route – intravenous or subcutaneous
of (1) prescription and (2) non-prescription drugs, (3) (increased risk of amyloid) associated with
recreational or illicit drugs and (4) herbal remedies. thrombophlebitis or cellulitis
Ward prescription charts and in-patient procedural – Risk factors for infective endocarditis
records such as anaesthetic charts, as well as redundant – Ketamine, cocaine, glue sniffing
completed drug charts, should be reviewed to identify
22 M. Khosravi et al.
Habitus Obesity (OSA), Bardet-Biedl (renal cysts), short stature: Noonan syndrome (short and webbed neck, renal
dysplasia), Turner’s syndrome (short stature webbed neck, horse-shoe kidney), Down’s syndrome (renal
dysplasia), lipodystrophy (MPGN), limb abnormalities-VACTERL association. Any form of CKD in childhood
can result in short stature
Hair Scaring alopecia (SLE), diffuse alopecia heavy metal poisoning (tacrolimus, steroids), hirsutism (cyclosporine)
Ears Otitis, inflammation of the pinna with GPA, pre-auricular pit, sensorineural deafness BOR syndrome, Alport’s,
Anderson-Fabry’s, CHARGE syndrome (ear abnormalities)
Nose Crusting, nasal bridge collapse (GPA) cocaine
Mouth Dentition (infective endocarditis (IE)), mouth ulcers (vasculitis, SLE, herpes viral infections and fungal
infections), macroglossia (useful sign of amyloid)
Polydactyly Bardet-Biedl
Nails Periungal fibromas (TSC), dysplastic nails (nail patella syndrome), splinter haemorrhages (IE), Muehrcke’s
bands (episodes of nephrotic syndrome)
Skin Signs of renal disease: vasculitic rashes, palpable purpura (HSP), palpable subcutaneous nodules/ulcers (PAN),
malar flush (SLE), cutaneous lupus erythematosus, alopecia (SLE, tacrolimus), neurofibroma, viral exanthem,
erythema nodosum, tracheostomy scar (previous ICU admission), xanthelasma, nicotine stains (atherosclerotic
disease); Janeway lesions (endocarditis); bruising (amyloid), livedo reticularis (cholesterol emboli, SLE,
anti-cardiolipin syndrome), angiokeratoma (AFD), Raynaud’s (SLE, scleroderma, anti-cardiolipin syndrome),
facial angiofibromas, ash-leaf macule and shagreen patch (TSC)
Signs of immunosuppression: purpura, thin skin, gum hypertrophy (cyclosporine), sebaceous gland hyperplasia,
actinic keratosis, Kaposi’s sarcoma, squamous cell carcinoma, basal cell carcinoma, hypertrichosis (cyclospo-
rine), Cushingoid features and striae (steroids)
Signs of advanced CKD: Xerosis, acquired perforating dermatosis, porphyria cutanea tarda, calciphylaxis
Eyes Retinopathy (hypertensive, diabetic); Retinitis pigmentosa/dysplasia (Bardet-Biedl, senior Loken syndrome-
nephronophthisis, Jeune’s syndrome, Kearns-Sayres mitochondrial cytopathy); uveitis (tubulointerstitial
nephritis with uveitis); uveitis, band keratopathy, sicca (Sjogren’s syndrome); corneal clouding (cystinosis);
lenticonus (Anderson-Fabry’s disease, Alport’s); proptosis (GPA, IgG-4-related disease); angiomatosis retinae
(VHL); coloboma (renal coloboma syndrome CHARGE and COACH syndromes), periorbital bruising
(amyloid), iritis, scleritis, retinal vasculitis (vasculitis), drusen (dense deposit disease)
Lymphoproliferative Lymphadenopathy (tuberculosis, lymphoma); splenomegaly (IE, sarcoid, lymphoproliferative disorder)
CVS Atrial fibrillation (Emboli), pericardial rub (SLE, infections, uraemic pericarditis), murmur/pacing wire
(endocarditis), radiofemoral delay/missing pulses (aortic coarctation/mid-aortic syndrome Takayasu’s arteritis);
bruits (renovascular disease, fibromuscular dysplasia), ventricular failure (right or left sided)
Chest Pneumothorax (tuberosclerosis); pleural rub (SLE, vasculitis, infection); asthma (eosinophilic granulomatosis
with polyangiitis); pulmonary fibrosis (systemic vasculitis, scleroderma, SLE, Sjogren’s, drugs); signs of
bronchiectasis (amyloid)
Abdominal Signs of chronic liver disease (hepato-renal syndrome, viral hepatitis); stoma (high output), absent abdominal
musculature (prune belly syndrome)
Neurological Asterixis/tremor (uremic encephalopathy, calcineurin inhibitor toxicity); hemiparesis (bladder dysfunction,
infection-associated amyloid), spina bifida (occulta)
Musculoskeletal Polyarthropathy (rheumatoid arthritis, SLE, ankylosing spondylitis), monoarthritis (hyperuricaemia), infection
including IE, Charcot joint, absent patellae (nail patella syndrome)
1.4.4 Aspects of the Clinical Examination to the outpatient department. Accurate fluid assessment
to Help Establish the Cause of a Renal will be critical to most presentations to the renal physi-
cian and is discussed in detail above. Alongside intravas-
Disorder
cular volume assessment, other findings on clinical
examination can provide an important clue to the aetiol-
A thorough clinical examination is an essential part of
ogy of a renal presentation. These examination findings
the approach to any patient presenting either acutely or
are summarised in . Table 1.17.
Assessment of the Renal Patient
23 1
1.5 Assessment of the Patient with Known . Table 1.18 Clinical assessment specific to the dialysis
Renal Disease patient
Patients with ESKD may have been receiving renal Complications of Anaemia, bone-mineral disorder
replacement therapy for many years and have been treated CKD and
treatment
with several treatment modalities. Renal physicians will
often be integral to the holistic care of patients on dialysis Transplant listing May impact on decisions regarding
programmes. Therefore, alongside dialysis-related issues, status transfusion
the renal specialist increasingly needs at least a basic Nutritional status Changes in ‘dry weight’, may indicate
understanding of a broad range of medical, surgical and chronic infection or malignancy
psychiatric problems so that appropriate further expertise
can be sought when necessary. When thinking about dial-
ysis-related problems, presentations will commonly be
related to dialysis access (including infection) and intra-
dialytic issues (instability, adequacy or complications). In addition, the management of immunosuppression-
Important considerations for the assessment of the related complications such as infection and malignancy
patient on dialysis are outlined in . Table 1.18. will need attention in transplant patients. . Table 1.19
outlines aspects of clinical assessment important in the
patient with a functioning renal allograft.
1.5.2 Patients with ESKD with Functioning
Kidney Transplants
1.5.3 Patients with ESKD on Conservative
Patients with kidney transplants will often present to Care Programmes
their ‘home’ transplant unit with a transplant related
issues and problems not immediately associated with Increasingly, renal units run large and successful conser-
function of the transplant. The management of graft vative care programs. One of the reasons patients may
dysfunction will represent a substantial workload for have decided that they do not wish to receive active care
any transplant unit, and again assessment of intravascu- for ESKD is to reduce time spent in a medical environ-
lar volume status is a critical element in the assessment. ment. Although these patients may have decided not to
24 M. Khosravi et al.
Case Study
Case 1 room air and afebrile. The patient was drowsy but easily
A 52-year-old man was referred by the intensive care rousable and orientated to time, place and person. His
team on the point of haemofiltration. He was admitted peripheries were cool. There was no oedema, and cardiac,
1 week before with sepsis secondary to biliary obstruc- respiratory and abdominal examinations were normal.
tion from a common bile duct stone for which he under- Urine output 20–40 mls/hour and dark.
went ERCP with stone removal and stenting. Upon straight leg raising, there was a 20/10 mmHg
Piperacillin-tazobactam was prescribed for Enterobacter increase in his BP as measured by his invasive arterial mea-
bacteraemia. His creatinine 6 months earlier was 82 surement.
micromole/L but on admission was 300 micromole/L, ris- His AKI was felt to have a significant pre-renal compo-
ing further to 450 micromole/L. The rest of his blood nent still, and he was given closely monitored fluid chal-
tests are as listed: sodium 160 mmol/L, urea 39 mmol/L, lenges followed by IV maintenance fluids and NG water.
potassium 5.0 mmol/L, haemoglobin 10.0 g/dL, white Within 1 day, the patient’s AKI and hypernatremia signifi-
cell count 15,000 per mcL and C-reactive protein cantly improved.
80 mg/L. This case illustrates the importance of an accurate
On clinical examination, his blood pressure was 110/80 fluid balance – whenever a patient is being given inotropes
supported with a low dose of noradrenaline; heart rate was and being haemofiltered, the first question you should ask
80 and regular. Respiratory rate was 18, with SaO2 99% on yourself is if the patient is in fact hypovolaemic.
26 M. Khosravi et al.
? Chapter Review Questions (a) Cocaine users with renal disease are often
1. The following are causes for chronic kidney dis- found to AA amyloid deposition on kidney
ease with preserved renal size except: biopsy.
(a) HIV nephropathy (b) Smoking is one of the few protective risk fac-
(b) Diabetic nephropathy tors for relapse of anti-glomerular basement
(c) Polycystic kidney disease membrane disease.
(d) Chronic glomerulonephritis (c) Tachycardia is a non-specific marker of intra-
(e) Renal amyloidosis vascular volume depletion and may be associ-
ated with excessive intravascular volume in
2. Which of the following is a known intrinsic renal
the context of heart failure.
cause of acute anuria?
(d) Aniline dye exposure puts one at an increased
(a) Anti-glomerular basement membrane disease
risk of focal segmental glomerulosclerosis.
(b) Membranoproliferative glomerulonephritis
(e) Balkan nephropathy is characterised by the
(c) Cryoglobulinemia
formation of multiple renal cysts.
Assessment of the Renal Patient
27 1
v Answers 2. Cannesson M, Besnard C, Durand PG, Bohé J, Jacques
1. (d) Chronic glomerulonephritis is a cause of bilat- D. Relation between respiratory variations in pulse oximetry
plethysmographic waveform amplitude and arterial pulse pres-
erally small kidneys
sure in ventilated patients. Crit Care. 2005;9:R562–8.
2. (a) Whilest most causes of intrinsic nephropathy 3. Monnet X, Teboul J-L. Passive leg raising: five rules, not a drop
can present sub-acutely, anti-GBM disease can of fluid! Crit Care. 2015;19:18.
render a patient anuric with alarming rapidity and 4. Dipti A, Soucy Z, Surana A, Chandra S. Role of inferior vena
requires a high index of suspicion to make a cava diameter in assessment of volume status: a meta-analysis.
Am J Emerg Med. 2012;30:1414–1419.e1.
timely diagnosis.
5. Feissel M, Michard F, Faller J-P, Teboul J-L. The respiratory
3. (e) Prune belly syndrome is triad of partial or variation in inferior vena cava diameter as a guide to fluid ther-
complete absence of the abdominal muscles, fail- apy. Intensive Care Med. 2004;30:1834–7.
ure of both testes to descend into the scrotum 6. Muller L, et al. Respiratory variations of inferior vena cava
(bilateral cryptorchidism), and/or urinary tract diameter to predict fluid responsiveness in spontaneously
breathing patients with acute circulatory failure: need for a cau-
malformations
tious use. Crit Care. 2012;16:R188.
4. (b) Turners syndrome does not classically affect 7. Olde Rikkert MG, Deurenberg P, Jansen RW, van’t Hof MA,
the eye. CHARGE syndrome is characterised by Hoefnagels WH. Validation of multi-frequency bioelectrical
coloboma. Alport and MPGN type II patients impedance analysis in detecting changes in fluid balance of
often have retinal drusen. Cystinosis is character- geriatric patients. J Am Geriatr Soc. 1997;45:1345–51.
8. Kumar S, Khosravi M, Massart A, Davenport A. Is there a role
ised by refractile cysteine crystals deposited in the
for N-terminal probrain-type natriuretic peptide in determin-
retina. ing volume status in haemodialysis patients? Nephron Clin
5. (a) False: – cocaine users can suffer from renal Pract. 2012;122:33–7.
ischaemia, vasculitis or rhabdomyolysis., (b) 9. Moghazi S, et al. Correlation of renal histopathology with
False: – smoking increases the chances of relapse sonographic findings. Kidney Int. 2005;67:1515–20.
10. van Lieburg AF, et al. Clinical phenotype of nephrogenic dia-
from anti-GBM disease., (c) True., (d) False: –
betes insipidus in females heterozygous for a vasopressin type 2
aniline dye exposure increases the chance of receptor mutation. Hum Genet. 1995;96:70–8.
developing urothelial malignancy., (e) False: – 11. Emma F, Salviati L. Mitochondrial cytopathies and the kidney.
Balkan nephropathy is associated with a chronic Nephrol Ther. 2017;13:S23–8.
tubulointerstitial nephritis. 12. Calderon-Margalit R, et al. History of childhood kidney dis-
ease and risk of adult end-stage renal disease. N Engl J Med.
2018;378:428–38.
13. Luyckx V, Nephrology, B. B.-N. R. & 2015, undefined. Birth
References weight, malnutrition and kidney-associated outcomes—a
global concern. nature.com.
1. Marik PE, Cavallazzi R, Vasu T, Hirani A. Dynamic changes in 14. Goldfarb DS. The exposome for kidney stones. Urolithiasis.
arterial waveform derived variables and fluid responsiveness in 2016;44:3–7.
mechanically ventilated patients: a systematic review of the lit- 15. Johri N, Jacquillet G, Unwin R. Heavy metal poisoning: the
erature*. Crit Care Med. 2009;37:2642–7. effects of cadmium on the kidney. Biometals. 2010;23:783–92.
29 2
Urine Analysis
Scott R. Henderson and Mark Harber
Contents
2.1 Introduction – 30
2.10 Summary – 43
References – 43
4. Microscope slides
5. Cover slips
6. Microscope (with phase contrast)
2 7.
8.
Appropriate bench space (usually dirty utility room)
Individual with responsibility for maintaining
equipment
. Table 2.2 Urinary dipstick abnormalities (for haematuria and proteinuria see below)
have a urological cause for haematuria can then be shapes including acanthocytes, best seen with phase
assessed by a nephrologist in reserved slots on the same contrast microscopy (. Fig. 2.4). A large quantity of
day. This takes a bit of organising, but the dividends for dysmorphic red blood cells is suggestive of an aggressive
the patient and the clinician are obvious in terms of pro- glomerular lesion, whereas scanty dysmorphic RBC are
viding an efficient and joined-up approach. more indicative of a sub-acute GN. The presence of a
Lower urinary tract bleeding is indicated by erythro- red blood cell cast (. Fig. 2.5) is highly suggestive of an
cytes (RBC) with essentially normal and homogeneous aggressive glomerulonephritis, and to paraphrase the
morphology. In haematuria due to glomerular disease, old adage, one RBC cast makes a Summer. As this is one
RBC presumably become distorted as they pass through of the most important and specific findings in urine
the glomerular basement membrane and down the microscopy, it is extremely helpful to train the nephrolo-
tubule resulting in heterogeneous and dysmorphic
34 S. R. Henderson and M. Harber
Microscope Indications
2 Phase contrast Allows best identification of cellular
elements, less need for special stains
Light Poor visualisation of contents with low
refractive index
Polarised light Positive birefringence allows detection of
crystalluria
Stains
Wright’s Lymphocytes
Papanicolaou’s ‘Decoy cells’ pathognomic of Bk viruria
May-Grünwald- Eosinophils
Giemsa
Hansel’s
Prussian blue Haemosiderin
. Fig. 2.4 Dysmorphic erythrocytes under polarised light at low
power. Red cells showing multiple blebs and extrusions
STOP
ABNORMAL NORMAL
Any one of – All of –
eGFR < 60ml/min eGFR ≥ 60ml/min
ACR ≥30 or PCR ≥50 ACR <30 or PCR <50
BP ≥140/90 BP <140/90
Cause identified
NEPHROLOGY ASSESSMENT
No cause identified
NB Direct referrals between Urology and Nephrology will depend on local commissioning guides
Urine Analysis
35 2
2.4.2 Isolated Proteinuria Urine analysis is absolutely critical in guiding the diag-
nosis and initial management of patients with AKI, and
The detection of protein on urine dipstick is affected by although the clinical picture is often complex, there are
(i) concentration (consider specific gravity), (ii) macro- several scenarios when urine analysis can substantially
scopic haematuria and (iii) urine pH >8.0. Urine dip- guide or cleverly make the diagnosis [1–5]. It is impor-
stick testing does however provide a semi-quantitative tant that your referring wards and emergency depart-
measurement of proteinuria as outlined in . Table 2.4, ments try, where possible, to obtain a fresh urine prior to
but whilst dipstick reagent testing is sensitive to albu-
min, it has low sensitivity to other proteins, such as
36 S. R. Henderson and M. Harber
Glomerular proteinuria Physiological – ACR <30 mg/24 hours (but raised acutely if febrile; see below)
2 Predominantly albumin and an early, important Microalbuminuria – ACR >30–300 mg/24 hours (not detectable with standard
indicator of glomerular injury. Standard dipsticks dipstick)
sensitive Overt proteinuria – ACR >PCR
Nephrotic range proteinuria – ACR> PCR>
Tubular proteinuria Rarely greater than 100 mg/mmol or 1 g/L
Suspect with low-level proteinuria especially if Indicated by normal ACR but raised PCR
uPCR out of proportion to dipstick/uACR, or Specific tests for tubular proteins include retinol-binding protein (RBP), α-1
accompanied by other features of tubular injury/ Microglobulin and N-acetyl β glucosamine (NAG)
inflammation such as sterile pyuria, or features of Causes include drug toxicity (e.g. cisplatinum, tenofovir, etc.), causes of acquired
Fanconi syndrome tubulointerstitial nephritis, heavy metal poisoning and Dent’s disease
Overflow proteinuria Overproduction of proteins, most commonly light chains
Not detected by standard urine dipsticks
Negative or low-level dipstick with disproportionate urine PCR may suggest
overflow or tubular proteinuria
Benign proteinuria ‘Physiological’: febrile proteinuria, post-exercise proteinuria
Orthostatic proteinuria: Isolated low-level proteinuria, often in young males,
possibly associated with ‘nutcracker kidney’ (arterial compression of renal veins
occasionally with loin pain). Proteinuria is absent on rising sample, present after
being ambulant so easily diagnosed with paired rising and ambulant uPCRs
2.6.2 Malignancy
to the laboratory swiftly for culture in order to confirm Box 2.3 Causes of Sterile Pyuria
the diagnosis and guide antimicrobial chemotherapy. 5 Urinary tract infection during or immediately
Urine analysis findings both in favour and against of a post antibiotics
2 significant/clinically relevant UTI in a MSU specimen
are shown in . Table 2.7. Sterile pyuria has to be con-
5 Children with pyrexia of non-urinary tract origin
5 Urinary tract infection with fastidious organism
sidered in the differential diagnosis prior to confirma- 5 Symptomatic patient but no bacteria:
tion of bacterial culture as hallmark ‘non-specific’ – Neisseria gonorrhoeae, Chlamydia trachomatis
features on initial urine analysis may also be explained – Mycoplasma genitalium
by the causes of sterile pyuria as outlined in 7 Box 2.3. 5 Asymptomatic tuberculosis, fungal infections
Pyelonephritis might be detectable by the presence of 5 Interstitial nephritis
white cell casts. More common than this is the presence 5 Chronic prostatitis
of ‘clue cells’ (see . Fig. 2.9), uroepithelial cells infected 5 Papillary necrosis
with uropathogenic bacteria. These can be seen with 5 Radiation or chemical cystitis
phase contrast microscopy and are indicative of lower 5 Renal stones
tract infection (often sub-acute). 5 Solvent abuse
Considerable thought also needs to be applied to the
interpretation of urine from patients with indwelling
catheters, ileal conduits and urostomies in that these 2.8 Urinary Electrolytes
frequently demonstrate all the features of a urinary
tract infection, a result of chronic colonisation, and Measurement of urinary electrolytes and osmolality is
these samples frequently do not represent clinically rel- often performed in clinical practice in an attempt to
evant UTI. guide diagnosis. However, interpretation is complex,
compounded by the intricate mechanisms regulating
solute excretion and osmolality. It is useful to remember
UNa+ urine sodium, UOsm urine osmolality, FENa+ fractional excretion of sodium, FEUrea fractional excretion of urea
Case Study
Case 1 Case 3
A 34-year-old woman under the care of rheumatology A 36-year-old man presented to A&E following a deliber-
with SLE and mixed connective tissue disorder presented ate suicide attempt. Regular medications included an anti-
with acute kidney injury (stage 2) and hypertension. Urine depressant. He was hypertensive on presentation and
dipstick testing confirmed the presence of 2+ blood and displayed signs of poor co-ordination with a GCS of
2+ protein on a Friday evening. The rheumatology team 14/15. He was normoglycaemic but acidotic with a raised
felt that her presentation represented a flare of SLE with anion gap. Serum creatinine measured 120 umol/l. Urine
renal involvement and recommended high-dose IV ste- analysis confirmed 1+ protein. Microscopy showed exten-
roids. Urine microscopy, however, demonstrated no evi- sive deposition of calcium oxalate bipyramidal crystals of
dence of an active glomerulonephritis (no casts and calcium (below . Fig. 2.10).
minimal RBCs that were not dysmorphic). On the basis of He later admitted drinking 400 ml of ethylene glycol.
this, steroids were withheld, and a subsequent renal biopsy Urine microscopy can be particularly useful in identifying
demonstrated histology consistent with scleroderma renal some of the causes of AKI, particularly in cases of crystal
crisis. High-dose steroids are not without risk and in this nephropathy.
case may well have exacerbated the patient’s scleroderma
renal crisis. Urine microscopy can sometimes be very effec- Case 4
tive at ruling in or out an active glomerulonephritis in the A 68-year-old woman with type 2 diabetes and hyperten-
context of AKI. sion was admitted from clinic with rapidly progressive
renal impairment (a rise from a baseline of 180 to 540 in
Case 2
A 44-year-old man presented to A&E after collapsing dur-
ing a half marathon. He had developed bilateral leg pain.
He had no significant past medical history and was not
taking any regular medications. He was tachycardic but
normotensive. There was no neurovascular deficit in either
legs, but both calves were very tender on examination.
Serum creatinine measured 363 umol/l on arrival with a
lactic acidosis. The patient was oliguric. Creatine kinase
measured 72,800 U/L. Renal ultrasound scan was normal.
Urine analysis showed 3+ blood and 1+ protein. After
aggressive fluid resuscitation, renal function improved,
and creatine kinase level fell. The use of urine dipstick test-
ing in the case highlights that the detection of blood in
urine testing may be a result of myoglobinuria. Myoglobin
is freely filtered at the glomerulus and produces a charac-
teristic red-brown urine discolouration. Dipstick is posi-
tive for blood, and orthotolidine test is also positive.
However, myoglobin has a short half-life, and so pigmen-
. Fig. 2.10 Numerous calcium oxalate crystals in urine
turia may be missed.
of case 3
42 S. R. Henderson and M. Harber
3 months). She was well, asymptomatic and afebrile, with in renal function was originally attributed, in part, to pro-
no obvious pre-renal elements nor obstruction on USS gression of diabetic nephropathy, but her renal function
2 (she had normal-sized kidneys). Urine dipstick was posi-
tive for protein 1+, leucocytes 3+ nitrites negative. Urine
responded well to intravenous antibiotics. Urine micros-
copy was able to narrow the differential diagnosis and sug-
microscopy demonstrated white cell casts consistent with gest a diagnosis here without the need for a biopsy or
pyelonephritis, and bilateral pyelonephritis was subse- missing a potentially reversible cause for progression.
quently confirmed with culture and imaging. Her decline
Contents
3.1 Introduction – 46
References – 64
1. Creatinine generation Low muscle mass: elderly, females, Increased muscle mass: athletes, Africans
3 malnourished, sarcopenic obesity
2. Dietary intake Vegetarian diet High meat diet, creatine supplements
3. Drugs interfering with tubular Trimethoprim, cimetidine, pyrimethamine, salicyclic
secretion acid, cobicistat, dolutegravir, fibric acid derivatives
4. Interference with creatinine assay Bilirubin Keto acids, glucose, some cephalosporins
A. Measured GFR
Indicated when eGFR is unreliable including:
1-Patients with abnormal muscle mass or body composition, anorectic, and obese patients.
2-When an exact value of GFR is required: before potential living kidney donation and the use of toxic drugs with narrow therapeutic range.
3-Non-kidney solid organ transplant recipients [4, 8].
1. Creatinine clearance CrCl = urine creatinine (mg/dl) X Used when eGFR is not 1. Overestimates GFR (tubular [9, 10]
(CrCl) urine volume (ml/24 h)/plasma reliable and mGFR is secretion of creatinine)
creatinine (mg/dl) X time interval for not practical or feasible 2. Errors of 24-hour urine
collection (1440 min “24-hour collections
collections”)
2. Inulin clearance IV infusion Gold standard (equals Laborious and expensive; [3, 11]
Timed-urine collections true GFR) inapplicable
3. 125I-iothalamate Ionic contrast medium Inexpensive 1. Long t1/2; long-term radiation [11, 12]
Subcutaneous or bolus IV exposure
2. GFR overestimation (Tubular
secretion)
3. Problems with thyroidal iodine
uptake
Iohexol Non-ionic contrast medium 1. Inexpensive marker, 1. Potential allergic reactions and [13, 14]
available, low nephrotoxicity
inter-laboratory 2. Small underestimation of
variation GFR (tubular reabsorption or
2. Low dose of iohexol: protein binding (1.5%))
safe, no severe adverse 3. Complex and expensive assay
events (HPLC)
3. Avoids radiation
4. Low extrarenal
clearance
Estimated GFR
Reliable for clinical decision-making and epidemiological studies in cases of poor renal function. eGFR within 30% of mGFR is satisfactory for
clinical interpretation [2]
Guidelines recommend to rely on eGFR rather than serum creatinine alone [4, 8]
Common limitations include:
1. Limitations of creatinine as endogenous filtration marker
2. Unavoidable differences between eGFR and mGFR
3. Variable performance among different ethnic groups
4. Inaccuracies at high or low kidney functions
5. More accurate in the steady state than in the non-steady state
1. Cockcroft-Gault The first widely used equation Estimates creatinine 1. Imprecise: [15]
equation Parameters used: clearance without urine Does not estimate GFR
1. Creatinine collection Current creatinine assay
2. Age differs from the assays
3. Weight performed to derive the
4. Gender equation
Clcr (ml/min) = (140 − age) × (wt 2. Requires measurement of
kg)/72 × scr(mg/100 ml) (× 0.85 if weight (and height for BSA)
female) 3. Influenced by weight: not for
very obese persons and
pronounced edema
2. MDRD study The four-variable MDRD equation Simple estimates of Imprecision: [16]
equation developed then re-expressed using GFR Underestimation of GFR at
standardized creatinine to improve More accurate than higher GFR values leading to
GFR prediction Cockroft-Gault equation overestimation of CKD stage 3
Parameters used: prevalence
1. Creatinine
2. Age
3. Ethnicity
4. Gender
GFR = 175 × standardized Scr−1.154 ×
age−0.203 × 1.212 [if black] × 0.742 [if
female]
3. CKD-EPI creatinine Developed to reduce bias in More accurate than Imprecision: underestimates [17]
equation MDRD-estimated GFR MDRD equation GFR and overestimates CKD
Parameters used: particularly at GFR prevalence
1. Creatinine >60 ml/min/1.73 m2
2. Age
3. Ethnicity
4. Gender
GFR = 141 × min(Scr/κ, 1)α×
max(Scr/κ, 1)−1.209 × 0.993Age × 1.018
[if female] × 1.159 [if black]
Where:
κ is 0.7 for females and 0.9 for males
α is −0.329 for females and −0.411 for
males
min indicates the minimum of Scr/ κ
or 1
max indicates the maximum of Scr/ κ
or 1
(continued)
50 A. M. Shendi
4. The CKD-EPI Parameters used: Cystatin C is less 1. Not more accurate than [18]
3 cystatin C equation 1. Cystatin C
2. Age
affected by non-GFR
determinants
creatinine-based estimates
2. Increased laboratory costs
3. Gender Usually agree with
GFR = 133 × min(Scys/0.8, eGFRcreatinine
1) − 0.499 × max (Scys/0.8,
1) − 1.328 × 0.996Age [×0.932 if
female]
Where:
min indicates the minimum of Scr/κ or
1, and
max indicates the maximum of Scys/κ
or 1
5. The CKD-EPI Parameters used: More accurate eGFR Increased laboratory costs [18]
creatinine-cystatin C 1. Creatinine than creatinine or
equation 2. Cystatin C cystatin C alone
3. Age Confirmatory test for
4. Ethnicity CKD
5. Gender
GFR = 135 × min(Scr/κ,
1)α × max(Scr/κ,
1) − 0.601 × min(Scys/0.8,
1) − 0.375 × max(Scys/0.8,
1) − 0.711 × 0.995Age [×0.969 if
female][×1.08 if black]
Where:
κ is 0.7 for females and 0.9 for males
α is −0.248 for females and − 0.207
for males
min indicates the minimum of
Scr/κ or 1
max indicates the maximum of
Scr/κ or 1
CKD chronic kidney disease, CrCl creatinine clearance, GFR glomerular filtration rate, Scr serum creatinine, Scys serum cystatin C,
BSA body surface area, BMI body mass index
3.2.3 Kidney Function Assessment During and both eGFR and CrCl equations are invalid. Short-
Pregnancy timed urine CrCl can be used [20].
Test Principles/method of assess- Clinical application Sensitivity Specificity Advantages Disadvantages Refer-
ment ences
A. Urine analysis
Urine analysis including testing for proteinuria has been discussed in 7 Chap. 2 “Urine Analysis”.
B. Markers of inflammation
Inflammatory markers can be used to monitor disease activity in various inflammatory kidney disorders
Laboratory Tests in Nephrology
Erythrocyte Measures the distance Surrogate marker of acute 1. Inexpensive, Increases with age, in [21,
sedimentation rate erythrocytes fall after 1 hour in phase reaction in quick, simple females, and with 22]
(ESR) vertical column of anticoagu- inflammatory renal 2. Better inflamma- pregnancy
lated blood under gravity disorders: tory marker than Affected by other
1. Monitoring disease CRP in factors, e.g., plasma
activity and response to autoimmune albumin, size, shape,
therapy diseases and number of RBCs
2. Prognostic marker particularly SLE and non-acute-phase
Extremely elevated ESR and some reaction proteins, e.g.,
(>100 mm/hr) has very low-grade bone immunoglobulins
low false-positive rate for and joint increase ESR
serious underlying disease: infections
(1) Infections. (2) Collagen
vascular disease. (3)
Malignant tumors
In proteinuric states: Mild
ESR elevations are
expected due to hypoalbu-
minemia; albumin in
plasma inhibits erythro-
cyte sedimentation
In patients with CKD:
Mild to moderate ESR
elevations; ESR gets more
elevated in patients with
ESRD on dialysis
(continued)
3 51
3
52
Test Principles/method of assess- Clinical application Sensitivity Specificity Advantages Disadvantages Refer-
ment ences
C-reactive protein Acute-phase protein synthe- Non-specific marker of 1. More specific and 1. Non-specific [22,
A. M. Shendi
(CRP) sized by hepatocytes in acute-phase reaction in sensitive than 2. Not recommended in 23]
response to pro-inflammatory acute inflammatory ESR SLE activity
cytokines during inflamma- response and to gauge 2. Rapid response to follow-up
tory/infectious processes chronic inflammation and inflammation: SLE is associated with
tissue damage concentrations ESR/CRP discordance:
exceed 5 mg/l by CRP is higher at
≈6 hours and baseline than in general
peak ≈48 hours population and during
3. Plasma t1/2 is activity than in
short (≈19 hours) remission (proposed
cutoff: 10 mg/l for active
SLE)
Synchronous elevation
of ESR and CRP
during concomitant
infections and during
flares in patients with
serositis and/or arthritis
C. Immunologic investigations
Laboratory assays which evaluate the immune response are valuable in establishing a diagnosis and/or monitoring disease activity of various immune-mediated kidney disorders
Complements Play role in pathogenesis of Assessment of comple- Patterns of Non-specific [24]
Routinely, serum antibody-mediated glomerulo- ment activity helps the complement activity Complement is an
C3, C4, and nephritis, C3 glomerulopathy, evaluation and follow-up characteristic for acute-phase reactant
possibly CH50 atypical hemolytic uremic of certain renal disorders: certain renal and so may be in the
Other analyses syndrome, ischemic- Low C3 and C4 indicate disorders normal range when
performed at reperfusion injury of immune complexes- consumed in the setting
specialized transplanted kidney, and mediated-classic pathway of sepsis
laboratories antibody-mediated renal activation, e.g. SLE Complement may be
allograft rejection Low C3 and normal C4 low in the setting of
suggest alternative liver failure
complement pathway
(AP) activation, e.g.,
C3G
Normal/low C3, often
undetectable C4 in
essential and type II
mixed cryoglobulinemia
Low C3 can be present
with AAV; indicates
severe disease
Auto-antibodies
ANA Autoantibodies that react with Screening for SLE and SLE: 93–95.2% SLE: High sensitivity and 1. Low specificity: high [25–
constituents of cell nuclei other autoimmune diseases (97.8% for ANA 57–83.3% negative predictive prevalence of 27]
Methods of detection: Prevalence: titer ≥1:80) SSc: value low-titer ANAs in
Indirect immune-fluorescence ANA titer >1:160 in SSc: 85–93.6% 54–84.2% healthy individuals
(IIF): 94–100% and ≥1:80 in Sjögren’s Sjögren’s (30% at 1:40, 10–15%
The most widely used initial ≈99.5% In LN: 100% syndrome: syn- at 1:80, 5% at 1:160)
test using human epidermoid Types of ANA: based on 48–88.4% drome:52– 2. Not useful for
carcinoma cell line (HEp-2) the nuclear antigen: MCTD: 100% 86.8% monitoring disease
The gold standard for ANA 1. Autoantibodies to DNA Drug-induced LE: activity or response to
Laboratory Tests in Nephrology
Test Principles/method of assess- Clinical application Sensitivity Specificity Advantages Disadvantages Refer-
ment ences
4. Anti-Sm Diagnosis of SLE 10–55% 98–100% High specificity 1. Low sensitivity [28]
A. M. Shendi
Test Principles/method of assess- Clinical application Sensitivity Specificity Advantages Disadvantages Refer-
ment ences
3. Anti-beta-2 Detected by ELISA; IgG and Plasma glycoprotein that 57.1% 79.2% The only aPL May identify antibodies [34,
A. M. Shendi
glycoprotein I IgM, and if negative and APS binds to anionic phospho- antibodies against different from those 37]
(anti-β2GPI) is still suspected IgA isotypes lipids on cell membranes specific protein relevant to the
Prevalence: syndrome
IgM: 65%; IgA: 47%
Anti-C1q Autoantibodies against C1q; can Diagnosis of SLE: 28% 92% Associated with Not specific: observed in [38]
antibodies result in decreased C1q in SLE Prevalence: 30–40% (In active LN: (In active hypocomplement- hypo-complementemic
Titers correlate with SLE 87%) LN: 92%) emia, disease urticarial vasculitis,
disease activity activity, and renal anti-GBM nephritis,
Good predicative marker involvement HIV infection
for active LN (40–100%)
Antineutrophil Auto-antibodies against 1. Diagnosis of ANCA- IIF: IIF: 1. Available assay 1. Large variability [39,
cytoplasmic antigenic targets in the associated vasculitis cANCA: cANCA: standardization. between IIF methods 40]
antibodies (ANCA) cytoplasmic granules of (AAV): GPA:65–77% 97–98% 2. ANCA specificity 2. ANCAs found in
neutrophils: myeloperoxidase PR3-ANCAs in: MPA: 5–6% pANCA: defines homoge- other conditions (e.g.,
(MPO) and leukocyte 1. ≈2/3 of GPA pANCA: 81–96% neous groups of anti-GBM, primary
proteinase 3 (PR3) 2. 25% of MPA GPA:11–15% Immunoassay AAV patients sclerosing cholangitis)
Methods of detection: MPO-ANCAs in: MPA:85–89% PR3-ANCA: 3. Patients diagnosed as
1. IIF using human neutrophils 1. Majority of MPA Immunoassay 98–99% having GPA or MPA
detects two staining patterns: 2. ≈25% of GPA PR3-ANCA: MPO- can be negative for
perinuclear (pANCA) and 2. Titers are related to GPA:77–81% ANCA: PR3 and MPO-
cytoplasmic (cANCA). Rare disease activity MPA: 5–9% 96–99 ANCA (11–17% by
Atypical pattern (A-ANCA) 3. Rising ANCA during MPO-ANCA: combining IIF IIF and 9–16% by
combines cytoplasmic and remission can predict GPA: 9–12% with ELISA: immunoassay)
perinuclear or nuclear staining relapse MPA:71–88% 98% 4. Difficult to differenti-
mostly in absence of vasculitis Combining IIF ate P-ANCA (or
2. Antigen-specific solid-phase with ELISA A-ANCA) patterns
assays (ELISA) for MPO decreased the from ANA staining
and PR3, the antigenic sensitivities to on IIF
targets of pANCAs and 67–82%
cANCAs, respectively
Antigen-specific assays should
be the primary screening method
Anti-GBM Auto-antibodies against the Diagnosis of anti-GBM 41.2% 85.4% Lack of sensitivity. [41]
antibodies non-collagenous (NC1) disease (renal limited Patients with atypical
domain of α3 chain of type IV anti-GBM and the anti-GBM (≈10%) do
collagen (α3[IV]NC1; complete Goodpasture not have identifiable
“Goodpasture autoantigen”) syndrome) in patients with circulating antibodies
Detected using enzyme RPGN
immunoassays or bead-based * Prevalence: 90%
fluorescence assays
Anti-podocytic antibodies
1. Anti- IgG antibodies (predominantly 1. Differentiation of IMN 81%. 100% (both High specificity [42,
phospholipase IgG4) that react with PLA2R, a from secondary forms (combined with serum 43]
A2 receptor glycoprotein expressed on and other glomerulopa- PLA2R tissue anti-PLA2R
(PLA2R) normal glomerular podocytes thies localization: and
antibodies and present in the glomerular * Prevalence: 70% of IMN 95.2%) glomerular
immune deposits in patients 2. Serum PLA2R-Abs PLA2R)
with IMN correlate with protein-
uria, disease activity,
and prognosis:
Laboratory Tests in Nephrology
Higher spontaneous
remission in negative and
low-titer PLA2R-Abs
Serial evaluation to
monitor response to
therapy
Pre-transplant PLA2R-
Ab could predict
recurrence of MN
post-transplant
2. Anti- IgG4 antibody specific for 1. Diagnosis of IMN [44]
thrombospondin THSD7A, podocyte membrane * Prevalence: 3–5%
type 1 domain antigen similar to PLA2R 2. Anti-PLA2R/THSD7A
containing 7A levels correlate with
(THSD7A) proteinuria, clinical
course, and outcomes
3. THSD7A-associated
MN characterized by
(1) female predomi-
nance and (2) associa-
tion with malignancy
(continued)
3 57
3
58
Test Principles/method of assess- Clinical application Sensitivity Specificity Advantages Disadvantages Refer-
ment ences
C3 nephritic factor IgG autoantibody that Identification of Strong disease 1. Uncertain pathogenic [45]
A. M. Shendi
elevated inflammatory
markers in sepsis-
induced AKI
Hemolytic anemia with
fragmented RBCs and
thrombocytopenia in
cases of AKI caused by
micro-angiopathic
hemolytic anemia
2. Fibrinogen: Soluble 340-kD protein mainly 1. Plasma fibrinogen: Not present in urine [47,
synthesized by the liver with 1. Detection of under normal 48]
the central function in hypo-fibrinogenemia conditions
hemostasis complicating plasma-
pheresis
2. Elevated levels predict
adverse cardiovascular,
stroke, and mortality
outcomes in patients
with CKD stages 3 and 4
2. Urinary fibrinogen:
* Elevated in proteinuric
kidney diseases
*Significantly higher in
FSGS than MCD and
may be used as biomarker
for differentiation
* Noninvasive method to
monitor kidney fibrosis
and prediction of CKD
progression
(continued)
3 59
3
60
Test Principles/method of assess- Clinical application Sensitivity Specificity Advantages Disadvantages Refer-
ment ences
3. Investigations for amyloidosis and related disorders (7 Chap. 50,Amyloid and the Kidney):
A. M. Shendi
2. Urine culture and antibiotic susceptibility testing for suspected urinary tract infection (7 Chap. 54;Urinary Tract Infection)
3. Blood culture and antibiotic susceptibility testing for suspected bloodstream infection
4. Viral screening for hepatitis C, hepatitis B, and human immunodeficiency virus (HIV) infections
Surveillance for HCV, HBV, and HIV infection using serologic and\or nucleic acid testing is recommended at the time of initial evaluation of glomerulopathies and CKD and during
evaluation for kidney transplantation. Guidelines for viral screening during hemodialysis are discussed in 7 Chap. 76
AAV ANCA-associated vasculitis, ANA antinuclear antibodies, aCL anti-cardiolipin, anti-β2GPI anti-beta-2 glycoprotein I, anti-THSD7A Anti-thrombospondin type 1 domain con-
taining 7A, anti-PLA2R anti-phospholipase A2 receptors, ANCA antineutrophil cytoplasmic antibodies, Anti-GBM anti-glomerular basement membrane, ASO anti-streptolysin O,
C3NeF C3 nephritic factor, C5NeF C5 nephritic factor, CKD chronic kidney disease, CRP C-reactive protein, ELISA enzyme-linked immunosorbent assay, ESR erythrocyte sedimenta-
tion rate, GPA granulomatosis with polyangiitis, GPL units IgG phospholipid units, IIF indirect immunofluorescence, IMN idiopathic membranous nephropathy, LN lupus nephritis,
MPA microscopic polyangiitis, MPL units IgM phospholipid units, PSGN post-streptococcal glomerulonephritis, RBCs red blood cells, RIA Farr radioimmunoassay, RNP ribonucleo-
protein, SSc systemic sclerosis, WBCs white blood cells
Laboratory Tests in Nephrology
61 3
Tips, Tricks, and Pitfalls
expect. It can be used to detect concurrent infec-
1. Despite the inevitable difference from true GFR, tions or in patients with arthritis and/or serositis.
eGFR is practical and reliable for clinical deci- 7. Mild-to-moderate elevations of ESR without any
sion-making in cases of poor renal function. It is other signs or abnormalities are not specific and
not accurate in patients with GFR >60 ml/ should not trigger extensive investigations to
min/1.73 m2. search for etiology. It should be repeated at some
2. It is not possible to routinely refer to mGFR in time weeks later.
daily clinical practice. However, it should be 8. ANA is the most sensitive test to screen for SLE
requested when eGFR is unreliable including and related autoimmune diseases. It should be
patients with abnormal muscle mass or body performed primarily by IIF, and if positive,
composition and when an exact value of GFR is ELISA testing to identify disease-specific anti-
required like before potential living kidney dona- bodies is performed.
tion and the use of toxic drugs with narrow ther- 9. Negative ANA can occasionally be encountered
apeutic range. with positive anti-dsDNA. First, ELISA testing
3. Each method of GFR measurement has its own for anti-dsDNA can be more sensitive than the
limitations. There is no clear recommendation IIF used for ANA. Second, Crithidia luciliae
for one method over the other, and choice would assay, an IF test, can yield false-positive anti-
thus depend mainly on availability and tradition. dsDNA.
4. The most accurate creatinine-based GFR estima- 10. Antigen-specific solid-phase assays should be
tion equation is CKD EPI, which should be used used as the primary screening method for ANCA,
as the primary equation. Cystatin C-based equa- and if negative but clinical suspicion of vasculitis
tions can then to be used as confirmatory. is high, then IIF can be resorted to.
5. GFR estimation equations cannot be used in 11. False-negative cryoglobulin is not infrequent
patients with AKI or in pregnant ladies. Serial mostly due to sample handling/processing error.
creatinine is the method of choice to monitor Thus the test should be repeated in cases with
kidney function with less frequent reference to high clinical suspicion.
creatinine clearance based on short-timed urine 12. Antiphospholipid antibody testing involves LA,
collection in AKI and 24-hours collection in aCL IgM and IgG, and anti-β2GPI IgM and
pregnancy. IgG. The three tests should be performed as no
6. CRP is generally used to monitor an inflamma- one can replace the others. Positivity of one test
tory response. In SLE, though it is higher at is sufficient to diagnose antiphospholipid syn-
baseline than the general population, during drome provided that it is accompanied by clinical
flares, it increases but not to the level we would criteria and remains positive after 12 weeks.
Case Studies
Case 1 Case 2
Creatinine of a patient with a stable renal transplant and A 58-year-old man presented with progressively rising serum
baseline creatinine of 140 μmol/l (eGFR 43 ml/ creatinine up to 406.6 μmol/l (from a baseline of 159.1 μmol/l)
min/1.73 m2) who developed a severe inflammatory after having an AKI following a bout of severe diarrhea
arthropathy. The fall in creatinine from 140 to 60 μmol/l (. Fig. 3.2). The patient had diabetes, hypertension, and
(and eGFR >90 ml/min/1.73 m2) was entirely due to mus- CKD diagnosed as diabetic kidney disease. Investigations
cle loss in this period with subsequent rise in creatinine not showed subnephrotic proteinuria with no hematuria, persis-
a consequence of falling GFR but recovering muscle mass tently elevated inflammatory markers (CRP 54 mg/l; ESR
(. Fig. 3.1). 95 mm/first hour), and negative virology and immunology
Interpretation of creatinine levels and eGFR should screen and angiotensin-converting enzyme. Serum amyloid
thus be judicious in patients with abnormal muscle mass. A and LDH were significantly elevated. Kidney biopsy was
62 A. M. Shendi
. Fig. 3.1 Serum creatinine decline in a patient with stable kidney transplant due to muscle loss during the course of severe inflam-
matory arthropathy
Immuunosuppression
500 70
450
60
400
350 50
Creatinine µmol/l
300
40
250 CRP mg/L
30
200
150 20
100
10
50
0 0
15
16
18
18
18
18
18
18
18
18
19
19
01
20
20
20
20
20
20
20
20
20
20
20
20
/2
8/
3/
6/
7/
7/
7/
8/
0/
1/
2/
0/
2/
/2
/0
/0
/0
/0
/0
/0
/0
/1
/1
/1
/1
/1
14
04
22
06
03
18
31
26
11
15
15
13
14
. Fig. 3.2 Time course of creatinine and CRP in a diabetic patient with sarcoidosis
Laboratory Tests in Nephrology
63 3
denied. PET/CT showed bilateral hypermetabolic pulmo- tion, initial stabilization of kidney functions (3-month
nary sub-pleural nodules with hypermetabolic bilateral hilar creatinine, 247.5 μmol/l; after 15 months, 353 μmol/l), and
and mediastinal lymph nodes (. Fig. 3.3). True cut biopsy decline of the inflammatory markers.
was characteristic for sarcoidosis. An unexplained inflammatory milieu together with
The patient received immunosuppression (predniso- progressive deterioration of kidney functions required
lone and MMF) with improvement of the general condi- thorough investigations to identify the underlying etiology.
. Fig. 3.3 Sarcoidosis as a cause of progressive CKD diagnosed by PET CT and elevated inflammatory markers. Right lower
lung lobe (lateral segment) irregular hypermetabolic sub-pleural soft tissue mass
basis of a creatinine-based eGFR of 45–59 ml/ 6. Stevens LA, Schmid CH, Greene T, Li L, Beck GJ, Joffe MM,
min/1.73 m2, without albuminuria or other mark- et al. Factors other than glomerular filtration rate affect serum
cystatin C levels. Kidney Int. 2009;75(6):652–60.
ers of kidney damage. If eGFRcys/eGFRcreat-
7. Foster MC, Levey AS, Inker LA, Shafi T, Fan L, Gudnason V,
cys is also <60 ml/min/1.73 m2, the diagnosis of et al. Non-GFR determinants of low-molecular-weight serum
CKD is confirmed. protein filtration markers in the elderly: AGES-kidney and
3. First, solid-phase assays are generally more sensi- MESA-kidney. Am J Kidney Dis. 2017;70(3):406–14.
3 tive and specific. P-ANCA staining pattern is 8. NICE guidance: Chronic kidney disease in adults: assessment
and management Clinical guideline [CG182] [Internet]. 2015
indistinguishable from ANA nuclear staining pat-
[cited Jan 6, 2020]. Available from: https://www.nice.org.uk/
tern, and thus not specific. Also, IIF staining does guidance/cg182/chapter/1-Recommendations#investigations-
not provide antigenic specificity, while solid-phase for-chronic-kidney-disease-2
assays are antigen-specific and thus can help 9. Lam YWF, Banerji S, Hatfield C, Talbert RL. Principles of
define homogeneous groups of AAV patients with drug administration in renal insufficiency. Clin Pharmacokinet.
1997;32(1):30–57.
different clinical characteristics: MPO and PR3
10. Shannon JA. The renal excretion of creatinine in man. J Clin
ANCA-associated vasculitis. Invest. 1935;14(4):403–10.
4. No, despite ANA at a titer ≥1:80 is prevalent in 11. Soveri I, Berg UB, Bjork J, Elinder CG, Grubb A, Mejare I,
≈99.5% of SLE cases and holding sensitivity of et al. Measuring GFR: a systematic review. Am J Kidney Dis.
97.8% to diagnose SLE, some cases can be nega- 2014;64(3):411–24.
12. Stevens LA, Levey AS. Measured GFR as a confirmatory test
tive for ANA. The 2019 American College of
for estimated GFR. J Am Soc Nephrol. 2009; 20(11):2305–13.
Rheumatology and European League against 13. Delanaye P, Ebert N, Melsom T, Gaspari F, Mariat C, Cavalier
Rheumatism classification criteria for SLE posi- E, et al. Iohexol plasma clearance for measuring glomerular fil-
tioned ANA positivity (≥1/80) as an entry crite- tration rate in clinical practice and research: a review. Part 1:
rion to diagnose SLE, yet this is still a matter of how to measure glomerular filtration rate with iohexol? Clin
Kidney J. 2016;9(5):682–99.
uncertainty since there remains a subgroup of
14. Delanaye P, Melsom T, Ebert N, Bäck S, Mariat C, Cavalier E,
patients who are persistently ANA negative. et al. Iohexol plasma clearance for measuring glomerular filtra-
Positive anti-dsDNA with negative ANA may tion rate in clinical practice and research: a review. Part 2: why
occur as the solid-phase assay used for anti- to measure glomerular filtration rate with iohexol? Clin Kidney
dsDNA and can have higher sensitivity than J. 2016;9(5):700–4.
15. Cockcroft D, Gault H. Prediction of creatinine clearance from
IIF. Moreover, LN can present without positive
serum creatinine. Nephron. 1976;41:31–41.
SLE serologies (seronegative LN) which may or 16. Levey A, Coresh J, Greene T, Stevens L, Zhang Y (Lucy), Hen-
may not convert to positive ones during follow-up. driksen S, et al. Using standardized serum creatinine values in
5. Anti-phospholipase A2 receptor (PLA2R) anti- the modification of diet in renal disease study equation for esti-
body is 100% specific for idiopathic membranous mating glomerular. Ann Intern Med. 2006;145(4):247–54.
17. Levey AS, Stevens LA, Schmid CH, Zhang YL, Iii AFC, Feld-
nephropathy (IMN); thus, it can reliably diagnose
man HI, et al. A new equation to estimate glomerular filtration
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and level of serum PLA2R-Abs correlate with 18. Inker LA, Schmid CH, Tighiouart H, Eckfeldt JH, Feldman HI,
proteinuria, disease activity, and prognosis. Greene T, et al. Estimating glomerular filtration rate from serum
creatinine and cystatin C. N Engl J Med. 2012;367(1):20–9.
19. Piccoli GB, Cabiddu G, Attini R, Vigotti F, Fassio F, Rolfo A,
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26. Jeong S, Yang D, Lee W, Kim G, Kim H, Ahn HS, et al. Diag- 40. Damoiseaux J, Csernok E, Rasmussen N, Moosig F, van Paas-
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2012;12(2):97–106. PC, Goodship TH, de Cordoba SR, et al. Sensitive and specific
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update of the classification criteria for definite antiphospho- coccal glomerulonephritis in childhood: prospective study and
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37. Parkpian V, Verasertniyom O, Vanichapuntu M, Totemchok-
chyakarn K, Nantiruj K, Pisitkul P, et al. Specificity and sensi- Further Reading and Guidelines
tivity of anti-beta2-glycoprotein I as compared with
KDIGO guidelines for CKD evaluation and management: https://
anticardiolipin antibody and lupus anticoagulant in Thai sys-
kdigo.org/guidelines/ckd-evaluation-and-management/.
temic lupus erythematosus patients with clinical features of
NICE guidance: Chronic kidney disease in adults: assessment and
antiphospholipid syndrome. Clin Rheumatol.
management Clinical guideline [CG182]: https://www.nice.org.uk/
2007;26(10):1663–70.
guidance/cg182/chapter/1-Recommendations#investigations-for-
38. Seelen MA, Trouw LA, Daha MR. Diagnostic and prognostic
chronic-kidney-disease-2.
significance of anti-C1q antibodies in systemic lupus erythema-
2019 European League Against Rheumatism/American College of
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Rheumatology Classification Criteria for Systemic Lupus
39. Csernok E, Moosig F. Current and emerging techniques for
Erythematosus: https://onlinelibrary.wiley.com/doi/full/10.1002/
ANCA detection in vasculitis. Nat Rev Rheumatol.
art.40930.
2014;10(8):494–501.
67 4
Kidney Biopsy
Lakshman Weerasekara, Nick Woodward, and Mark Harber
Contents
4.1 Introduction – 68
4.4 Contraindications – 70
References – 78
n Learning Objectives
5 To appreciate the indications, contraindications
and risks of renal biopsy.
5 To illustrate the techniques and alternative
approaches of renal biopsy and to consider the
entire patient pathway in terms of information and
after care.
4
4.1 Introduction
treatments, and thus benefits of a biopsy predominantly biopsy can act as a barometer of disease control in the
relate to prognosis for the patient (particularly for insur- absence of other less-invasive markers. Most commonly
ance purposes), especially in the context of potential live this is in the context of connective tissue diseases such as
donation, and family if excluding a heritable glomerular vasculitis and SLE with an active urine deposit. However,
basement membrane abnormality (GBM) abnormality. a biopsy may demonstrate deposition of light chains in
In practical terms and in the absence of the indications myeloma and evidence of endocarditis or of HIV-related
above, most units will merely recommend observation nephropathy which might provoke a change in manage-
unless hypertension or renal impairment intervenes; ment. Similarly, biopsy of enlarged kidneys with dys-
4 however with newer therapies for IgA and other condi- function can diagnose infiltration and escalation of
tions on the horizon, the benefits of a PRB in this group treatment in lymphoproliferative disorders.
may increase.
4
4.6 Anatomy and Complications
and Consent
Complication rates in the literature vary significantly
depending on definition, how studiously they were
looked for and how high risk the biopsy is. There is
almost certainly a significant publication bias in favour
of low rates. What follows is a rough and hopefully rea- . Fig. 4.4 Intracapsular haematoma causing gross compression of
sonable summation of the risks; ultimately complica- the kidney (Page kidney) and anuria in a transplant recipient. Urine
tions will depend on local practice and experience, but flow was restored instantly with surgical decompression
individuals and units should be audited against these
outcomes on a regular basis and quote their complica-
tion risks to patients when consenting [8–10].
Temporary local pain and discomfort on administra-
tion of local anaesthetic is universal but should subside
rapidly, and patients should be prewarned of this. Native
renal biopsies tend to be more uncomfortable than biopsy
of a superficial denervated renal transplant kidney.
1. Bleeding is the commonest and the major complica-
tion of renal biopsy (see . Figs. 4.3, 4.4 and 4.5). In
a meta-analysis of 34 studies involving more than
9000 patients who underwent real-time native kidney
. Fig. 4.6 Angiogram demonstrating a large AV fistula following a function was a Page kidney (see below) or an AVM; the latter was
native renal biopsy. The only hint of this initially was a post-biopsy suspected by auscultating a loud bruit Embolisation risks permanent
deterioration in renal function (creatinine increasing from 104 to loss of perfusion to a significant portion of the kidney, but if not
145). The lower half of the kidney had very little perfusion as blood spontaneously resolving, a high output shunt may grow and render
rapidly short-cut to the renal vein. The differential for decline in the rest of the kidney increasingly ischaemic
74 L. Weerasekara et al.
secondary to a significant steal from the kidney On discharge patients should be educated to avoid
should raise suspicion). heavy exercise and contact sports for at least 10 to
14 days to minimise post-biopsy bleeding risk. We rec-
Acute oligoanuria post-transplant is likely due to the ommend that patients do not drive a vehicle for at least
following: 24 hours post-biopsy.
(a) Shock: this is usually pretty obvious.
(b) Clot retention: easily diagnosed by US or catheteri-
sation.
4.8 Day-Case Vs Inpatient Procedure
4 (c) Page kidney: subcapsular haematoma may tampon-
ade the kidney and cause complete anuria in a
In the last two decades, standard-risk PRBs have been
transplant recipient or patients with a solitary native
increasingly performed as day-case procedures. The
kidney, but often missed in native biopsies once
published audits seem to have a good safety record, ben-
identified urgent surgical decompression can
efits to patients and significant cost savings [9, 12, 13].
instantly restore perfusion to a transplant kidney
There are no standard guidelines for who is suitable
but risks further bleeding by removing any tampon-
for day-case biopsy, but the criteria below seem to have
ade; the optimum option is to surgically decompress
been arrived at independently by several units and repre-
the kidney and perform selective radiological
sent a reasonable starting place.
embolisation immediately if haemostasis cannot be
Suggested criteria for day-case renal biopsy:
achieved. Missed Paged kidney following a native
1. Two kidneys ≥10 cm.
kidney biopsy might cause chronic hypertension, or
2. Blood pressure ≤ 150/90.
a step decline in GFR immediately after the biopsy
3. eGFR ≥30,
which may persist or improve over time.
4. Hb ≥10 g/dl.
(d) Urinary leak: this seems to be a very rare complica-
5. Platelets ≥100.
tion but important not to miss. Likely to be associ-
6. INR ≤1.2 PTT ≤1.2.
ated with raised inflammatory markers and pain, it
7. Off aspirin or clopidogrel for 7 days.
may be identifiable on delayed film MAG-3.
8. Lack of significant cardiovascular comorbidity.
Persistent urinary leak can cause urinoma forma-
9. BMI ≤30 (not significant centripetal obesity).
tion and associated complications.
10. A responsible adult to transport home and at home
to provide care and support for 24 h post-transplant.
11. Experienced operator and day ward staff.
4.7 Post-Biopsy Monitoring
The good outcome data presumably, in part, reflects that
Typical post-biopsy monitoring would be pulse and patients suitable for a day-case biopsy are carefully
blood pressure monitoring as follows: every 15 min for selected; thus, if the above criteria are breached, then the
an hour; then if stable, every 30 min for 2 h; then if sta- decision to proceed as a day-case biopsy must be dis-
ble, every hour for 4 h; and then if stable and the patient cussed with the patient and should be made at a senior
has passed urine (without haematuria), mobilise and level.
discharge; if an inpatient (high-risk patient), then con- Example of day-case and inpatient renal biopsy pro
tinue 4-hourly monitoring for 24 hours. forma are attached and can be modified for local practice.
The most critical aspect of post-biopsy monitoring is For inpatient biopsies it is less easy to be absolutist
that nursing and medical staff are familiar with the pro- because there may be compelling reasons to perform a
cedure and are comfortable escalating monitoring and biopsy despite the increased risk, and depending on
requesting medical review at the first sign of a complica- local expertise, options such as open, laparoscopic or
tion. Performing renal biopsies on wards not familiar transjugular biopsy might be employed.
with post-biopsy observations and appropriate escala-
tion is to be avoided.
The timing of complications is important and some-
what controversial; one large study detected 38% of 4.9 Alternatives to PRB in High-Risk
complications within 4 h, 67% by 8 h, 89% by 12 h and Patients (. Table 4.3)
91% by 24 h [12]. This data would imply that day-case
biopsies would not be safe, yet a third of complications As levels of obesity and comorbidity increase, we will be
occurring after 8 h does not seem to be general experi- increasingly faced with high-risk patients. There are a
ence, and day-case biopsies in standard-risk patients variety of alternatives to stand PRB nicely summarised
seem to have a high safety record. in a review by Stiles et al. [14].
Kidney Biopsy
75 4
Open biopsy Direct vision, very high diagnostic General anaesthetic, Single kidney, kidney with multiple cysts, obese
yield, direct haemostasis, suitable for long recovery and patient, patient unable to cooperate with breath
ventilated patient hospitalisation, cost holding
Laparo- Direct vision, very high diagnostic General anaesthetic, Single kidney, kidney with multiple cysts, obese
scopic yield, direct haemostasis, less invasive long recovery and patient, patient unable to cooperate with breath
biopsy than open biopsy, suitable for hospitalisation, cost holding
ventilated patient
Transvenous Suitable for grossly obese, contrac- Contrast load, smaller Simultaneous liver kidney biopsy, concomitant
biopsy tures preventing PRB, abnormal sample size predomi- with dialysis line placement, obese patient,
clotting, diagnostic yield 78–97% nance of medulla bleeding diathesis, patient unable to cooperate with
Suitable for ventilated patient breath holding
4.10 Open Renal Biopsy (ORB) vein, (c) any acute extracapsular bleeds demonstrated at
the time can be embolised if significant, (d) tissue can be
The definitive series of ORB was of 934 patients and obtained in patients in whom the percutaneous approach
reported 100% tissue adequacy with apparently no sig- is not feasible, e.g. grossly obese and (e) occasionally it
nificant complications [15]. Open (and laparoscopic) may be combined with TJ liver biopsy in patients with
approaches offer the distinct advantage of direct vision workup for liver disease. Diagnostic yields of 78–97%
and direct haemostasis and thus can be helpful in have been reported and, in the largest study to date,
patients with cysts or other focal abnormalities as well major complications of only 1% [16], but other smaller
as other high-risk patients and those already ventilated. studies have had significantly higher complication rates,
The need for general anaesthetic and significant recov- and it is easy to inadvertently perforate the capsule.
ery time however are not justified in standard-risk Since the technique requires a small amount of contrast,
patients. the contrast-induced nephropathy is also a potential
complication of TVRB. In short TVRB is a useful albeit
rarely used technique for high-risk patients if there is
sufficient local expertise; however, it is not without risk
4.11 Laparoscopic Renal Biopsy (LRB) and remains extremely important to correct coagulopa-
thies as much as possible prior to biopsy.
There are several case series of LRB usually in the set-
ting of high-risk patients. As with ORB direct vision
means the diagnostic yield approaches 100% and imme- 4.13 Standards for Renal Biopsy
diate haemostasis can be performed. This offers a signifi-
cant advantage in patients with a body habitus preventing In 2010, the British Association for Paediatric
PRB, mild bleeding disorders or focal abnormalities of Nephrology published suggested standards for renal
the kidney. As with ORB this technique obligates a gen- biopsy [2] which are also a useful benchmark for adult
eral anaesthetic but is less invasive, and the recovery time patients with some amendments to consider (added in
is likely to be less than for an ORB and again can be italics):
considered in patients already ventilated on ITU. 1. All patients should receive an appropriate patient
information leaflet (PIL) about the biopsy proce-
dure1 (in advance and, ideally, in their first language)
4.12 Transvenous Renal Biopsy (TVRB) (the patient or guardian should have a clear under-
standing of the indication for the biopsy).
Transvenous renal biopsy (TVRB) (usually transjugu-
lar) has been reported in the setting of bleeding diathesis
[16–19] or obesity [20] (mean BMI 44). The theoretical 1 The renal association has produced a PIL available on the web-
advantages are that (a) the capsule is less likely to be site (7 www.renal.org), and there is a similar PIL available on
punctured, (b) any bleeding should be back into the MedlinePlus and includes Spanish translation.
76 L. Weerasekara et al.
2. Complication rates for macroscopic haematuria, Informative, detailed request forms greatly assist the
transfusion, embolisation and loss of kidney (if single pathologist, while uninformative ones do not; it is thus
or transplant) should be quoted as part of consent. good practice to ensure that the indication and clinical
3. For both native and transplant biopsies, ≤3 passes details are of a high standard.
should be achieved in 80% of occasions. The workup of a renal biopsy is reviewed in more
4. There should be adequate tissue for diagnosis on detail elsewhere [21]; however, assessment requires light
95% of occasions.2 microscopy always, immunohistochemistry frequently
5. Major complications (defined as delay in discharge and electron microscopy occasionally. Although there
4 as a result of post-biopsy complications or require- are many different approaches to technical aspects of
ments for further investigations or monitoring) these, the most important factor is the competence of
should be <5% of biopsies. the pathologist who is giving a report on the specimen.
6. There should be on-site access to interventional radiol- Different pathologists have their own preferences for
ogy and surgeons experienced in dealing with a major the number of sections, whether serial sections are cut,
renal bleed. which stains are used, whether immunofluorescence
7. Operators should maintain a prospective audit of ade- usually on frozen sections or an enzyme method such
quacy and complications. as immunoperoxidase on paraffin sections is used for
immunohistological studies and whether electron
microscopy, if available, is necessary on a particular
2 Adequacy: the general consensus is that for native renal biopsies, specimen. Importantly if your laboratory processes
10–15 glomeruli are an optimal number to exclude a focal glo- biopsies for immunoperoxidase, then it is often possible
merulonephritis (>20 ideal), but this definition of adequacy may
be a little rigid as sometimes it is possible to make the diagnosis
to retrospectively obtain tissue for electron microscopy
on a single glomerulus. Conversely, a sample of less than 10–15 (see Howie [22]). Renal pathology is a highly special-
may miss focal disease and therefore be unable to rule out other ised field, and it is important to have close liaison
disease (such as interstitial nephritis or rejection in transplanta- between clinicians and pathologists as well as consider
tion). For transplant biopsies, the Banff classification requires presenting difficult cases between renal teams and
>10 glomeruli and two arteries with a minimum of seven glom-
eruli and one artery. A more pragmatic definition of adequacy is
pathologists.
that if the cause of the renal dysfunction is identified, then the Finally, pathology MDT meetings are an invaluable
sample was adequate, if not, then adequate only if containing liaison between clinicians and pathologists, and it is
≥10–15 glomeruli. important to document, in real time (ideally electroni-
In the transplant setting, one large study reported a sensitivity cally), conclusions of these discussions and consequent
for the diagnosis of acute rejection of 91% with a single core and treatment plans.
99% for two cores suggesting that if the index of suspicion for
rejection is high then a second core should be taken if possible [23]
(Colvin R B 1997 JASN (8) 1930–41).
Case Study
The procedure was abandoned, the patient admitted for and taken to theatre where a perforated gallbladder was
observation, and a CT with contrast is performed which removed.
demonstrated no haematoma and was essentially normal. A unit that performs enough biopsies will at some
The following morning the patient appeared well and hae- point have a serious complication; having a high index of
modynamically stable with no change in haemoglobin and suspicion, close monitoring and a rapid MDT (radiologi-
on initial inspection well enough to go home, but his CRP cal and surgical) review are critical to reducing the risk
was markedly elevated 245. On further assessment he had posed by such complications.
a pleural effusion on the side of biopsy and mild tender-
ness in the RUQ and flank. A repeat CT confirms the pleu- Case 3
ral effusion and demonstrated free fluid in the paracolic A 38-year-old woman with systemic lupus erythematosus
gutter. The differential diagnosis included haemothorax, and a creatinine of 123 and two equal-sized kidneys
perforated colon, perforated gallbladder, small bowel/duo- (10.5 cm) underwent an uncomplicated PRB. She was
denal puncture or pancreatic puncture. reviewed with the result 10 days later and noted to be
The use of contrast CT is critical when assessing post- hypertensive and with a creatinine of 195. A MAG-3 scan
biopsy complications, in this case ruling out blood and a revealed a non-functioning right kidney, and an urgent
haemothorax. The absence of blood on the scan and the Doppler ultrasound demonstrated a subcapsular haema-
rapidly rising CRP were highly suggestive of a perforated toma and minimal diastolic flow although a patent artery.
viscus. The patient was given broad-spectrum antibiotics The diagnosis was of a Page kidney: high intra-renal pres-
a b
. Fig. 4.7 a Showing distance from the skin to the lower pole of the kidney. b Change in position of the kidney with the
patient in lateral position. c Shortened distance to the kidney at time of biopsy in left lateral position
78 L. Weerasekara et al.
sures reducing arterial perfusion. Over the next 4 weeks, increase in creatinine post-biopsy may indicate this com-
her blood pressure settled and renal function improved to plication. In a patient with a single kidney (transplant or
a baseline of 140. Subsequent MAG-3 scans showed the otherwise) anuria and a rapid rise in creatinine, it is more
right kidney producing 30% of total renal function with no obvious and serious. Surgical decompression of the kidney
improvement over time. (if identified rapidly) resolves the problem, but decom-
A Page kidney can easily be missed in a patient with pressing the tamponade may release extensive bleeding,
two kidneys and good function. Hypertension and a step and this needs to be anticipated.
4
Imaging in Nephrology
Ciara N. Magee, Arum Parthipun, Antony Goode, and Asmat Abro
Contents
5.1 Introduction – 82
n Learning Objectives
. Table 5.1 Radiation dose for common imaging protocols
1. To understand the advantages and disadvantages
of each imaging modality in order to choose the Examination Effective dose (mSv)
most appropriate test, based both on the clinical
question and pertinent patient factors. 1 day of background radiation 0.006
2. To understand the role interventional radiology Chest X-ray 0.02
and nephrology can play in the management of the
Abdomen X-ray 0.7
renal patient.
CT chest 7
CT pulmonary angiogram 15
5 5.1 Introduction CT KUB (low dose) 5
. Table 5.2 The sensitivity and role of ultrasound, CT scan and MRI for different renal pathologies
Ultrasound CT MRI
Paren- Mass 20% sensitivity for lesions <1 cm, 76% sensitivity for lesions 100% sensitivity and 94%
chyma lesions 70% sensitivity for lesions sized <1 cm, 95% sensitivity for specificity for solid mass detection
1–2 cm lesions sized 1–2 cm. Allows
Allows Bosniak characterisation of assessment of fat, calcium
cystic lesions. Superior to CT and soft tissue content and
enhancement pattern with IV
contrast
1. Previous reaction
2. Asthma – Increases risk of a severe reaction by six to ten
times Neither term indicates a causal link between the admin-
istration of intravenous contrast media but rather
3. Renal impairment (up to date eGFR or creatinine is essential
when making a radiology request)
acknowledges correlation.
4. Multiple allergies
5. Diabetes – Risk of development of lactic acidosis in patients
CI-AKI denotes the subset of CA-AKI cases where a
with renal impairment when taking metformin. Consider causal relationship between the contrast media and
stopping metformin for 48 hours after contrast in patients episode of AKI can be established.
whose eGFR<60 ml/min/1.73m2
. Table 5.6 Risk factors for CA-AKI 5.3.3 Intravenous Pyelography (IVP)
Chronic kidney disease (adults with an eGFR <40 ml/ IVP is rarely performed now, as CT is superior for most
min/1.73 m2 are at particular risk) applications. The IVP is, however, the investigation of
Diabetes mellitus choice in the diagnosis of medullary sponge kidney and
papillary necrosis, as the superior spatial resolution of
Co-incident use of nephrotoxic agents
film radiography over CT better demonstrates the typi-
Reduced renal perfusion (e.g. heart failure) cal findings of both these conditions.
Hypovolaemia
Hypoalbuminuria
5.3.4 Magnetic Resonance Imaging (MRI)
Increasing volume of contrast agent
Intra-arterial administration of contrast medium with first-pass MRI utilises the interaction between hydrogen ions
renal exposure (protons) and radiofrequency waves in the presence of a
high magnetic field, producing images that are depen-
Imaging in Nephrology
87 5
ease (ESKD) have a 1–7% chance of developing NSF;
. Table 5.8 Contraindications for MRI scanning with
implants
repeated exposure confers increased risk. While the
exact cause of NSF has not been definitively proven, the
Absolute contraindi- Pacemaker, otic implant, metal in hypothesis is that gadolinium ions are released from
cation eye or orbit, implanted cardiac chelates in GBCAs due to the prolonged clearance time
defibrillator in patients with advanced kidney disease, as a result of
Likely contraindica- Heart valve or aneurysm clip displacement of the gadolinium ion by another metallic
tion installed before 1996 ion, such as calcium or zinc, in a process known as
Possible contraindica- Heart valve or aneurysm clip
transmetallation. The gadolinium ion binds with free
tion installed after 1996, any type of anions and precipitates out in various tissues resulting in
prosthesis fibrosis. The European Medicines Agency (EMEA) has
Usually allowable Passive implants, weakly ferromag-
classified the various GBCAs as low, medium and high
6–8 weeks after netic (e.g. coils, filters and stents; risk: GBCAs with linear chelates appear to have greater
implantation metal sutures or staples) risk than those with cyclical chelates.
Usually allowable Passive implants, non-ferromagnetic
Clinical features include initial pain, pruritus, swell-
immediately after (e.g. bone/joint pins, screws or rods) ing and erythema, usually starting in the legs. This pro-
implantation gresses to thickening and fibrosis of the skin and
subcutaneous tissues, characterised by a “woody” tex-
ture with development of plaques and associated con-
tractures. Systemic fibrosis, involving the diaphragm,
heart, liver and lungs, is also seen. Cachexia may
dent upon the chemical composition of the tissue rather
develop, and death occurs in a proportion of patients
than density. It provides an excellent contrast between
[12]. Time of onset ranges from the day of exposure to
soft tissue structures and is superior to CT for the imag-
several months. Patients with acute kidney injury, CKD
ing and assessment of tumours and soft tissue masses; it
Stage 4 and 5 and ESKD on dialysis are considered
is also often used to investigate the renal vascular sys-
higher risk, alongside patients with reduced renal func-
tem. Its use is complicated, however, by its contraindica-
tion who have had or are awaiting liver transplantation;
tion in the presence of certain implanted metallic
patients with CKD 3 (GFR 30–59 ml/min/1.73 m2) and
objects; some orthopaedic and cardiac implants can
children aged less than 1 year are considered low risk
safely be imaged with MRI (. Table 5.8), and it is there-
[12]. In these patient cohorts, alternative imaging tests
fore vital to obtain accurate records of any medical, cos-
or MRI without gadolinium should first be considered.
metic or other implants.
If, following review, use of a low-risk agent is deemed
Gadolinium-based contrast agents (GBCAs) are
appropriate or if it is necessary to use a medium-risk
widely used in MRI and allow assessment of the
agent, the single lowest dose possible can be used (not to
enhancement patterns of lesions and visualisation of
exceed 0.1 mmol/kilogram body weight) and should not
vessels to assess for anatomy and stenosis. GBCAs work
be repeated for at least 7 days; use of a high-risk agent is
by harnessing the paramagnetic properties of the gado-
contraindicated.
linium ion; free gadolinium ions are highly toxic but,
No cases of NSF have been reported in patients with
when formulated as a chelated compound, are rendered
an eGFR >60 ml/min/1.73 m2, and it appears that the
safe for use. The incidence of anaphylactoid reactions
few cases reported in patients with an eGFR >30 ml/
with gadolinium is <0.01%, with an increased risk in
min/1.73 m2 were associated with an episode of AKI, in
patients with previous reactions, the second reaction
which eGFR is inappropriate and misleading. The influ-
often being more severe. Asthma or atopy also confers a
ence of various possible co-factors in the pathogenesis
3.7x adverse reaction rate.
of NSF is not proven, but both hyperphosphataemia
and erythropoietin use are suspected to play a role.
5.3.4.1 Nephrogenic Systemic Fibrosis (NSF) Guidance on the use of gadolinium in patients with kid-
NSF is a rare but serious multi-system disorder charac- ney disease is available from a variety of sources [12, 17].
terised by the deposition of collagen in the skin; sys-
temic involvement is also seen, including involvement of
the lungs, liver, muscles and heart. There is a well- 5.3.5 Nuclear Medicine
documented link between exposure to GBCAs and
development of NSF; the diagnosis is made using a Nuclear medicine examinations also involve the use of
combination of clinical and pathological factors known radiation; however instead of projecting a beam of
as the Girardi criteria [16]. Patients with CKD Stage 5 X-rays through the patient as in plain radiography or
(eGFR <15 ml/min/1.73m2) and end-stage kidney dis- CT, a radioactive isotope is chemically bound to a phar-
88 C. N. Magee et al.
Counts/sec
60
300 50
(%)
40
200 30
100 20
10
0 0
0 5 10 15 20 25 30
Minutes
Markers Tx kidney (RT)
c
. Fig. 5.1 [99mTc]Tc-MAG 3 renogram in a 3-day post-operative tubular function. c Coronal fused SPECT-CT images of the same
transplant kidney. a Serial planar images show normal uptake in the kidney show absent uptake in the upper pole due to infarction of an
lower pole but absent uptake in the upper pole (arrows). b There is a upper pole transplant artery
slowly rising time-activity curve over the lower pole indicating poor
(. Fig. 5.1a–c). Some studies have suggested that the bladder, a second acquisition is performed while the
MAG3 can differentiate early rejection from acute tubu- patient micturates into a specially designed commode.
lar necrosis in the early post-operative period. The per- Reflux into the kidneys from the bladder is evident by
fusion index, a measure of the blood flow in the measuring the activity in the kidneys over time and iden-
transplant kidney relative to the external iliac artery, is tifying an increase in activity during micturition [22].
usually preserved in acute tubular necrosis. Sequential Sensitivity for reflux is limited and often only reflux into
imaging with MAG3 can be useful in assessing graft the kidneys can be identified.
function in the post-operative period and is highly sensi-
tive, but non-specific, for evaluating transplant kidney Captopril Renography
pathology [18]. Finally, because MAG3 is excreted into Captopril renography involves performing a MAG3
the collecting system and bladder, it can be used to non- examination before and after administration of an
invasively assess for post-operative urine leaks [19]. angiotensin-converting enzyme inhibitor, typically cap-
topril. The technique is used to identify renovascular
Indirect Micturating Cystoscintigraphy causes of hypertension and renal artery stenosis.
As MAG3 is excreted into the collecting system and Although captopril renography is not as sensitive or spe-
bladder, a micturating study can be performed to assess cific for renal artery stenosis as MR angiography, it
for vesicoureteric reflux [20, 21]. This has the advantage remains a useful examination for renovascular disease in
over a direct micturating cystogram performed using patients with preserved renal function [23], and to a
contrast because catheterisation of the bladder is not lesser extent patients with chronic kidney disease, in pre-
required. The study is performed by injecting 99Tc- dicting the beneficial effect of revascularisation [24].
MAG3 followed by imaging similar to a standard reno- Renal artery stenosis is diagnosed if there is a fall in
gram. Once the tracer has drained from the kidneys into function of one kidney by at least 5% or if there is a
90 C. N. Magee et al.
delay to peak activity to 10 minutes in one kidney after increased uptake on FDG PET-CT. Approximately 20%
the administration of captopril [25]. However, if the of FDG is eliminated by urinary excretion, with the rest
split function of a single kidney is less than 20% on the undergoing radioactive decay. As a result, the kidneys
baseline study, then captopril renography is unlikely to and bladder can show intense uptake on PET-CT.
be accurate, limiting its usefulness in certain patients FDG PET-CT is most commonly used in tumour
with chronic kidney disease. imaging, particularly in the diagnosis, staging and mon-
itoring of Hodgkin’s disease, non-Hodgkin’s lym-
5.3.5.2 DMSA phoma, breast cancer, lung cancer, melanoma and
In this examination, dimercaptosuccinic acid is chelated gastrointestinal malignancies; it is not generally useful
with technetium-99 m to form the radiopharmaceutical. in the detection of renal cell carcinomas (RCCs); how-
After injection, this concentrates within the renal cortex ever, due both to the high level of uptake in the kidneys
5 and becomes bound to proximal tubular cells; only 10% and the lack of FDG avidity of most RCCs. FDG
is excreted into the urine in the first few hours after PET-CT is also often used to identify occult malignan-
injection, providing high-resolution images of the renal cies in patients with unexpected weight loss or to iden-
cortex. tify a primary malignancy in patients with metastatic
Unlike the dynamic nature of MAG3, DMSA is disease.
used to assess the renal parenchyma for anatomy or FDG PET-CT can be used to assess post-transplant
scarring. As such, it is useful in cases of horseshoe or lymphoproliferative disease (PTLD) following renal
solitary kidneys or for localisation of an ectopic kidney transplant [32, 33] and adds value over other imaging
[26, 27]; it is also used to assess renal scarring and paren- modalities. FDG can identify sites of PTLD in lymph
chymal damage in acute pyelonephritis in children and nodes that are not enlarged on anatomical imaging, can
adults [28, 29]. The relative function of the two kidneys aid diagnosis by identifying a target for biopsy and can
is also calculated, useful for surgical planning [30]. As confirm extranodal sites of disease such as in the liver,
DMSA is only minimally excreted in the urine, it can lungs and bone that may be occult on other imaging
more accurately assess relative function in patients with modalities (. Fig. 5.2a–c). There is also some evidence
chronic kidney disease [31] than MAG3. that FDG can be used to assess treatment response in
Once the radiopharmaceutical is injected, the patient PTLD [34].
waits approximately 3 hours for it to accumulate within FDG accumulates in activated leukocytes, and
the kidneys before images are acquired with a gamma PET-CT can therefore be used to evaluate inflammatory
camera. Planar imaging in multiple views is standard and infectious processes, including the identification of
practice, but some centres perform SPECT or SPECT-CT sites of infection in patients with pyrexia of unknown
to improve anatomical localisation of scarring. origin [35, 36], and can guide further management such
as therapeutic intervention or biopsies. As well as iden-
5.3.5.3 PET-CT tifying sources of bacterial infection, FDG PET-CT is
The use of PET-CT scans, most often performed using useful in identifying active TB, sarcoidosis, large vessel
fluorodeoxyglucose (FDG) labelled with fluorine-18, is vasculitis and Still’s disease. It is increasingly used in the
increasingly widespread. PET-CT has greater spatial res- diagnosis and management of IgG4-related retroperito-
olution compared to SPECT-CT imaging, but the short neal fibrosis.
half-life of 18F (110 minutes) limits its availability. As a As FDG is excreted by the urinary system, its role in
glucose analogue, FDG is taken up by cells and phos- evaluating the kidneys and bladder is somewhat limited
phorylated but cannot then be further metabolised as it by the physiological activity of these organs. However,
lacks the necessary 2-hydroxyl group present in glucose. FDG PET-CT can be used to diagnose transplant pyelo-
FDG uptake is therefore a good indicator of glucose nephritis and infected cysts in patients with polycystic
uptake by cells in the body, and organs with high glucose kidney disease [37, 38] (. Fig. 5.3a–b). Despite a rela-
metabolism, such as the brain, myocardium and brown tively poor sensitivity, the absence of iodinated contrast
adipocytes, will show increased uptake on PET-CT media in PET-CT makes it a useful examination in
scans at baseline; tissues with abnormal high metabolic patients where the risk of contrast-induced nephropathy
activity, including malignant tumours, will also show is considered excessive (. Table 5.10).
Imaging in Nephrology
91 5
a b c
. Fig. 5.2 2-[18F]FDG PET-CT images of a 30-year-old transplant (arrow) and mesenteric lymphadenopathy (arrow heads). c Maxi-
recipient with new cervical lymphadenopathy. a Axial fused PET-CT mum intensity projection (MIP) imaging in the same patient with a
image through the level of the oropharynx showing a left tonsillar tonsillar mass (arrow) and caecal mass (open arrow). A biopsy con-
mass (arrow). b Coronal fused PET-CT image showing a caecal mass firmed a diagnosis of post-transplant lymphoproliferative disease
a b
. Fig. 5.3 2 [18F]FDG PET-CT scan of a 48-year-old transplant uptake in the cortex of the transplant kidney (arrows) which are in
recipient being investigated for pyrexia of unknown origin. a Coro- keeping with transplant pyelonephritis
nal and b axial fused PET-CT images show multiple foci of increased
92 C. N. Magee et al.
. Table 5.11 The advantages and disadvantages of ultrasound, CT, MRI and nuclear medicine are compared in the table 5.10
Disad- 1. Small field of view (single 1. Risk of radiation and 1. Time – Can take many 1. Risk of radiation and
vantages plane at one time) – The cancer minutes. Patients are additional risk to other
view directly in front of 2. Artefact – Movement required to lie still patients, carers and staff as
the probe and breathing during 2. Availability – Less readily body fluids are radioactive
2. Operator skill and the scan can produce available due to high cost with radiopharmaceutical
experience dependent blurred images and time consumption 2. Poor spatial resolution
3. Image review – Due to obscuring pathology 3. Claustrophobia – The bore giving low anatomical
the factors above, an 3. Poor soft tissue of the scanner, inside which details; some investigations
ultrasound can only resolution on a plain the patient is placed for are therefore combined
really be interpreted by CT – Although this is imaging is about 60 cm, with CT (e.g. PET-CT and
the person who has improved by the use of smaller than a CT. Wide SPECT-CT) to enable
performed it unlike CT IV contrast, this bore or open MRI scanners spatial localisation of the
or MRI scan where carries its own risks are available at specialist physiological data shown
whole sequence of institutes, although image by the nuclear medicine
images will be available quality is usually poorer component
for later review with these magnets 3. Time-consuming to gain
4. Patient dependent – necessary data despite
Movement, breathing recent advancements, as
and presence of large scans aim to look at
amount of subcutaneous physiological processes
fat in obese patients, for
example, can affect the
image quality
The procedure is often performed with the use of include extensive distal tumour, ureteric injury and
intravenous sedation and analgesia, as venous dilatation reimplantation of the ureter, e.g. a transplant kidney.
is typically very painful. For a native AV fistula, no anti- Urgent drainage should be considered in an obstructed
biotics are given; however for an AV fistula with a pros- infected pelvicalyceal (PC) system or obstructed single
thetic graft, antibiotic prophylaxis with Gram-positive, kidney (including transplant) with acute derangement
Gram-negative and anaerobic cover is commonly given. of renal function.
The procedure requires IV analgesia, sedation and
kComplications antibiotic prophylaxis.
5 Haemorrhage: this is not usually clinically significant
at the puncture site, even when an arterialised seg- kComplications
ment of fistula vein has been punctured, as manual 5 Haemorrhage: may be sufficient to threaten kidney
compression is sufficient to obtain haemostasis. or life. Bleeding may occur from the kidney, or from
5 Infection: prosthetic grafts at risk; see above for anti- the abdominal wall.
biotic prophylaxis. 5 Infection: puncture of an obstructed infected PC
5 Rupture of fistula: risk greatest if there has been very system may result in septic shower and rapid instabil-
recent surgical revision of the fistula or if there is ity of the patient.
infection present. 5 Deterioration in renal function: haemorrhage may
5 Central venous perforation: this may occur due to lead to loss of the kidney, or renal compression and
perforation by a guidewire or during angioplasty of reduced function, while secondary infection may
a central vein and carries the potential for significant also cause injury.
intrathoracic haemorrhage.
phalic veins, SVC, IVC or iliac veins. These patients may is not usually performed due to the difficulty in treat-
need associated venoplasty to facilitate line insertion, or ing in-stent restenosis should this occur.
an unusual access site such as a translumbar or transhe- 5 Renal artery stenosis with flash pulmonary oedema –
patic inferior vena cava (IVC) line, and some may stent insertion may reduce episodes of pulmonary
require insertion of a line surgically, for example, oedema.
directly into an iliac vein. 5 New deterioration of renal function in established
Antibiotic prophylaxis is not usually given for line renovascular disease.
insertion. 5 Severe stenosis and single kidney with significant
impairment of renal function.
5.4.4 Percutaneous Peritoneal Dialysis Many patients with renal disease require peripheral
5
Catheter arterial revascularisation. The preparation is the same
as for renal angiography, although the complication rate
While peritoneal dialysis catheters are traditionally is higher, at 4%, and includes arterial damage or haem-
inserted surgically under general anaesthetic, they may orrhage at the puncture site, and distal embolisation fol-
also be inserted percutaneously, using local anaesthesia. lowing angioplasty, which at worst may be
This procedure may be performed by interventional limb-threatening (<1%). Antibiotic prophylaxis is not
nephrologists or radiologists and is typically confined to usually necessary.
patients who have not previously had any abdominal
surgery and who may be deemed unfit for general anaes-
thesia. 5.5 Tips for Requesting Imaging
a b
c d
. Fig. 5.4 (Case 1) MR angiography shows multiple parenchymal and ectasia typical of polyarteritis nodosa (PAN) c. MR angiogram
perfusional defects a. and normal renal arteries b. Renal digital sub- shows improved appearance of renal arterial tree with fewer paren-
traction angiography (DSA) shows multiple small vessel strictures chymal perfusional defects following treatment d
Case Study
a b
c d
. Fig. 5.5 (Case 2) MR angiogram with no stenosis (but did not Repeat MR angiogram confirming presence of renal artery stenosis
include the origin of renal artery a. Doppler US showing a typical c. Renal angioplasty resulting in successful treatment of renal artery
“tardus-parvus” waveform suspicious for renal artery stenosis b. stenosis (d. and e.)
98 C. N. Magee et al.
a b c
5
. Fig. 5.6 (Case 3) MR angiography showing typical features of fibromuscular dysplasia (FMD) in left renal artery a. DSA confirming
FMD b. Post-angioplasty angiogram which is usually abnormal following successful angioplasty in FMD c
a b
. Fig. 5.7 (Case 4) MRA showing a lesion involving the bifurca- successful treatment of the lesion with two “kissing” stents from the
tion of the main left renal artery with significant stenosis of the ori- main artery into each branch c
gins of both branches a. confirmation on formal angiogram b.
Imaging in Nephrology
99 5
a b
. Fig. 5.8 (Case 5) CT KUB showing hydronephrosis a. and an obstructing left ureteric calculus b. nephrostomy insertion for treatment c
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103 6
Contents
References – 110
Clinical Electronic Patient-related information including diagnostic and procedure Hospitals, clinics, community
medical records codes, discharge destinations, medication prescriptions, health services data, social care
inpatient complications data
Diagnostic Imaging, laboratory results Laboratories, radiology
departments
Biomarkers Genomic, proteomic, metabolomic Universities, diagnostic
companies
Administrative Admission, discharge and transfer data Healthcare providers, insurance
databases companies
Renal registries Demographics, renal-specific diagnoses, treatment/modality UKRR, ANZDATA, USRDS,
history, complications, outcomes ERA-EDTA, OPTN
Claims Medical Financial medical reimbursement claims Healthcare providers, insurance
insurance claims companies
Prescriptions Prescription reimbursement claims (including drug, dosage, National pharmacy datasets,
duration, collection) insurance companies
Clinical Clinical trials Design parameters (intervention tested, effect size, endpoint) Universities, pharmaceutical
research companies, medical journals
Patient- Social media Web-board discussions Electronic health portals, social
generated media websites
Wearable/ Smartphones, fitness monitors, dialysis machine automated Device integration systems,
sensors feedback systems technology firms
Clinical studies Quality of life surveys, patient-reported outcome measures Pharmaceutical companies,
universities
UKRR United Kingdom Renal Registry, ANZDATA Australia and New Zealand Dialysis and Transplant Registry, USRDS United
States Renal Data System, ERA-EDTA European Renal Association – European Dialysis and Transplant Association
surveillance system worldwide), the European Renal large amounts of data on the people they sell services to.
Association – European Dialysis and Transplant Although not a renal-specific dataset, the Kaiser
Association (ERA-EDTA, established in 1964 though Permanente Research Bank is the second largest bio-
with progressively more European members joining), bank in the USA (including between 20 and 50% of
and the Canadian Organ Replacement Register each regional area’s insured population) with a wealth
(CORR). of de-identified medical record information, health sur-
In addition to compiling routine annual reports on vey results, and bio-specimens available to scientists for
the incidence and prevalence of CKD, ESKD, and RRT genetic, epidemiological, and other research. Multiple
patterns, registries are increasingly being used to iden- cohort studies have been published, both for Kaiser
tify cohorts of people with ESKD with which other Permanente patients with ESKD and with CKD – an
datasets of interest are linked, in large-scale cohort stud- advantage over many of the ESKD registries.
ies. These studies harness the power of routinely and Finally, the pharmaceutical industry (and to a lesser
prospectively collected, comprehensive data with a long extent, academia) generates ever increasing volumes of
duration of follow-up, helping to make the most effi- data. This data growth is generated from several sources
cient use of pre-existing data. Linkage with rare disease including the research and development (R&D) process
registries – such as the National Registry of Rare Kidney itself, retailers, patients, and caregivers. Effectively uti-
Diseases (RaDaR) – allows otherwise prohibitively lizing these data may help pharmaceutical companies
expensive or time-consuming cohort studies to be better identify new potential candidate drugs and
conducted. develop them into effective, approved, and reimbursed
In the United States (USA), large healthcare compa- medicines more quickly. The European Union (EU)
nies (including insurers and care providers) also compile Drug Regulating Authorities Clinical Trials Database
106 T. Oates
UKRR United Kingdom Renal Registry; ANZDATA Australia and New Zealand Dialysis and Transplant Registry; USRDS United
States Renal Data System; ERA-EDTA European Renal Association – European Dialysis and Transplant Association; ESKD PPS
End Stage Renal Disease Prospective Payment System
IT and Data in Nephrology
107 6
(EudraCT) collates information on interventional clini- offering of statin treatment [12], suggesting that driving
cal trials on medicines conducted in the EU or the up CKD coding could improve outcomes.
European Economic Area (EEA) which started after Additionally, there is evidence that the efficacy of
2004. Currently, there are 33,690 clinical trials for renal technology-enabled interventions subsequent to detec-
disease registered with a EudraCT protocol. The paral- tion of CKD may differ. A recent randomized trial of 93
lel US-based 7 ClinicalTrials.gov currently identifies primary care practices [15] found that blood pressure
7701 studies for “kidney diseases” and includes regis- control in patients with CKD was significantly improved
trations and protocols for interventional and observa- in practices that were part of an audit-based education
tional studies. In addition to primary analyses, trial intervention scheme compared with those practices
data are increasingly used in secondary studies: synthe- using usual care or EHR-based guidelines and prompts
sis of data across multiple RCT of similar interventions about CKD. Audit-based education is a validated qual-
in meta-analyses allows more robust estimates of treat- ity improvement intervention that depends upon IT sys-
ment effects (as well as exploration of clinical heteroge- tems to extract and make comparisons between practices
neity), and linkage of data from participants in and against evidence-based guidelines.
randomized controlled trials (RCT) to either renal-spe- Similarly, in the USA – partly as a result of the fed-
cific registries or other large electronic datasets has eral government paying for most dialysis care since
allowed nested cohort studies using data linkage to 1972 – Medicare’s large administrative datasets have had
examine long-term outcomes for rare disease and a central role in the evaluation and development of pub-
expensive interventions which are beyond the scope of lic policy, helping to identify trends in costs, access to
most clinical trials. dialysis care, and quality of care delivered. Studies using
Chronic kidney disease (CKD) management often Medicare data – including the Dialysis Outcomes and
involves primary and secondary care providers working Practice Patterns Study – have enabled care provider
toward the achievement of disparate outcomes dictated comparisons with the generation of an outcome-
by payment systems. As a result, aligning outcomes and focussed national ESKD Quality Incentive Program
facilitating information flow between providers may (QIP) in which key quality metrics (including vascular
result in improved quality of care. Basic interventions in access, hospitalizations, infections, and use of blood
earlier stages of CKD may retard progression of CKD transfusions) determine financial reimbursement in an
and prove to be cost-effective [6]. effort to improve quality of care.
Medical coding, the process of transforming descrip-
tions of medical diagnoses and procedures into univer-
sal numeric codes, has been rapidly enabled by the 6.4 Using and Analysing Big Data
growth of electronic health records (EHRs). Intelligent
use of coded data to examine the efficacy and cost- Big data analytics has the potential to transform clinical
effectiveness of interventions, track new trends in medi- pathways for efficient delivery of care, set priorities for
cal needs, and guide reimbursement of healthcare patient-centred clinical research, and – by recognizing
providers represents one of the key goals of data usage patterns and detecting disease associations – facilitate
in medicine. autonomous decision-making. In clinical practice, big
Coding of individuals’ disease status, often followed data analytics can also help in the personalization of
by inclusion in primary care disease registers, may asso- predictions of disease trajectory and the estimation of
ciate with differences in outcomes. Recently, the UK risks and benefits associated with different treatment
National CKD Audit collected data from over 400,000 options and support clinical decision-making aids.
patients registered with 1005 primary care practices in Different techniques can be applied to analysing big
the UK [12]. This showed a striking association between data depending on the healthcare application
lack of a CKD code in patients with CKD and second- (. Table 6.3).
ary care outcomes. An increasing likelihood of death, Nephrology has been a leader in embracing big data
unplanned hospital admission, and acute kidney injury both by design and by necessity. The multiple, recurrent
was seen in patients with uncoded CKD as eGFR fell. nature of episodic care that nephrologists provide to
However, given that this was audit data collected only to people with ESKD on RRT – as well as the emerging
interrogate CKD, potential confounders cannot be epidemic of chronic kidney disease – means that
adjusted for, limiting potential conclusions. Additionally, nephrologists need to be able to use big data to monitor
patients with uncoded CKD were less likely to have and ensure equity and quality of service delivery, detect
basic management interventions such as achieving blood disease, assess benefits and harms of new interventions,
pressure targets, quantification of urine protein, and and predict likely future healthcare outcomes and needs.
108 T. Oates
patient-HCP relationship into a collaborative partner- 4. Bodenheimer T, et al. Patient self-management of chronic dis-
ship [4]. Traditionally, these programmes were delivered ease in primary care. JAMA. 2002;288(19):2469–75.
5. Colbert GB, et al. The social media revolution in nephrology
face to face. Recently, online IT solutions have been education. Kidney Int Rep. 2018;3(3):519–29.
used, which have achieved concurrent improvements in 6. Couser WG, et al. The contribution of chronic kidney disease to
PAM and medical endpoints such as HbA1c in patients the global burden of major noncommunicable diseases. Kidney
with diabetes [4, 14] and hospital admissions [1]. Int. 2011;80(12):1258–70.
Although such programmes may expand access to 7. Farnan JM, et al. Online medical professionalism: patient and
public relationships: policy statement from the American Col-
healthcare, support engagement, and provide durable lege of Physicians and the Federation of State Medical Boards.
development in health behaviours, ultimately resulting Ann Intern Med. 2013;158(8):620–7.
in improved patient outcomes and cost savings, the rela- 8. Graham-Brown MPM, Oates T. Social media in medicine: a
tionship between these aspects is complex, and further game changer? Nephrology, Dialysis, Transplantation: Official
research is needed to elucidate the relationships between Publication of the European Dialysis and Transplant Associa-
tion - European Renal Association. 2017;32(11):1806–8.
PAM and health literacy, information needs and deliv-
6 ery, and which outcomes to measure before the full
9. Hibbard JH, et al. Development of the patient activation measure
(PAM): conceptualizing and measuring activation in patients and
potential is reached. consumers. Health Serv Res. 2004;39(4 Pt 1):1005–26.
10. Horne KL, Selby NM. Recent developments in electronic alerts
for acute kidney injury. Curr Opin Crit Care. 2015;21(6):479–84.
11. James MT, et al. Weekend hospital admission, acute kidney
6.9 Conclusions injury, and mortality. J Am Soc Nephrol. 2010;21(5):845–51.
12. Kim LG, et al. How do primary care doctors in England and
Systematic community-wide approaches to detection Wales code and manage people with chronic kidney disease?
and management of kidney disease have previously Results from the National Chronic Kidney Disease Audit.
Nephrology, Dialysis, Transplantation: Official Publication of
shown efficacy [17]. Modern IT presents huge opportu-
the European Dialysis and Transplant Association - European
nities to enhance collection and analysis of digitized Renal Association. 2018;33(8):1373–9.
data and information, build networks of relevant pro- 13. Kolhe NV, et al. Impact of compliance with a care bundle on
fessionals and patients, and create new care models in acute kidney injury outcomes: a prospective observational study.
kidney disease, thus expanding and exceeding these pre- PLoS One. 2015;10(7):e0132279.
14. Lorig K, et al. Online diabetes self-management program: a ran-
vious approaches.
domized study. Diabetes Care. 2010;33(6):1275–81.
The advances discussed in this chapter suggest an 15. de Lusignan S, et al. Audit-based education lowers systolic blood
environment that is highly conducive to the develop- pressure in chronic kidney disease: the quality improvement in
ment of “learning health systems” in nephrology; sys- CKD (QICKD) trial results. Kidney Int. 2013;84(3):609–20.
tems in which the clinical, scientific, infrastructural, and 16. Mehta RL, et al. Acute kidney injury network: report of an ini-
tiative to improve outcomes in acute kidney injury. Crit Care Soc
cultural environment supports improvement and inno-
Crit Care Med. 2007;11(2):R31.
vation by supporting best practice and capturing new 17. Rayner HC, et al. Does community-wide chronic kidney disease
knowledge. If the field of nephrology can harness the management improve patient outcomes? Nephrology, Dialysis,
potential of IT and data in the near future and coalesce Transplantation: Official Publication of the European Dialysis
around the idea of learning health systems calibrated to and Transplant Association - European Renal Association.
2014;29(3):644–9.
collect key data, focus relentlessly on outcomes, upskill
18. Sawhney S, et al. Acute kidney injury-how does automated
patients in self-care, and engage key HCPs, meaningful detection perform? Nephrology, Dialysis, Transplantation: Offi-
improvements in the health of those living with kidney cial Publication of the European Dialysis and Transplant Asso-
disease are highly likely to result. ciation - European Renal Association. 2015;30(11):1853–61.
19. Selby NM, et al. Design and rationale of “tackling acute kidney
injury”, a multicentre quality improvement study. Nephron.
2016;134(3):200–4.
References 20. Selby NM, Kolhe NV. Care bundles for acute kidney injury: do
they work? Nephron. 2016;134(3):195–9.
1. Ahn S, et al. The impact of chronic disease self-management 21. Wilson FP, et al. Automated, electronic alerts for acute kidney
programs: healthcare savings through a community-based inter- injury: a single-blind, parallel-group, randomised controlled
vention. BMC Public Health. 2013;13:1141. trial. Lancet. 2015;385(9981):1966–74.
2. Ancker JS, et al. Patient activation and use of an electronic 22. Wouters OJ, et al. Early chronic kidney disease: diagnosis, man-
patient portal. Inform Health Soc Care. 2015;40(3):254–66. agement and models of care. Nature reviews. Nephrology.
3. Bellomo R, et al. Acute renal failure - definition, outcome mea- 2015;11(8):491–502.
sures, animal models, fluid therapy and information technology 23. Zimbudzi E, et al. Factors associated with patient activation in
needs: the second international consensus conference of the an Australian population with comorbid diabetes and chronic
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111 7
Renal Pathology
Lauren Heptinstall and Paul Bass
Contents
References – 149
7.4.2 Glomerulus
Terminol- Definition
ogy
Glomerulus
Lesion Description Differentials
Capsule
Fibrosis Chronic lesion Sclerosed/sclerosing glomeruli
Thickened, multi-layered membrane best seen on PAMS or PAS Ischaemia
Adhesion An area of attachment of the glomerular tuft to the capsule Non-specific, represents a scar implying
damage of the tuft has occurred
Can be an early feature of FSGS
Rupture Acute lesion Necrotising glomerulonephritis, e.g.
A break in the capsule, usually with associated inflammation and ANCA-associated GN, anti-GBM disease,
possibly fibrin IgA nephropathy
Best seen on PAMS
Urinary space, visceral and parietal epithelial cells
Crescents Cellularity decreases as fibrosis increases over time, so the propor- Cellular
(a form of tion of each indicates the age/maturity of the lesion Many differentials, particularly vasculitis
extracapillary Cellular (<25% fibrosis) (ANCA, anti-GBM), immune complex-
hypercellularity) Acute lesion mediated glomerulopathy, e.g. IgA disease
(. Fig. 7.11) Proliferation of parietal epithelial cells extending into the urinary Implies a response of parietal epithelial
space from the capsule, at least two cells thick. Often includes cells to rupture of a capillary wall
karyorrhectic debris, inflammatory cells or fibrin from the Fibrocellular/fibrous
damaged tuft Non-specific. Healed/healing vasculitis,
Fibrocellular (>25% of cells and fibrosis) immune complex-mediated glomerulopa-
A subacute lesion thy, ischaemia, sclerosis
A mixture of parietal epithelial cells and fibrosis (collagen)
Fibrous (<25% cells)
Chronic lesion
Fibrosis in urinary space, containing few/no nuclei. Fibrosis is
highlighted on PAMS
Renal Pathology
117 7
Glomerulus
Lesion Description Differentials
Podocyte/visceral Increased number of visceral epithelial cells, which may contain Collapsing FSGS
epithelial cell PAS-positive protein resorption droplets Seen to a lesser extent in many conditions
hyperplasia as a non-specific feature (e.g. ischaemia)
(a form of
extracapillary
hypercellularity)
Foamy visceral Podocytes are enlarged with abundant foamy/bubbly cytoplasm Lysosomal storage disorders, such as
epithelial cells Fabry’s disease
Capsular drops Hyaline material attached to the capsule Diabetic nephropathy
Capillary walls
Spikes, chains Spikes arranged perpendicular to the GBM, extending into the Membranous glomerulopathy (primary or
(. Fig. 7.4) urinary space, or holes (chains) in the capillary wall when viewed secondary)
obliquely, caused by basement membrane extending between or Lupus nephropathy (class V)
surrounding subepithelial immune deposits Amyloidosis involving capillary walls
Best seen on PAMS causes feathery spike formations/spicules
Double contour A double-layered appearance of the capillary wall, caused by Subendothelial electron dense deposits:
(‘tram track’, mesangial interposition and new basement membrane formation Immune complex-mediated (type I)
splitting, inside the original MPGN, C3 glomerulopathies, SLE,
duplication) Best seen on PAMS cryoglobulinemia, PIGN
(. Fig. 7.5) Organised deposits, e.g. amyloid, fibrillary,
immunotactoid or fibronectin glomeru-
lopathy
Chronic endothelial injury: Chronic TMA,
pre-eclampsia, transplant glomerulopathy
(CAMR)
Wire loop Very thick, glassy capillary walls, caused by large subendothelial An active feature of SLE
(. Fig. 7.7) deposits
Thickening Thickened capillary walls without definite spikes or double Diabetic nephropathy, an early form of
contours any of the above capillary wall lesions
If vacuolated, LCAT deficiency
Hyaline cap Hyaline material deposited between the glomerular basement Diabetic nephropathy
membrane and the endothelium, often in sclerotic areas, may Non-specific in sclerosed foci
occlude the capillary lumen
Endotheliosis Endothelial cell swelling causing thickened capillary walls and Pre-eclampsia, eclampsia, other causes of
shrinkage of the capillary lumen, which appears bloodless thrombotic microangiopathy (TMA)
Capillary lumen
Endocapillary Lumen narrowed/occluded by cells (can be endothelial and/or Acute PIGN (especially if diffuse and
hypercellularity inflammatory cells) neutrophilic), C3GN, MPGN, SLE, IgA/
(. Fig. 7.10) HSP, vasculitis, infection-associated GN,
glomerulitis (ABMR)
Microaneurysm Ectasia of capillary loops due to destruction of the mesangial Diabetic nephropathy
(. Fig. 7.13) matrix Heals to form mesangial nodules
Thrombus Occlusion of the lumen by fibrin thrombus Acute TMA, pre-eclampsia, renal vein
(. Fig. 7.12) thrombosis, sickle cell nephropathy,
hyperacute rejection
Hyaline thrombus A pseudothrombus, composed of cryoglobulins, with the glassy, Cryoglobulinaemia, an active feature of
eosinophilic appearance of hyaline (with IHC/IMF positivity) lupus nephritis
Sickle cells Dysmorphic, sickle-shaped erythrocytes Sickle cell disease
118 L. Heptinstall
Glomerulus
Lesion Description Differentials
Mesangium
Proliferation More than three cells in a group within a peripheral mesangial IgA nephropathy, lupus nephritis (class
(. Fig. 7.9) area (away from the hilum) II), secondary membranous glomerulopa-
thy
Increased matrix Diffuse; maintains the normal distribution of the matrix, but more Diabetes, amyloid, monoclonal immuno-
(. Fig. 7.6.) material is present globulin deposition disease (MIDD),
Nodular; rounded areas of matrix with a rim of mesangial cells idiopathic nodular glomerulopathy
Mesangiolysis Injury and destruction of mesangial matrix and cells releasing the Diabetes, TMA, malignant hypertension,
anchoring points of adjacent capillary loops, which merge, radiation nephropathy, rarely a non-
forming one large, microaneurysmal capillary loop specific feature of various glomerulone-
phritides with mesangial deposits
Multicompartmental lesions
7 Segmental
sclerosis and
A segment of the glomerular tuft shows increased mesangial
matrix with obliteration of capillary loops. Represents a segmental
FSGS primary or secondary
Most commonly a non-specific feature in
hyalinosis scar many types of glomerulonephritis, which
(. Fig. 7.8) May be attached to the capsule forming an adhesion should be excluded before giving a
May contain foam cells diagnosis of FSGS
May be adaptive enlargement of uninvolved glomeruli
Begins at the cortico-medullary junction
The morphology and location within the tuft determine the
variant of FSGS (see ‘classification systems’)
Hyaline is glassy acellular material which often forms part of a
sclerosed area. Formed from insudated plasma proteins in
response to endothelial injury
Global sclerosis A chronic feature A non-specific feature
The end point of any glomerular injury Can be accepted as a normal feature
Complete replacement of the tuft by fibrosis. Highlighted on depending on patient age and the number
PAMS of glomeruli involved (see above)
Chronic ischaemic Small tuft, urinary space fibrosis (collagen deposition inside the Chronic hypoperfusion of any cause, e.g.
change capsule), wrinkled capillary walls (highlighted on PAMS), renal artery stenosis, atherosclerosis,
contracted mesangium, the urinary space may appear enlarged thromboemboli
Ischaemic glomeruli are often seen as a
non-specific feature of many renal diseases
Necrosis Cell death (mesangial, epithelial, endocapillary or inflammatory) Any highly active glomerulopathy,
(. Fig. 7.11) with associated karyorrhectic debris. Once capillary walls are particularly vasculitic diseases
involved, fibrin deposition, haemorrhage and crescents may be
seen
Hypertrophy Enlargement of the glomerulus A compensatory response to nephron loss
of any cause
Can be a helpful clue to suggest covert
FSGS if sclerosing lesions are not evident
Renal Pathology
119 7
7
. Fig. 7.9 Glomerulus showing mesangial proliferation in a case
of IgA nephropathy. H&E. X400
7.4.3 Tubules (. Figs. 7.15, 7.16, 7.17, 7.18, 7.19, 7.20, and 7.21)
Tubules
Lesion Description Differentials
Tubular cells
Acute tubular injury ATI – Simplification (loss of the proximal tubular brush Primary; ATI/ATN due to toxic/ischaemic injury
(ATI) border and thinning/flattening of the cytoplasm), luminal Secondary; acute glomerular injury or vascular
(. Fig. 7.15) ectasia, nuclear enlargement, prominent nucleoli, injury of any cause
Acute tubular blebbing/sloughing of cytoplasm into the lumen (forming Vacuolation may be particularly prominent in
necrosis (ATN) casts), vacuolisation and variation in cell size and shape ATI due to particular toxins or hyperosmolar
(. Fig. 7.18) ATN – Severe form of ATI involving loss of tubular injury (hyperkalaemia, mannitol)
nuclei and detachment, necrosis and fragmentation of Histological changes can be mild even in
tubular epithelial cells with denudation of the basement clinically severe AKI
membrane ATI can be seen in glomerular and vascular
Often associated with interstitial oedema diseases, which should be excluded before giving
a diagnosis of ATI
Tubulitis Leukocytes (usually lymphocytes) infiltrating tubular TIN (any cause), pyelonephritis, acute T
(. Fig. 7.16) epithelial cells (within the tubular basement membrane) cell-mediated rejection
with acute tubular injury
Crystalline inclusions Proximal tubular injury (as seen in ATI/ATN), with Light chain proximal tubulopathy
crystalline or needle-shaped inclusions and cytoplasmic
monoclonal light chain deposition. May only be visible
on electron microscopy
BK viral cytopathic Appearances range from normal to marked cytopathic Acute T cell-mediated rejection
changes change (enlarged and hyperchromatic). Causes basophilic TIN
intranuclear inclusions Other viral infections, e.g. CMV, adenovirus
Often also see tubulitis and interstitial inflammation (with different viral cytopathic appearances)
ATI/ATN
122 L. Heptinstall
Tubules
Lesion Description Differentials
Infarction Areas of infarction are likely to involve all the compart- The cause is not usually present in the biopsy,
(. Fig. 7.18) ments within the affected area, which will show but possibilities include hypoperfusion, vascular
coagulative necrosis, meaning that the architecture thrombosis, thromboembolism or vasculitis, and
remains visible, but the cytological details (cytoplasm and the included vessels may show evidence of these
nucleus) are lost, leaving a pale, ghostly outline. Often
there is also extensive haemorrhage, particularly in infarc-
tion due to venous thrombosis
Atrophy A chronic feature A non-specific finding, but the pattern of atrophy
(. Fig. 7.17) Atrophic tubules appear small with thick basement can help suggest aetiology. Patchy atrophy is
membranes; over time, these tubules disappear and are classically seen in reflux nephropathy, whereas
replaced by fibrous tissue stripy atrophy suggests chronic CNI toxicity. The
Another form of tubular atrophy is called ‘thyroidisation’ endocrine type can suggest renal artery stenosis
(because the histological appearance is similar to that of
normal thyroid follicles). These tubules are dilated, with
flattened epithelial cells and filled with hyaline cast
7 material
Another form of atrophy is endocrine type (because the
appearance resembles parathyroid glands); small cuboidal
tubular cells with very little/no visible lumen and no
thickened basement membrane
All types are usually associated with interstitial fibrosis
Hypertrophy Large tubules with large tubular epithelial cells and an An adaptive change to a reduced number of
increased volume of cytoplasm tubules
Often also see glomerular hypertrophy This may be because the kidney is small relative
to body mass (e.g. low birth weight, obesity,
some transplants), or due to loss of tubules due
to chronic damage
Vacuolation Fine (small) or coarse (large) vacuoles within the tubular Can be a non-specific sign of acute tubular
cytoplasm injury, specific causes include CNI toxicity,
osmotic tubular injury, mannitol, contrast, IVIg,
hypo/hyperkalaemia
Resorption droplets Eosinophilic, PAS-positive, small, round cytoplasmic Any cause of glomerular proteinuria
inclusion, formed from protein
Luminal material
Casts
Hyaline casts The most common type of cast, composed of Tamm- Non-specific, increased in chronically damaged
(. Fig. 7.19) Horsfall protein. Appear glassy, eosinophilic, PAS-posi- tubules
tive and solid
Myeloma/light chain Composed of monoclonal immunoglobulins mixed with Myeloma/plasma cell dyscrasia
casts Tamm-Horsfall protein, appears cracked/fractured/
(. Fig. 7.20) crystalline with a surrounding inflammatory cell reaction
(giant cells, macrophages, neutrophils or lymphocytes),
usually shows restriction on IHC/IMF for kappa or
lambda light chains
ATI also seen
Myoglobin casts Red/brown granular cast material Myoglobinuria
(. Figs. 7.21 and Myoglobin immunostain positive
7.22) ATI also seen
May see rhabdomyolysis in any skeletal muscle present
Red blood cells or Red blood cells filling the tubular lumen A few red blood cells are acceptable as part of
red cell casts biopsy-related trauma
(. Fig. 7.23) Larger numbers may be due to vasculitis or any
necrotising glomerulopathy
If there is no evidence of this, more levels should
be examined
Renal Pathology
123 7
Tubules
Lesion Description Differentials
Inflammatory cell Inflammatory cells and cellular debris Pyelonephritis, reflux nephropathy
casts May be an associated interstitial infiltrate and ATI Can be seen occasionally in any cause of
interstitial inflammation, e.g. TIN, ACR, GN
Bile casts Brown cast material, stains with Fouchet, usually with Hyperbilirubinaemia of any aetiology
ATI (a rare diagnosis)
Crystals
Calcium oxalate Fan-shaped colourless crystals within tubules, refractile A large number are seen in primary hyperoxal-
crystals under polarised light uria and ethylene glycol toxicity, whereas less are
(. Fig. 7.24) Do not dissolve during processing usually present in secondary hyperoxaluria. A
small number can be seen as a non-specific
finding in severely damaged/end-stage kidneys
2,8-dihydroxyadenine Single or clusters of birefringent, brown needle/ 2,8-Dihydroxyadeninuria
crystals (2,8-DHA) rod-shaped crystals in tubules, tubular cytoplasm and
interstitium, predominantly within the cortex
May see an inflammatory cell reaction including giant
cells
Do not dissolve during processing
Appear black on PAMS and blue on trichrome
Cystine crystals Birefringent hexagonal or rhomboid colourless crystals Cystinosis
within glomerular and tubular cells and in interstitial
macrophages
Multinucleated tubular epithelial cells and podocytes and
atrophic proximal tubules (‘swan neck’ deformity) are
also seen
Crystals dissolve during processing so are best seen in
frozen tissue. In processed tissue, empty clefts remain as
evidence of crystal deposition
Monosodium urate Clusters of birefringent, needle-shaped crystals in tubules Uric acid nephropathy/gout
crystals or interstitium, predominantly in the medulla (within
(. Fig. 7.25) collecting ducts)
May be surrounded by a granulomatous inflammatory
response, forming a tophus
Monosodium urate crystals are birefringent and
needle-shaped, but dissolve during processing, so are best
seen in frozen tissue. In processed tissue, empty clefts
remain as evidence of crystal deposition
Calcium phosphate Granular, purple deposits within tubules and interstitium Nephrocalcinosis (hypercalcaemia, hypercalciuria,
deposits Not birefringent hyperphosphataemia, hyperphosphaturia of any
Do not dissolve during processing cause)
Stain black on von Kossa Occasional incidental calcium phosphate deposits
are often seen in areas of chronic damage
124 L. Heptinstall
7
. Fig. 7.15 Acute tubular injury and red cell casts in a case of
pauci-immune glomerulonephritis. H&E x200 . Fig. 7.17 Chronically damaged parenchyma showing atrophic
tubules (black arrow), fibrotic interstitium and a globally sclerosed
glomerulus (blue arrow). H&E. x100
Interstitium
Lesion Description Differentials
7.4.5 Vascular
Extra-glomerular vessels
Lesion Description Differentials
Vasculitis Inflammation within an arterial/arteriolar wall, with fibrinoid Any cause of vasculitis, most commonly seen are
(. Fig. 7.27) necrosis and schistocytes (fragmented erythrocytes) if severe ANCA vasculitis, anti-GBM disease, IgA
Inflammation may be lymphocytic, neutrophilic, eosinophilic vasculitis
or granulomatous
Can be seen with thrombi, interstitial inflammation,
haemorrhage or infarction
Endothelialitis Arterial/arteriolar subendothelial lymphocytes, extending Acute vascular rejection
Endarteritis through to the media if severe
May see reactive (enlarged) endothelial nuclei and subendo-
thelial swelling
Capillaritis Increased numbers of leukocytes within peritubular Acute antibody-mediated rejection
capillaries
Thromboemboli Lumenal material in vessels. Can be fibrin thrombus, Most commonly embolisation of an atheroma-
atheroma (cholesterol crystals) (rare with others such as fat tous plaque in atherosclerosis
or tumour cells)
Hypertensive Fibrointimal proliferation with multiplication of the elastic Hypertension (essential or secondary to any
vasculopathy lamina (fibroelastosis), medial thickening of arterioles, cause, including chronic renal disease)
(. Fig. 7.28) hyaline arteriolosclerosis Renal artery stenosis
Highlighted on elastin stain Scleroderma
Hyaline Eosinophilic, glassy amorphous material within the Hypertension
arteriolosclerosis arteriolar wall Diabetic nephropathy
(. Fig. 7.29) CNI-related, classically ‘nodular’ in appearance
Renal Pathology
129 7
Extra-glomerular vessels
Lesion Description Differentials
Accelerated/ Fibrinoid necrosis and thrombi, ‘onion-skinning’ (multilay- Accelerated/malignant hypertension
malignant ered intima of arterioles), mucoid intimal thickening (pale Thrombotic microangiopathy, Scleroderma
hypertensive bluish acellular matrix material)
changes
(. Fig. 7.30)
Amyloid Eosinophilic material within the vessel wall, appears red/pink Amyloidosis
on Congo red stain. When the Congo red stain is viewed
under polarised light, amyloid classically shows ‘apple green’
birefringence
Often also present in glomeruli and interstitium
Atherosclerosis Intimal thickening composed of foam cells (lipid-laden Atherosclerosis
macrophages), cholesterol clefts, amorphous material, all
present underneath the endothelium
Acute thrombotic Endothelial swelling obstructing the lumen, intramural Many, including HUS, aHUS, TTP, malignant
microangiopathy schistocytes (fragmented erythrocytes), fibrin thrombi and hypertension, pre-eclampsia, scleroderma,
(. Fig. 7.31) fibrinoid necrosis antiphospholipid syndrome, acute antibody-
mediated rejection
Capillary wall subepithelial ‘spikes’ (. Fig. 7.4) Membranous glomerulopathy (primary or secondary)
Class V lupus nephritis
Amyloidosis (spicules)
Endocapillary hypercellularity IgA nephropathy/Henoch-Schonlein nephritis
(. Fig. 7.10) Lupus nephritis
Acute postinfectious glomerulonephritis (neutrophilic)
Cryoglobulinaemic glomerulonephritis
C3 glomerulopathy
HIV-associated immune complex kidney disease (HIVICK)
Diffuse mesangial matrix expansion (. Fig. 7.6) Monoclonal immunoglobulin deposition disease
Amyloidosis
Diabetic nephropathy
Cryoglobulinaemic GN
Immunotactoid GP
Fibrillary GN
7.5 Immunohistology listed in the table below. IHC often show some back-
and Immunofluorescence ground staining, which is non-specific, particularly
within the mesangial regions and areas of sclerosis.
Once a pattern has been identified, immunohistology
(IHC) or immunofluorescence (IMF) allows for a more
specific diagnosis. The typical glomerular findings are
Immunoglobulin dominant
. Fig. 7.32 IgA stain showing mesangial staining in a case of IgA . Fig. 7.33 An immunohistochemical stain for IgG shows granular
nephropathy. X200 subepithelial capillary wall positivity in a case of membranous glo-
merulopathy. x400
134 L. Heptinstall
Tubules
Light chain cast Kappa or Pathogenic casts
nephropathy lambda
restriction
Monoclonal light Kappa or Tubular basement
chain mediated lambda membranes
tubulointerstitial restriction
nephritis
Myoglobin cast Myoglobin Pathogenic casts
nephropathy positive
(. Fig. 7.22)
Interstitium
. Fig. 7.35 C1q immunohistochemistry showing mesangial (black IgG4 disease IgG4 Plasma cells
arrow), subendothelial (blue arrow) and subepithelial (red arrow) positive Ratio of
positivity in case of lupus nephritis. X400 IgG:IgG4 > 40% or
>10 IgG4+ plasma cells
per high-power field (x40
objective)
Renal Pathology
135 7
7.6 Electron Microscopic Findings usual findings in the conditions listed. Usually only one
or two glomeruli are assessed. As with the other modali-
As stated above, EM is not always crucial for the diag- ties previously discussed, EM findings are not always
nosis; however, it is helpful to confirm, refine and clarify specific and can be difficult to interpret. Also, focal and
the light microscopy findings, and in some cases, it is segmental lesions may not be represented (. Figs. 7.37
essential. The table below shows a description of the and 7.38).
Organised deposits
7 . Fig. 7.37 Electron micrograph showing mesangial amyloid . Fig. 7.38 Electron micrograph of amyloid fibrils with measure-
deposits (black arrow), in a case of amyloidosis. X1200. (Image ments, in a case of amyloidosis. X12000. (Image courtesy of Leices-
courtesy of Leicester Royal Infirmary electron microscopy depart- ter Royal Infirmary electron microscopy department)
ment)
. Fig. 7.39 Expanded mesangial region containing organised . Fig. 7.40 A closer view showing the randomly organised fibrils,
mesangial deposits (black arrow) in a case of fibrillary glomerulopa- with an average diameter of 18 nm, in a case of fibrillary glomeru-
thy. X1500. (Image courtesy of Leicester Royal Infirmary electron lopathy. X8000. (Image courtesy of Leicester Royal Infirmary elec-
microscopy department) tron microscopy department)
Renal Pathology
137 7
Disease EM Findings
Dense deposit disease (. Fig. 7.42) Elongated “ribbon-like” very dense intramembranous and mesangial deposits
Lupus nephritis (. Fig. 7.43) Mesangial, subendothelial and subepithelial EDD can all be present. Endothelial
cell cytoplasm may contain tubuloreticular inclusions
Fabry’s disease (. Fig. 7.45) Lamellated lysosomal inclusions (myelin/zebra bodies) particularly within
podocytes, but can be seen in all renal cells
BK nephropathy Intranuclear viral particles 30 to 50 nm diameter (typically seen in tubular
epithelial cells)
Tubuloreticular inclusion Approximately 20 nm organised structures seen in lupus nephritis, viral infection
(particularly HIV) and interferon therapy (typically found in the endoplasmic
reticulum of endothelial cells)
Structural changes
Minimal change nephropathy (. Fig. 7.46) Extensive foot process effacement (FPE) of podocytes, typically no other
abnormalities
FSGS Focal FPE overlying areas of sclerosis and in non-sclerotic glomeruli
Thin basement membrane disease (. Fig. 7.47) Diffusely thin GBM (compared with age-matched controls, generally <250 nm in
adults [3]).
Alport syndrome Variably thinned and thickened GBM with a multilaminated, ‘basket weave’
appearance of the lamina densa
Lupus podocytopathy Extensive FPE (as in minimal change nephropathy), may see mesangial EDD but
no capillary wall EDD
Diabetic nephropathy (. Fig. 7.48) Thickened glomerular basement membrane (often >600 nm), FPE, increased
mesangial matrix, hyaline material (can resemble EDD)
Thrombotic microangiopathy Acute; expansion of the lamina rara interna, endothelial cell swelling; may see
fibrin tactoids and thrombi
Chronic; duplication of theGBM, mesangial cell interposition
Chronic allograft glomerulopathy (. Fig. 7.49) Duplication of the GBM and lamination of the peritubular capillary basement
membranes
138 L. Heptinstall
7 . Fig. 7.41 Electron micrograph showing subepithelial hump . Fig. 7.42 Electron micrograph showing highly dense intramem-
deposits in a case of post-infectious glomerulonephritis. Black branous and mesangial deposits. X2500. (Image courtesy of Leices-
arrow, subepithelial deposit; blue arrow, basement membrane; green ter Royal Infirmary electron microscopy department)
arrow, effaced podocyte foot process, X2500. (Image courtesy of
Leicester Royal Infirmary electron microscopy department)
. Fig. 7.44 Electron micrograph showing mesangial electron dense . Fig. 7.45 Zebra bodies (black arrow) within podocyte cytoplasm
deposits (black arrow) in a case of IgA nephropathy. X1000. (Image in a case of Fabry’s disease. X4400. (Image courtesy of Leicester
courtesy of Leicester Royal Infirmary electron microscopy department) Royal Infirmary electron microscopy department)
Renal Pathology
139 7
. Fig. 7.46 Electron micrograph showing widespread podocyte . Fig. 7.48 Electron micrograph showing thickened glomerular
foot process effacement (black arrows) in a case of minimal change basement membrane with measurements, in a case of diabetic
nephropathy. X1000. (Image courtesy of Leicester Royal Infirmary nephropathy. Blue arrow, effaced podocyte foot process; black arrow,
electron microscopy department) endothelium. X4000. (Image courtesy of Leicester Royal Infirmary
electron microscopy department)
. Fig. 7.47 Electron micrograph showing thinning of the glomeru- . Fig. 7.49 Electron micrograph showing duplication of the glo-
lar basement membrane. Black arrow, erythrocyte; blue arrow, endo- merular basement membranes, visible as double contours on light
thelium; green arrow, effaced podocyte foot process. X8000. (Image microscopy, in a case of transplant glomerulopathy. Black arrow,
courtesy of Leicester Royal Infirmary electron microscopy depart- endothelial cell nucleus; blue arrow, podocyte nucleus; green arrow,
ment) original basement membrane; red arrow, reduplicated basement
membrane. X1200. (Image courtesy of Leicester Royal Infirmary
electron microscopy department)
7.7 Reaching a Diagnosis usually be sufficient for diagnosis. In some cases, there
will be uncertainty, either due to unusual features, a lack
Given the variety of features on clinical, light micro- of convincing or definitive features, suboptimal func-
scopic, IHC/IMF and electron microscopy assessment tionality of one or more tests or insufficient tissue. While
of renal biopsies, and the fact that very few are specific all cases benefit from discussion in a multidisciplinary
for a single diagnosis, it is easy to see how each in isola- setting, this is particularly helpful for these ‘difficult’ or
tion may not be diagnostic. However, the combination less conclusive cases, where the differential and clinical
of each of these modalities with the clinical context will management options can be discussed.
140 L. Heptinstall
Requires exclusion of any diagnosis from the Banff diagnostic categories 2–4, 6
Category 2: Antibody-mediated changes
(use the diagnostic criteria groups to reach one diagnosis)
Diagnoses Diagnostic criteria groups
C4d staining without evidence of rejection Criteria group 1 AMR activity:
Banff lesion score C4d > 1 (IF on fresh frozen tissue) OR Banff lesion score g > 0 in the absence of glomerulonephritis and/
C4d > 0 (IHC on paraffin-embedded tissue) or Banff lesion score ptc > 0 in the absence of TCMR or
AND borderline
Banff lesion scores t0, v0, no arterial intimal fibrosis with Banff lesion score v > 0
mononuclear cell inflammation in fibrosis and formation of Acute thrombotic microangiopathy in the absence of any other
neointima, no criterion from group 1 (AMR activity), no cause
criterion from groups 4 (histologic features of AMR chronicity), Acute tubular injury in the absence of any other apparent cause
no increased expression of thoroughly validated gene transcripts/
classifiers in the biopsy tissue strongly associated with AMR
Active AMR Criteria group 2 antibody interaction with tissue:
No criterion of AMR chronicity (criteria group 4) Banff lesion score C4d > 1 (IF on fresh frozen tissue) OR C4d > 0
AND (IHC on paraffin-embedded tissue)
At least one criterion from criteria group 1 (AMR activity) At least moderate MVI (g + ptc >1) in the absence of recurrent or
AND de novo glomerulonephritis; borderline (diagnostic category 3) or
At least one criterion from criteria group 2 (antibody interaction acute T cell-mediated rejection (TCMR; diagnostic category 4). If
with tissue) borderline, acute TCMR or infection is present (Banff lesion
AND scores g + ptc) >1 is not sufficient and Banff lesion score g > 1 is
At least one criterion from criteria group 3 (DSA or equivalents) required
Increased expression of thoroughly validated gene transcripts/
classifiers in the biopsy tissue strongly associated with AMR
Chronic active AMR Criteria group 3 DSA or equivalents:
At least one feature of AMR chronicity (criteria group 4) DSA (anti-HLA or other specificity)
AND Banff lesion score C4d > 1 (IF on fresh frozen tissue) OR C4d > 0
At least one criterion of antibody interaction with tissue (criteria (IHC on paraffin-embedded tissue)
group 2) Increased expression of thoroughly validated gene transcripts/
AND classifiers in the biopsy tissue strongly associated with AMR
At least one criterion of DSA or equivalents (criteria group 3)
Chronic AMR Criteria group 4 histologic features of AMR chronicity
Banff 2017 permits the use of this term for biopsy specimens Banff lesion score cg > 0 (by LM or EM), excluding biopsies with
showing TG and/or peritubular capillary basement membrane evidence of chronic thrombotic microangiopathy
multilayering in the absence of criterion of current/recent Seven or more layers in one cortical peritubular capillary and five
antibody interaction with the endothelium (Criteria Group 2) or more in two additional capillaries, avoiding portions cut
but with a prior documented diagnosis of Active or Chronic tangentially by EM in available
Active or documented prior evidence of DSA Arterial intimal fibrosis of new onset, excluding other causes
leukocytes within the sclerotic intima favour chronic AMR if there
is not prior history of biopsy-proven TCMR but are not required
Renal Pathology
141 7
7.9.1 The Oxford Classification of IgA 7.9.2 The Columbia Classification of Focal
nephropathy [6] Segmental Glomerulosclerosis
The diagnosis of FSGS can be problematic, as segmen-
Variable Score tal lesions are non-specific and there are many possible
aetiologies (genetic, viral, drug, adaptive, underlying
Mesangial hypercellular- ≤50% glomeruli M0 glomerulopathy). This classification can be used in pri-
ity (≥4 cells in a single >50% glomeruli M1
mesangial area)
mary or secondary forms and is based on light micro-
scopic features. Given the focal nature of the diagnostic
Endocapillary hyper- Absent E0 features, it has been suggested that 25 glomeruli and
cellularity Present E1
multiple sections are required to reliably detect lesions.
Segmental glomerulo- Absent S0 The juxtamedullary region is thought to be affected ini-
sclerosis Present S1 (with a comment tially; therefore, biopsies ideally will include this area.
indicating the presence/absence of
podocytopathic features)
The NOS variant is the commonest and is thought to
develop from the other variants [5].
7 Tubular atrophy and
interstitial fibrosis
<25% T0
26–50% T1
>50% T2
Cellular/fibrocellular Absent C0
crescents In at least one glomerulus C1
In >25% of glomeruli C2
FSGS NOS (not At least one glomerulus with segmental increase Exclude perihilar, cellular, Standard
otherwise specified) in matrix obliterating the capillary lumina tip and collapsing variants
There may be segmental glomerular capillary
wall collapse without overlying podocyte
hyperplasia
Perihilar variant At least one glomerulus with perihilar Exclude cellular, tip and Good
hyalinosis, with or without sclerosis collapsing variants
>50% of glomeruli with segmental lesions must
have perihilar sclerosis and/or hyalinosis
Cellular variant At least one glomerulus with segmental Exclude tip and collapsing Intermediate between
endocapillary hypercellularity occulding lumina, variants collapsing and NOS
with or without foam cells and karyorrhexis variants
Tip variant At least one segmental lesion involving the tip Exclude collapsing variant Excellent
domain (outer 25% of tuft next to the origin of Exclude perihilar sclerosis Highest rate of complete
the proximal tubule) remission
The tubular pole must be identified in the
defining lesion
The lesion must have either an adhesion or
confluence of podocytes with parietal or tubular
cells at the tubular lumen or neck
The tip lesion may be cellular or sclerosing
Collapsing variant At least one glomerulus with segmental or None Poor
global collapse and overlying podocyte Highest rate of ESRD
hypertrophy and hyperplasia
Renal Pathology
143 7
7.10 ISN/RPS Classification of Lupus Modified NIH Definition Score
Nephritis Activity Index
Class III Focal lupus Active or inactive, focal or Modified NIH Definition Score
nephritis global endo-extracapillary chronicity index
glomerulonephritis, involving
Total glomeru- Global and/or segmental 0–3
<50% of glomeruli
losclerosis glomerulosclerosis in % of
Class IV Diffuse lupus Active or inactive, focal or glomeruli:
nephritis global endo-extracapillary <25% (1+) 25–50% (2+) >50%
glomerulonephritis, involving (3+)
≥50% of glomeruli
Fibrous Fibrous crescents in % of 0–3
Class V Membranous Global or segmental crescents glomeruli:
lupus nephritis subepithelial immune <25% (1+) 25–50% (2+) >50%
deposits, with or without (3+)
mesangial changes
Tubular Tubular atrophy in % of the corti- 0–3
Class VI Advanced >90% of glomeruli globally atrophy cal tubules:
sclerotic lupus sclerosed, with no residual <25% (1+) 25–50% (2+) >50%
nephritis activity (3+)
Interstitial Interstitial fibrosis in % of the 0–3
fibrosis cortex:
<25% (1+) 25–50% (2+) >50%
(3+)
Total 0–12
144 L. Heptinstall
Glomerular score
7 Tips and Tricks
0 – No globally sclerosed glomeruli
1 – <20%
5 Look for a second diagnosis, particularly in
2 – 20–50%
3 – >50% common conditions such as diabetic or IgA
nephropathy.
Tubular score
5 Atrophic tubules are generally accepted as the
0 – No atrophic tubules main determining factor of irreversible damage in
1 – <20% the kidney and so are a key prognostic indicator
2 – 20–50%
[10].
3 – >50%
5 The percentage of chronic parenchymal damage
Interstitial score within a core biopsy is assumed to be representa-
0 – No interstitial fibrosis tive of the whole kidney, but this is not always the
1 – <20% case, particularly in subcapsular samples, which
2 – 20–50% may overestimate the amount of damage [11].
3 – >50%
Case Studies
Case 1
Clinical Scenario.
A 73-year-old male with renal impairment, haematuria
and proteinuria.
The H&E image (. Fig. 7.50) shows a nodular glomeru-
lopathy. Differentials are diabetic glomerulopathy, amyloido-
sis, monoclonal light chain deposition disease or idiopathic
nodular glomerulopathy (a diagnosis of exclusion).
The silver stain (PAMS, . Fig. 7.51) shows that the
mesangial material is silver negative (excluding diabetic
glomerulopathy).
The Congo red stain shows that the mesangial material is
Congo red positive and shows ‘apple green’ birefringence
under polarised light (. Fig. 7.52) diagnostic of amyloidosis.
Light chain immunohistochemistry shows stronger
mesangial positivity for lambda than kappa (. Fig. 7.53),
giving a diagnosis of AL (lambda) amyloidosis.
Diagnosis: AL amyloidosis.
Clinical Correlation: The patient was found to have a
plasma cell neoplasm on bone marrow biopsy. . Fig. 7.50 Case 1 H&E. x400
Renal Pathology
145 7
. Fig. 7.53 Case 1. Kappa (right) and lambda (left) light chain immunohistochemical stains. X400
146 L. Heptinstall
Case 2
Clinical Scenario.
A 25-year-old lady with increasing proteinuria and low
serum complement levels.
The initial H&E (. Fig. 7.54) shows a glomerulus
with a segment of necrosis and a small cellular crescent. At
this point, it is apparent that there is an active glomerular
process (necrosis and cellular crescent).
The PAMS stain (. Fig. 7.55) demonstrates diffuse,
global spike formation along the capillary walls indicating
that there are subepithelial deposits producing a membra-
nous pattern.
Immunostains (. Figs. 7.56 and 7.57) show granular
capillary wall and mesangial positivity for immunoglobu-
7 lins G, A and M and complement component C3 and C1q.
This implies that immune deposits are present both in the
capillary walls and the mesangium. The capillary wall
. Fig. 7.55 Case 2. PAMS x400
deposits are predominantly subepithelial, with occasional
subendothelial deposits.
Electron microscopy (. Fig. 7.58) shows subepithelial
(green arrow), mesangial (black arrow) and occasional
subendothelial (blue arrow) electron dense deposits.
Tubuloreticular inclusions are seen within endothelial cells
(. Fig. 7.59).
Diagnosis: Lupus nephritis, class III + V.
Clinical correlation – this lady had positive ANA and
dsDNA antibodies and fulfilled clinical criteria for a diag-
nosis of SLE.
Case 3
Clinical Scenario.
A 44-year-old man, recipient of a DBD renal trans-
plant 16 months ago. Best creatinine 170, now risen to 236.
Initial H&E sections (. Fig. 7.60) show acute tubular
injury with some nuclear pleomorphism and focal tubulitis.
No acute vascular rejection is seen. There is moderate
chronic damage. Some glomeruli (not shown) are poorly
perfused but show no other acute changes. At this point,
the differential lies between acute cellular rejection and BK
nephropathy. Without confirmatory tests, it can be very dif-
ficult to reliably distinguish these possibilities. In this case,
viral cytopathic changes are present, and further clinical
history was sought, making the diagnosis straightforward.
7 Further tests show positive tubular nuclei on BK
immunohistology (. Fig. 7.61).
Diagnosis: BK nephropathy.
Clinical correlation – this patient was compliant with
. Fig. 7.61 Case 3. Immunohistochemical stain for SV40.
immunosuppressive therapy, and a serum BK viraemia
X200
was identified.
Contents
References – 179
Acute Kidney Injury Epidemiology and Causes
155 8
n Learning Objectives disease [2]. The Acute Kidney Injury Network (AKIN)
1. To understand the definition of acute kidney injury. comprising the ADQI group and others later modified
2. To understand the epidemiology of acute kidney this definition [3] based on the recognition that even
injury in terms of incidence, prevalence and pat- small changes in serum creatinine are associated with
terns of distribution. increased mortality. At the same time, the term Acute
3. To understand the important risk factors for AKI. Kidney Injury (AKI) was introduced to encompass the
4. To understand the pathophysiology and mecha- entire spectrum of renal injury from minor changes in
nisms of AKI. kidney function to dialysis dependency. Most recently
5. To identify the common causes and mechanisms of the international guideline group Kidney Disease:
AKI in at-risk patient groups. Improving Global Outcomes (KDIGO) agreed a defi-
nition and staging system that harmonises the previous
systems proposed by both ADQI and AKIN [4]. It has
8.1 Introduction now been globally adopted and dramatically assisted the
identification and quantification of AKI which will per-
Acute kidney injury (AKI) is one of the common- mit assessment of the incidence, outcomes and efficacy
est medical emergencies, and the spectrum of AKI is of therapeutic interventions for AKI.
strongly influenced by environmental, socio-economic Under the KDIGO classification scheme, AKI is
and health-care-related factors. AKI carries a high mor- defined as an abrupt (within 48 hours to 1 week) rise in
tality (roughly 20% globally) and is likely to be on the serum creatinine or as a sustained (more than 6 hours)
increase, yet as many cases of AKI are preventable pro- reduction in urine output. It is further classified into
tection from death by AKI was recently portrayed as a three stages based on the absolute or relative increase in
human right by the International Society of Nephrology serum creatinine or duration and magnitude of reduc-
initiative for zero preventable deaths from AKI by 2025 tion in urine output (. Table 8.1). These classifications
(0by25) [1]. Achieving this target will require a new and help define the degree of kidney dysfunction at diag-
holistic approach including improvements in health nosis, aid in tracking of the clinical course, are widely
policy and infrastructure, public awareness and educa- validated and have been shown to predict outcomes in
tion and medical management; nephrologists have a key diverse patient populations and in large international
role to play in promoting these improvements. In this databases. Under all classification schemes, loss of kid-
chapter we will define acute kidney injury; describe its ney function requiring dialysis for more than 3 months
epidemiology, pathophysiology and causes; and discuss constitutes end-stage kidney disease.
a few special groups of patients who are particularly at
high risk of AKI.
. Table 8.1 KDIGO classification of acute kidney injury (3)
8.2 Definitions and Classifications AKI Serum creatinine criteria Urine output
Stage criteria
The clinical syndrome of acute kidney injury (AKI) is 1 Increase in serum creatinine of <0.5 mL/kg/
characterised by a sudden decline in glomerular filtra- ≥26 μmol/L (0.3 mg/dL) within hour for >6
tion rate (GFR) over a period of hours to days and 48 hours or increase to ≥1.5 to 1.9 consecutive
manifests as retention of fluid and metabolic waste x baseline serum creatinine within hours
1 week
products which are normally excreted by the kidneys. It
includes a spectrum of patients ranging from those with 2 Increase in serum creatinine to >2.0 <0.5 mL/kg/
minor deviations detected on laboratory testing to those to 2.9 x baseline serum creatinine hour for >12
consecutive
with life-threatening abnormalities of fluid and solute
hours
balance. Various groups have attempted to develop a
consensus definition for AKI which is sensitive, reliable 3 Increase in serum creatinine greater <0.3 mL/kg/
than threefold from baseline or hour for >24
and convenient and of practical and prognostic value.
serum creatinine of ≥354 μmol/L consecutive
In 2000 the Acute Dialysis Quality Initiative (ADQI) [≥4.0 mg/dL] or commenced on hours
developed a consensus definition with AKI stratified renal replacement therapy Or anuria for
based on the severity and duration of injury into stages irrespective of stage 12 hours
of Risk, Injury, Failure, Loss and End-Stage (RIFLE)
156 D. Wijayaratne et al.
8.3 Epidemiology: The Incidence This increase, therefore, needs to be interpreted with
and Burden of AKI some caution as it may be partially explained by the
changing definitions of AKI, increased awareness and
The true worldwide incidence and distribution of AKI coding of AKI as well as alterations in clinical practice
is still poorly understood because of under-reporting, such as increased blood testing or hospital admission.
regional disparities and differences in definition. More In particular, increased recognition of milder forms of
recently, the adoption of KDIGO or KDIGO equivalent AKI could be the cause of a rising incidence alongside
definitions of AKI worldwide has brought in some com- an apparent reduction in mortality. However, beyond
parable data from regions such as Africa and Southeast a reporting bias, it seems likely that there is a genuine
Asia, where data was previously scarce. Especially in increase in some settings particularly in the setting of
low-resource settings, much of the data are derived from an ageing and increasingly comorbid population. If so,
studies done in tertiary-care hospitals and may not be this is clearly important for a condition with an average
representative of the total disease burden. mortality of 20% and no effective treatment other than
AKI has been reported to affect about 13.3 million supportive measures (. Fig. 8.2).
people annually, 85% of whom live in developing coun- The clinical presentation of community-acquired
tries. In high-income countries, it affects 3000–5000 AKI in various parts of the world is influenced by sev-
per one million population per year. In a recent meta- eral factors.
1. Geographical location and natural environment.
8 analysis of the worldwide epidemiology of AKI, which
2. Socio-economic factors.
included 765 studies and over 77 million patients, the
pooled incidence of AKI was 21% of hospital admis- 3. Cultural practices.
sions with 2% requiring dialysis (11% of all AKI). 80% 4. Health-care services and infrastructure.
of AKI was KDIGO stage 1 [1, 5]. The overall pooled
mortality was 21%, with those with KDIGO stage 3
AKI, or requiring dialysis having a mortality of 42% 8.4 Geographical Location and Natural
and 46%, respectively (. Fig. 8.1). Environment
There has been a significant increase in the incidence
of reported AKI over the past few decades. Recent data In a snapshot of AKI in 72 countries in 2014, 58%
on AKI comes from large databases which use ICD cod- of AKI was community-acquired. This was lower in
ing or creatinine change criteria to diagnose AKI [7]. high-income countries (HICs) at approximately 50%,
. Fig. 8.1 Global epidemiology of AKI: Published incidence of with AKI. (Reproduced with permission from Global epidemiology
AKI using KDIGO criteria vary widely across regions. The percent- and outcomes of acute kidney injury. Nature Review Nephology.
ages shown represent the proportion of the hospitalised population 2018; 14:607–625 [6])
Acute Kidney Injury Epidemiology and Causes
157 8
a 40 b
6000
5224
35 5000 4536
Overall
Cases per 1000 discharges
4000 3883
30 3227
3000
25
2000
20 1000
0
15 1996– 1998– 2000– 2002–
1997 1999 1001 2003
10 Community-based incidence
rates (per million person years)
92
93
94
95
96
97
98
99
00
01
of non-dialysis requiring
19
19
19
19
19
19
19
19
20
20
Year ARF by calendar year
c d
350
700 Absolute cases (weighed) 180,000
300 295
267 Population incidence rate 160,000
600
195 500
200 120,000
50 60,000
200
40,000
0
1996– 1998– 2000– 2002– 100
20,000
1997 1999 1001 2003
0 0
Community-based incidence
00
01
02
03
04
05
06
07
08
20
20
20
20
20
20
20
20
20
of dialysis requiring
ARF by calendar year Year
. Fig. 8.2 Temporal trends in the hospital-based and population- California (USA) using administrative codes and creatinine-based
based incidence of acute kidney injury (AKI). (a) Hospital-based definitions, respectively. (d) Population incidence of dialysis-
incidence in AKI among elderly (aged >65 years) Medicare benefi- requiring AKI using the Nationwide Inpatient Sample and US Cen-
ciaries using administrative codes (USA). (b, c) Community-based sus data. (Reproduced with permission [7])
incidence of non-dialysis- and dialysis-requiring AKI in Northern
compared to 80% in low-income countries (LICs) [8]. disasters such as acute kidney injury due to rapid spread
Regardless of GDP, hypotension and dehydration were of water-borne infection (e.g. leptospirosis, hantavirus,
the commonest precipitants of AKI. In LICs, how- cholera and other diarrhoeal illnesses following flood-
ever, this predominantly relates to a single illness such ing) and traumatic rhabdomyolysis in the setting of
as infectious diseases, obstetric complications or toxins earthquakes. In HICs or tertiary centres in LMICs, the
[9]. For LICs in the tropics, severe malaria, diarrhoeal pattern is different with much of AKI being related to
illnesses and nephrotropic infections such as leptospi- drugs, trauma, surgery, cardiac illness or other comor-
rosis are common and account for a significant burden bidity in an older population [10]. Importantly, increases
of AKI. Animal and plant poisons are also, not infre- in international travel mean that patients may present
quent, causes of AKI in tropical countries (see below). with AKI secondary to less familiar insults and toxins
Intermittently, there are spikes of AKI related to natural (. Table 8.2).
158 D. Wijayaratne et al.
4. Impaired cardiac output (reduced renal perfu- Severe renal hypoperfusion associated with septic abor-
sion). tion, envenomation and severe sepsis or hypotension
5. Sepsis (reduced renal perfusion). may result in acute tubular necrosis or cortical necro-
6. Prolonged surgery (any, but especially if involving sis. But it is important to note that most AKI does not
cross clamping of the aorta or renal arteries). result in necrosis (tubular or cortical). In fact, a striking
7. Jaundice. feature of most acute tubular injury (ATI) is how dispro-
8. Exposure to toxins. portionate the functional impairment maybe compared
(a) Endogenous. to the minimal histological changes. Typically, the most
(b) Exogenous. common findings are mitochondrial enlargement, loss
of PCT brush border with flattening of the distal and
160 D. Wijayaratne et al.
8 . Fig. 8.3 (Left) H&E stain of a patient with AKI in the setting of tened tubular cells and myoglobin casts, demonstrated clearly in right
rhabdomyolysis. Biopsy shows marked blebbing of the tubular cells, flat- image stained for myoglobin. Slides courtesy of Lauren Heptinstall
proximal tubular cells with consequent dilatation of the blood flow leading to reduced oxygen and substrate
tubules (Swiss cheese appearance) (see . Fig. 8.3) and delivery but also a relative increase in oxygen demand
desquamation of epithelial cells. Tubular cells may dem- by the tubular cells. In all forms of AKI, including non-
onstrate mitosis if recovering or apoptosis with tubular ischaemic, nephrotoxic injury, there is an early and sig-
necrosis only in severe injury. There may be cellular casts nificant reduction in renal blood flow. In health, reduced
if the cause is a rapidly progressive glomerulonephritis; renal perfusion and GFR result in reduced sodium
granular casts composed of exfoliated tubular cells if the delivery to the macular densa. This results in afferent
injury is predominantly tubular; pigment casts if myo- renal artery vasodilatation via adenosine and efferent
globin, haemoglobin or light chain casts present; and artery vasoconstriction via renin, both of which serve to
crystals if, for example, oxalate is the principle cause. maintain/increase GFR in a process known as tubular
Vacuolisation of the proximal tubular cells if the patient glomerular feedback (. Fig. 8.4). However, acute isch-
has been exposed to osmotic stress such as mannitol, aemia is associated with a loss of renal autoregulation,
hyperosmolar contrast, hydroxyethyl starch colloids, endothelial dysfunction and vasoconstriction rather
sugars and dextrans, for example, with IgG treatment. than the usual autoregulatory renal vasodilatation
In addition, there may be interstitial oedema and cel- that occurs in response to decreased renal perfusion.
lular infiltration with inflammatory cells depending on Moreover, outer cortical blood flow is disproportion-
the aetiology of the AKI. Somewhat surprisingly, there ally reduced, and outer medullary congestion is another
is not yet a morphological score to quantify AKI, and prominent feature that may worsen the relative hypoxia
predicting recovery remains very subjective. in the outer medulla and thus potentiate hypoxic injury
(. Fig. 8.5).
Pressure in the proximal tubulars increases rapidly
8.11 Functional partly due to the accumulation of luminal debris or
casts. As this pressure increases, the ability of glomeruli
There are two principal components that contribute to to produce filtrate reduces further, and there is trans-
the acute decrease in GFR in AKI, a “vascular” compo- tubular back leak of filtrate (see . Fig. 8.6) leading to
nent and a “tubular” component which are intimately interstitial inflammation. The latter occurs via the pro-
connected. Ischaemic injury to the kidney is the most duction of chemo-attractants by injured epithelial cells
common cause of AKI, but it must be remembered that that recruit inflammatory cells and potentiate further
contributory factors include not only diminished renal inflammation [13].
Acute Kidney Injury Epidemiology and Causes
161 8
. Fig. 8.4 Diagram of the nephron in health. The macular densa lus and forms part of the causes afferent arteriole dilatation (proba-
(MD) which is situated next to the afferent and efferent arterioles bly via adenosine and in part mediated through prostaglandins
forms part of the juxtaglomerular apparatus (JGA). The JGA also blocked by NSAIDs). Low sodium chloride delivery to the MD also
includes the terminal portion of the afferent arteriole with its renin- results in release of renin which causes general arteriolar (but espe-
producing cells and the beginning of the efferent arteriole. In cially efferent arteriole) constriction (blocked by RAS inhibition).
response to reduced sodium concentration in the thick ascending Vasodilatation of the afferent and vasoconstriction of the efferent
limb of Henle following reduced renal perfusion, the macular densa arterioles helps maintain glomerular vascular perfusion and GFR
(MD), which is situated next to the vascular pedicle of the glomeru-
Injury to the PCT cells results in failure to dilute the adaptive response to protect the kidney and individual
filtrate by sodium reabsorption. This leads to delivery against further deleterious effects of AKI.
of higher than normal concentrations of sodium to the
DCT, which is sensed by the macular densa and results
in a physiological negative feedback loop (tubulo- 8.12 Key Causes of AKI
glomerular feedback (TGF)). The macular densa (situ-
ated between the afferent and efferent arterioles of With an understanding of the pathogenesis of AKI, it
the same nephron) generates adenosine that results in is not difficult to appreciate the key reasons a kidney
constriction of the afferent arteriole via the A1 recep- may suffer AKI. The causes of AKI can be grouped
tor and results in reduction in glomerular filtration. into those that lead to decreased renal blood flow (pre-
Vasoconstriction and shutting down of the glomeruli renal acute kidney injury, 40–70% of patients), those
in the setting of ischaemia or toxic injury may seem to that lead to direct renal parenchymal damage (intrinsic
compound the damage. However, given that the kidney acute kidney injury, 10–50% of patients) and those that
is the funnel for many toxins and that the reabsorption lead to obstructed flow of urine (post-renal acute kid-
of about 178 L of filtrate a day is dependent on healthy ney injury, 10% of patients). Although not to be missed,
oxygen and energy replete tubules, autoregulated shut- AKI secondary to rapidly progressive glomerulonephri-
down of glomeruli and temporary oliguria may be an tis is relatively rare. Very frequently there will be mul-
162 D. Wijayaratne et al.
. Fig. 8.5 Diagram showing pathogenesis of acute tubular injury. endogenous or exogenous toxins. Crystals may form in any part of
In AKI tubular dysfunction from whatever cause may result in the tubule causing obstruction and inflammation. Similarly tubular
increased delivery of sodium chloride to the MD and negative (tubu- casts (most commonly casts from shed tubule-epithelial cells but also
loglomerular) feedback to the afferent arteriole causing vasocon- red cell casts from glomerulonephritis, pigment casts, myeloma cast,
striction reducing glomerular perfusion and GFR. Generalised white cell casts) can obstruct the tubules and cause back leak of
vasoconstriction from sympathetic activity and renin secondary to tubular fluid. Urinary tract obstruction has a similar effect on tubu-
hypotension further contributes to reduced (especially cortical tubu- lar drainage. Many of these pathways result in activation and recruit-
lar) blood supply. Filtration of toxins exposes all of the tubule to ment of inflammatory cells which may contribute to further damage
tiple components contributing to renal dysfunction, and tance. This renal auto-regulation mainly depends on a
rapid identification of the causes is critical (. Fig. 8.7). combination of pre-glomerular arteriolar vasodilata-
tion, mediated by prostaglandins and nitric oxide, and
post-glomerular arteriolar vasoconstriction, mediated
8.13 Pre-Renal Causes of Acute Kidney by angiotensin II. Drugs that interfere with these media-
Injury tors may provoke pre-renal acute kidney injury. In par-
ticular clinical settings, most notably NSAIDs block the
Pre-renal causes are the most common and include any normal adaptive response to hypoperfusion mediated by
condition that leads to under-perfusion (reduced effec- prostaglandins, and RAS inhibition thwarts the second
tive arterial perfusion) of the kidney (see . Table 8.3). compensatory mechanism to maintain GFR-efferent
They can be divided into: artery vasoconstriction. This explains why NSAIDs and
1. Hypovolaemia. RAS inhibition can be so problematic in the setting of
2. Reduced cardiac output. CKD and acute hypoperfusion such as shock or hepa-
3. Redistribution of cardiac output (sepsis and hepa- torenal syndrome.
torenal syndrome). At-risk populations include older people with athero-
4. Impairment of local vascular supply (aortic or renal sclerotic cardiovascular disease, those with pre-existing
artery compromise, impairment of renal microcircu- CKD and those with chronic renal hypoperfusion (e.g.
lation, venous thrombosis or abdominal compart- cardiac failure, hepatorenal syndrome, recurrent high
ment syndrome). fluid losses (usually gastrointestinal or renal)). In criti-
cal care units, the most common cause of AKI is sepsis
Renal blood flow and GFR remain roughly constant causing systemic vasodilatation and reduced effective
across a wide range of mean arterial pressures due to renal blood flow despite an increased cardiac output. In
changes in pre- and post-glomerular arteriolar resis- tropical and developing countries pre-renal AKI com-
Acute Kidney Injury Epidemiology and Causes
163 8
Causes Examples
a b
. Fig. 8.8 a Aortogram of patient who attempted suicide by jump- with atrial fibrillation and sudden onset of loin pain following an
ing from a bridge and developed immediate anuric AKI. The study embolus to the left kidney and mild AKI. The arrow shows an area
8 shows abrupt lack of perfusion to both kidneys secondary to dissec- or markedly reduced perfusion and localised swelling
tion of the renal arteries. b CT with contrast of kidneys in a patient
Causes Examples
Glomerular disease
a. Inflammatory Post-infectious glomerulonephritis
Henoch-Schönlein purpura
Systemic lupus erythematosus
Antineutrophil cytoplasmic antibody glomerulonephritis
Antiglomerular basement membrane disease
Cryoglobulinaemic vasculitis
b. Occlusive Disseminated intravascular coagulopathy
Thrombotic microangiopathy, haemolytic uraemic syndrome
Malignant hypertension
Cholesterol embolism
Plasmodium malaria
Sickle cell crisis
Tubular injury Ischaemia secondary to prolonged renal hypoperfusion
Toxins:
Exogenous
Drugs
(i) Direct tubulotoxins, e.g. aminoglycosides, amphotericin
(ii) crystals (e.g. acyclovir, indinavir, sulphonamides)
(iii) vasoconstrictors (e.g. cocaine)
Radio contrast
Natural toxins (e.g. envenomation, toxic plants, fungi)
Heavy metals
Crystals, oxalate (e.g. ethylene glycol, star fruit)
Endogenous
Pigments, myoglobin and haemoglobin
Immunoglobulin light chains
Hypercalcemia
Crystals, urate (e.g. tumour lysis syndrome) and oxalate
Interstitial nephritis 1. Allergic: Drug-induced, e.g. NSAIDs and antibiotics, allopurinol, proton-pump inhibitors
2. Autoimmune: e.g. sarcoidosis, Sjogren’s syndrome, tubule-interstitial nephritis with uveitis (TINU), SLE,
vasculitis
3. Infectious: Pyelonephritis, leptospirosis, hantavirus, etc.
4. Infiltrative: Lymphoma, etc
Acute Kidney Injury Epidemiology and Causes
165 8
8.15 Toxins and AKI
8.16 Rhabdomyolysis
Hyperthermia or hypothermia
Metabolic
Hypokalaemia
Medical causes: Hypophosphataemia
Hyponatraemia
Hypothyroidism
Diabetic ketoacidosis
Hyperosmolar non-ketotic diabetic coma
Infectious
Viral (Influenza, adenovirus, echovirus, HIV, EBV, Coxsackie, enterovirus)
Bacterial (staphylococcus aureus, streptococcus pneumoniae, salmonella) all can cause direct bacterial myositis (typhoid,
shigella, e.coli, leptospirosis, legionella, chlostridium perfringes)
Drugs
Muscle enzyme defects Deficiency of glycol(geno)lytic enzymes Rare causes, usually presenting before the age
Myophosphorylase deficiency 20. Look out for history of:
(McArdle’s) exercise intolerance
Phosphorylase kinase deficiency cramps
Phosphorylase mutase deficiency intermittent dark urine
Lactate dehydrogenase deficiency family history (most
Abnormal lipid autosomal recessive)
Carnitine palmitoyltransferase More than one episode of
deficiency rhabdomyolysis with minor exercise
Carnitine deficiency or no obvious precipitant
Miscellaneous
Neuroleptic malignant syndrome
Malignant hyperthermia If suspicious refer for muscle biopsy
Myoadenylate deamine deficiency
Idiopathic rhabdomyolysis
Drug Comments
include toluene-induced renal tubular acidosis, and a 8.25.3 Ecstasy and Other Amphetamines
more recently described syndrome of AKI seen with
bath salts. Ecstasy is known to cause rhabdomyolysis and/or
hyperpyrexia syndrome which can result in acute kid-
ney injury. Drug abusers often drink large quantities of
8.25.1 Opiates water after taking ecstasy to try to prevent dehydration,
and dilutional hyponatraemia results as a consequence.
Heroin (diacetylmorphine, diamorphine) is the most
commonly abused drug in this group. There are sev-
eral renal complications from its abuse. Coma from 8.25.4 Anabolic Androgenic Steroids
overdose or underestimated drug potency leads to
pressure-induced muscle damage and rhabdomyolysis. Renal effects of AAS abuse in humans are primar-
There is a high rate of viral, bacterial and fungal con- ily described in case reports and small case series. It is
tamination associated with intravenous drug misuse, known to cause elevations in serum creatinine and sub-
including heroin, and consequently users are at risk of stantial proteinuria. The mechanism of renal injury in
a variety of infections. Glomerulonephritis (GN) may the setting of AAS abuse is not well established and is
be associated with these chronic infections. Secondary likely multifactorial. Hyperfiltration injury is an impor-
(AA) amyloidosis is seen in chronic parenteral drug
8 users, particularly among those who inject drugs sub-
tant factor in the causation of renal damage.
Snake bites are a common and important cause of AKI Aristolochic acid nephropathy (AAN) was first
in the tropics of Asia, Africa and Central and Latin described in a group of Belgian women who presented
America. The common snakes associated with AKI are with rapidly progressive tubulointerstitial nephritis and
a b
c d
. Fig. 8.12 Common snakes causing acute kidney injury across the world: a Russell’s viper, b hump-nosed viper, c Crotalus, d Bothrops.
(Source: (a,b) Anslem de Silva, Herpetologist, Sri Lanka (c,d) Marcelo Ribeiro Duarte, Assistant Research Biologist, Brazil)
172 D. Wijayaratne et al.
AKI and acute hepatitis following consumption of raw carpgall baldder. Used as a
traditional medicine in South East Asia. Toxicity may be due to nephrotoxicity of bile
or pre-renal factors
. Fig. 8.14 Poisonous mushrooms associated with acute kidney injury: Left Amanita phalloides. Right Gyromitra esculenta
174 D. Wijayaratne et al.
(continued)
176 D. Wijayaratne et al.
area [37]. AKI in this group is often multifactorial and vascularly depleted. Malignancy is a commoner cause
is pre-disposed to by age-related deterioration in fluid of AKI in this age group and may be intrinsic, as in the
and salt homeostasis, such as reduced thirst response, setting of myeloma or obstructive as in the setting of
urine concentrating ability and salt reabsorption. Many prostatic or other pelvic malignancies. The limitations
of the elderly are on drugs such as NSAIDs, RAAS of serum creatinine to estimate GFR are much more
blockade and diuretics which contribute to pre-renal pronounced in the elderly, including its dependence on
AKI in the setting of a minor added insult. In older muscle mass and the presence of multiple drug use and
people the commonly used signs to gauge volume comorbidities [38]. Older age is also associated with a
depletion can be misleading. Severely ill patients may greater risk of non-recovery of renal function back to
have gross oedema while at the same time being intra- baseline, which, given the increasing incidence of AKI,
Acute Kidney Injury Epidemiology and Causes
177 8
8.33 Cancer
As mentioned above, AKI is a common complication in thy, nephrotic syndrome or cirrhosis) and large tumour
patients with cancer. The incidence and severity depend burden. Common causes of malignancy-associated AKI
on the type of cancer and its stage, treatment regimen include those resulting from the malignancy itself (e.g.
and other co-existing clinical conditions. The develop- obstruction or infiltration, cast nephropathy in multiple
ment of AKI is associated with poor prognosis although myeloma, paraneoplastic syndromes such as hypercal-
early recognition and treatment are associated with bet- caemia), those resulting from treatment (e.g. nephrotoxic
ter outcomes [39]. It is difficult to assess the overall drugs, tumour lysis syndrome, interstitial nephritis) and
prevalence, but studies carried out in specific diseases general causes (e.g. volume depletion, sepsis, radiocon-
such as multiple myeloma have shown that 15–30% of trast) (see . Table 8.8).
patients have evidence of renal impairment [40]. In a
7-year Danish study of 37,267 incident cases of cancer,
the 1-year risk of acute kidney injury, as defined by the 8.34 Summary
Risk, Injury, Failure, Loss of kidney function and End-
Stage kidney (RIFLE) disease classification was 17.5%. It is clear that AKI has a very significant mortality and
The 5-year risk for the individual risk, injury and fail- a high and increasing global incidence. The aetiology
ure categories was 27.0%, 14.6% and 7.6%, respectively. of AKI is very dependent on geography and socio-
Furthermore, 5.1% of patients in whom acute kidney economic factors with young people in LICs, being dis-
injury developed required long-term dialysis within proportionally affected by infection and pre-renal AKI,
1 year [41]. Important risk factors are volume depletion, whereas CKD, multimorbidity and medication are much
older age, use of nephrotoxic drugs, pre-existing renal more significant factors in HICs.
impairment, renal hypoperfusion (due to cardiomyopa-
178 D. Wijayaratne et al.
Case Study
33. Coca SG, Cho KC, Hsu CY. Acute kidney injury in the elderly: patients: a Danish population-based cohort study. Eur J Intern
predisposition to chronic kidney disease and vice versa. Med. 2011;22:399–406.
Nephron Clin Pract. 2011;119(Suppl 1):c19–24; Epub 2011 38. Howard SC, Jones DP, Pui C-H. The tumor lysis syndrome. N
Aug 10. Engl J Med. 2011;364:1844–54.
34. Haase M, Story DA, Haase-Fielitz A. Renal injury in the 39. Denker B, Robles-Osorio ML, Sabath E. Recent advances in
elderly: diagnosis, biomarkers and prevention. Best Pract Res diagnosis and treatment of acute kidney injury in patients with
Clin Anaesthesiol. 2011;25(3):401–12. cancer. Eur J Intern Med. 2011;22(4):348–54.
35. Ganesan C, Maynard SE. Acute kidney injury in pregnancy: 40. Humphreys BD, Soiffer RJ, Magee CC. Renal failure associated
the thrombotic microangiopathies. J Nephrol. 2011;24(5):554– with cancer and its treatment: an update. J Am Soc Nephrol.
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37. Christiansen CF, Johansen MB, Langeberg WJ, Fryzek JP, ejim.2011.05.005; Epub 2011 Jun 8.
Sørensen HT. Incidence of acute kidney injury in cancer
8
181 9
Contents
1 Increase in serum creatinine of Increase in serum creatinine Risk: Increase in serum creatinine <0.5 mL/kg/
≥26 μmol/L (0.3 mg/dL) within 1.5–2x baseline ≥1.5x baseline within 7 days, hour for >6
48 hours or increase to ≥1.5 to 1.9 x or ≥ 26 μmol/L (0.3 mg/dL) persists for ≥24 hours consecutive
baseline serum creatinine within within 48 hours hours
1 week
2 Increase in serum creatinine to >2.0 Increase in serum creatinine Injury: Increase in serum <0.5 mL/kg/
to 2.9 x baseline serum creatinine 2–3x baseline creatinine to ≥2x baseline hour for >12
consecutive
hours
3 Increase in serum creatinine to Increase in serum Failure: Increase in serum <0.3 mL/kg/
greater than threefold from baseline creatinine>3x baseline creatinine greater than threefold hour for >24
or serum creatinine of ≥354 μmol/L or ≥ 354 μmol/L [≥4.0 mg/dL] from baseline or serum creatinine consecutive
[≥4.0 mg/dL] or commenced on or commenced on renal of ≥354 μmol/L [≥4.0 mg/dL] or hours
renal replacement therapy irrespec- replacement therapy commenced on renal replacement OR anuria for
tive of stage therapy 12 hours
Loss: Loss of kidney function
sustained for >4 weeks
ESRD: ESRD for >3 months
Assessment and Investigation of Acute Kidney Injury (AKI)
183 9
9.3 Recognition of Biochemical Changes the innate immune system, and, in AKI, NGAL mRNA
Suggesting Acute Kidney Injury is upregulated in the kidney, liver and lungs. Increased
transcription and reduced clearance secondary to a fall
Agreement on AKI diagnostic criteria based on the mag- in in GFR contribute to the observed increases in plasma
nitude and timing of changes in serum creatinine has NGAL in AKI [8]. Cystatin C is an inhibitor of cysteine
allowed the introduction of algorithms for the auto- proteases and is produced by all nucleated cells. It is
mated detection of patients who may have AKI. When freely filtered and then reabsorbed and catabolised by the
biochemical changes are compared with clinical coding proximal tubule and is less dependent on age, muscle
of AKI, the specificity of biochemical changes is approx- mass and liver function than serum creatinine [8]. The
imately 90% [5]. However, it is important to remember utility of these tests was evaluated using a systematic
that imperfections in the techniques available to measure review and meta-analysis in an NIHR health technology
creatinine, biological causes for change in creatinine assessment in 2018 [9]. The clinical studies that were
other than AKI and circumstances under which this reviewed included small studies, and the design of the
approach is not validated may lead to biochemical studies was heterogeneous. The authors concluded that
changes in the absence of a true AKI. Notwithstanding the combined urinary TIMP-2 and IGFBP-7 test
these caveats, automated ascertainment of biochemical appeared to be the most promising of the three with high
changes suggestive of AKI is likely to enhance early rec- sensitivity and moderate specificity for AKI in a critical
ognition of AKI. It is possible that timely identification care setting. Plasma NGAL had moderate sensitivity
of a precise AKI phenotype facilitates therapeutic gains and high specificity for detecting AKI, but there was
using existing and new treatments. There are several lim- greater heterogeneity between studies than for the com-
itations to the use of creatinine and urine output for the bined urinary TIMP-2 and IGFBP-7 test. There was
diagnosis of AKI, and other biomarkers may offer the weaker evidence for urinary NGAL and cystatin C test-
opportunity to more accurately describe the phenotype ing with considerable variation between studies. Despite
of the kidney injury and identify this earlier in the course the heterogeneity of reported studies, novel biomarkers
of the patient’s illness. Novel biomarkers in AKI are dis- have the potential to improve care of patients who are at
cussed further below. risk of AKI, and this area warrants further research.
AKI
PRE-RENAL
RENAL POST-RENAL
ANATOMICAL ↓EFFECTIVE
RENAL
PERFUSION
UPPER OR
LOWER TUBULAR
↑INTRA- TRACT
ABDOMINAL
PRESSURE
↓INTRA-
9 VASCULAR
VOLUME ↓CARDIAC
REDISTRIBUTION
MECHANICAL FUNCTIONAL
OUTPUT
or recent hypoperfusion of the kidneys. This is usually patients where this is not the case or where patients’
caused by the presence of one or more of four factors: recovery does not proceed as anticipated, comprehen-
(a) hypovolaemia, (b) reduced cardiac output (c) sive review of live and historical information held in the
regional hypoperfusion associated with splanchnic vaso- case notes and other records is very important. This
constriction and reduced renal perfusion most typically often reveals factors predisposing to AKI and repeated
in sepsis or hepatorenal syndrome and (d) less com- minor insults, the significance of which are much more
monly reduced perfusion because of increased abdomi- easily interpreted when a clear sequence of events is
nal pressure reducing renal venous drainage. Finally, described.
renal hypoperfusion may complicate vascular events Although monitoring of renal function in groups at
including aortic clamping or stenting, renal arterial dis- high risk of CKD has been incentivised in many set-
section and occlusion by thrombosis or emboli. tings, AKI may occur in patients without prior measure-
“Renal” or intrinsic causes of AKI can be subdi- ment of renal function. Patients without previous serum
vided into glomerular, vascular, interstitial and tubular creatinine measurements may not trigger the algorithms
(. Fig. 9.2). Tubular causes can be further subdivided for automated ascertainment of AKI. In the absence of
into extrinsic (exogenous) or intrinsic (endogenous) previous measurements, it is more difficult to categori-
causes (. Fig. 9.3). Urinalysis is often extremely helpful cally distinguish between AKI and progressive CKD.
in narrowing the differential diagnosis for AKI. The The clinical setting in which patients from high-
finding of significant blood and/protein in the urine is income settings with AKI are identified has only limited
much more suggestive of a glomerular/vascular cause, influence on variation in the aetiology of acute kidney
than a tubular or interstitial cause. This is discussed injury. However, obstruction is a more common cause of
more fully below in the section on near patient testing. AKI in community-acquired AKI in high-income coun-
tries [10]. For the remainder of the chapter, community-
and hospital-acquired AKI are considered together.
9.5.1 AKI Assessment May be Complicated Two cases are presented to illustrate the value of com-
prehensive assessment. The cases highlight the dispersal
It is important to arrive at an accurate and precise diag- of helpful information to more than one record that is
nosis to ensure timely initiation of treatment for the often seen in a real-world setting. Additionally, it is com-
cause of AKI given the high mortality and morbidity mon for patients to need to be assessed more than once.
associated with admissions complicated by AKI. It may The nature and precision of the renal diagnosis may
be that the mechanism of injury is obvious, but for those change as additional information becomes available.
Assessment and Investigation of Acute Kidney Injury (AKI)
185 9
ACTIVE
URINE
RENAL
DEPOSIT
GLOMERULAR
and INTERSTITIAL
VASCULAR
PRIMARY SECONDARY
INACTIVE
URINE INFECTION
DEPOSIT
PREGNANCY
TUBULAR AUTOIMMUNE
DRUGS
AUTOIMMUNE ALLERGY
MALIGNANCY INFILTRATION
INFECTION
TUBULAR
EXTRINSIC INTRINSIC
TOXINS TOXINS
TUMOUR
LYSIS
PRESCRIBED SYNDROME
ENVIRONMENTAL SEPSIS
TOXINS TOXINS
. Fig. 9.3 Diagnostic classification for ‘renal’ AKI where the establish what has been prescribed such as vasoconstrictors and
injury is predominantly tubular in origin. In searching for extrinsic intravenous contrast (in what quantity), which potentially tubule-
environmental causes, some events such as snake bites may be readily toxic drugs have been prescribed and in what quantity or what drugs
recalled, but a careful history may be required to reveal ingestion of that might precipitate as crystals
a natural or artificial toxin. In the medical setting, it is important to
186 M. Prendecki and E. Kingdon
Case Study
. Fig. 9.4 Observation chart for the patient in case 1. Contrast administration is marked by the blue
arrow and amikacin dosing by black arrows
Assessment and Investigation of Acute Kidney Injury (AKI)
187 9
Case 2
The importance of reassessing patients with AKI as addi-
tional information becomes available is illustrated in case
2. A 79-year-old woman presented with breathlessness and
was found to have AKI on a background of chronic kidney
disease (baseline creatinine of 120 mmol/L). Comorbidities
included ischaemic heart disease, coronary artery bypass
grafting, type 2 diabetes and cardiac failure (echocardiog-
raphy identified an ejection fraction of 25–30%). At pre-
sentation, her serum creatinine was 360 mmol/L. On
examination, she had peripheral oedema; admission chest . Fig. 9.5 Chest X-ray at the time of presentation
X-Ray is shown in . Fig. 9.5. She was treated for heart
failure with diuretics. Post-renal causes of AKI were cardiorenal syndrome would not extend her life outside the
excluded, and renal size and cortical thickness were seen to hospital. However, despite the diagnosis of cardiorenal
be preserved at CT scanning. History and examination did syndrome, the blood pressure was persistently around
not reveal additional insults. Urinalysis showed isolated 160/80, and a repeat echocardiogram showed no deteriora-
proteinuria, and this was quantified in the laboratory tion in LVEF. Review of the results of laboratory tests
(urine protein/creatinine ratio (UPCR) of 270). There were identified disproportionate anaemia. Immunoglobulins
no recent uPCRs for comparison, but the patient was and serum protein electrophoresis had been undertaken
known to have diabetic retinopathy, and the urine albumin/ and were unremarkable. Further tests were undertaken as
creatinine ratio was known to have been significantly ele- the AKI remained unexplained. These revealed Bence
vated in the past. Renal immunological investigations were Jones proteinuria and an excess of serum free light chains
unremarkable, and AKI was attributed to cardiorenal syn- (kappa/lambda ratio of 188), and a diagnosis of multiple
drome. She was treated with diuretics, and the serum cre- myeloma with light chain nephropathy was made.
atinine continued to rise. Ceilings of treatment were Challenging the clinical diagnosis when findings are discor-
discussed by the parent medical team. A consensus was dant may prompt additional tests that identify potentially
arrived at that renal replacement therapy in the context of treatable causes of AKI.
9 Intrinsic
renal
Systemic or renal
limited inflamma-
Fever, weight loss, night sweats
Mouth ulcers, myalgia, arthralgia,
disease tory disease malaise, rashes, epistaxis, red eyes,
haemoptysis, sicca symptoms
Tubular toxicity Prescribed and “over-the-counter”
medications
Rhabdomyolysis
Prolonged immobility
Compartment syndromes
Extreme exercise
Myeloma
Back pain
Cholesterol embolisation
Recent angiography, vascular
surgery or onset of anticoagula-
tion
Post-renal Urinary tract Stone disease Pain
obstruction Prostatic enlargement Visible haematuria
Malignancy (uterine, Post-menopausal bleeding
cervical, ovarian, prostatic, Passage of gravel/grit PU
bladder and ureteric) Treated urinary tract infection
Solitary kidney LUTS – Lower urinary tract symp-
toms
of intravenous contrast media. Volume of urine output (a) medication prescribed in primary care, (b) over-the-
may be helpful in narrowing the differential diagnosis; counter medication, (c) herbal medications and (d) rec-
the presence of complete anuria is usually due to rapidly reational drugs. Common drug causes of
progressive glomerulonephritis (RPGN), acute cortical tubulointerstitial disease include antibiotics and proton
necrosis, complete obstruction of the urinary tract or pump inhibitors (AIN); chemotherapeutic agents
renal infarction. Further suggestions for specific points (tumour lysis syndrome); and acyclovir (crystal nephrop-
in the history are summarised in . Table 9.2. athy). Aminoglycoside antibiotics can cause acute tubu-
A review of medication charts is essential as medica- lar injury via direct toxicity to proximal tubular cells
tions may have been started prior to the recognition of particularly with substantial cumulative exposure.
AKI and contributed to its development. This includes Additionally medications such as ACE inhibitors and
Assessment and Investigation of Acute Kidney Injury (AKI)
189 9
angiotensin receptor antagonists may be associated with
haemodynamic changes within the kidney and changes 5 The second BP should be measured after standing
in creatinine. for 1 minute.
5 A third BP should be measured after standing for
3 minutes.
9.7 Examination 5 Symptoms of dizziness, light-headedness, vague-
ness, pallor, visual disturbance, feelings of weak-
Bedside observations in in-patient settings routinely ness and palpitations should be documented.
incorporate patient’s level of consciousness (AVPU – 5 Postural or orthostatic hypotension is identified by:
alert, voice, pain, unresponsive), temperature, blood – A drop in systolic BP of 20 mmHg or more
pressure, pulse rate, respiratory rate and oxygen satura- (with or without symptoms).
tion. Abnormalities in early warning scores which aggre- – A drop to below 90 mmHg on standing even if
gate weighted scores for abnormalities in these the drop is less than 20 mmHg (with or with-
physiological parameters segregate with poor outcomes out symptoms).
and are used in many healthcare organisations to sup- – A drop in diastolic BP of 10 mmHg with
port decision-making, recognition of deteriorating symptoms.
patients and treatment escalation. A careful assessment
of the patients’ volume status including pulse rate and
volume, blood pressure, postural blood pressure, JVP It is important to recognise assessment of intravascular
and peripheral perfusion is essential. volume status may be an area in which clinicians lack
Assessment of peripheral circulation is important confidence and that frequently repeated assessment fol-
but is influenced by cardiac output, arterial tone and lowing intravenous fluids may be difficult to deliver in
intravascular volume. Serial assessments of skin turgor hard-pressed clinical settings. It is important to empha-
and mucous membranes are more useful than isolated sise the difference between signs that reliably indicate
observations. increases or decreases in intravascular volume and those
that identify fluid maldistribution and elevated total
body salt and water. In this context, the internal jugular
Signs Assessing Peripheral Perfusion venous pressure and the presence of a third heart sound
5 Cap refill. are discriminant signs, but clinicians may find these dif-
5 Peripheral temperature. ficult to detect with certainty.
5 Skin turgor. Inspection of the JVP is an important element of the
5 Mucous membrane. assessment of whether a pericardial effusion is present.
A pericardial effusion causing cardiac tamponade would
be expected to cause tachycardia, hypotension and a
Blood pressure needs to be reviewed in the context of raised JVP [13].
the patient’s usual BP and whether they are usually and
currently taking antihypertensive drugs. Patients may
have significant hypotension relative to their habitual Signs of Tamponade
levels and yet have readings that remain within the Tachycardia, Hypotension, Raised JVP.
expected and accepted range. Pulsus paradoxus – This can be determined using a
Response to a fluid bolus with a sustained or tran- manual sphygmomanometer. The observer identifies
sient rise in blood pressure or JVP can be helpful in the difference between the peak systolic BP during
determining if a patient is volume replete. In a critical expiration and the BP at which Korotkoff sounds are
care setting with access to appropriate monitoring, vari- audible during inspiration and expiration. When the
ation in stroke volume and pulse pressure and the difference between the two is greater than 10 mmHg, a
response to passive leg raising (PLR) can be used to esti- paradoxical pulse is present.
mate fluid responsiveness. Kussmaul’s sign – A paradoxical rise in jugular
Postural BP may be more easily replicated than venous pressure (JVP) on inspiration, or a failure to
assessment of the JVP and provide useful information. observe the expected and appropriate fall in the JVP
during inspiration.
early in the course of these conditions so there is much nitrites are observed in pyelonephritis. Isolated pyuria
to be lost by delayed diagnosis and initiation of treat- may be seen in interstitial nephritis.
ment. Such signs may be found in all systems and com- On occasions, dipstick testing may be misleading. In
prehensive examination of the skin, eyes and nervous pigment nephropathies myoglobin or haemoglobin in
system should be part of AKI assessment. the urine of patients with rhabdomyolysis or intravascu-
lar haemolysis may cause acute tubular injury. In such
cases, a dipstick test will be strongly positive for blood
Signs of Systemic Inflammatory Disease but in the absence of a glomerular lesion.
5 Skin, hair and nails: rash, livedo reticularis, splin-
ter hemorrhages, alopecia. 9.8.1.2 Urine Microscopy
5 ENT: mouth ulcers, nasal bridge collapse. Fully automated bright field microscopy is used in
5 Eyes: iritis, conjunctivitis, scleritis and episcleritis. microbiology departments with digital imaging software
5 Nervous system: isolated mononeuropathy, mono- employed to identify cellular and other elements found
neuritis multiplex, cranial nerve lesions. in un-centrifuged urine. This is an effective means by
which to quantify white and red cells in midstream urine
samples [15].
Other more specific clinical signs may point to the aeti- It is important to remember that red cells lyse in
ology of AKI such as a drug rash in patients with acute dilute urine and that this technique may underestimate
interstitial nephritis (AIN), livedo reticularis (and a his- the incidence of red cells in dilute, alkaline urine and in
tory of angiography or cardiac bypass) in cholesterol samples with prolonged transportation to the labora-
9 emboli and anticardiolipin antibody syndromes, clinical tory. However, haematuria on dipstick urinalysis in the
evidence of heart failure suggesting cardiorenal syn- absence of red blood cells at microscopy may be seen in
drome, signs of liver failure or jaundice suggesting con- pigment nephropathies such as from rhabdomyolysis or
sideration of the hepatorenal syndrome, tense ascites intravascular haemolysis.
causing abdominal compartment syndrome or a palpa- Phase contrast microscopy of the re-suspended pel-
ble bladder from bladder outflow obstruction. let of a freshly and gently centrifuged urine may, in the
hands of an experienced observer, yield information
unavailable using automated urine microscopy tech-
9.8 Investigation of AKI niques described above.
. Table 9.3 Haemoatological, biochemical and microbiology tests to be considered in the investigation of patients with AKI
Haematology FBC, blood film Thrombocytosis and leucocytosis in systemic disease such as ANCA-associated
small vessel vasculitis
Thrombocytopenia, high reticulocytes and red cell fragments in thrombotic
microangiopathy (TMA)
MAHA in sepsis-associated disseminated intravascular coagulation (DIC)
Eosinophillia in AIN, cholesterol embolisation or eosinophilic granulomatosis
with polyangiitis
Leucopaenia and thrombocytopaenia in SLE
Coagulation Changes in APPT and PT in association with SLE, anti-phospholipid syndrome
or DIC
Clotting normal in context of thrombocytopaenia in HUS and TTP
Biochemistry Electrolytes Marked hyperkalaemia in tumour lysis syndrome or rhabdomyolysis
Bone profile Hyperkalaemia, hyperphosphataemia and hypocalcaemia with high CK in
rhabdomyolysis
Hypercalcaemia in multiple myeloma and metastatic malignancy
Serum protein electrophoresis Diagnostic in plasma cell dyscrasias
(SPE) immunoglobulins
Serum free light chains
(SFLC)a
Urine BJP
CRP Elevated in sepsis or infection and systemic inflammatory conditions
LFTs Abnormal in underlying liver disease
Raised bilirubin in TMA/haemolysis
Virology Hepatitis B and C, HIV May be found in patients with AKI and proteinuria
Essential screening to mitigate risk of nosocomial infection in all patients who
may need RRT/dialysis
Point of care/ ABG Marked acidosis in rhabdomyolysis or sepsis
near patient Mild-moderate acidosis common in all causes of AKI
testing
Microbiology Blood and urine cultures If infection suspected
aSerum free light chains and protein electrophoresis have high sensitivity for detection of plasma cell dyscrasias and urine immuno-
fixation may not be required unless AL amyloidosis is suspectedb
bDispenzieri A, Kyle R, Merlini G, Miguel JS, Ludwig H, Hajek R, et al. International Myeloma Working Group guidelines for serum-
free light chain analysis in multiple myeloma and related disorders. Leukemia. 2009;23(2):215–24
9.8.2 Further Investigation between the two syndromes may be of little impact clin-
ically as even transient “pre-renal” failure is associated
9.8.2.1 Urine Biochemistry with high mortality [20].
Traditionally, differential rises between urea and creati-
nine and fractional urinary sodium and urea excretion
have been used to distinguish pre-renal from intrinsic 9.9 Other Blood Tests
renal failure due to acute tubular necrosis. These investi-
gations are not often helpful with very limited utility in Blood tests are complimentary to a thorough clinical
patients receiving diuretics, those with pre-existing renal assessment of patients with AKI, and it is frustrating
or cardiac disease and those with sepsis [18]. More that on occasions, an extremely expensive array of blood
recently, several studies have identified the presence of tests is undertaken before evaluation of fluid balance,
tubular damage in patients with transient “pre-renal” review of the drug chart, dipstick urinalysis and consid-
AKI, and diffuse tubular necrosis may not always be eration of the patient’s escalation plan have been com-
present in intrinsic AKI [19]. Crucially, distinguishing pleted. However, in addition to narrowing the differential
192 M. Prendecki and E. Kingdon
Contents
References – 224
Prevention and Treatment of Acute Kidney Injury
199 10
n Learning Objectives dence of AKI varys in different settings; approximately
In this chapter, we aim to cover: 7 to 18 percent of hospitalized patients, 30 to 70 percent
1. Generic preventative measures that can be of patients admitted to the intensive care unit (ICU) and
employed to reduce the risk of AKI. 20 to 200 per million population in the community can
2. Treatment options and management of established have AKI [1, 2]. Among patients with AKI, the data
AKI describing the evidence for those treatments suggests that even a modest rise in creatinine of
with merit. 27 mmol/l can result in a seven-fold increase in mortality
3. Specific management of AKI in conditions that adding to poor patient outcome [3].
benefit from unique treatments: Recently, AKI and chronic kidney disease (CKD)
– Contrast-induced acute kidney injury. have been recognized as interconnected entities and may
– Tumour lysis syndrome. represent a continuum of the same disease process. Thus,
– Pigment-induced AKI. AKI survivors can progress to CKD and later end-stage
– Crystal-induced AKI. kidney disease (ESRD) requiring dialysis [4]. The exact
– Envenomation. pathophysiological process linking AKI and CKD
remains unclear. However, acute kidney disease (AKD)
is recognized as a disease entity which links AKI and
10.1 Introduction CKD (. Fig. 10.1) with underlying maladaptive repair
leading to chronic inflammation, fibrosis, nephron loss
Acute kidney injury (AKI) is common and associated and CKD. Intervention taken during this stage to correct
with increased morbidity, mortality and extended length reversible factors of AKI may be important in prevent-
of hospital stay. It is recognized not only among hospi- ing the disease progression [5]. The presence of pre-
talized patients but also in the community. The inci- existing kidney disease, increased severity and duration
CKD
Injury AKI AKD to
ESKD
0 7 90 180
. Fig. 10.1 The continuum of acute kidney injury (AKI), acute kidney disease (AKD) and chronic kidney disease (CKD)* [5]
200 D. H. Sudusinghe et al.
100
Renal function 75
50
25
0
Time line
of AKI are associated with rapid decline in kidney func- revealed weaknesses in supply chains and resilience in
tions following an episode of AKI (. Fig. 10.2). the system, emphasizing the critical importance of pre-
vention in AKI as well as the importance of advanced
10 care planning.
Over the last 10 years, multiple clinical guidelines to
Acute kidney disease is acute or subacute damage or
loss of kidney function between 7 and 90 days after prevent AKI have emerged including 2012 KDIGO
initial exposure to acute kidney injury. [7], ‘Think Kidneys’ in the acute kidney injury best
practice guidance [8] and 2019 National Institute for
Health and Care Excellence (NICE) guidance [9]. The
London AKI network has produced pragmatic and
Acute kidney injury is an abrupt decrease in kidney practical guidelines to improve care bundles for the
function over 7 days or less. management of patients with AKI which can be modi-
fied to suit local practice and London AKI app [10].
The International Society of Nephrology (ISN) ‘0by25’
initiative has come up with several strategies to eradi-
Chronic kidney disease is described as persistence of cate worldwide preventable deaths due to AKI by 2025
kidney damage beyond 90 days. [11]. The Renal Association has produced comprehen-
sive guidelines on the management of AKI and RRT in
the context of the COVID-19 pandemic (7 https://
renal. org/wp- content/uploads/2020/10/Clinical-
In addition to adverse clinical outcomes, AKI admis- Practice- Guideline_RRT- for- Critically- Unwell-
sions have a significant impact on healthcare costs due Adult-Patients). Despite growing wealth of novel and
to prolonged hospital stays. The estimated cost of AKI- accessible AKI tools and strategies, their implementa-
related inpatient care to NHS England over a 1-year tion into clinical care and application into routine clini-
period is around £1 billion, accounting for about 1% of cal practice have been suboptimal, and much more
the NHS budget [6]. This has been brought into sharp needs to be done. The National Confidential Enquiry
relief for all of us given the huge impact of COVID-19 into Patient Outcome and Death (NCEPOD) report,
on renal services and ICUs not to mention our patients. which analysed the deaths of patients in the UK with
UK data shows that one in four patients admitted to AKI, found that 30% of AKI-related deaths were avoid-
ICU in the UK due to COVID-19 requires renal replace- able and were a result of significant failures in the deliv-
ment therapy (RRT). These patients had a mortality of ery of basic care [12]. Thus, AKI remains a significant
up to 80% compared to 44% for those who did not and preventable endemic challenge, and there is a clear
require RRT. Moreover, these patients spent roughly need to improve the awareness of this common condi-
three times as long in ICU compared to those without tion among healthcare workers and the general public
AKI. The vast spike in AKI and critically ill patients to improve the standards of care.
Prevention and Treatment of Acute Kidney Injury
201 10
10.2 Prevention of AKI pled with a systematic process to disseminate
information. Awareness of AKI needs to improve in all
Given that there is a notable dearth of effective ‘cures’ levels of the healthcare system, where educational pro-
for established AKI, prevention is profoundly impor- grams should reach all non-specialist medical practitio-
tant. The NCEPOD report has provided useful recom- ners, nurses and allied personnel working in health care.
mendations on the prevention and management of AKI
after reviewing deaths of patients with AKI in the UK
(. Fig. 10.3), and it has set a challenging but not an 10.2.2 Identifying Patients at Increased
unreasonable target to prevent all avoidable AKIs (and Risk of AKI
to better manage the unavoidable). The 0by25 initiative
focuses on optimum management of AKI considering The identification of risk factors of AKI is a crucial
five domains, namely, risk assessment, early recognition, aspect of care (. Table 10.1). Some patients are at
response, renal support and rehabilitation (. Fig. 10.4). greater risk of developing AKI than others. Therefore,
Nephrologists can and should have an important impact there needs to be a systematic and robust mechanism for
on implementing these recommendations through train- ensuring that all such patients at risk are identified.
ing, audit and support as well as contributing to systems Over the last few years, working alongside the
that assess risk and identify AKI [12]. increasing electronic evolution of healthcare systems,
Considering current evidence and recommendations, there has been a drive to implement AKI e-alerts to
there are four main aspects of prevention: (1) improve assist in the early identification and initiation of treat-
awareness, (2) identifying patients at increased risk of
AKI, (3) avoidance of renal insult and (4) prophylactic
treatment. These themes have underpinned the develop- Edited Recommendations from NCEPOD
ment of AKI care bundles which have proved useful in • All emergency admissions should be assessed for risk of AKI
reducing the progression of AKI, length of hospital stay • All acute admissions should receive adequate senior
and associated mortality [13]. review (consultant review within 12 hours)
• There should be sufficient critical care and renal beds to
allow rapid escalation of care when required
• Undergraduate and post-graduate medical training should
10.2.1 Improve Awareness include the diagnosis, prevention, and management of AKI
Response
Correct reversible
factors
Risk assessment • Maintain adequate Rehabilitation
Early Recognition Follow-up
Susceptibility hydration,
• Genetic Diagnosis Renal support • Team approach
haemodynamics,
• Risk scores • Urine output RRT modalities (GP, specialist,
haematocrit and
Surveillance • Serum creatinine • Dosing nurse, social worker,
oxygenation
• Electronic (e-) • New biomarkers • Duration and family)
• Relieve urinary
alerts • Timing • Recovery-target
Staging obstruction...etc
• Drug dosage • Initiation and intervention
• RIFLE Nephrotoxins
modification withdrawal of (blood pressure
• AKIN • Halt or correct drug
Primary prevention treatment control)
• KDIGO dose for renal
• Identify high-risk • Functional
AKI duration function
patients and assessment -quality
Referral of life
prevent exposures • Early nephrology
consultation
. Fig. 10.3 Recommendations from the UK National Confidential Enquiry into Patient Outcome and Death (NCEPOD, 2009) report to
prevent AKI [12]
202 D. H. Sudusinghe et al.
80
70
60
50
Mortality (%)
40
30
20
10
0
Before/On the day Next day 2-4 days 5+ days
Timing of CCOT review in relation to AKI alert
. Fig. 10.5 Increasing mortality with the time between initial AKI alert and review by critical care team secondary to other triggers such
as hypotension (p = 0.018) Prendecki M et al. (Reproduced with permission from postgraduate medical journal [15])
Prevention and Treatment of Acute Kidney Injury
203 10
Reviewed prior to or on the day
of AKI alert . Table 10.2 Nephrotoxic medications and endogenous
25.00 toxins (* TLC tumour lysis syndrome)
Reviewed from the day following
AKI alert Endogenous
Light chains
20.00 * Hypercalcaemia
Patients requiring acute RRT (%)
5.00
10.3 Resuscitate Intravascular Volume replacement equipment. This huge natural experiment
and Restore Renal Perfusion has been an important reminder of the critical impor-
tance of maintaining appropriate hydration and intra-
High-risk patients can be pre-hydrated either orally vascular volume. Therefore, the importance of fluid
(with specific instructions, e.g. ‘drink 1L before coming resuscitation should not be underestimated.
to hospital’) or parenterally to expand intravascular vol- Intravenous fluids should be given only when indi-
ume. This is worth considering for anyone at risk of cated, and it should be prescribed like any other drug
AKI following a surgical procedure, planning use of that is being prescribed to a patient. For example, it is
potentially nephrotoxic agents such as contrast, receiv- recommended to consider ‘four Ds’ of fluid therapy in
ing chemotherapy (ifosfamide, cisplatin, mitomycin) or patients with septic shock, drug, dosing, duration and
taking drugs causing crystal nephropathy (acyclovir, de-escalation, to avoid volume overload in non-volume-
indinavir, triamterene, sulphonamides, methotrexate). responsive patients [17]. Background history, examina-
The type of fluid used for hydration can vary depending tion, monitoring charts and investigations are key
on the clinical circumstance. factors to determine appropriate fluid therapy
Early resuscitation with intravenous fluids is funda- (. Fig. 10.7).
mental to ameliorate AKI in patients with hypovolemia, Aggressive fluid therapy can have adverse conse-
and the COVID-19 pandemic has demonstrated the quences, and one should be cautious, specifically in
importance of adequate fluid maintenance in those who patients at risk of fluid overload and progression to pul-
are sick but not overtly hypovolaemic. Therefore, clini- monary oedema. A large multicentre study focusing on
cal assessment of fluid status is a crucial step in managing critically ill patients with AKI has shown that those with
patients at risk of AKI. Timely reversal of volume fluid overload (10% weight gain) at the time of initiation
depletion in patients with pre-renal AKI can improve of dialysis had an odds ratio for death of 2.07 (95% con-
10 renal perfusion and prevent progression to acute tubular fidence interval of 1.27–3.37). Thus, excessive fluid is
necrosis (ATN). For instance, the increased rate of AKI dangerous not just by precipitating pulmonary oedema
in the early stages of COVID-19 has been the impact of but in terms of mortality [18, 19]. To obtain the best
‘running patients dry’ to avoid provoking adult respira- clinical outcomes, serial fluid status assessment in line
tory distress syndrome. Inadequate resuscitation and with the cardiovascular and renal functions are impor-
maintenance fluids almost certainly contributed to a tant. Central hemodynamic measurements can be used
huge excess of AKI and a global shortage of renal to assess volume responsiveness in intensive care settings.
. Fig. 10.7 Factors that need to be assessed to determine the type sure); RR (respiratory rate); PR (pulse rate); BP (blood pressure);
and amount of fluid therapy. PMH (past medical history); NSAID NG (nasogastric); PEG (percutaneous endoscopic gastrostomy); IV
(non-steroidal anti-inflammatory drugs); JVP (jugular venous pres- (intravenous); TPN (total parenteral nutrition)
Prevention and Treatment of Acute Kidney Injury
205 10
10.3.1 How to Determine the Type . Table 10.4 Comparison of AKI rates in SPLIT (Effect
of Resuscitation Fluid? of a Buffered Crystalloid Solution vs Saline on Acute Kidney
Injury Among Patients in the Intensive Care Unit), SALT
There are two major classes of fluids, crystalloid solu- (Balanced Crystalloids versus Saline in Noncritically Ill
Adults) and SMART (the Isotonic Solutions and Major
tions and colloids (. Table 10.3). 5% dextrose is not Adverse Renal Events Trial) trials according to the type of
used as a resuscitation fluid due to the risk of severe fluids administered (buffered crystalloid group and saline
hyponatremia. Initial choice of replacement fluid ther- group) [22, 23, 24]
apy depends on the cause of hypovolemia. For instance,
blood products are used to treat haemorrhagic shock Study Results
and crystalloids and colloids containing solutions for
SPLIT N = 2092
the non-haemorrhagic shock.
AKI in buffered crystalloid 102 of 1067 P = 0.77
10.3.1.1 Crystalloids group (%) (9.6)
Normal saline (0.9% saline) is inexpensive, and it is the AKI in saline group (%) 94 of 1025 (9.2)
most used crystalloid solution. It is hyperchloraemic SALT N = 13,347
relative to the plasma, and the use of large volumes can
lead to hyperchloraemic metabolic acidosis. AKI in balanced crystalloid 315 of 6708 P = 0.01
group (%) (4.7)
Hyperchloraemia theoretically can exacerbate AKI due
to increased renovascular resistance. Among a group of AKI in saline group (%) 370 of 6639
healthy volunteers, administration of 0.9% saline has (5.6)
been associated with increased extravascular volume SMART N = 15,802
and reduced renal perfusion compared to buffered solu- AKI in balanced crystalloid 1139 of 7942 P = 0.04
tions [20]. To explore this association, a study conducted group (%) (14.3)
by Yunos et al. comparing normal saline and buffered
AKI in saline group (%) 1211 of 7860
solutions has shown reduced AKI rates in the buffered (15.4)
solution group (8.4% vs 10%) [21]. In contrast, the SALT
trial found no significant difference between both types
of fluids [22]. Similar findings were observed in SPLIT
study with no difference in AKI in ICU patients receiv- sistent renal dysfunction [24]. Therefore, buffered crys-
ing buffered solutions and normal saline although this talloids are a reasonable alternative to normal saline
study was criticized for including postoperative patients when large volumes of resuscitation fluids are required
that received relatively smaller resuscitation volumes or if hyperchloraemic acidosis is a concern. It is impor-
(median, 2 L) [23]. The follow-up of the SALT trial, the tant to remember that buffered crystalloids are modestly
SMART study, demonstrated similar figures hypotonic and associated with the development of
(. Table 10.4); however, use of balanced crystalloids hyponatremia. Thus, the choice between buffered solu-
resulted in a lower rate of composite outcome of death tions and normal saline is individualized and depends
from any cause, new renal replacement therapy or per- on the patient’s biochemical parameters and estimated
volume of resuscitation fluid.
. Table 10.3 Types of resuscitation fluids 10.3.1.2 Colloids
Types of fluids
Albumin
Albumin appears to be relatively safe in critically ill
Crystalloids Normal saline (0.9% saline) patients except in patients with a history of traumatic
Buffered solutions brain injury. A large RCT meta-analysis showed the use
Lactated Ringer’s
of albumin when compared to other fluid solutions in
Plasmalyte
Bicarbonate severe sepsis/septic shock was associated with decreased
mortality (OR 0.82) [25]. The Saline versus Albumin
Colloids Synthetic
Fluid Evaluation [SAFE] trial has demonstrated that
Hyperoncotic starch, dextran, gelatin
Human albumin use of 4% human albumin solution and 0.9% saline has
Blood products shown similar renal outcome and mortality results and
Packed red cells can be used as an alternative or adjunct in fluid resusci-
Blood substitutes (FFP, cryoprecipitate) tation especially in patients who are at risk of pulmo-
nary oedema with larger volume of replacements fluids
206 D. H. Sudusinghe et al.
[26]. Furthermore, albumin infusion is also indicated in nous fluid over colloids for treating patients with pre-
patients with liver cirrhosis with AKI due to hepatore- renal AKI due to non-haemorrhagic causes, and it is
nal syndrome. cost-effective over colloids.
. Fig. 10.8 Risk factors for CI-AKI (contrast-induced acute kidney injury) [34]
volume expansion improves renal perfusion and con- other concomitant nephrotoxins to prevent CI-AKI and
trast elimination. A recent non-inferiority clinical trial anything else are distractions.
(AMACING) challenges the protective effects of intra-
venous fluids and results to show that there was no sta-
tistical difference between hydration and no hydration 10.4.2 Tumour Lysis Syndrome
groups regarding incidence of AKI. However, the valid-
ity of results was not convincing due to under-enrolment, Tumour lysis syndrome (TLS) is an oncological emer-
low rate of intra-arterial and interventional procedures gency and a relatively predictable cause of AKI requir-
and having a higher number of patients with less severe ing coordinated management between the oncologist
renal impairment [35]. and the nephrologist. AKI is mainly due to metabolic
In addition to normal saline, isotonic bicarbonate derangement in TLS, and aggressive lymphomas and
can be used to hydrate patients to prevent leukaemias are known to associate with TLS
CI-AKI. Theoretically, urinary alkalinization can (. Fig. 10.10) [38, 39]. Monitoring serum uric acid,
reduce oxidative free radical generation during contrast potassium, calcium and phosphate within 3 days before
procedures. However, the Prevention of Serious Adverse and 7 days after is important for early detection and
Events Following Angiography (PRESERVE) study initiation of treatment. Prevention of renal toxicity is
demonstrated no additional benefit of bicarbonate com- important because renal impairment is not only
pared to isotonic saline. Similar rates of AKI (9.5% ver- dangerous but can limit the continuation of further
sus 8.3%), need for dialysis at 90 days (1.3% versus 1.2%) chemotherapy.
or persistent kidney impairment by 90 days (1.1 versus The main prophylactic therapy in TLS is hydration
1.0) and death (2.4 versus 2.7) were seen in the bicarbon- with isotonic saline or balanced crystalloids. The aim of
ate and saline treatment groups, respectively [36]. hydration is to improve renal perfusion and increase
Similarly, oral N-acetylcysteine delivers no clinical urine output (achieve 2 ml/kg/hour) to minimize pre-
benefits [7]. cipitation of uric acid and calcium phosphate within
A variety of studies have looked at dialysis or filtra- renal tubules. Diuretics (furosemide) are not routinely
tion pre- or post-contrast to reduce AKI. A meta- recommended and can be only considered to maintain
analysis by Cruz et al. showed that haemodialysis, urine output in euvolemic or overloaded patients with-
hemofiltration or hemodiafiltration has no benefit in out obstructive uropathy to achieve desired urine out-
prevention of CI-AKI, preservation of residual renal put. Hydration should be continued until there is no
function, volume overload or osmotically induced elec- evidence of TLS or patients can continue oral fluids to
trolyte shift with iodinated contrast. Therefore, dialysis maintain urine output. Urinary alkalinization as a mode
patients can proceed with the next scheduled dialysis of preventive strategy is not recommended as it increases
session following contrast administration [37]. the risk of calcium phosphate deposition in patients
In summary, condensing vast numbers of papers on with marked hyperphosphataemia.
CI-AKI, the bottom line is that reducing exposure to Pharmacotherapy with hypouricaemic agents (allo-
contrast in high-risk patients where possible and ensur- purinol or febuxostat) can be used to control uric acid
ing adequate hydration pre- and post-contrast, avoiding burden. Treatment can be started with allopurinol in
208 D. H. Sudusinghe et al.
Patient on
RRT
10
1. Discuss with renal specialist
*This is one of the commonly used regimes in in-patients, however, the amount
of fluid that can be given should be guided by the volume status, renal and
cardiac functions of the patient.
. Fig. 10.9 Stepwise approach to prevent CI-AKI (contrast-induced acute kidney injury)
patients with an intermediate risk of TLS and pre- to 7 days depending on biochemical derangements.
treatment uric acid levels <8 mg/dl. Allopurinol dose Febuxostat (xanthine oxidase inhibitor) can be used in
should be adjusted according to renal functions. patients who cannot tolerate allopurinol and who have
However, in high-risk patients (uric acid level >8 mg/dl) renal dysfunction or if rasburicase is unavailable or con-
with deranged renal functions rasburicase (recombinant traindicated (glucose-6-phosphate dehydrogenase defi-
urate oxidase) is preferable over allopurinol. It breaks ciency) [40].
down poorly soluble uric acid to an inactive and more RRT is indicated in patients with established AKI
soluble metabolite of uric acid, allantoin, and rapidly despite optimum supportive therapy. Indications to initi-
reduces uric acid concentration (preferably within ate renal replacement therapy are like those with other
4 hours of initiation of therapy). It is commonly given causes of AKI. However, a low threshold to initiate dial-
as a single dose (0.2 mg/kg), and the average duration of ysis can be considered due to rapid biochemical derange-
therapy is 2 days; however, treatment can be extended up ment. HD can remove uric acids as well as phosphates,
Prevention and Treatment of Acute Kidney Injury
209 10
Breakdown of tumour
cells
Release of intracellular
contents (nucleic acids,
proteins, and electrolytes)
into the systemic circulation
Principles of treatment
• Hydration
• Hypouricaemic agents -
allopurinol/febuxosat,
rasburicase
• Renal replacement therapy
. Fig. 10.10 Pathophysiology and principles of treatment in TLS (tumour lysis syndrome)
but CVVHD is better tolerated and effective than inter- Early initiation of goal-directed therapy is paramount
mittent HD to prevent rebound hyperphosphatemia [41]. to prevent progression to AKI (. Fig. 10.11). Accurate
fluid status assessment, monitoring UOP and electrolytes
are important to prevent adverse consequences.
10.4.3 Pigment-Induced AKI
10.4.3.1 Volume Resuscitation
Pigment-induced AKI is a known complication of rhab- Volume depletion is more common in patients with
domyolysis and intravascular haemolysis (IVH). Renal rhabdomyolysis than IVH due to sequestration of fluids
injury is thought to be due to intravascular volume within the affected muscles. Therefore, vigorous fluid
depletion and tubular damage from haem pigments. therapy is the key to prevent AKI and should be started
Identifying patients at risk of AKI is important to pre- preferably within the first 6 hours of muscle injury at a
vent renal damage. Advanced age, severity of muscle rate to maintain a urine output of 200 to 300 mL/h. This
damage or haemolysis, baseline serum creatinine, initial will require an infusion of around 1.5 L/h of intrave-
serum phosphate and cause of pigment formation are nous fluids. Volume status of the patient should be fre-
the main risk factors. Treating the underlying cause of quently assessed to prevent iatrogenic fluid overload,
pigment nephropathy is critical in reducing the severity especially in patients who are not established to have
of the AKI as well as reducing long-term damage. adequate diuresis.
210 D. H. Sudusinghe et al.
Specific choice of fluid with a greatest benefit is not caemia, and caution is recommended if patients are
clear and isotonic saline can be used as the initial resus- already hypocalcaemic [43].
citation fluid. Multiple litres of 0.9% saline can lead to
hyperchloraemic metabolic acidosis, which can theoreti- 10.4.3.3 Mannitol
10 cally decrease urinary clearance of myoglobin. Mannitol is an osmotic diuretic which was originally
Therefore, balanced crystalloids can be combined with thought to increase renal blood flow, reduce renal cast
isotonic saline after initial volume resuscitation [42]. formation and act as a free-radical scavenger. However,
Correction of intravascular volume depletion will to date there are no randomized controlled trials to sup-
improve renal perfusion and avoid ischemic renal tubu- port the use of mannitol in pigment-induced
lar injury. Increase in urine volume can dilute haem pig- AKI. Higher doses of mannitol (>200 g per day or accu-
ments and minimize formation of intratubular casts, mulated doses of >800 g) have been associated with
and increase in urine flow rate can wash out partially acute kidney injury due to renal vasoconstriction and
occluded casts within renal tubules. Patients with CK tubular toxicity (osmotic nephrosis), and routine use of
>5000 unit/L are at increased risk of AKI, and intrave- mannitol is not recommended. If it is used, plasma
nous fluids should be continued until CK level starts osmolality and the osmolar gap should be monitored
falling and <5000 units/L. In patients with IVH, hydra- frequently, and treatment should be discontinued if ade-
tion should continue until haemolysis is controlled quate diuresis is not achieved or the osmolar gap rises
unless the patient develops signs of volume overload. above 55 mOsm per kilogram [44].
Indinavir is a protease inhibitor that is used to treat Review cultures Consider alternative in high-risk patients
after initial dose
human deficiency virus infection. It can cause kidney
damage by crystal deposition and nephrolithiasis. Once daily Clear evidence of enhanced effect and
Indinavir has a low solubility at urinary pH of 6 but is dosing reduced toxicity
much more soluble at lower pH values. However, acidifica- Antibiotic Review choice, dose, monitoring and
tion of urine is difficult to achieve and potentially harm- control team length of treatment
ful; thus, urine acidification is not recommended. Increased Appropriate This is not done well generally – Proto-
fluid intake (around 2–3 L/day) prior to each oral dose monitoring of cols linking pharmacists, microbiologists
may decrease the risk of crystal formation and allows to levels and the lab are worth developing
continue indinavir in approximately 75% of patients [45]. Dose adjustment The renal drug handbook or
for renal e-prescribing tools
impairment
10.8.1 Aminoglycoside-Induced Avoid concomi- Loop diuretics in high dose, CNIs and any
tant nephrotoxins other tubular toxins
Nephropathy
10 Aminoglycosides deserve special mention as cheap and
highly effective bactericidal antibiotics which are par-
AKI is recognized as an independent predictor of
ticularly useful for initial treatment of sepsis. However,
mortality, and bite to hospital time or bite to needle time
drugs such as gentamicin, tobramycin and amikacin are
more than 2 hours, hypotension, regional lymphade-
associated with significant proximal tubular toxicity
nopathy, cellulitis, low serum albumin, prolonged bleed-
(and ototoxicity) potentially exacerbating AKI.
ing time, prolonged prothrombin time, low haemoglobin
The bactericidal effect of aminoglycosides is depen-
and high total bilirubin are found be risk factors for the
dent on the peak dose, whereas toxicity is time-dependent
development of AKI [51]. Therefore, both pre-hospital
and correlates with trough levels. Aminoglycosides are
and in-hospital management are important to prevent
taken up by the megalin receptor of the proximal convo-
progression to AKI (. Fig. 10.12).
luted tubule which is saturated at high doses. This means
Bleeding from the bite site (fang mark), swelling or
that divided doses have the highest toxicity, while once-
blistering (typical of hump-nosed viper bite) can be seen
daily dosing and a single initial dose have a low risk of
following snakebites (. Fig. 10.13). Community aware-
nephrotoxicity. Nomograms have been developed for
ness is important to discourage applying tourniquets,
patients with renal impairment including 36- and 48-hour
local incisions, suction of venom or application of cow
dosing [48]. While we need these antibiotics, inappropri-
dung on the bite site because these measures are associ-
ate usage and dosing and poor monitoring are very com-
ated with adverse complications; especially, use of tight
mon [49]. . Table 10.5 suggests some ways in which
tourniquets is known to increase the risk of renal injury
nephrologists might collaborate with colleagues to reduce
due to rhabdomyolysis [50].
the risk of nephrotoxicity from these important drugs.
In-hospital management depends on the presence or
Dialysis removes aminoglycosides and might be consid-
absence of envenomation, and it is important to identify
ered in patients with toxic levels and poor renal function.
whether the victim has evidence of systemic envenom-
ation. AKI is known to occur 48–72 hours after snake-
bite and sometimes can extend up to 3–5 days. Therefore,
10.8.2 Envenomation victims should be closely monitored in the hospital or in
the community for development of AKI even if the
10.8.2.1 Snakebite Envenomation renal involvement is not evident at presentation. Delay
Snakebites are common in tropical countries, especially in diagnosis and treatment can lead to irreversible corti-
in the south, southeast Asia and sub-Saharan Africa, cal necrosis needing RRT.
and most of the affected individuals are young and AV is the definitive treatment of snakebite and early
engaged in agricultural activities. administration is helpful to prevent complications
Prevention and Treatment of Acute Kidney Injury
213 10
Management of snake bite
Pre-hospital management Avoid
• Reassurance and attempts to • Excessive activity of the affected area
identify the snake • Applying constricting bands over
• Immobilization of the bitten the bitten extremity
extremity • Applying suction
• Quickly transfer the victim to the
nearest hospital
In hospital management
• Detail clinical assessment and species identification
• Observe up to 24 to 48 hours to look for signs of envenomation
• Commence supportive therapy as early as possible
• Careful fluid resuscitation in hypotensive patients
• Tetanus toxoid
• Support systemic involvement - ventilation, renal replacement therapy
• Bite site management - wound care, look for evidence of compartment syndrome
• Antivenom(AVS) therapy, observe response and determine need for repeat doses
a b
. Fig. 10.13 a Red arrow points towards bleeding from fang mark following a snakebite, b white arrow points blistering following hump-
nosed viper bite. (Image courtesy to Anjana Silva and Kalana Maduwage, Sri Lanka)
10
Bite to needle time and risk of AKI
AKI No AKI
25
21.8 22.2
20.6
20
Bite to needle time (hours)
15
10
7.63
5.2
4.1
5
2 2 3.2 2.7
0
P S Priyamvada L, Harshavardhan Dharod et al. 2013 Danis R et al. 2009 Athappan et al.
et al. 2019 et al. 2013 2008
gist. Common histological findings are cortical necrosis lowing anaphylactic shock is the main cause of AKI fol-
and acute interstitial nephritis, and glomerulopathy can lowing bee stings. Intravascular haemolysis,
be seen rarely. rhabdomyolysis and direct toxicity of the venom com-
ponents to the renal tubules are other aetiologies for
AKI. The severity of AKI seems to be associated with
10.9 Hymenoptera Envenomation the number of stings; creatinine levels were reported to
be higher in most cases when there were more than 1000
Although mass attacks from bees, wasps and hornets are stings [55].
rare, cases remain a serious problem in China, South There is no specific treatment for AKI beyond rapid
Asia, Southeast Asia as well as Latin America. Mass hospitalization, fluid resuscitation and dialysis [56].
attacks can result in AKI, and arterial hypotension fol- Removal of the inoculated stings from the victim’s body
Prevention and Treatment of Acute Kidney Injury
215 10
should be carried out as soon as possible to avoid longer 10.12 Intrinsic Renal Disease
sting-to-skin contact time to prevent higher venom inoc-
ulation. The type of removal (by scraping or pinching) is In most cases of intrinsic renal disease, management
considered irrelevant and should be as fast as possible to depends on the underlying cause and is covered in sub-
shorten exposure time. However, it is important to sequent chapters. As with endogenous toxins, the key is
remove the stinger without squeezing it. Nonetheless, early diagnosis (haematuria, proteinuria or pyuria being
this approach should not delay the medical treatment. important clues) and prompt investigation (several days’
AKI caused by Hymenoptera envenomation is asso- wait for an anti-GBM antibody level is not appropriate
ciated with high mortality, and avoidance of envenom- if Goodpasture’s syndrome is the real diagnosis), and
ation is paramount to prevent complications. All urgent nephrological assessment of all patients sus-
patients with a history of severe reactions to insect bites pected to have intrinsic renal disease needs to be built
should avoid Hymenoptera insects to the best of their into local care pathways. Service level agreements with
ability and should always carry an epinephrine auto- immunology departments and alerting the nephrologist
injection pen. on call to any positive anti-GBM result will enable early
initiation of treatment. Similarly, myeloma kidney is a
medical emergency requiring rapid diagnosis and
10.9.1 AKI in Pregnancy prompt initiation of treatment.
ing 20 RCTs with over 2600 patients with AKI or at risk clinical data and use of dopamine to treat AKI is not
of AKI found that furosemide did not have an impact recommended.
on mortality or need for RRT [62]. A prospective, double-blind randomized controlled
It is important to avoid furosemide in acutely hemo- study by Lauschke et al. including 30 intensive care
dynamically unstable patient due to its venodilatory patients with AKI, to investigate the effect of ‘low-
effects. A potential indication for furosemide in patients dose’ dopamine on renal resistance indices (determined
with AKI is fluid overload with stable blood pressure. by Doppler ultrasound), found that ‘low-dose’ dopa-
While loop diuretics have no role in preventing AKI, mine can worsen renal perfusion in patients with
they may (typically as an infusion) have a useful role in AKI. These findings add to the rationale for abandon-
managing potassium and volume in volume replete ing the routine use of ‘low-dose’ dopamine in critically
patients with established AKI (. Table 10.6). ill patients [64].
Control infection
• Diagnosis - two sets of blood cultures (aerobic and anaerobic)
• Early empirical broad spectrum antibiotics (within 1 hour)
• Source control (imaging to identify anatomic diagnosis of
infection, remove intravascular access devices)
Supportive care
• Initial resuscitation - 30 mL/kg of IV crystalloids
Management of S-AKI
. Fig. 10.16 Parallel and sequential steps in the management of sepsis-associated AKI
Mortality
ing for 20–30 kcal/kg/day and protein of 0.8–1 g/kg/day
25.0%
(increasing if on RRT or catabolic) [7].
20.0%
Mobilization with physiotherapy support (if
15.0%
required) should be instigated as soon as possible. Stable
patients on CRRT may benefit from early conversion to 10.0%
intermittent haemodialysis in ICU to permit mobiliza- 5.0%
Bicarbonate (mmol/L)
tion. Getting patients into clothes, if possible, out of the 0.0%
ward for breaks, providing talking books, games and 0-15 16-21 22-29 30-33 34-45
clear explanations of projected recovery and future are
. Fig. 10.17 A retrospective study of over 500 patients with AKI,
often somewhat neglected aspects of care in patients presenting bicarbonate as a predictor of mortality. In those with a
recovering from a serious illness. bicarbonate <22 mmol/L, mortality was 25.7% compared with 16.9%
when bicarbonate was 22–29 mmol/L and 27.5% when >29 mmol/L
(p = 0.047). This was most pronounced in patients with AKI stage 1;
mortality is 24.3% when bicarbonate <22 mmol/L, 12.0% when
10.15.3 Management and Avoidance 22–29 mmol/L and 25.6% when >29 mmol/L (p = 0.015). Signifi-
of AKI Complications cantly more patients with an abnormal bicarbonate required ITU
admission; 25.7% when <22 mmol/L, 14.7% when 22–29 mmol/L and
The NCEPOD enquiry into AKI deaths demonstrated 24.1% when >29 mmol/L (p = 0.015). The need for acute RRT was
greatest in those with low bicarbonate compared with the two other
that fluid overload, acidosis and hyperkalaemia were
groups, 7.3% vs 2.2% vs 1.7% (p = 0.019). Prendecki M et al. (Repro-
quite common complications of AKI, and despite being duced with permission from postgraduate medical journal [15])
predictable hazards these complications were not infre-
quently missed.
Management of fluid overload has been touched on need for renal replacement in a patient with the poten-
above, and it is important to actively resuscitate a patient tial for rapid recovery from AKI.
who is intravascularly depleted. Once AKI is estab- Hyperkalaemia is extremely common in AKI, a
lished, there is no evidence in favour of pushing fluids common indication for renal replacement therapy,
beyond maintenance requirements. Ensuring that oligu- hence, the importance of identifying the problem and
ric patients are not iatrogenically overloaded is impor- causes of hyperkalaemia. Ceasing drugs that might be
tant. For those who are fluid overloaded, venodilators contributing, treating acidosis and provoking a diuresis
such as GTN (as an infusion) may be helpful, and for in auric patients who are intravascularly replete and
those who are not anuric but who have pulmonary insulin and dextrose are often lifesaving, etc.
oedema, they may respond to diuretics (e.g. loop diuretic Newer potassium binders, sodium zirconium and
infusion). Ultimately, RRT may be the only option, but patiromer, appear to be much more effective and rapidly
pulmonary oedema is a situation best avoided in the first acting than polystyrene sulfonates (e.g. calcium reso-
instance. nium) and may have a role in avoiding dialysis or per-
Acidosis is a common complication and a predictor mitting safe transfer to a dialysis unit if employed early
of outcome. . Fig. 10.17 is from a retrospective study enough but are not a substitute for renal replacement in
of inpatients with AKI. On the day of the AKI presen- the setting of pulmonary oedema or uraemic encepha-
tation, a single serum bicarbonate measurement pre- lopathy [66].
dicted patient mortality and renal replacement therapy.
This may simply indicate that abnormal bicarbonate
levels are a biomarker of sickness, but awareness that 10.16 Indications for Renal Replacement
the patient with an abnormal bicarbonate is at greater Therapy
risk is an important alert [14]. Correction of bicarbon-
ate is not straightforward, and rapid corrections are Despite treatment, some patients may progress to severe
potentially dangerous. However, oral or cautious intra- AKI requiring renal replacement therapy (RRT).
venous bicarbonate solution can be particularly helpful Detailed discussion of RRT is discussed in 7 Chap. 10
in managing hyperkalaemia and potentially avoiding the and this section gives an overview of RRT in AKI.
220 D. H. Sudusinghe et al.
. Table 10.7 Indications for haemodialysis . Table 10.8 Suggested inter-hospital transfer criteria
(London AKI network)
Conventional indication for haemodialysis in AKI
Suggested inter-hospital transfer criteria (London AKI
Hyperkalaemia If resistant to medical treatment network)
Uraemia Impaired consciousness, pericardial Acidosis pH ≥7.2, venous bicarbonate 12 mmol/L, lactate
rub ≤4 mmol/L
Drug intoxications Methotrexate, salicylate, lithium, Cardio- Heart rate ≥ 50 and ≤ 120 bpm, systolic blood
hyperoxalosis vascular pressure ≥ 100 mm hg (sustained), mean arterial
pressure ≥ 65 mm hg, lactate ≤4 mmol/L
Respira- Respiratory rate ≥ 11 bpm and ≤ 26 bpm,
tory saturations ≥94% on not more than 35% oxygen.
When AKI is complicated with some of the meta- If required CPAP then independent of this for
bolic and volume status-related complications ≥24 hours
(. Table 10.7), the patient needs RRT. However, when Neuro- Glasgow coma scale ≥12
severe AKI is not complicated with conventional indica- logical
tions, it is unclear whether the patient may benefit by
early initiation of RRT. Commencing RRT may improve
the patient’s outcome, and there may be a need to antic-
10 ipate the requirement for RRT in severe AKI. Therefore,
is it important to ensure early referral to the ICU or 10.17 Transfer Criteria
local renal unit to ensure time is factored in for the
patient transfer especially if the dialysis unit is at a dif- Many but not all patients with AKI can be managed
ferent hospital. locally. For those that cannot and need inter-hospital
The current practice is to offer dialysis as clinically transfer to a renal unit, then the transfer should be
indicated due to lack of evidence regarding the most speedy, but clear criteria need to be established regard-
effective timing for initiation of such therapy. Thus, ing patient stability and suitability as death on transfer
nephrologists identify patients who are not going to is not unheard of. The London AKI network generated
recover safely with medical therapy and make a robust the following guidelines which are a very useful start-
plan to provide RRT in a safe and timely manner. A ing position for negotiation, are common sense and
recent multinational randomized controlled trial involv- can be modified locally depending on resources
ing 2927 critically ill patients with AKI compared stan- (. Table 10.8).
dard versus accelerated initiation of renal replacement
therapy in acute kidney injury (STARRT-AKI). As per
the study results, accelerated renal replacement strategy 10.18 Treatment Escalation Plans
was not associated with a lower risk of death at 90 days and Ceilings of Care
compared to standard strategy (relative risk, 1.00; 95%
confidence interval [CI], 0.93 to 1.09; P = 0.92). Adverse Finally, the COVID-19 pandemic has starkly high-
events (mainly hypotension and hypophosphataemia) lighted the need for an early holistic assessment of
occurred in 346 of 1503 patients (23.0%) in the patients with serious illness. Nephrologists are increas-
accelerated-strategy group and 245 of 1489 patients ingly referred to frail patients with significant comor-
(16.5%) in the standard-strategy group (P < 0.001). bidity who have developed AKI due to an intercurrent
Among survivors at 90 days, a higher percentage of illness. Frequently, the question is ‘does this patient
patients were continued dependence on renal replace- need acute renal replacement therapy?’ and ‘if the renal
ment therapy in the accelerated-strategy group (10.4% function did not recover would they be suitable for
vs 6.0%). Thus, this suggests that greater exposure to long-term dialysis?’. These are often exceedingly diffi-
renal replacement therapy, possibly modified according cult decisions made at a time when the patient is at their
to baseline risk (e.g. the presence of chronic kidney dis- most vulnerable stage, and the decision is often made
ease), may compromise kidney repair and the return of with limited information. These are challenging deci-
baseline kidney function [67]. sions and should not be made casually. However, early
Prevention and Treatment of Acute Kidney Injury
221 10
thoughtful assessment of ceilings of care is important compared to patients with CKD who do not have an
when appropriate and needs to be carefully discussed episode of AKI.
with the patient and the next of kin. This is an extremely
important part of nephrology care with a significant
responsibility. 10.20 Follow-Up of AKI
Case Study
u mol/L
nificant AKI is critical.
240
Case 2
A 79-year-old man presented to his family doctor com- 120
plaining of blood in his urine. He had symptoms of blad-
der outflow tract obstruction but little else. Blood tests 0
revealed an increase in baseline creatinine to 160 μmol/L,
. Fig. 10.19 Fall in creatinine following insertion of the
and he was referred to urology but presented shortly after urinary catheter
in urinary retention with a creatinine of 590 μmol/L and
potassium of 7.6 mmol/L. A urinary catheter relieved given a 500 ml fluid challenge, his potassium was medically
1.5 L residual, and a non-contrast CT-KUB confirmed a treated, and once euvolaemic his previous hours’ urine
very thick-walled bladder, bilateral upper tract obstruction output was replaced with crystalloid overnight. This is a
and blood in the renal pelvis and ureter (. Fig. 10.18, a relatively safe way of treating post-obstructive diuresis in a
and b). He was assessed as being mildly hypovolaemic, and patient who is adequately filled for short periods initially,
providing electrolytes are closely monitored and any drop
in urine output provokes a careful reassessment. Over the
a Bilaterally
dilated renal next few days, his creatinine fell as shown in . Fig. 10.19
pelvis with
dilated ureters
(arrow shows catheterization), and he was discharged by
containing the urologists with an indwelling catheter and a diagnosis
blood
of bladder outflow tract obstruction secondary to a large
prostate but requiring a CT IVU as an outpatient to inves-
tigate the pre-catheterization haematuria.
The nephrologists were asked to review his high urine
Grossly PCR of 4000 mg/dl which raised possibilities of
thickened
bladder wall malignancy-associated glomerulonephritis, but uPCR is
not possible to interpret in the context of gross haematu-
ria, and transient proteinuria is common in acute obstruc-
tion. However, the concern was raised that his creatinine
had not fallen as swiftly as one might have expected with
decompression of the system and his creatinine had lev-
b Bilateral elled off at a higher than expected level (300 μmol/L).
hydronephros
is and blood There might be many reasons for failure to recover, but a
in renal pelvis significant risk is that there was persistent vesico-ureteric
obstruction and possibly not just related to a hypertro-
phied bladder wall (which had been anticipated to resolve
spontaneously).
An urgent ultrasound (. Fig. 10.20) 2 weeks after the
initial catheterization demonstrated persistent bilateral
upper tract dilatation. He underwent bilateral nephrosto-
mies with subsequent improvement in creatinine to
125 μmol/L, and the proteinuria disappeared. Widespread
bladder tumour was found to be obstructing both ureters.
This case illustrates the importance of reassessing a patient
. Fig. 10.18 (a and b) Images shows bilateral dilatation if the diagnosis or progress does not fit and ensuring that
hydronephrosis and blood in renal pelvis and grossly thick- loose ends are followed up and resolved rapidly.
ened bladder wall
224 D. H. Sudusinghe et al.
. Fig. 10.20 Ultrasound image of the kidneys demonstrating persistent hydronephrosis following initial catheterization
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https://doi.org/10.1007/s00134-017-4683-6. dopamine worsens renal perfusion in patients with acute renal
56. Daniels R, Nutbeam T, McNamara G, Galvin C. The sepsis six failure. Kidney Int. 2006;69(9):1669–74. https://doi.
and the severe sepsis resuscitation bundle: a prospective obser- org/10.1038/sj.ki.5000310.
vational cohort study. Emerg Med J. 2011;28(6):507–12. https:// 65. Study Investigators NICE-SUGAR, Finfer S, Chittock DR,
doi.org/10.1136/emj.2010.095067. et al. Intensive versus conventional glucose control in critically
57. Asfar P, Meziani F, Hamel JF, et al. High versus low blood-pres- ill patients. N Engl J Med. 2009;360(13):1283–97. https://doi.
sure target in patients with septic shock. N Engl J Med. org/10.1056/NEJMoa0810625.
2014;370(17):1583–93. https://doi.org/10.1056/NEJMoa1312173. 66. Dépret F, Peacock WF, Liu KD, et al. Management of hyper-
58. Pollard S, Edwin SB, Alaniz C, Inotropes H, SSC 2012. Vaso- kalemia in the acutely ill patient. Ann Intensive Care. 2019;9:32.
pressor and inotropic management of patients with septic https://doi.org/10.1186/s13613-019-0509-8.
shock. P & T: A Peer-Reviewed Journal for Formulary Man- 67. Investigators STARRT-AKI, et al. Timing of initiation of
agement. 2015;40(7):438–50. renal-replacement therapy in acute kidney injury. The New
59. Bellomo R, Cass A, Cole L, et al. Intensity of continuous England journal of medicine vol. 2020;383(3):240–51. https://
renal-replacement therapy in critically ill patients. N Engl J doi.org/10.1056/NEJMoa2000741.
Med. 2009;361:1627–38. 68. Uchino S, Kellum JA, Bellomo R, et al. Acute renal failure in
60. Petros S, John S. Die Sepsisleitlinie der surviving sepsis cam- critically ill patients: a multinational, multicenter study. JAMA.
paign 2016 [the 2016 surviving sepsis campaign sepsis guide- 2005;294(7):813–8. https://doi.org/10.1001/jama.294.7.813.
line]. Med Klin Intensivmed Notfmed. 2017;112(5):454–8. 69. Xue JL, Daniels F, Star RA, et al. Incidence and mortality of
https://doi.org/10.1007/s00063-017-0298-5. acute renal failure in Medicare beneficiaries, 1992 to 2001.
61. Daniels R, Nutbeam T, Mcnamara G, et al. The sepsis six and 70. Garg AX, Suri RS, Barrowman N, et al. Long-term renal progno-
the severe sepsis resuscitation bundle: a prospective observa- sis of diarrhea-associated hemolytic uremic syndrome: a system-
tional cohort study. Emerg Med J. 2011;28:507–12. atic review, meta-analysis, and meta-regression. JAMA.
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227 11
Contents
References – 236
Every hospital should have a written guideline Quality statement 5: People with AKI have the manage-
detailing how the clinical areas where patients Discussion with a ment of their condition discussed with
with AKI are treated (critical care unit, the renal nephrologist a nephrologist as soon as possible and
unit and the non-specialist ward) interact to with 24 hours of detection if they are
ensure delivery of high-quality, clinically at risk of intrinsic renal disease or if
appropriate care for patients with AKI they have stage 3 AKI
Recogni- All acute admissions should receive adequate Quality statement 6 People with AKI who meet the criteria
tion of senior reviews (with a consultant review within for RRT are referred immediately to a
severity of 12 hours of admission) nephrologist or critical care specialist
illness
There should be sufficient critical care and renal
beds to allow escalation of care if appropriate
Organisa- All acute admitting hospitals should have
tion of access to either onsite nephrologists or a . Table 11.3 Quality domains and measures employed in
renal dedicated nephrology service within reasonable studies of AKI care
services distance of the admitting hospital
Quality Measure examples
All acute admitting hospitals should have access domain
to a renal ultrasound scanning service 24 hours a
day including the weekends and the ability to Effective- In-patient mortality, critical care admission,
provide emergency relief of renal obstruction ness residual chronic kidney disease, residual
requirement for RRT
All level 3 critical care units should have the
ability to deliver renal replacement therapy; and Efficiency Length of stay, cost of care episode
where appropriate these patients should receive
clinical input from a nephrologist Patient Patient experience measures (PEM)
centred Delivery of care that is respectful of and
responsive to individual patient preferences,
needs and values
Care close to home
and reliable delivery of simple proven interventions Equity Unwarranted variation segregating with personal
has an impact on many domains of the quality of characteristics (gender, ethnicity, geographic
location, or socioeconomic status)
care. In AKI these might include effectiveness, effi-
ciency, avoidable harm, equity, accessibility and Safety Avoidable harm
patient experience (see . Table 11.3). In addition to Timely Reducing waits and harmful delays
interventions that can be evaluated as they are intro- Review within aspirational time window
duced, that other healthcare provider attributes Transfer to tertiary care Centre within specified
including skill mix, staffing density and quality assur- time frame
Critical care RRT for patients with single organ
ance of patient pathways influence outcomes for
failure
patients with AKI.
230 S. Hildebrand et al.
. Table 11.4 Heterogeneity of studies designed to evaluate interventions to improve care in patients with AKI
Single acute care Controlled Identification of patients at risk of AKI In-reach review by visiting specialist
organisation trial nephrologists at acute sites without
on-site renal service
Multiple acute QI project Automated ascertainment of patients with AKI Post-discharge AKI clinics
care organisations
Whole system Observa- Identification of AKI phenotype AKI review by specialist AKI nurses
tional study (CCOT or AKI-dedicated)
NB high−/ Reliable delivery of proven clinical interventions in On-site provision of pharmacy and
middle−/ patients with AKI (isolated interventions or as part dietetic review at acute sites without
low-income settings of a care bundle) on-site renal service
The published literature is heterogeneous, and hospital-acquired AKI following the deployment of a
. Table 11.4 lists examples of the settings, study design, clinical prediction rule identifying those at risk of AKI
intervention and service reconfiguration in studies in alongside electronic alerts for those with AKI [14].
this area which the authors will refer to in the remainder Identifying Patients with AKI and Messaging
11 of this chapter. Clinicians Delivering Their Care.
Physicians may not always recognise the clinical sig-
nificance of changes in creatinine, and a number of
11.3 Improving Outcomes in AKI: Domains algorithms are available that allow the magnitude and
of Care timing of changes in serum creatinine and comparison
with baseline levels to be used to identify patients who
11.3.1 Identification of Those at Risk of AKI may have AKI. The specificity of the UK National AKI
algorithm is >90% when AKI warning test alerts are
Models incorporating comorbidity, physiological compared with clinical coding of AKI in hospital epi-
parameters and variables related to treatment and ill- sode statistics [15]. A randomised controlled study com-
ness severity factors have been used to estimate risk of paring electronic AKI alerting (text messaging of the
developing AKI in a variety of clinical contexts. AKI warning test result) to the covering doctor and
Precise estimates of risk might inform targeting of pharmacist with standard care did not identify improve-
particular elements of care in those at highest risk of ment in the composite outcome of maximum increase in
AKI. Risk scores are available in cardiac and non-car- creatinine, renal replacement therapy or death [16].
diac surgery, but there are few examples of clinical Alerting was one of three interventions in the step-
implementation [11] wedge Tackling AKI RCT study [17]. This study did not
The largest study addressing this question in patients achieve its primary endpoint of a reduction in mortality.
attending for acute medical care found that risk factor In contrast a single centre propensity score matched
modelling offered limited discrimination in identifica- cohort study found an advantage when alerting was
tion of patients who would go on to develop hospital- combined with targeted education and use of a care
acquired AKI [12]. This is consistent with the earlier bundle [18]. Prendecki and colleagues explored whether
finding from a service evaluation study in 4 Welsh medi- the impact of delayed review of sick patients might be
cal assessment units that prediction models based on ameliorated by use of an AKI alert system in a retro-
risk factors added little to risk stratification based on spective study [19]. They found that an AKI alert would
age [13]. More recently a controlled before-and-after predate recruitment of specialist review by physiological
study has demonstrated reductions in the incidence of parameters by up to 2 days.
Establishing an AKI Service
231 11
11.3.2 Care Bundles dle (b) e-Alerting of AKI warning test results and (c) an
educational package.
The Institute for Healthcare Improvement defined a Three large well-conducted quality improvement QI
bundle as: projects in the NHS in the Northwest of England also
tested the effectiveness of a care bundle in patients with
AKI [23–25]. These studies have demonstrated improve-
“a structured way of improving the processes of care ments using statistical process control methodology.
and patient outcomes: a small, straightforward set of The interventions tested in the QI studies are sum-
evidence-based practices that, when performed col- marised in . Table 11.5 alongside the outcome mea-
lectively and reliably, have been proven to improve sures described in the studies.
patient outcomes.” Medication review and assessment and optimisation
of fluid balance are frequent components of AKI care
bundles. Targeted fluid therapy with frequent reassess-
In the context of AKI, there is some variation in which ment of the patient, provided by the specialist and gen-
practices or interventions are included in such a bundle eralist members of the clinical team, is an important
and the outcomes against which they are assessed. There intervention in this context [26]. Patients with severe
is also heterogeneity in the methods used to evaluate AKI in whom goal-directed fluid therapy is unsuccessful
these interventions and to deliver evidence of effective- may require renal replacement therapy
ness: controlled trials, QI and the observational studies Medication review is an intervention that often fol-
[20, 21, 22]. lows an AKI warning test result and which is frequently
The ambitious RCT study, Tackling AKI [17], tested one of the elements in an AKI care bundle. The advent
three interventions in a stepped-wedge design. The study of electronic prescribing, with an integrated AKI alert-
was powered to identify a 20% reduction in in-patient ing system, can highlight medications that require dose
mortality but did not meet its primary endpoint. The adjustment or discontinuation to prevent toxicity [27].
study had three interventions: (a) STOP-AKI care bun- E-alerting systems to tackle AKI can anticipate those at
high risk and reduce the risk of AKI. The NINJA sys- 11.4.2 Follow-Up of AKI Patients
tem electronically identified children at risk of a drug-
related AKI due to nephrotoxin exposure. In the Patients who have had an episode of AKI have a greater
paediatric setting in which routine phlebotomy is judi- risk of developing chronic kidney disease (CKD) and
ciously used, identification of high-risk individuals progression up to ESRD in the future [31]. Repeated
enables either discontinuation of medication or ade- episodes of AKI are associated with progression of
quate monitoring to ensure any subsequent AKI is CKD and incomplete recovery from an episode of AKI
promptly identified and managed [28] is also associated with a poor prognosis [32]. With these
observations in mind, follow-up in specific AKI survivor
clinics is well established in some centres [33]. These
11.4 Service Reconfiguration offer the opportunity to deliver patient education and
identify and mange CKD, reconciliation of prescribed
11.4.1 Which Clinicians Should Review medication and rational re-introduction of treatments
Patients with AKI? associated with prognostic gain that are temporarily
interrupted at the time of AKI. Nephrologists and
Stage 3 AKI warning test results are a minority of all nephrology guidelines often advocate specialist follow-
AKI WTRs, and parenchymal inflammatory renal dis- up after an episode of AKI. However, there is limited
ease and systemic disease account for a small propor- evidence that such follow-up is delivered [34] and uncer-
tion of cases of AKI. The National Institute for tainty if such follow-up improves patient outcomes. An
Health and Care Excellence (NICE) has described cri- uncontrolled study of patients who received transient
teria for renal referral (see . Table 11.6). Questions RRT study for AKI identified a lower mortality in those
remain about how best to bring the remaining cases of who were followed up by nephrologists than was
AKI to the attention of clinicians responsible for care observed in those who were not followed [35]. This area
of affected patients, which professional group should merits further investigation.
11 review the patients and whether this requires face-to-
face review. Telephone-based advice for clinicians
managing AKI has been described [29]. Many acute 11.5 Patient and Carer Engagement,
trusts have critical care outreach teams who may be Education and Sick Day Rules
recruited to review patients based on the presence of
deteriorating physiological parameters or subjective Delivery of patient-appropriate educational materials is
impressions of patient deterioration. The impact of used as a process measure in some AKI QI projects [36].
an AKI outreach team is being investigated in Despite this approach being widespread, many AKI sur-
unselected AKI in the Acute Kidney Outreach to vivors’ knowledge of their illness and future risks
Reduce Deterioration and Death (AKORDD) trial: remains limited [37]. AKI survivor clinics may increase
the protocol for a large pilot study [30]. AKI literacy amongst survivors [38]. The introduction
of “sick day rules”, temporary interruption of medica-
tions at the time of acute illness, for those at risk of AKI
has been the subject of much interest. Qualitative assess-
ments suggest significant challenges when AKI sick day
. Table 11.6 NICE AKI Guidelines 2014 suggests the
rules are considered in a primary care setting [39], and
following indications for renal referral
description of the effect of AKI sick day rules on patient
Indications for renal referral outcomes, unintended consequences and the use of
healthcare resources are awaited . The authors are
Stage 3 AKI
unaware of studies of patient experience of care in AKI
Stage 2 AKI with failure to respond to medical treatment or of formal experience-based co-design in this context.
Complications of AKI failing to respond to medical treatment
Indication for dialysis present
11.6 AKI in a Primary Care Setting
A possible systemic inflammatory cause for AKI
Blood or protein on urine dipstick indicating possible intrinsic Acute kidney injury may accompany patient episodes
renal disease that begin outside the hospital (community-acquired
AKI) and may complicate hospital admissions. Episodes
Establishing an AKI Service
233 11
of AKI beginning more than 48 hours after admission secondary care. Although these are specific to the
are often termed hospital-acquired AKI (HA-AKI). English health economy, they do address more wide-
This is a somewhat arbitrary distinction as almost half spread challenges associated with management of AKI.
of the cases satisfying the CA-AKI criterion had had 5 Lancashire Teaching Hospitals NHS FT.
earlier measurements of creatinine as part of in-patient
or emergency department care in the 30 days before 7 https://www. thinkkidneys. nhs. uk/aki/wp- content/
CA-AKI diagnosis [40] uploads/sites/2/2016/01/Lancashire- Teaching-
A minority of episodes of community-acquired AKI Hospitals-NHS-FT-Establishing-an-AKI-Service-in-
are managed exclusively outside the hospital [41]. a-Tertiary-Renal-Centre-.pdf
Changes in creatinine sufficient to meet the criteria for 5 Wrightington, Wigan and Leigh NHS FT.
AKI ascertainment algorithms may be encountered
when blood tests are performed in primary care settings, 7 https://www.thinkkidneys.nhs.uk/kquip/wp-content/
both in response to acute illness and as part of chronic uploads/sites/5/2016/11/Wrightington- Wigan- Leigh-
disease surveillance or to guide safe prescribing. Case-Study-Improving-Patient-Safety-and-Reducing-
Several elements need to be considered when consid- Harm1-1.pdf
ering AKI in primary care: When commissioning renal services, commissioners
(a) Messaging of AKI warning test result from the bio- may need to consider incidence of AKI, the nature of
chemistry laboratory to the community-based prac- the local case mix and the need for specialised services to
titioner. be concentrated in a limited number of tertiary sites or
(b) Timely responses upon receipt of an AKI warning co-terminus with other specialised services. Tertiary-
test result in primary care [42]. level renal services are able to provide standard ward-
(c) Management of a patient discharged from the hos- based care in addition to renal replacement therapy and
pital after community-acquired or HA-AKI. in some locations may also be sufficiently well staffed
and skilled to deliver critical care functions. However,
There is evidence that the use of an e-alert has improved whatever the complexity of supportive care available,
response times in the context of community-acquired renal units that are servicing a referral practice for a
AKI [43] and of higher rates of creatinine monitoring large population are likely to need to offer specialist
[44]. However, e-alerts are also associated with higher diagnostic and treatment services, including immuno-
rates of hospitalisation [44]. National guidance on the logical testing, immunosuppression prescribing and
nature and timeliness of responses to AKI warning test delivery, percutaneous renal biopsy and plasma
results in primary care has been informed by a RAND/ exchange [45].
UCLA Appropriateness Method study [42]. Guidance The speed with which patients are transferred from
in this area has been reviewed by the UK Royal Col- critical care facilities offering continuous RRT to spe-
lege of General Practitioners (RCGP), and a toolkit is cialist renal units is likely to influence time taken to
available online (7 https://www.rcgp.org.uk/clinical- make a definitive diagnosis, critical care bed availability
and-research/resources/toolkits/acute- kidney-injury- and the cost of an AKI episode.
toolkit.aspx). The second phase of an RCGP-sponsored A tertiary care centre is likely to sit at the hub of a
AKI quality improvement project that will focus on network of secondary care hospitals from which refer-
post-discharge AKI care and guidelines to support clin- rals are received. The nephrologist may provide an
ical decision-making about follow-up of patients who advice service, often visiting the secondary care centre,
have sustained AKI is awaited. and a pathway for patient transfer to the tertiary care
centre. These services need to be carefully evaluated in
light of the catchment population served to justify cap-
11.7 Commissioning AKI Services ital investment and revenue costs necessary to sustain
in a High-Income Setting them.
Many networks publish criteria that determine
The earlier sections of this chapter discuss how configu- whether the patient is sufficiently stable to transfer
ration of existing services might be influenced by recent between settings and physical sites. The London AKI
published trials, observational studies and QI projects. network has parameters of these in an openly accessible
The UK Think Kidneys website includes useful case app (7 www.healthcreatives.co.uk/work/london-aki-
studies describing how to establish an AKI service in network.html) generated by consensus.
234 S. Hildebrand et al.
11.8 AKI Services in Low- and Middle- 5 Risk: Public health measures may influence the
Income Settings prevalence of infectious disease associated with
AKI [47], and socioeconomic and cultural factors
The availability of resources influences healthcare priori- may influence health-seeking behaviours putting
ties and delivery. This is of particular relevance in kidney individuals at a higher risk of more severe AKI.
disease, as long-term provision of renal replacement 5 Recognition: Correctly identifying those at risk of
therapy for chronic kidney disease is prohibitively expen- AKI and appropriate use of point-of-care testing are
sive in most low- and middle-income countries. AKI, on likely to enhance recognition of AKI. Telemedicine
the other hand, is largely a preventable and treatable con- may support access to specialist advice and onward
dition with relatively limited resource. Establishing an referral to more specialist services if required.
AKI service may support the development of a nephrol- Repeated measurement of serum creatinine during
ogy service with gains unrelated to AKI, and small the course of hospital admission is far less common
improvements in the provision of AKI care can save lives in developing countries [48], but ongoing assessment
no matter where you are in the world (case history 1). is vital in those at high risk of development of AKI
Managing AKI in low- and middle-income settings during a hospital admission [49].
provides substantial challenges. These include a lack of 5 Response: Smaller renal units, outside large tertiary
education and training of healthcare professionals care centres, support delivery of specialist input in
involved in the management of AKI; a lack of availabil- cases of moderately severe AKI that are not referred
ity of even basic laboratory tests (e.g. serum creatinine) onwards to tertiary care centres. These function opti-
required for the diagnosis of AKI; a patient population mally with close liaison with the tertiary care centre,
at extremely high risk of kidney injury from acute infec- either for knowledge or practical support [50].
tious illness on a background of an ongoing epidemic of 5 Renal support: In low-income settings, on-stie renal
HIV and emergent cardiovascular disease; and limited replacement therapy is not widely available. However,
resources for AKI monitoring and management, rang- protocols developed in other settings can be adopted
and adapted to enable the initiation of emegency
11 ing from a lack of basic equipment such as catheter bags
management of AKI (for example acute peritoneal
to monitor urine output to the provision of renal
replacement therapy and critical care. dialysis) and delivery of care underpinned by tele-
The International Society of Nephrology (ISN) has medicine support from dedicated geographically dis-
made significant efforts to improve AKI service provision tant renal physicians [51]. Peritoneal dialysis is the
in low-income settings worldwide through a number of most commonly employed modality of renal replace-
its programmes focused on education, training, advocacy ment reflecting resource availability and ease of train-
and research (7 https://www.theisn.org/programs). ing for local renal and non-renal physicians [52].
These are encompassed within the ISN 0by25 initiative 5 Rehabilitation: Most of the reports are of the out-
(7 https://www.theisn.org/all-articles/616-0by25#0by25- comes following tertiary-level care for the AKI. A
initiative), which aims to eliminate preventable deaths significant proportion of affected individuals do not
from AKI worldwide by 2025 [46]. It has identified a have a fully recovered renal function [53]. Thus ongo-
number of potential targets for improvement in AKI ing support and chronic kidney disease management
care: are required to provide optimal kidney care [54].
Case Study
Case 1: Establishing an AKI Service in Blantyre, components of the development of this AKI service have
Southern Malawi included the following.
The ISN supported a sister renal centre partnership 1. Establishing the Epidemiology of AKI.
between Queen Elizabeth Central Hospital (QECH),
Blantyre, Malawi, and Barts Health NHS Trust, London, A number of observational studies were undertaken at
UK, from 2013 to 2019. Prior to this partnership, there QECH in medical, paediatric and obstetric cohorts to
was no renal expertise in the region. Establishing an determine the incidence, aetiologies and outcomes of AKI
AKI service has been the focus of developing nephrol- (Evans et al. BMC nephrol 2017; Cooke et al. BMC
ogy services more generally in Southern Malawi. Key nephrol 2018; Evans et al. PDI 2018; Mwanza et al. BMC
Establishing an AKI Service
235 11
nephrol 2018). AKI was found to be common (17% of Sustainability of any new AKI service is paramount, but
adult medical admissions), predominantly due to prevent- particularly in low-income settings. The AKI service at
able and treatable causes (acute infective illness and pre- QECH is now locally led by Malawian nurses and clini-
eclampsia), with poor outcomes despite tertiary care (44% cians who have been trained in the provision of AKI care
in-hospital mortality with any AKI in adults). during exchange visits as part of the sister renal partner-
2. Establishing the Need for and Providing Education ship. Malawi’s first fully trained nephrologist will return to
and Training to Healthcare Professionals. lead the service later this year having undertaken an ISN
fellowship in Cape Town.
followed by nephrologists in a developing country. Nephrology digitally-enabled care pathway for the recognition and manage-
(Carlton, Vic). 2016;21(4):327–34. ment of acute kidney injury. F1000Res. 2017;6:1033.
54. Sobrinho A, da Silva LD, Perkusich A, Pinheiro ME, Cunha 56. Connell A, Montgomery H, Martin P, Nightingale C, Sadeghi-
P. Design and evaluation of a mobile application to assist the Alavijeh O, King D, et al. Evaluation of a digitally-enabled care
self-monitoring of the chronic kidney disease in developing pathway for acute kidney injury management in hospital emer-
countries. BMC Med Inform Decis Mak. 2018;18(1):7. gency admissions. NPJ Digit Med. 2019;2:67.
55. Connell A, Montgomery H, Morris S, Nightingale C, Stanley S,
Emerson M, et al. Service evaluation of the implementation of a
11
239 12
Contents
References – 258
Acute Renal Replacement
241 12
n Learning Objective depending upon the immediate and projected trajectory
1. To appreciate the indication and timing of dialysis of the clinical situation, clinician experience and local
in the setting of AKI. institutional practices and resources. For example, RRT
2. To understand the issues relating to dialysis of is typically initiated for oliguria, acidosis and correction
patients with acute co-morbidity (such as brain or of volume overload in the intensive care unit (ICU),
cardiac injury or significant electrolyte abnormali- whereas in the renal ward, azotaemia and hyperkalae-
ties). mia are more common triggers to initiate RRT.
3. To compare different modalities of renal replace- The indications for RRT depend on both or either
ment in the setting of AKI, including elements the clinical scenario or biochemical abnormalities and
such as dose and anticoagulation. also on whether the situation is expected to improve fol-
lowing appropriate resuscitation or supportive or inter-
ventional management, and as such indications may
12.1 Initiation of Dialysis be relative or absolute (. Table 12.1). Current clinical
practice is to consider initiating RRT in patients with
The decision when to initiate replacement therapy AKI, defined by an abrupt fall of glomerular filtration
(RRT) in patients with acute kidney injury (AKI) is rate, who are at risk of clinically significant solute imbal-
extremely variable and tends to be based on empiricism, ance, toxicity or volume overload.
. Table 12.1 Clinical and biochemical indications to consider initiation of renal replacement therapy. Rifle criteria relate to
changes in baseline serum creatinine [1], discussed in Chap. 8
12.2 Does the Timing of RRT Influence tion with intravenous fluids alone, is identified early and
Outcome in AKI? RRT anticipated rather than precipitated as an emer-
gency”.
Historic data suggests that “early” initiation of RRT in
AKI was associated with improved survival when RRT
was started with BUN levels of 100 mg/dl (35.7 mmol/l) 12.3 When Should RRT Be Withdrawn
or less. in AKI?
More recently, several retrospective studies reported
improved clinical outcomes with earlier institution There have been no formal studies performed as to when
of dialysis at urea levels <21.5 mmol/l or initiation of to switch patients from CRRT to intermittent dialytic
CRRT in post-cardiac surgery patients with a urine therapies or withdraw RRT. Typically withdrawal of
output of <100 mL/8 hr, and an observational study RRT is an empiric decision made by clinicians based on
reported a twofold increased mortality starting RRT a falling pre-dialysis urea or creatinine concentrations,
at higher urea concentrations. However, a prospective increasing urine output and general improvement in
randomized study did not show any survival advantage the clinical condition of the patient. As such, some cli-
with early initiation, although this study was somewhat nicians favour abrupt cessation, whereas others reduce
underpowered. the dose of CRRT or intermittent dialytic therapies and
Early introduction of RRT as soon as a patient then if no deterioration in chemistries stop RRT. It is
enters RIFLE-F or AKI stage 3 [2] may be of poten- now realized that just as with conventional intermittent
tial benefit, so that the patient is not exposed to the haemodialysis, the blood supply to the kidney is reduced
potential deleterious effects of metabolic abnormalities when patients are treated by CRRT. This is why patients
or volume overload. However, early initiation of RRT apparently oligo-anuric whilst on CRRT may suddenly
could equally cause some patients to suffer complica- appear to start passing urine when CRRT is stopped.
tions of RRT, including hypotension, access catheter- For those undergoing continuous RRT, there may be an
associated bacteraemia and anticoagulant induced advantage transitioning the recovering patient to IHD
haemorrhage. In addition, some patients with AKI, to permit greater mobility and physiotherapy. Either
especially those with single organ failure, may recover way, it is important to establish close liaison between
12 renal function without ever requiring RRT. Indeed, one ITU and the renal unit who may inherit patients with
study from Pittsburgh which followed over 5000 patients multiple medical problems.
admitted to ICU reported that <1% of 2273 who devel-
oped RIFLE-I required RRT and only 14% of 1511 who
developed RIFLE-F [3]. 12.4 Treatment Options for RRT
There have been three prospective studies of early vs
later initiation of RRT in the modern era [4–6]. A single- Whereas in the early 1980s the options for RRT therapy
centre study reported a benefit from starting at RIFLE were limited to intermittent haemodialysis (IHD) and
grade 2 vs grade 3 [5], whereas the two multicentre tri- peritoneal dialysis (PD), the currently available thera-
als showed no benefit from an early start approach, and pies in the developed world now include various forms
almost 50% of patients in the delayed start group did of continuous renal replacement therapy (CRRT).
not require RRT, suggesting that an early start strat- . Figure 12.1 shows the difference between convective
egy would lead to treating many patients who would (haemofiltration) and diffusive (haemodialysis) blood
otherwise not require RRT [6]. On the other hand, the purification techniques. Newer “hybrid” therapies vari-
early start patients did not appear to suffer any adverse ously termed extended duration dialysis (EDD), sus-
consequences from being treated by RRT [4–6]. In view tained low-efficiency dialysis (SLED) and prolonged
of the ongoing uncertainty, larger trials have been pro- intermittent renal replacement therapy (PIRRT) and
posed [7]. the single batch dialysate Genius® system (Fresenius,
Although retrospective and observational studies Bad Homberg, Germany) [8] (. Table 12.2) offer a
suggest that “early” initiation of RRT in AKI is associ- variety of alternative approaches. In the intensive care
ated with improved patient survival, this remains to be setting, a variety of additional therapies are currently
confirmed by appropriately powered, prospective multi- being trialled as add-on therapies for treating septic
centre randomized trials. In every day clinical practice, patients including dialyzers designed to enhance endo-
clinicians typically start RRT earlier in critically ill toxin clearance, additional endotoxin filters and plasma
patients with multiple organ failure, than in those with separators with adsorption cartridges.
single organ AKI alone “It is important to ensure that The significant difference in urea clearance between
the sick oliguric patient who is unlikely to recover func- modalities is emphasized in . Fig. 12.2.
Acute Renal Replacement
243 12
Pre-dilution
replacement
Blood flow fluid
Blood flow
Mid-dilution Effluent
replacement dialysate
fluid
Filtrate Fresh
dialysate
. Fig. 12.1 Comparison of haemodialysis and haemofiltration modalities for acute renal replacement
CVVH continuous veno-venous haemofiltration, CVVHD haemodialysis, CVVHDF haemodiafiltration, PD peritoneal dialysis,
PIRRT prolonged intermittent renal replacement therapy, IHD intermittent haemodialysis
12.5 Does Modality of Renal Replacement failed to confirm this supposition. In many of the ear-
Therapy Affect Outcomes? lier trials, the more critically ill patients received CRRT
rather than IHD, and as such, mortality was greater for
12.5.1 Mortality patients treated with CVVH [9]. Correcting for illness
severity mortality was similar for both modalities.
Seven randomized prospective controlled trials have
Although it is widely perceived that CRRT is superior
compared CRRT and IHD. These trials excluded very
to IHD in haemodynamically unstable critically ill adult
seriously ill patients with limited life expectancy, and
patients, prospective randomized clinical trials have
244 A. Davenport
60
20
0
HD HF PIRRT CVVHD CVVH PD
also some of the trials had a high crossover of patients, led to the suggestion that CRRT may be associated with
typically CRRT switching to IHD due to recurrent an increased likelihood for recovery of renal function.
problems with circuit clotting and IHD to CRRT due Interestingly, in the Hemodiafe study, there were a simi-
to hypotension. No trial showed that modality impacted lar number of hypotensive episodes during both IHD
12 on overall survival. Several trials observed greater car- and CRRT and no difference in dialysis dependence in
diovascular stability with CRRT. However, the largest the survivors [10]. As such, the risk of remaining dialy-
of the these studies, the Hemodiafe study, a multicentre sis dependent would appear to be related to episodes of
randomized controlled trial of 359 patients, success- hypotension rather than treatment modality per se.
fully delivered IHD to patients despite marked haemo- Studies comparing other forms of RRT have been
dynamic instability with very little crossover between limited. No studies have directly compared “hybrid”
treatment groups [10]. In this trial, IHD used cooled treatments to either IHD or CRRT, although “hybrid”
dialysate combined with a higher dialysate sodium con- therapies have been shown to provide similar haemo-
centration compared to the serum sodium and extended dynamic stability and solute control when compared to
session time to minimize cardiovascular instability dur- CRRT. Although peritoneal dialysis is widely used in
ing IHD and compared to other studies delivered the paediatric practice, more and more units are using vari-
highest Kt/V dose in the IHD group. ous forms of CRRT and hybrid technologies, but as of
Although there have been few comparisons of yet there is no comparative data.
PIRRT and CRRT, those which have been reported have As such, analysis of the currently published studies
not shown any effect of modality on patient survival [8]. does not allow evidence-based guidelines for the selec-
tion of RRT modality for the treatment of AKI. The
modality chosen should therefore be guided by the indi-
12.5.2 Recovery of Residual Renal Function vidual patient’s clinical status, local medical and nursing
expertise and availability of equipment.
Although there was no obvious difference in overall sur-
vival, two large prospective observational studies reported
greater recovery of residual renal function and dialysis 12.6 Tailoring Intermittent Therapies
independence in survivors treated by CRRT compared for Patients with Acute Kidney Injury
to IHD. One study from the Cleveland Clinic reported
that intradialytic hypotension during the first IHD ses- 12.6.1 Haemodialysis
sion predicted dialysis dependence in survivors [11], and
as many ICU patients have haemodynamic instability In the 1980s, IHD in the ICU was typically delivered
and intra-dialytic hypotension during IHD is more likely thrice weekly, using bio-incompatible low-flux cellulosic
in hypotensive patients requiring vasopressors, this has dialyzers, low-sodium, acetate-based dialysate warmed
Acute Renal Replacement
245 12
to body temperature and with dialysis machines that did of intra-treatment hypotension was similar between dif-
not have accurate volume regulation. However, just as ferent dialysis modalities provided the same degree of
CRRT has developed, so has IHD with the introduc- cooling was achieved. Typically cooling is greater with
tion of volumetric dialysis machines, fitted with relative pre-dilution rather than post-dilution fluid replacement
blood volume monitoring, temperature control modules (. Fig. 12.1).
and biofeedback control, along with synthetic high-flux IHF as with CRRT requires a sterile replacement
bio-compatible membranes and bicarbonate dialysate. solution. IHDF in the outpatient dialysis clinic uses
In addition, the importance of daily or at least alter- online ultrapure water to reduce costs. Many ICUs only
nate day extended treatments designed to reduce ultra- have access to a domestic water supply, rather than the
filtration requirements coupled with higher sodium and specialized water treatment plant in the chronic hae-
lower dialysate temperatures to reduce the frequency of modialysis unit. However, with the addition of simple
intradialytic hypotension is now recognized, such that particle filters, in combination with carbon filters and
the introduction of this so-called “bundle” effect has portable reverse osmosis machines, some units can
been shown to have had a marked impact on reducing provide water of ultrapure quality, when using dialysis
IHD-associated hypotension reducing the frequency of machines fitted with ultrafilters.
intradialytic hypotension to that of CRRT [10].
However, the limitation of these technological
advances has to be appreciated. For intermittent hae- 12.6.3 Continuous Renal Replacement
modialysis/haemodiafiltration, relative blood volume Therapies (CRRT)
measurements (BVM) which are the cornerstone of
biofeedback systems, designed to regulate ultrafiltra- CRRT initially started with continuous arterio-venous
tion rates, coupled with changing dialysate sodium or haemofiltration (CAVH), but as the clearances achieved
temperature, depend upon the concept that if the rate were often low, then many patients required supplemen-
of ultrafiltration exceeds plasma volume refill, then tal haemodialysis sessions to control biochemistries. To
haematocrit and whole blood viscosity increase. There improve efficiency, countercurrent dialysate was added,
are a number of errors that need to be considered. The continuous arterio-venous haemodialysis (CAVHD)
main error with BVM is determining the starting point, and then a blood pump to allow veno-venous systems.
and then as ultrafiltration proceeds, the normal physi- Initially, there were no specialized replacement solu-
ological response is to close down small capillaries, but tions or dialysates, so peritoneal dialysates were often
as the haematocrit in these smaller vessels is less than used. Over time commercial sterile replacement fluids
that in the inferior vena cava, blood returning to the and dialysates based on extracellular fluid composition
central veins is relatively dilute, so minimizing changes became available.
recorded by the blood volume monitoring modules. In Although CRRT machines are volumetrically con-
addition, there is a marked intra-patient variation in trolled, as the fluid management systems are often based
response to ultrafiltration, which is more marked in the on 24-hour periods, then volume errors can occur with
ICU patient, particularly those with sepsis and liver fail- reprogramming following repeatedly over riding error
ure by affecting endothelial function and integrity. As messages and replacing circuits due to clotting.
such the changes recorded by these modules lag behind
in real time as to what is actually occurring in the body,
and although these devices can reduce the frequency 12.6.4 Hybrid Therapies
and severity of intradialytic hypotension, they cannot
prevent hypotension [12]. Hybrid therapies encompass a group of treatments which
are essentially based on extending the duration and slow-
ing down the rate of diffusion of IHD. Most regimens use
12.6.2 Haemofiltration standard IHD machines with slower blood and dialysate
flow rates (. Table 12.1). There is in addition there are
Intermittent haemofiltration (IHF) which was intro- batch IHD machines (NxStage system 1, and Genius®,
duced in the late 1970s has mainly been superseded Fresenius Bad Homberg, Germany) in which the blood
by intermittent haemodiafiltration (IHDF). IHF was and dialysate flows are linked by a single pump, so that
reported to reduce the frequency of hypotensive epi- the flow rates are of similar magnitude, and this treat-
sodes compared to IHD. Initially this was thought to be ment can be extended for more than 12 hours by slowing
due to the convective loss of cardio-depressant factors the flow rates down to 100 ml/min, although 150–200 ml/
but was more likely to be due to the cooling effect of min is more common in clinical practice. In the USA,
IHF, as subsequent studies showed that the frequency there has been increasing use of the NxStage haemo-
246 A. Davenport
dialysis machine in providing dialysis treatments in the abdominal surgery and high catabolic demands. Double
ICU. This haemodialysis machine, originally developed cuffed catheters can be inserted under local anaesthesia
for home haemodialysis, can use sterile bagged dialysate using an open Seldinger technique or closed with direct
or batch dialysate and as with the Genius® benefits from visualization using peritoneoscopy. Infections can be
lower dialysate and blood flows [13]. minimized by covering catheter insertion with prophy-
Depending on the design, hybrid therapies can pro- lactic antibiotics and applying topical antibiotic creams
vide diffusive clearances of small solutes such as urea to the exit site. To minimize the risk of early leaks,
of around 36 ml/kg.h and greater solute clearances of most centres limit the initial exchange volumes to 750–
vitamin B12 or beta 2-microglobulin, some 50–66% of 1000 ml, with a 85% tidal prescription and dwell time of
that with CRRT. In addition hybrid therapies can also 70–90 minutes and, then providing there are no leaks,
be set up to provide haemodiafiltration, then achieving increasing the fill volume to 2.0 l for the average 70 kg
comparable larger solute clearances to CRRT. patient and increasing the dwell time to 90–120 minutes
Whereas circuit thrombus formation has been and reducing the tidal component. Initially peritoneal
reported in 20–25% of hybrid therapies using standard dialysis is continuous 24 hours a day, but a longer dwell
haemodialysis machines, clotting is much less frequent using 7.5% icodextrin can be substituted to reduce nurs-
with the batch dialysate therapies, such as the Genius®. ing time and costs. Despite these larger fill volumes, no
This may be due to the difference in blood pump tech- increase in the frequency of peritoneal leaks has been
nology between the systems, with much greater leuko- reported, and similarly the larger intra-peritoneal fill
cyte and platelet activation with standard occlusive volumes have not been shown to impair alveolar gas
roller pump. Genius® is also reported to reduce the risk exchange or delay weaning from ventilators. In addi-
of hypotension due to cooling of blood. The NxStage tion, these larger fill volumes have not been reported to
machine does not operate with a venous air detector increase the risk of ventilator-associated pneumonia,
chamber, a source for thrombus formation in the extra- despite increasing intraperitoneal hydrostatic pressure
corporeal circuit. and increasing the risk of reflux. However, as most
patients have sepsis, and are fast peritoneal transporters,
the majority require dialysate glucose concentrations in
12.7 Peritoneal Dialysis excess of 2.0% to achieve adequate ultrafiltration, and
12 as such, this may lead to increase insulin requirements to
Although the role of peritoneal dialysis for adult AKI is maintain euglycaemia, particularly for diabetic patients.
declining in Europe and North America, it is still used Earlier studies using smaller shorter dwells volumes
in developing countries, for paediatric AKI, particularly reported an advantage for CRRT over peritoneal dialy-
post-cardiac surgery, and in patients with single organ sis, although the dose of dialysis delivered by peritoneal
failure. Peritoneal dialysis machines are useful but not dialysis was somewhat low. Even so, higher volumes and
obligatory. Clearances achieved in paediatric AKI are longer dwell times only achieved clearances similar to
certainly comparable to those targeted for chronic kid- those of spontaneous arterio-venous haemofiltration
ney disease. and/or dialysis. Some authors have therefore suggested
However, there have been debates as to whether that peritoneal dialysis may not be able to control chem-
peritoneal dialysis can provide adequate clearances for istries in patients with hypercatabolic AKI, and this has
treating adult AKI. Traditionally acute peritoneal dialy- led to the development of novel techniques, such as con-
sis was practised by using rapid small volume cycling tinuous flow through peritoneal dialysis, with recycling
designed to minimize peritoneal leaks [14], typically of the peritoneal dialysate effluent.
0.5 l cycles with short inflow times of 5 minutes, dwell However, the number of patients suitable for perito-
20–25 minutes and 5–10 minutes of drainage. However, neal dialysis may be limited by surgical procedures, and
this type of prescription provided much lower clear- complications include mechanical leaks and peritonitis
ances than that achieved by low-volume CRRT. More (. Table 12.3).
recently this low-volume rapid cycle prescription has
been challenged, with studies from Brazil, using 2 litre
fill volumes, with longer dwell times of 65–80 minutes, 12.8 Choosing Dialysis Modality
so allowing greater diffusion of solutes reporting aver- for Patients
age urea clearances of 17.3 ± 5 ml/min. Peritoneal dialy-
sis can be an effective treatment particularly for patients In an ideal world, all patients with AKI would have their
with single organ failure, such as post-cardiac surgery dialysis tailored to their specific circumstances. However,
[15]. However, not all patients may be suitable for peri- in practice, no one centre can provide every possible
toneal dialysis due to recent or previous major intra- treatment modality, and as such depending upon local
Acute Renal Replacement
247 12
Modality Machine technology Machine costs Special requirements Nurse time training Therapy cost
HF haemofiltration, OL-F online fluid production. Costs – assuming no online fluids for CRRT and intermittent haemofiltration
. Table 12.4 Theoretical advantages and disadvantages of different renal replacement modalities
facilities, equipment, staffing and nursing skills, centres mittent haemodialysis should be considered. Although
should aim to provide high-quality treatment limited to CRRT and peritoneal dialysis could be suitable options,
a few modes of RRT. mesenteric blood flow is reduced by noradrenalin, so
For example, the risk of intradialytic hypotension is potentially compromising clearances and fluid removal
greatest for hypotensive patients requiring vasopressor by peritoneal dialysis. CRRT limits patient mobility, so
support, and therefore an alternative treatment to inter- would be not be an ideal option for patients with single
248 A. Davenport
organ failure, and peritoneal dialysis may be the pre- and the initial industry sponsored studies reported
ferred option in a patient with extensive burns involving improved patient survival and recovery from AKI with
the neck and groins (. Table 12.4). synthetic dialyzer membranes, although later larger ran-
domized trials failed to show a difference. Meta-analyses
subsequently showed that although there was a possible
12.9 Convection or Diffusion? patient survival and renal recovery advantage when syn-
thetic membranes were compared to unmodified cupro-
When haemofiltration was introduced, haemofilter phane membranes, there was no difference between
design differed from that for diffusive clearance for hae- synthetic and the newer modified cellulosic membranes.
modialysis, to maximize hydrostatic pressure-driven con- As blood initially flows across the dialyzer, anaphyl-
vective losses. As such haemofiltration membranes were atoxins, such as C3a and C5a, can be generated along
typically shorter in length, with wider diameter fibres and with bradykinin and nitric oxide, resulting in hypoten-
high flux made from synthetic polymers, whereas dialysis sion, which can potentially be profound. This reaction
used low-flux cellulosic membranes. This led to increased depends upon a number of factors including membrane
losses of middle-sized molecular weight solutes with hae- surface charge, structure, polymer composition and
mofiltration compared to dialysis, with diffusional losses. dialyzer design, but also the negative charge from the
On the other hand, haemodialysis was a more effective priming fluid (typically saline), and anticoagulant (hep-
treatment in clearing small solutes, including potassium. arins). However, in the critically ill patient, this reaction
In the intensive care setting, it was hypothesized is more dependent upon patient factors, being greatest
that convective modes could increase the clearance of for those with severe sepsis and acute liver failure, than
larger solutes such as inflammatory cytokines and other the choice of dialyzer. However, the prescription of
inflammatory mediators. However, in clinical practice, angiotensin-converting enzyme inhibitors and to a lesser
much of the observed increased clearance was due to extent angiotensin receptor antagonists can increase the
membrane adsorption rather than convective clearance risk of hypotensive reactions when commencing dialysis.
into the ultrafiltrate. As studies of high-flux dialyzers in patients with
As convection depends upon the bulk movement of AKI did not show any advantage, dialyzer manufac-
water across the haemofilter membrane, convective losses turers have further modified membranes for patients
12 can be increased by increasing hydrostatic pressure and with AKI. These newer developments have produced
reducing osmolality and haematocrit by adding pre-dilu- a range of high permeability membranes, termed high
tional fluid (. Fig. 12.1). However, pre-dilutional fluid cutoff, designed to increase cytokine and inflammatory
reduces concentration gradients which reduces diffu- mediator clearances and also to alter surface composi-
sional losses, and as such smaller solute clearances tend tion to increase endotoxin adsorption, as prospective
to be lower with pre-dilutional fluid replacement com- observational studies have reported increased mortal-
pared to post-dilutional fluid replacement. In addition, ity in patients with high plasma cytokines, irrespective
as some of the fresh pre-dilutional fluid is removed dur- of whether they be pro-inflammatory (IL-6) or anti-
ing its first passage through the haemofilter, more fluid is inflammatory (IL-10). Preliminary trials have failed to
required to achieve solute clearances, so increasing costs. demonstrate any advantages for these newer techno-
The development of dialyzers for haemodialysis has logical developments on patient outcomes. Membrane
produced a newer generation of high-flux modified cel- adsorptive properties can also be used to adsorb hepa-
lulosic and synthetic membranes, which allow a degree rin, potentially allowing intermittent haemodialysis/
of internal convection even during standard haemodial- haemodiafiltration treatments without the need or a
ysis. As such in clinical practice, modern-day dialysis is a reduction in anticoagulant requirement. Trials of endo-
diffusional technique with a varying amount of convec- toxin absorbing membranes have also failed to demon-
tion, whereas filtration modes are based on convective strate any improvement in patient survival.
losses with a varying amount of diffusional clearance.
2 mmol/l or less, and higher dialysate calcium concentra- tion or post-dilution mode. As such sodium and calcium
tions between 1.35 and 1.5 mmol/l, although there is a balances are most positive with post-dilutional fluid
suggestion that a further increase in dialysate calcium replacement, whereas chloride gains are greatest with
concentrations may actually cause cardiovascular insta- pre-dilutional fluid replacement. Again, as sodium and
bility. In addition, bicarbonate-based dialysates provide calcium content of fluids also vary, the actual electrolyte
greater cardiovascular stability than acetate. Cooling of balances will vary with different fluid compositions and
the dialysate also reduces the risk of intradialytic hypo- ultrafiltration.
tension. Dialysis machines may have dialysate tempera-
ture modules, which can reduce the dialysate temperature
to prevent patient warming or an increase in heat energy, 12.14 Choice of Anticoagulation During
as during dialysis, blood skin flow falls, so reducing ther- IHD/Hybrid and CRRT
mal energy dissipation and increasing core temperature,
which if it reaches a critical threshold can cause reflex AKI is often associated with systemic inflammation,
vasodilatation. Recent studies have shown that greater and as such these patients are more likely to have clot-
cardiovascular stability can be achieved by simply cool- ting problems with extracorporeal circuits than chronic
ing the dialysate to 35 °C. One of the differences between kidney disease patients attending for routine haemodi-
haemodiafiltration compared to haemodialysis is the alysis. Other systemic anticoagulants may be contraindi-
additional cooling achieved with haemodiafiltration, cated as patients with AKI may have recently undergone
which is greatest with pre-dilution mode. surgery or be at increased risk of haemorrhage.
Lactate and acetate have been used as the primary buf- Clotting in the extracorporeal circuit typically occurs
fers for both replacement fluids and dialysates for CRRT, in the dialyzer, venous air detector chamber and cath-
due to ease of sterility and prolonged storage life. Lactate eter access. The risk of clotting can be reduced by care-
and acetate are indirectly metabolized, in the liver and ful priming to remove air from the circuit, so reducing
skeletal muscle, through to bicarbonate. The blood lactate air-blood interfaces, and using tubing within minimum
level can increase during lactate-based CRRT, if the rate changes in lumen diameter and joints to minimize areas
of administration exceeds the rate of metabolism, par- of turbulence.
ticularly in patients with pre-existent lactic acidosis and/
12 or impaired hepatic function, potentially contributing to
increased protein catabolism and impaired myocardial 12.14.1 Anticoagulation Free Options
contractility. Relatively recently, commercially available
bicarbonate-buffered fluids have been introduced for Although prefilter normal saline flushes can be used
CRRT, and although there has been no study showing to avoid anticoagulation during intermittent haemodi-
a significant effect on patient survival, some studies have alysis, particularly for short sessions by reducing hae-
reported improved cardiovascular stability and control of moconcentration during passage through the dialyzer,
metabolic acidosis with bicarbonate-based fluids. other options include heparin adsorption to the dialyzer
There are a wide range of commercially available and citrate dialysate. Unfractionated heparin (UFH) is
dialysates and replacement fluids for CRRT. As the very negatively charged and as such can adsorb to dia-
amount of lactate and chloride is balanced to sodium lyzer membranes. This has led to a number of centres
and other cations, if a fluid has a high chloride concen- devising their own protocols, recirculating 10–20,000 IU
tration, then the lactate concentration will be lower and UFH for 30–60 minutes and then rinsing out the cir-
vice versa. As such the spectrum of fluids available var- cuit to avoid systemic anticoagulation. Taking this one
ies from 95 mmol/l of chloride and 46 mmol/l of lac- step further, the polyacrylonitrile membrane has been
tate to 115 mmol/l chloride and 30 mmol/l lactate. As specially modified to increase UFH adsorption and is
such, after a few days, and more noticeably with higher now commercially available (AN 69ST®) [19], although
volume exchanges, patients may potentially develop a trials have not shown an advantage over standard no-
hypochloraemic alkalosis with the first electrolyte com- anticoagulant practices. Citrate is an effective anticoagu-
bination, and conversely a hyperchloraemic acidosis lant by binding calcium. Formal citrate anticoagulation
with the second electrolyte composition. adds a degree of cost and complexity to CRRT circuits
In addition, during purely convective therapies, as (see . Fig. 12.3), and an alternative is to replace ace-
the dialyzer membrane is charged, the ratio of a small tate in the dialysate with citrate. As such the patient is
cation in the ultrafiltrate will be less than that of plasma exposed to a low concentration of citrate (Citrasate®),
water, and conversely anions greater. This effect also which may permit short session systemic anticoagulant
depends upon whether fluids are replaced in pre-dilu- free dialysis, or reduced anticoagulant requirements [20].
Acute Renal Replacement
251 12
Citrate anticoagulation for CRRT
Step 6
Citrate is
metabolized
primarily in
Step 4
liver and also
Returning blood
muscle to Spent
combines with mixed
HCO3–
venous blood
bound Ca2+ is Dialysate out
increasing iCa2+ so
released
preventing systemic
anticoagulation
Step 3
Post Filter iCa2+ is
monitored and used to
titrate citrate rate to
assure anticoagulation
. Fig. 12.3 Shows circuit for continuous citrate anticoagulation with calcium replacement
Anticoagulant free CRRT is possible particularly IHD in patients with chronic kidney disease, UFH may
with careful priming to exclude all air, minimizing cir- be less effective in AKI, as many critically ill patients
cuitry, with pre-dilutional fluid replacement, so mini- have reduced levels of anti-thrombin, especially with
mizing haemoconcentration and also for patients with CRRT. In addition, heparin is associated with a risk of
thrombocytopenia. bleeding and with the development of heparin-induced
thrombocytopenia (HIT). LMWHs can equally be used
for CRRT, with either an initial bolus followed by an
12.14.2 Systemic Anticoagulants infusion or simply starting with a greater infusion rate
and then titrated according to anti-Xa activity, aiming
UFH is typically administered as a bolus (500–1000 Iu for a target of around 0.4 antiXa IU/ml. Regional hepa-
depending on the risk of haemorrhage), and as it has rinization protocols, with reversal of heparin by infusion
a relatively short half-life then continuously infused of protamine into the return line, have been developed
(500–1000 IU/h) until 30–60 minutes prior to the end of to prevent systemic anticoagulation and minimize bleed-
the session. Low-molecular-weight heparins (LMWHs) ing risk. Unfortunately, these protocols are cumber-
have a more prolonged half-life and as such typically are some, may be associated with paradoxical increased risk
administered as a single bolus (tinzaparin 1500–2500 IU, of bleeding if excess protamine is infused and do not
enoxparin 0.4–0.8 mg/kg depending upon duration of alter the risk of HIT. Protamine may cause anaphylaxis,
session and risk of haemorrhage). UFH is a series of particularly in patients allergic to salmon.
large molecules, but LMWHs are smaller molecules, and If patients with HIT develop thrombosis, or other
as such there can be loss if administered as a single bolus major complications, then systemic anticoagulation
immediately prior to a high flux or high permeability with either heparinoids, danaparoid, fondiparinux, or
dialyzer, before it has become protein coated. As such direct thrombin inhibitor argatroban is required. If
administration into the venous limb of the circuit or however, patients have HIT antibodies, but no symp-
delaying the administration into the arterial limb of the toms or signs of thrombosis, then other anticoagulants,
circuit by a few minutes reduces LMWH requirements. including prostacyclin (prostaglandin I2), nafamostat
UFH remains the most widely used anticoagulant and citrate, are safe in patients with a history of HIT,
for CRRT. Although an effective anticoagulant for provided all exposure to heparin has ceased. In the labo-
252 A. Davenport
ratory there may be cross reaction between the hepari- for citrate systems. The advent of these commercially
noids and HIT antibodies, although only occasionally available fluids for citrate-based anticoagulation has
has this led to clinical cross reactivity. Heparinoids, increased the usage in both adult and particularly pae-
such as danaparoid, have an increased half-life in AKI diatric practice, where circuit clotting has been a greater
and require anti-factor Xa monitoring. For CRRT, fol- clinical problem. There have been few prospective com-
lowing an initial bolus dose of 1500 anti-Xa U and an parative studies of UFH and citrate anticoagulation;
infusion rate of 150 U/h which has to be then adjusted in two such CRRT studies, the median circuit survival
to maintain anti-Xa levels between 0.2 and 0.4 IU/ml. time was significantly prolonged with citrate (70 hours
Argatroban, derived from l-arginine, requires a continu- vs 40 hours and 124 vs 38 hours) with reduced blood
ous infusion, starting at 0.5 ug/kg/min followed by dose transfusion requirement and/or haemorrhage in the
adjustment to maintain an aPTTr of 1.8–2.0, and addi- citrate groups.
tional dose reduction in liver disease (starting at 0.02 ug/ In AKI, citrate is primarily metabolized in the liver
kg/min). The major metabolite of argatroban has bio- and muscle, so patients with acute liver failure and car-
logical activity and accumulates with time. In addition, diogenic shock may not be able to adequately metabo-
argatroban also prolongs the prothrombin time, and this lize citrate, leading to an increase in total serum calcium,
may complicate the transfer from argatroban to oral with a lowered ionized calcium, due to an increasing
warfarin. calcium-citrate complexes, termed the calcium gap, and
a metabolic acidosis. Citrate accumulation, or toxicity,
is likely when the ratio of total serum calcium to ionized
12.14.3 Regional Anticoagulants calcium exceeds 2.5 [22]. Treatment includes increasing
dialysate flow to increase circuit citrate losses, stopping
Over the last decade, citrate has emerged as a very effec- or reducing the rate of citrate infusion and increasing
tive regional anticoagulant for CRRT. Citrate is infused blood flow. On the other hand, excess citrate delivery,
into the pre-filter line and works by chelating calcium, which is metabolized through to bicarbonate, can lead
aiming for a pre-filter ionized calcium of 0.2–0.4 mmol/l. to a metabolic alkalosis.
As such the amount of citrate to be infused depends Other regional anticoagulants include prostacyclin
upon blood flow (. Table 12.5). Calcium is then re- (5–10 ng/kg/min), which is a potent vasodilator. As
12 infused separately, or into the return line, to maintain a such patients should be made volume replete prior to
normal systemic ionized calcium [21]. Citrate comes as a administration and infusions started at 0.5 ng/kg/min
sodium salt, either trisodium citrate or acid citrate dex- and titrated upwards prior to starting CRRT. In Japan,
trose, and each citrate molecule is indirectly converted to nafamostat maleate is used as a regional anticoagulant
three bicarbonates, so there can potentially be changes and appears to have similar efficacy and safety profile
in sodium balance and acid-base status depending upon to citrate.
the citrate load and the ability of the patient to ade-
quately metabolize citrate. Thus, most centres that used
citrate developed their own in-house calcium free dialy- 12.15 Acute Brain Injury
sates and re-infusion fluids. It is only more recently that
pharmaceutical and dialysis companies have marketed During a standard intermittent outpatient haemodialy-
specialized dialysates and re-infusion fluids designed sis session, the brain swells. This is due to a combina-
tion of a relatively faster fall in serum urea compared
to that in brain extracellular fluid and astrocytes, which
. Table 12.5 Citrate dose for varying blood flows (Qb)
regulate the blood-brain barrier. As water moves some
20 times faster through aquaporin channels than urea
Qb ml/min 4% TCA ml/h ACD-A ml/h through urea transporters, water passes back into the
brain along a concentration gradient. In addition, as the
100 175 210 effective plasma volume decreases, then middle cerebral
150 262 315 artery blood flow falls. In patients with acute traumatic
brain injury or acute cerebral oedema, then autoregula-
200 350 420
tion may not be intact, and as such intradialytic hypoten-
250 438 525 sion may lead to a fall in cerebral perfusion pressure with
300 525 630 increased local cerebral oedema in areas of ischaemia.
As such the two key objectives for RRT in patients
TCA trisodium citrate, ACD-A acid citrate dextrose with acute brain injury are to maintain cardiovascu-
lar stability and avoid a rapid reduction in serum urea.
Acute Renal Replacement
253 12
Patients with intracranial monitoring devices, particu- above the serum concentration up to 145 mmol/l. To
larly intraventricular drains and subdural catheters, are maintain cardiovascular stability, then the ultrafiltration
at increased risk of local bleeding around these devices rate needs to be slowed by extending dialysis session time
if given systemic anticoagulants. in combination with higher dialysate sodium, potas-
In clinical practice, acute brain injury requiring RRT is sium and calcium concentrations, with the dialysate
encountered in two main scenarios, firstly chronic dialysis cooled to 35 °C. So, in essence, haemodialysis becomes
patients who have sustained an intracranial haemorrhage PIRRT. Pre-dilutional haemodiafiltration would pro-
or ischaemic stroke and secondly acute traumatic brain vide additional cooling. Daily treatments would lower
injury or cerebral oedema and AKI. As the brain typi- ultrafiltration requirements and also help prevent rises
cally takes 10–14 days to adapt to injury, RRT should be in serum urea, leading to a lower time-averaged urea
modified during this period. In patients with compromised concentration. If there are contraindications to systemic
cerebral perfusion pressure (<60 mmHg) or major midline anticoagulation, then pre-dilutional fluid replacement,
shift on brain scanning, then standard intermittent haemo- with either citrate in the dialysate or citrate anticoagu-
dialysis should be avoided. Peritoneal dialysis is an option, lation, would be preferable. Both hypertonic saline and
as changes in serum urea are slower than those during mannitol can be administered during haemodialysis as
intermittent haemodialysis, but dialysates are hyponatrae- short infusions.
mic, and patients may require additional hypertonic saline. To minimize the risk of hypotension when first con-
Large-volume cycles, particularly using hypertonic glucose necting the patient to the extracorporeal circuit, then
dialysates, can alter cardiac filling by sudden changes in priming with isotonic bicarbonate, by reducing negative
intraperitoneal pressure and compression of the inferior charge, reduces the risk of anaphylatoxin and bradykinin-
vena cava, and so may lead to sudden falls in cerebral per- induced vasodilatation. Similarly, if a bolus of UFH or
fusion pressure. As such, tidal exchanges or smaller fill LMWH is administered into the venous limb of the cir-
cycle fill volumes are to be preferred. CRRT provides the cuit, this reduces the charge effect from anticoagulants.
greatest cardiovascular stability, and haemofiltration is less Some centres prime the circuit with albumin to precoat
effective at clearing urea than dialysis and so causes slower the dialyzer with proteins prior to directly connecting the
reduction. By performing pre-dilution CVVH, patients patient to the RRT circuit.
achieve greater cooling and so are less likely to suffer hypo-
tension, and pre-dilution reduces urea clearance compared
to post-dilution. In cases of raised intracranial hyperten- 12.16 Cardiorenal Syndrome
sion, with lower or borderline cerebral perfusion, hyper-
tonic saline infusions can be given during CRRT, to raise Increasingly nephrologists are encountering patients
serum sodium, or 20% mannitol. with cardiac failure who have developed AKI following
Typically, in cases of AKI following acute traumatic an additional insult.
brain injury, or acute cerebral oedema with liver failure, Although cardiorenal syndromes can occur with
urea and creatinine concentrations are not high, and both acute cardiac and renal dysfunction following
RRT is initiated for oliguria and metabolic acidosis, so drugs or toxins, and acute myocardial infarction, most
disequilibrium due to too rapid urea shifts is less likely, patients developing a cardiorenal syndrome do so, on a
but maintaining cerebral perfusion pressure and cardiac background of both chronic heart and kidney disease
output are key to patient management, and so dialysis [23]. Patients with acute multi-organ dysfunction should
machines equipped with relative blood volume monitor- preferably be managed in the ICU setting by CRRT. As
ing are preferred. Whereas in cases of acute intracranial although peritoneal dialysis is technically possible, low
haemorrhage in established dialysis patients, then urea blood pressure in cases of cardiogenic shock will limit
levels are often raised, and the major management deci- mesenteric blood flows, so reducing solute clearances
sion is to balance the risks of early RRT to deferring and water removal.
treatment but then starting with a higher urea and risk- Most patients with heart failure have a normal or
ing greater disequilibrium. Although there have been increased cardiac output, and only a minority, around
no randomized trials, most centres aim to maintain the 10% with cardiogenic shock and reduced cardiac output
serum urea <15 mmol/l. If haemodialysis is the only [24] (taken from the European Heart Society guidelines
modality available, then the rate of change in plasma on heart failure). As such peritoneal dialysis may be an
osmolality can be reduced by using a smaller surface effective therapy. Increased right-sided cardiac filling pres-
area dialyzer (0.6–0.8 m2), slowing blood flow to 200 ml/ sures contribute to renal dysfunction, and as such fluid
min with a slower dialysate flow of 200–300 ml/min, removal by peritoneal dialysis using smaller fill volumes
switching the dialysate flow from counter current to may help restore renal function. Typically, these patients
concurrent, and using a dialysate sodium of +5 mmol/l behave as fast peritoneal transporters, and 7.5% icodex-
254 A. Davenport
trin exchanges may be required to achieve ultrafiltration sodium can reduce this fall in osmolality and so better
without exposing the patient to hypertonic glucose dialy- maintain blood pressure. Most studies have advocated a
sates. After stabilization some patients can be discharged dialysate sodium set at 5 mmol/l above serum sodium up
home on a single overnight icodextrin exchange. However, to a maximum dialysate sodium of 147 mmol/l. Advances
for some patients, peritoneal dialysis is not initially effec- in haemodialysis machine technology have brought a
tive in correcting volume overload, due to increased peri- new generation of dialysis machines that can monitor
toneal permeability and loss of glucose gradients, and relative blood volume, based on changes in haematocrit
for these patients, CRRT or daily intermittent dialysis or or blood viscosity, and can therefore sense if the ultrafil-
PIRRT is required. Later, when stabilized, these patients tration rate exceeds plasma refilling. This can be visually
may well return to peritoneal dialysis. As outlined above displayed allowing the supervising dialysis nurse or tech-
for dialysing patients with brain injury, dialysis needs nician to respond to sudden changes. The more sophisti-
to be tailored to improve cardiovascular stability and cated machines have feedback loops which automatically
minimize ultrafiltration rates, utilizing machines capable adjust ultrafiltration rate and/or dialysate sodium to
of relative blood volume monitoring. For patients with these changes, so reducing the risk of intra-dialytic hypo-
acute cardiorenal syndromes treated by haemodialysis, tension. When dialysis first starts, the passage of blood
there is an increased risk of intra-dialytic hypotension, across the dialyzer leads to activation of platelets and leu-
which may then convert a potentially reversible acute kocytes, with pulmonary sequestration and fall in arterial
episode into one of established dialysis-dependent kid- oxygen tension, typically during the first 20 minutes, and
ney failure. The main risk of hypotension is due to an this then tends to resolve after 1 hour. In cases of patients
ultrafiltration rate which removes plasma water at a rate who have recently suffered myocardial ischaemia, then
faster than tissue fluid can refill the plasma water. Even supplemental oxygen should be considered to prevent
for a healthy dialysis outpatient, once the ultrafiltration any reduction in arterial oxygen tension. Several reports
rate exceeds 10 ml/kg/h, the risk of intradialytic hypoten- have advocated haemodiafiltration over haemodialysis
sion rises exponentially. Thus, to minimize ultrafiltration due to the additional cooling effect in maintaining car-
rates, patients should be dialysed more frequently, ide- diovascular stability whilst achieving required ultrafiltra-
ally daily if possible. The risk of arrhythmias on dialysis tion. As fluid volume control is achieved, then cardiac
depends upon both relative intravascular hypovolaemia biomarkers such as NTproBNP fall.
12 and also electrolyte shifts. To minimize electrolyte shifts,
patients should be dialysed against a dialysate potassium
of at least 2 or 3 mmol/l, to reduce the gradient between 12.17 Chronic Cardiorenal Syndromes
serum and dialysate potassium concentration. Dialysate
calcium concentrations also affect cardiovascular stabil- Patients who have recovered from a major myocardial
ity, and although higher dialysate calcium concentrations infarction or patients with other cardiac pathology, such
confer cardiovascular stability over lower concentrations as cardiac amyloid infiltration, may be left with chronic
(1.5 vs 1.0 mmol/l), too high a calcium (>1.5 mmol/l) also hypotension and symptomatic dyspnoea. As such,
increases the risk on cardiac instability. Dialysate bicar- quality of life may be poor, and the decision whether
bonate also affects the flux of ions between the plasma to offer such patients dialysis to help control fluid vol-
water and cells, and although bicarbonate-based dialy- ume should not be taken lightly. However, if patients
sate confers cardiovascular stability compared to acetate- can tolerate chronic hypotension and wish to have pal-
based dialysate, then higher bicarbonate concentrations liative dialysis, then peritoneal dialysis using a single
(>32 mmol/l) and acetate (≥3 mmol/l) increase the risk of overnight 2 l exchange of 7.5% icodextrin may help
electrolyte fluxes. Cooling the dialysate also reduces the contain volume overload without significantly reducing
risk of intradialytic hypotension. Some dialysis machines systemic blood pressure. As patients are often incapaci-
can be programmed to provide isothermic dialysis, so as tated, then exchanges may have to be performed by a
the patient starts to warm up during dialysis due to the family member or assistant. Over time, the underlying
relative increase in core blood flow and reduced skin cardiac pathology will typically progress, and patients
blood flows, the dialysis machine automatically cools the may lose residual renal function, so requiring standard
dialysate to prevent any increased body temperature. If peritoneal dialysis. At this stage, the role of palliative
this technology is available, then simply setting the dialy- peritoneal dialysis should be reassessed, as ultrafiltra-
sate temperature to 35 °C will be equally, if not more, tion volumes are often unpredictable with peritoneal
effective. During dialysis, the plasma urea concentration dialysis, leading to periods of volume overload inter-
falls exponentially and so reduces plasma osmolality, and spersed with hypotensive episodes, as typically patients
this may reduce plasma water refilling rate and so risk require higher glucose exchanges to sustain adequate
intradialytic hypotension. Thus using a higher dialysate ultrafiltration.
Acute Renal Replacement
255 12
mic dialysates (Na 132/133 mmol/l), and haemodialysis
. Table 12.6 Dialysis prescription for patients with acute
cardiorenal syndrome secondary to myocardial infarction
machines are typically designed to deliver dialysates
of 136–145 mmol/l, and outside this range, machines
Modality Haemodiafiltration preferred to haemodialysis would have to recalibrated to provide more hyponatrae-
mic dialysates. Even so this would be prone to errors,
Frequency Preferably daily and accurate concentrations could not be guaranteed.
Duration 3–4 hours Depending upon the clinical situation, dialysis
would be designed to increase the serum sodium to
Dialyzer Small surface area bio-compatible dialyzer
125 mmol/l over the first 12–24 hours. As such only
Dialysate Sodium +5 mmol/l above serum sodium CRRT would allow a slow rise in serum sodium from
Potassium 3 mmol/l 110 mmol/l or so compared to peritoneal or intermit-
tent therapies, especially as the risk to pontine demy-
Calcium 1.35–1.5 mmol/l
elination also depends on cerebral oxygen delivery and
Bicarbonate 32 mmol/l perfusion [25]. Although the replacement fluids and
Isothermic or cooled dialysate to 35 °C dialysates for CRRT come with a fixed sodium (typically
138–144 mmol/l), it is possible to tailor the composition
Dialysate flow 500 ml/min
of the dialysate/replacement fluid by using a combina-
Blood 250–300 ml/min tion of commercial fluids and Hartmann’s, dextrose and
pump
either 0.9% saline or dextrose saline, to achieve an initial
speed
dialysate 5 mmol/l above the serum dialysate (e.g. 5 l of
Ultrafil- <5 ml/kg/h commercial fluid Na 143 mmol/l, 4.0 l Hartmann’s with
tration
a sodium of 132 mmol/l and 1.0 l of 5% dextrose provide
rate
a sodium of 124 mmol/l). Reducing exchange volumes
Anticoagu- Depends on whether patient systemically to 1.0 l/hour, and using post-dilution CVVH, also slows
lation anticoagulated with bivalirudin, low-molecular-
the rate of rise in serum sodium. Regular monitoring
weight heparin or antiplatelet agents
of the serum sodium allows a controlled rise in serum
sodium and determines changes in replacement fluid/
dialysate sodium composition, so that a serum sodium
Some patients may opt for haemodialysis, but this of 125 mmol/l is achieved over 24 hours. Thereafter,
needs to be viewed as a palliative therapy. As haemodi- serum sodium can be steadily increased.
alysis risks exacerbation of hypotension, then patients
typically require more frequent dialysis sessions (4–6 ×
week) to allow adequate volume control. Patients should 12.18.2 Hypernatraemia
be dialysed with cooled dialysate and higher potassium
and calcium dialysates (. Table 12.6), but continuous As with hyponatraemia, volume status needs to be
exposure to high dialysate sodium will lead to increased assessed, as if the patient has hypovolaemic hypernatrae-
thirst and weight gains, and as such dialysate sodium mia, and this should be corrected before initiating RRT
should be set to around 140 mmol/l. For patients with due to the risks of hypotension with RRT. Similarly
excessively low systemic blood pressures (<80 mmHg), serum sodium concentration should be reduced slowly.
then vasoconstrictive agents such as midodrine or terli- Whereas peritoneal dialysis and haemodialysis machines
pressin may prevent intradialytic hypotension, but risk have relatively fixed dialysate sodium concentrations,
ischaemia to the gastrointestinal tract, and other organs, CRRT allows the possibility of tailoring the dialysate/
and these risks have to considered on an individual basis. replacement solution sodium concentration, by adding
hypertonic saline to achieve the desired composition.
cium concentrations, these fluids are not hypocalcaemic. 12.18.5 Volume of Distribution
Similarly, standard dialysates for haemodialysis start at
1.0 mmol/l and thus will allow calcium clearance with Although RRT is most effective when treating drugs/
haemodialysis, down to an ionized calcium of 1.0 mmol/l. toxins with a small volume of distribution, they may be
To increase calcium losses, a large surface area dialyser a role in treating tissue/protein bound compounds, if a
should be coupled with a prolonged session time, so temporary reduction in plasma concentration results in
moving from intermittent haemodialysis to PIRRT. The reversal of life-threatening toxic effects.
standard dialysates and fluid replacement fluids designed
for CRRT are typically hypercalcaemic, as they were
designed for critically ill patients who are often hypocal- 12.18.6 Haemodialysis
caemic. However, following the introduction of citrate as and Haemodiafiltration
an anticoagulant for CRRT, there are now commercially
available fluids designed for citrate which contain no cal- HD provides rapid clearance for water-soluble drugs/
cium. As such these fluids will correct hypercalcaemia, toxins, particularly those of a low-molecular-weight
and a greater calcium loss is achieved with pre-dilution with a small volume of distribution, including alcohols,
rather than post-dilution mode, with 3 l hourly cycles. If organic acids (which accumulate in urea cycle defects
these fluids are not available, then CRRT could be per- of metabolism), aminoglycosides, atenolol and lithium
formed using 0.9% saline with potassium and phosphate (. Table 12.8). Larger drugs such as amphotericin
supplements as appropriate. (9241 D) can be cleared using high-flux dialyzers and
by adding in pre-dilutional HDF. As such HDF is the
preferred option for clearing valproate, vancomycin
12.18.4 Poisoning and hirudin. In cases of cardiovascular instability, then
CRRT with high-volume exchanges should be consid-
RRT should be considered in severe cases of poisoning ered, but clearances will not be as effective as intermit-
or drug intoxication that have not responded to stan- tent HD or HDF.
dard supportive medical treatment, and patients have In cases of drugs which have substantial tissue bind-
serum levels of drugs and/or poisons which are known ing and haemoperfusion is not available, then HD and
12 to result in significant risk of patient mortality and/ HDF may still be effective in reducing drug toxicity,
or organ failure, and also if the rate of extracorporeal provided that session times are prolonged to PIRRT
clearance exceeds that of endogenous hepatic and/or For example, methotrexate can be effectively cleared
renal clearance (. Table 12.7). by extending haemodialysis times to 6 hours and per-
forming two dialysis sessions with only a short break
between.
. Table 12.7 Serum drug/poison concentrations at which
extracorporeal removal may be beneficial
Case Study
This man has long-standing chronic kidney disease creatinine 650 umol/L and potassium 6.3 mmol/l, and
and is not volume overloaded. Choosing a high bicar- sodium 138 mmol/l, and requested dialysis.
bonate dialysate will increase the risk of hypocalcaemia Would you dialyse this patient, and if so what dialysis
and hypokalaemia. As such, a lower dialysate bicarbon- prescription would you prescribe?
ate of 28 mmol/l with an acetate of 3.0 mmol/l would be Standard outpatient haemodialysis treatments cause an
appropriate, in combination with a higher dialysate cal- increase in brain swelling and water content. As such stan-
cium of 1.5 mmol/l and potassium of 3.0 mmol/l. As dard dialysis increases the risk of further brain injury. A
there is a risk of dialysis disequilibrium, then a shorter serum urea >15 mmol/l increases the risk of brain oedema;
dialysis session time of 2 hours, with reduced blood and as such, dialysis is required to reduce further brain swelling
dialysate flows, should be chosen in combination with a and ischaemic injury. There are two key issues: first is mini-
small surface area dialyser and dialysis planned for the mizing cerebral oedema. This requires a change of dialysis
following day. prescription to shorter daily dialysis sessions of 2 hours,
coupled with reducing blood and dialysate flows of 250 ml/
Case 4 min and 300 ml/min and a small area dialyzer of 1.5 m2.
A 75-year-old lady who had chronic kidney disease and The second is to reduce the risk of cerebral ischaemia by
attended for thrice-weekly haemodialysis was admitted reducing the risk of hypotension, as cerebral autoregula-
with an acute stroke. She was thrombolysed, and the acute tion is impaired. This can be done by cooling the dialysate
stroke team contacted the dialysis centre as her serum to 35 °C and increasing the dialysate sodium to 10 mmol/l
chemistries were as follows, serum urea 25 mmol/l, serum above the serum sodium, up to a maximum of 145 mmol/l.
Common Electrolyte
Abnormalities
Alfredo Petrosino, Domenico Bagordo, Antje Fürstenberg-Schaette,
and Chris Laing
Contents
References – 296
Common Electrolyte Abnormalities
265 13
n Learning Objectives Hypernatraemia carries the highest mortality (11%–
1. Electrolytes homeostasis is tightly regulated as 75%) which remains substantial even after the correc-
essential to vital functions: its disturbances are tion of the disorder. Hyperkalaemia follows with a 10%
associated with increased morbidity, hospitalisa- mortality. Acid-base disorders are commonly an associ-
tion and mortality. ated finding and confer additional mortality risk [4].
2. Age, poly-drug therapies and comorbidities are Hyponatraemia, hypernatraemia, hypokalaemia and
strongly associated with the risk of developing hypercalcaemia are associated with increased length of
electrolytes disturbances, which are predicted to stay (3 to 6 days on average).
increase in the future. The causality link between electrolytes disturbances
3. Understanding the physiology of electrolyte bal- and adverse outcomes remains debated. Hyponatraemia
ance and analysis of trends is key to the diagnosis offers a paradigmatic example: on one extreme, several
of electrolyte disturbances. critically ill patients develop hyponatraemia without this
4. The first step in the management of electrolytes being the cause of death. At the opposite, rapid changes
disorders should be the identification of life- in plasmatic sodium can be rapidly lethal in otherwise
threatening risks arising from the disorder itself or fit people (e.g. hyponatraemia in endurance athletes). In
its correction. between, some diseases can facilitate the development
of hyponatraemia which can increase the risk of death
(e.g. increasing the risk of confusion and falls), despite
13.1 Introduction not being the only factor [5, 6].
13.1.2 Sodium and Water Disorders large hospital showed 42.6% of patients had sodium
levels below 136 mmol/l either at presentation (28%) or
Sodium is the dominant extracellular cation. Its abil- at some point during their stay (14%), with 6.2% below
ity to move across membranes is tightly regulated, and 126 mmol/L and 1.2% below 116 mmol/L. [7] Hypo-
as membranes are almost freely permeable to water, natraemia is more common in certain settings such as
sodium defines and defends the extracellular volume. post-operatively and in heart failure, cirrhosis, old age
Changes in extracellular fluid volume elicit compensa- and dementia (. Table 13.1). Low body mass, mal-
tory changes in renal sodium handling, while variations nourishment, drugs (diuretics, antidepressants, etc.)
in extracelllar osmolarity affect the renal free water and comorbidities such as diabetes are other significant
clearance. Plasmatic sodium is a ratio (sodium/water), risk factors. The disorder is also increasingly recognised
and it is not indicative per se of the total body sodium among endurance athletes [8].
and water content. Sodium disorders are the result of
both sodium and water balance dysregulation (with the
latter being most commonly the problem). 13.1.4 Clinical Features of Hyponatraemia
a c
b d
. Fig. 13.1 a and b: Brain CT scan showing diffuse cerebral tremia leading to acute cerebral edema and early evidence of hernia-
oedema, effacement of quadrigeminal cistern and loss of sulci in the tion. Neurocrit Care 6, 195–199 (2007). 7 https://doi.org/10.1007/
context of hyponatraemia. c and d: Resolution after administration s12028-007-0032-x)
of hypertonic saline. (From Carpenter, J. et al. Inadvertent hypona-
death. Young (pre-menopausal) women, prepubescent mia, electrolytes can be transferred out of the neurons
children (large brain/skull ratio) and those with associ- rapidly to reduce intracellular osmolality. The reduction
ated hypoxia appear to be at greatest risk. in organic intraneural osmolytes, however, takes longer,
The brain is normally protected from osmotic injury explaining why sudden drops in sodium (<48 hours) are
by the regulation of intracellular electrolytes and small more dangerous than worse hyponatraemia that devel-
organic molecules contributing to osmoregulations ops slowly. Even mild “asymptomatic” hyponatrae-
(polyols such as myoinositol and sorbitol; amino acids mia, despite often felt to be harmless, has been shown
as taurine, glutamate, aspartate and glycine; and methyl- to have adverse effects not only on the neurological
amines as glycerophosphorylcholine). In hyponatrae- state (with significant delay in response to audiovisual
268 A. Petrosino et al.
Hypo-osmolar hyponatraemia
Pregnancy
Hypoadrenalism
Salt-losing nephropathies
(e) Extra-renal loses(low urinary sodium) Sweating (and water intake) endurance
exercise, vomiting, diarrhoea
Urinary sodium Low (<20mmol/L): associated with cirrhosis, heart failure, nephrotic syndrome,
hypovolaemia of any cause and water intoxication
High (>20mmol/L): associated with renal loss, SIADH and renal impairment,
diuretics
Urine osmolality
Urinary potassium
Thyroid function, Adrenal function Both hormones required for maximal free water clearance
to maximise electrolyte-free water excretion. Although it kin-6). Many athletes with symptomatic EAH present
may appear easy to identify what is preventing a physi- with an unexpectedly increased body weight as sign of
ological response to hyponatraemia in hyponatraemic fluid overload. Risk factors seem to relate to body size,
patients, in complex cases with multiple comorbidities, duration of exercise, fluid intake (most sports drinks
it can be challenging (. Figs. 13.3 and 13.4). are hypotonic) and the use of NSAIDs. Menstruating
Investigations in . Fig. 13.3 are a useful but not females would be at increased risk as estrogens may
comprehensive guide. impair the cerebral adaptation to rapid osmolar
changes. Clinical manifestations are mainly neurological
with cerebral oedema up to brainstem herniation, but
13.1.7 Some Specific Causes non-cardiogenic pulmonary oedema can also present in
13 of Hyponatraemia severe cases. Rapid identification and treatment can save
lives: acute hyponatraemia should always be considered
z Psychogenic Polydipsia and Beer Potomania in case of collapse in an endurance athlete. IV hyper-
A person with normal diet and kidney function can tonic saline is the treatment of choice in severe cases.
excrete up to 12–14 L of free water per day (assuming Drink according to thirst remains the main prevention
the availability of average solute load to excrete). This strategy.
amount is rarely achieved, and hyponatraemia second-
ary to psychogenic polydipsia is rare. Conditions in z Drugs
which the kidney function and (mainly) the osmotic Some medication has a particular association; thiazide
solute load are decreased (poor generation of urea in diuretics and selective serotonin uptake inhibitors both
malnourishment) cause a significant decrease in the have a high incidence. Again, it is the elderly and low
maximal free water clearance. Hyponatraemia can body weight that have the highest risk for this. For thi-
then start to develop with a “moderate” fluid intake of azides, those gaining weight within 48 hours of start-
just more than 4 L per day (so-called beer potomania ing have increased risk. Fortunately, for both classes
and “Tea and toast” syndrome). Moreover with dedi- of medication, hyponatraemia usually becomes appar-
cated polydipsia, the counter-current multiplier will get ent within 2 weeks, and testing at this time in high-risk
washed out, and the ability to generate free water clear- patients is likely to identify most.
ance is further reduced. Post-operative hyponatraemia is common and
Endurance sports are becoming increasingly popu- related to SIADH (stress, opiates, pain and nausea
lar, and “exercise-associated hyponatraemia” (EAH) is result in the non-osmotic release of ADH) combined
common. This is probably the combination of excessive with fluid intake and can have very severe consequences.
fluid intake and fluid retention secondary to exercise- Ecstasy-induced hyponatraemia can cause deaths
associated (non-osmotic) ADH release. The latter may in otherwise healthy young adults and appears to be
be sustained by physical stress and pain, nausea, heath, a combination of polydipsia and inappropriate ADH
drugs (NSAIDs) and inflammatory cytokines (interleu- secretion. The advice to drink copious quantities of
Common Electrolyte Abnormalities
271 13
HYPONATREMIA
EXCLUDE HYPERGLICEMIA OR
OTHER CAUSES OF HYPOTONIC
HYPONATREMIA
HYPOTONIC HYPONATREMIA
SEVERE SYMPTOMS
US GUIDELINES: BOLUS 3% NaCl
ACUTE OR
YES TREATMENT (100 mL over 10 min x 3 as needed)
SEVERE SYMPTOMS?
EU GUIDELINES: bolus 3% NaCl
(150 mL over 20 min 2-3 times as needed)
NO
MODERATE SYMPTOMS
URINE OSMOLALITY US GUIDELINES: Continous infusion 3% NaCl
(0.5-2mL/Kg per h)
POSSIBLE DIAGNOSIS:
- PRIMARY POLYDIPSIA
- LOW SOLUTE INTAKE
- BEER POTOMANIA
URINE SODIUM
IS PATIETN ON
DIURETICS?
LOW EFFECTIVE ARTERIAL
BLOOD VOLUME
YES NO
CONSIDER DIURETICS
IF HYPERVOLAEMIA CONSIDER:
- HEART FAILURE
AS CAUSE IF HYPERVOLAEMIA CONSIDER:
- LIVER CIRRHOSIS - VOMITING
- NEPHROTIC SYNDROME CONSIDER OTHER CAUSES - PRIMARY ADRENAL INSUFFICIENCY
- RENAL SALT WASTING
IF HYPOVOLAEMIA CONSIDER:
- CEREBRAL SALT WASTING
- DIARRHOEA AND VOMITING
- THIRD SPACING
IF EUVOLAEMIA CONSIDER:
- REMOTE DIURETICS
- SIADH
- SECONDARY ADRENAL INSUFFICIENCY
- (HYPOTIROIDISM)
. Fig. 13.4 Diagnostic flow chart for hyponatraemia and treatment for acute or life-threatening symptoms. (SIADH syndrome of inap-
propriate secretion of antidiuretic hormone)
water to avoid heat-related illness and rhabdomyolysis is a urinary sodium >20 mmol/L. Other causes of hypo-
probably inappropriate. natraemia such as hypothyroidism, hypoadrenalism
Hyponatraemia in institutionalised elderly is very or renal impairment should however be excluded. The
common, and the cause is multifactorial including precipitating cause may be obvious such as pneumo-
polypharmacy, low body weight and low solute intake. nia or surgery, but, if not, further steps to consider are
It can have a profound effect decompensating patients suspending any potentially culpable medication and a
with comorbidity. Patients receiving IV fluids or medical search for malignancy.
feeding are particularly at risk. Dissecting the principle Cerebral salt wasting syndrome (CSWS) is a rare
cause of hyponatraemia may be very difficult, and iden- cause of hyponatraemia that may onset after brain injury.
tifying the patient at risk is critical. An association has been described with aneurysmal sub-
Syndromes of inappropriate ADH secretion is a rela- arachnoid haemorrhage but has been described also with
tively common cause of hyponatraemia (. Table 13.2). head trauma, stroke, intracranial tumours/metastases,
The diagnosis is suggested by hypo-osmolar serum viral and bacterial infections and after neurosurgery. The
(<275 mmol/L), a relatively high urine osmolality main features are elevated urinary sodium excretion and
(>100 mmol/L) in a euvolaemic patient as supported by hypovolaemia. The pathophysiology may be related to
272 A. Petrosino et al.
natriuresis induced by inappropriate brain-natriuretic- cies. Patients can become polyuric and over-correct, so
peptide release. The differential diagnosis with SIADH is close monitoring on initiation is important, and fluid
important as the treatment is substantially the opposite: restriction may need to be limited or reversed (caution
rehydration and sodium supplements. with patients who do not have free access to fluids and
do not use simultaneously with hypertonic saline and
diuretics). There is a danger that vaptans will be used
13.1.8 Treatment of Hyponatraemia willy-nilly, but concerns over liver toxicity, extortionate
cost and lack of long-term outcome benefits mean the
The main concern with treating hyponatraemia is that role of these drugs for long-term conditions is not yet
rapid correction of serum osmolality causes osmotic established: it seems likely that in the right setting and if
dehydration of neural cells (osmotic demyelination carefully handled, they could be a welcome addition to
syndrome, ODS). Classically at risk is the central pons the therapeutic armamentarium [12].
(central pontine myelinolysis, CPM), but extrapontine In summary:
areas as basal ganglia and cerebellum can be involved 1. Hypovolaemic and sodium-depleted patients: the
as well. Clinical manifestations of CPM usually develop treatment is usually with saline replacement and
few days after the insult with seizure, altered state of treating the underlying cause such as gastrointestinal
consciousness, changes in gait and respiration up to losses, correcting adrenal or thyroid insufficiency or
emotional lability, spastic quadriparesis and pseudobul- sodium supplementation in patients with salt-losing
bar palsy. Having shed organic osmolytes and electro- nephropathies. Potassium deficits if present should
lytes, neurons are particularly vulnerable to an increase be corrected. Vaptans are contraindicated.
in plasma osmolality as reaccumulation of osmolytes 2. Euvolaemic patients: require treatment of the under-
(such as the major osmolyte myoinositol) is slower than lying condition and fluid restriction. Demeclocycline
their loss (uraemia representing an interesting exception (300–600 mg bid, which inhibits cAMP in the col-
where myoinositol reuptake is faster, causing somewhat lecting duct, inducing nephrogenic diabetes insipidus
protection from CPM). and AVP resistance) can be used in SIADH, but it
Treatment relies on identifying and addressing the is slow acting and potentially nephrotoxic. Urea is
specific causes (sodium deficit, SIADH or sodium and another option but is not well tolerated. Vaptans
water excess; . Fig. 13.4). The fundamental rules to achieve free water clearance without natriuresis
maintain patient safety and avoid CPM are however or kaliuresis and are well suited to treatment of
very frequent monitoring and slow correction. In a euvolaemic hyponatraemia if progress is not made
13 seminal study looking at patients with severe hypona- with simpler measures. In hyponatraemic emergen-
traemia (<105 mmol/L), no patients who had incre- cies, hypertonic saline and/or loop diuretics are the
ments of ≤12 mmol/L in 24 hours or 18 mmol/L in treatment of choice and should be used as a tempo-
48 hours suffered neurological injury [11]. The two rary measure to make a gentle increment in serum
common limits used in practice are [1] <8–10 (up to 12 sodium while correcting the underlying cause.
according to some Authors) mEq/L in the first 24 hours 3. Salt- and water-overloaded patients: fluid restriction,
and <18 mEq/L in the first 48 hours if hyponatraemia is usually diuretics, and treatment of the underlying
likely to have been present for ≥48 hours. In those with condition, in combination with chronic salt restric-
hyponatraemic encephalopathy (seizures, neurological tion. Vaptans have been used to promote free water
signs, neurogenic pulmonary oedema), the initial correc- clearance in these conditions of elevated ADH.
tion should be no greater than 8–10 mmol/L/24 hours
to be achieved with 100mls of 3% (hypertonic) saline In case of excessively rapid correction of hyponatraemia,
plus or minus an infusion of the same at 1–2 ml/kg/ sodium re-lowering is supported by the fact that while
hour. This can be given in conjunction with loop diuret- the neuronal response to hyponatraemia is achieved
ics, but again the concern is that correction may be too rapidly (48 hours), the re-accumulation of intracellular
rapid if not monitored extremely closely. Oxygenation is osmoles can take 5–7 days. As a result hyponatraemia
important in anyone at risk of hyponatraemic encepha- secondary to excessive sodium re-lowering would have a
lopathy. Non-peptide vasopressin receptor antagonists significantly lower risk of causing cerebral oedema. Fur-
(vaptans), such as conivaptan (IV) and tolvaptan (oral), thermore, the process of osmotic demyelination would
offer an elegant way of promoting free water clear- be reversible to some extent, even after symptom onset.
ance acting on V1a and V2 receptors (tolvaptan more Therefore, it is experts’ opinion that sodium re-lowering
selectively on the latter). They are effective at increas- should be considered [1] after a too rapid correction in
ing sodium in euvolaemic and hypervolaemic states and high-risk patients (alcohol abuse, cirrhosis, malnutri-
appear safe but contraindicated in hypovolaemia and tion, hypokalaemia, initial severe hyponatraemia), aim-
not the treatment of choice in hyponatraemic emergen- ing for the therapeutic correction targets reported above,
Common Electrolyte Abnormalities
273 13
and [2] in patients with initial signs of CPM/ODS. Re- This is also relatively common in the hospital setting
lowering of plasma sodium should be achieved with a affecting between 1 and 5% of hospitalised patients
combination of desmopressin (2–4 mcg IV or SC every and associated with very high mortality (40–75%) when
6 hours) and glucose 5% (3 ml/Kg/h for a 1 mmol/l/h severe. It is caused by either loss of body water or, less
correction of plasmatic sodium), and desmopressin only commonly, a gain in total body sodium and water. Pow-
should be continued after the achievement of target erful protective mechanisms usually prevent hyperna-
plasma sodium. traemia, and in the former scenario it is usually related
Prevention of hyponatraemia is probably underprac- to impaired thirst, reduced access to water, impaired
tised. Important measures would be to vigilate against AVP release or impaired AVP responsiveness. Conse-
the routine use of hypotonic solutions post-operatively, quently the elderly, confused, debilitated and ventilated
identify and closely monitor patients at risk (particularly and infants are at greatest risk. A list of causes is shown
the elderly and institutionalised), check plasma sodium in . Table 13.3 and can be categorised in the same way
within 2 weeks of starting thiazides or SSRI and advise as hyponatraemia based on EABV. Of note, more than
endurance athletes to avoid NSAIDs and drink accord- one cause may be in play.
ing to thirst.
13.1.10 Hypernatraemia
13.1.12 Assessment and Investigation
of Hypernatraemia
Hypernatraemia is defined as a plasma sodium of As with hyponatraemia, hypernatraemia is usually
>145 mmol/L. detected either incidentally or in the investigation of a
patient who has impaired mental state. A careful his-
Increased EABV Excessive e.g. Cushing’s syndrome, Conn’s usually associated hypokalaemia and hypertension and low
(hypervolaemia) mineralocorticoid urinary sodium
activity
Excessive salt Hypertonic feed, hypertonic saline, normal saline and colloid have a sodium of 155 mmol/L,
intake high salt load medication (e.g. some antibiotics, sodium bicarbonate, glucocorticoids and
mineralocorticoids), associated with high urinary sodium
Normal EABV Renal water loss Nephrogenic diabetes insipidus
(euvolaemia)
Central diabetes insipidus
Extra renal water (with inadequate water intake) insensible losses hyperventilation
loss
Reduced EABV Renal water losses Diuretics, osmotic diuresis, vaptans
(hypovolaemia)
Extra renal water Vomiting, diarrhoea, sweating, NG suction
loss
274 A. Petrosino et al.
The water restriction test helps distinguish diabetes Stop the test once any of the following endpoints are
insipidus from primary (psychogenic) polydipsia, and reached:
furthermore central diabetes insipidus (CDI) from 1. Appropriate response: Uosm >600 mosmol/kg.
nephrogenic diabetes insipidus (NDI). Water depriva- 2. Inappropriate response:
tion would normally cause a rise in Posm, which stimu- 5 Uosm is stable on two to three successive hourly
lates ADH secretion. ADH then leads to increased renal measurements despite a rising Posm.
water reabsorption (via aquaporin-2 water channel 5 Posm exceeds 295 to 300 mosmol/kg.
insertion in the distal tubule and the collecting duct). 5 PSodium is 145 meq/L or higher.
Subsequently the Uosm will rise to a maximum value of 5 Body weight falls below 97% from baseline.
800–1400mosm/kg, and UVolume will fall to <0.5 ml/min
reflecting the maximum ADH effect on the kidney. This Desmopressin (dDAVP) can then be administered for fur-
is reached when Posm is 285–295mosm/kg. ther differentiation (10 mcg by nasal insufflation or 1–2
In individuals with defects in either ADH release mcg intravenously), and Uosm and UVolume are monitored
(CDI) or ADH effect (NDI), their Uosm remains inap- every 30 min over the following 2 hours. Desmopressin
propriately low despite a rise in Posm to levels ≥295 administration should lead to an increase in Uosm of at
mosm/kg. least 50% or a significant fall in urine output in CDI, but
Test instructions: will have no or only little effect in NDI (. Table 13.5).
Common Electrolyte Abnormalities
275 13
Test Limitations. The water restriction test establishes
. Table 13.5 Water restriction test interpretation [14–16]
the correct diagnosis in 80%; however, the main limitation
Condition Urine osmolality in Uosm rise in response seems to be the differentiation between partial CDI and
mOsm/kg, after water to dDAVP adminis- primary polydipsia, as some patients with partial CDI
deprivation tration have an upregulation of ADH receptors. Those patients
are polyuric at normal Posm, but will be able to concentrate
Normal >800 No response
their urine normally when Posm rises to 295. They will not
response
respond to dDAVP administration. Hence, they may be
Primary >600a No response mistakenly diagnosed with primary polydipsia. In equivo-
polydipsia
cal cases, a trial of desmopressin may be helpful as patients
CDI <300 >100% (complete with partial CDI will get quick relief of the polyuria,
CDI) whereas patients with primary polydipsia may have some
15–50% (partial
fall in urine output, but if they continue to have excessive
CDI)
water intake, they may develop severe hyponatraemia.
NDI <300 ≤45% (partial NDI)
No response
(complete NDI)
13.1.14 Treatment of Hypernatraemia
aprimary polydipsia will be associated with a rise in urine
osmolality, usually above 500–600 mosmol/kg, but maximum In the majority of cases, management consist in treating the
concentrating ability is frequently impaired in this disorder. underlying cause and supplying adequate free water and/
This defect may be due to downregulation of the release of or diuretics (excretion of sodium). The estimated absolute
AVP in response to hypertonicity in those patients [17]
water deficit, below, will give an idea of the amount of
water replacement to achieve normal hydration.
Total Body Water ! 0.6 " # Body Weight $ mortality, seizure nor cerebral oedema [18]. Finally, in
hypervolaemic hypernatraemia, diuretics are used in
(assuming 60% of body weight is water, in the elderly, combination with free water to induce negative sodium
50% may be used) balance.
The estimated water deficit is not a prescription for
replacement, as it does not account for ongoing renal or
other losses. For most patients, correction merely involves 13.1.15 Diabetes Insipidus (DI)
providing ready access to water; for the infirm, it may
be via NG water or 5% dextrose. Titration with regular DI is relatively rare but can result in severe and recur-
measurement and clinical assessment is critical. There rent hypernatraemia. On etiological basis, it is classified
are no evidence-based guidelines available for sodium as central and nephrogenic (. Table 13.6). Congenital
correction in hypernatraemia. Hypovolaemia should causes of cranial or pure nephrogenic DI usually pres-
be corrected with balanced crystalloid. Experts usually ent in infancy with dehydration, failure to thrive and
suggest that rapid correction of acute (≤48 hour) hyper- hyponatraemia. Children may give a history of drinking
natraemia is relatively safe due to neuronal adaption water from any source including puddles, and polyuria
(by increasing osmolytes or retaining electrolytes) and manifests as urinary frequency, nocturia and enuresis.
up to a maximum rate of 1 mmol/l/hr. is recommended Urine outputs of up to 20 L can occur (although more
for very acute cases. In chronic hypernatraemia, how- commonly less than this), and bladder dysfunction can
ever, rapid correction can cause cerebral oedema, and result from chronic bladder distension. Other genetically
experts support a 0.4 mmol/L/hr. for anything remotely acquired renal diseases can also result in predominantly
chronic, with a total maximum decrease in sodium of collecting tubule damage and usually a milder version
10 mmol/l in 24 hours. Interestingly, some study found of NDI as the disease progresses. Urine osmolality is
no differences between rapid (>0.5 mmol/L/hr) and slow low in the face of high plasma osmolality, whereas uri-
(0.5 mmol/L/hr) sodium correction in terms of 30 days nary sodium is variable.
276 A. Petrosino et al.
CDI is treatable with nasal or oral desmopressin (DDAVP). Potassium is the main intracellular cation ~100 mmol/L
NDI is more tricky to treat, and addressing any secondary (and around 98% of total body potassium is intracel-
cause is important (treating hypercalcaemia and avoiding lular), which is why necrosis can be associated with
culpable medication). Lithium should be stopped or the fulminant hyperkalaemia. The large gradient between
dose decreased when possible. Alternatively, amiloride intra- and extracellular compartments is actively
may be employed to compete for lithium uptake, poten- maintained by the Na + -K + -ATPase. It is via the
tially reducing its toxicity. A high water intake (with plan- Na+-K+-ATPase that β2-adrenoreceptor agonists
ning for this and toilets) and low-salt and modest protein and insulin act to shift potassium into cells, acido-
diet are first line. If symptoms cannot be controlled with sis and α1-adrenoreceptor stimulation (increased in
these, then thiazide or amiloride diuretics may help induce CKD) having the opposite effect. The concentration
a mild contraction of the effective arterial blood volume. of extracellular potassium is critical as it influences
Non-steroidal anti-inflammatory drugs can be useful for the voltage difference across cell membranes [19].
NDI and lithium-induced DI. The proximal tubule is the site of reabsorption of the
Patients need to have a clear understanding of majority (55%) of filtered potassium via paracellular
the condition (7 www.patient.co.uk/health/diabetes- diffusion and some reabsorption via the Na+-K+-2Cl−
insipidus), avoid excessive fluid intake while on DDAVP, co-transporter in the thick ascending limb of the loop
and keep a close eye on daily weights, especially if unwell. of Henle. Potassium is also actively secreted via the
A MedicAlert bracelet of equivalent is very sensible. ROM-K transporter. Only 10% of filtered potassium
Patients with chronic profound polyuria should have reaches the distal convoluted tubule and cortical col-
surveillance ultrasound to check for functional “high- lecting duct where critical control of potassium secre-
pressure” obstruction. tion occurs.
Common Electrolyte Abnormalities
277 13
13.1.18 Hypokalaemia detected (such as diarrhoea and diuretic treatment or
malnourishment).
Oral intake is approximately 100 mmol/day. 95% of The clinical manifestations of hypokalaemia are
potassium excretion is via the kidney and 5% from the mainly related to cardiac dysrhythmias (usually below
colon. Hypokalaemia is relatively uncommon in healthy 3.0 mmol/L or higher in those predisposed to dysrhyth-
individuals as in health the kidney is able to avidly retain mias), including atrial or ventricular dysrhythmias, due
potassium (less than 15 mmol/day). to increased myocardial excitability, but muscle weak-
ness may also occur (see Appendix 1). Hypokalaemia
increases renal ammonia production predisposing to
Thus hypokalaemia, defined as serum potassium less
decompensation of hepatic encephalopathy. Acute
than 3.5 mmol/l (moderate 2.5–3.0 mmol/L, severe
and chronic hypokalaemia may cause polyuria. Finally
<2.5 mmol/L).
chronic hypokalaemia was thought to cause tubuloint-
erstitial damage, but this is somewhat controversial and
may merely be an association with the primary causes of
hypokalaemia.
Is normally the consequence of significant underlying Investigation of hypokalaemia (. Table 13.8) aims
pathology or drug use and is extremely common in to determine if it is a problem of intra-extracellular
hospitals (up to 20% of patients). Mostly this relates redistribution (intracellular uptake), of poor intake or
to medication, fluid losses, fevers, malnutrition, eating of excessive losses (and in this case if renal or extra-
disorders and potassium-lite fluid replacement [19]. renal losses) of potassium.
Gastrointestinal losses are a common cause of hypo- Urinary potassium (as total urinary potassium or
kalaemia (and hypomagnesaemia) globally and can the quicker “potassium fractional excretion”, FEK+,
be fatal in severe diarrhoea particularly in countries and “transtubular potassium gradient”, TTKG) is a
with limited health care. Causes of hypokalaemia are useful test to discriminate between renal and non-renal
shown in . Table 13.7, and in patients who develop losses. Non-renal losses from any cause (usually the GI
hypokalaemia, multiple associated causes are often tract) will be associated with an appropriately reduced
avomiting can be associated with high urinary potassium because of secondary hyperaldosteronism
278 A. Petrosino et al.
Dent’s disease comprises a heterogeneous group of Apparent mineralocorticoid excess is a rare autoso-
rare X-linked proximal tubulopathies associated with mal recessive syndrome of juvenile hypertension associ-
nephrolithiasis, nephrocalcinosis (75%), hypercalciuria ated with a metabolic alkalosis and hypokalaemia but
(95%) and hypophosphataemia low-molecular-weight with a low serum aldosterone. It is caused by mutations
proteinuria. It results from mutations in CLCNS (encod- in the HSD11B2 gene encoding for 11β-hydroxysteroid
ing for the chloride/hydrogen exchanger) in Dent’s dehydrogenase type 2. This enzyme normally con-
disease-1 or mutations in OCRL-1 encoding for phos- verts cortisol to cortisone (temporary inhibition of
phatidylinositol bisphosphate 5-phosphatase in Dent’s 11β-hydroxysteroid dehydrogenase type 2 is how exces-
disease-2. As yet there is no clear genotype/phenotype sive liquorice is thought to cause hypertension). This
correlation and there is considerable variation between conversion is important as cortisol activates the miner-
families, some patients presenting with incomplete FS alocorticoid receptor as powerfully as aldosterone, and
and low-molecular-weight proteinuria may be the only the plasma cortisol concentration is orders of magnitude
clue. higher than aldosterone. AME is also glucocorticoid
Clinical features are of proximal tubular dysfunc- responsive and may be treated with dexamethasone,
tion, Fanconi syndrome, hypercalciuria, nephrocalci- which suppresses endogenous cortisol production with-
nosis and low-molecular-weight proteinuria (beta-2 out stimulating the mineralocorticoid receptor, or by
microglobulin, retinol-binding protein). Detection inhibiting ENaC using amiloride, or the receptor itself
of low-molecular-weight proteinuria can be a useful with eplenerone or spironolactone. AME secondary
screening test in female carriers. Dent’s disease is one to excess liquorice ingestion just requires a little more
of the few causes of nephrocalcinosis associated with restraint in the confectionary department.
end-stage renal disease, and 30–80% of affected males
require renal replacement therapy between the third and
fifth decade of life which is thus an important (albeit 13.1.20 Treatment of Hypokalaemia
rare) cause of unexplained renal failure. Renal trans-
plantation is curative. As most potassium is intracellular, low serum potassium
Lowe’s syndrome is a very rare (estimated at roughly often represents a profound deficit in total body potas-
1 in a million) X-linked oculocerebrorenal syndrome with sium, potassium of <3.0 and <2.0 representing deficits
a similar renal phenotype to Dent’s disease also result- of ~200 and 300 mmol of potassium, respectively, and
ing from mutations of the OCRL gene encoding the PIP thus it may take several days to become replete [19].
13 phosphatase involved in endosomal trafficking. Aside
from a relatively mild FS and metabolic acidosis, male
Administration of IV potassium is helpful especially
when depletion is severe, when oral intake is insufficient
patients develop severe cataracts antenatally, glaucoma is or unreliable and in hypokalaemic emergencies such as
common and visual deficit is almost universal. Hypotonia arrhythmias. Intravenous potassium chloride may be
results in severe motor developmental delay, and scolio- given peripherally in normal saline or 5% dextrose at
sis is common often resulting in chest infections. Severe a rate of up to 10 mmol/h. The risk of phlebitis limits
hypophosphataemia may result in rickets. Although faster infusion via a peripheral route, whereas rates of
rare, this condition is relevant to adult nephrologists as up to 40 mmol/h are felt to be safe via a central line with
patients may live to middle age, often have complex needs, cardiac monitoring.
and patients have been successfully transplanted [20]. Potassium may be given orally as potassium chloride
Glucocorticoid remedial hyperaldosteronism (or type and potassium citrate, titrated against response with
1 familial hyperaldosteronism) is a rare autosomal dom- the caveat that effervescent potassium is poorly toler-
inant disease caused by a mutation resulting in a chime- ated in large amounts (dose should be split) and slow
ric CYP11B1/CYP11B2 gene. This causes aldosterone release potassium has the nasty habit of accumulating
synthetase in the zona glomerulosa of the adrenal cor- before absorption and causing oesophageal ulcers if
tex to become sensitive to ACTH and inappropriately taken before bedtime. Treating the underlying causes, be
upregulated. A happy consequence of this is that it also they extra-renal or renal in origin, is obviously impor-
becomes suppressible by physiological doses of gluco- tant as is correcting any concomitant hypomagnesae-
corticoid. As this is a condition of hyperaldosteronism, mia. In chronic potassium-wasting conditions (such
there is hypertension, metabolic acidosis and hypokalae- as Gitelman, Barrter and renal Fanconi syndrome,
mia. Clinical features include fatigue, headaches, muscle syndromes of mineralocorticoid excess or diuretic
cramps, polyuria and consequent polydipsia. The condi- dependence), other strategies including the use of ACE
tion is usually diagnosed in childhood or adolescence as inhibitors and potassium-sparing diuretics amiloride
part of the investigation of secondary hypertension. and spironolactone may need to be considered.
Common Electrolyte Abnormalities
281 13
13.1.21 Hyperkalaemia . Table 13.10 Causes of pseudohyperkalaemia
. Fig. 13.5 A patient with CKD and hypersplenism who under- hyperkalaemia (up to 7 mmol/L) despite a significant improvement
went a splenectomy. His baseline platelet count went from around in GFR. Blood analysed from a lithium heparin tube gave a value
15,000/uL to 800,000/uL, and associated with this was progressive almost 2 mmol/L less than the EDTA sample
282 A. Petrosino et al.
13.1.22 Causes of Hyperkalaemia patients, particularly in the absence of ECG changes (see
. Table 13.10). Here a fresh sample should be rapidly
Causes of hyperkalaemia are reported in . Table 13.11. spun and separated (avoiding haemolysis or ongoing red
Of note a reduced GFR is a key risk factor as are drugs cell potassium leakage).
that reduce renal potassium excretion. Dietary excess 24-hour urinary potassium excretion is the gold stan-
only really comes into play if a patient is predisposed dard and will differentiate renal from non-renal hyperka-
by reduced renal excretion. Less common are endocrine laemia; <20 mmol/24 hrs, in the face of hyperkalaemia,
causes of reduced urinary potassium loss such as min- suggests a problem with renal excretion. Alternatively,
eralocorticoid deficiency (Addison’s disease, resulting and more conveniently, potassium excretion can be
in aldosterone deficiency) or pseudohypoaldosteronism assessed using the transtubular potassium gradient
(aldosterone resistance), and, as with hypokalaemia, (. Table 13.8) from a spot urinary potassium. A value
redistributive shifts between ECF and ICF can result in of less than 5 in the face of hyperkalaemia is abnormal,
significant changes in serum levels. while a value of >7 is considered appropriate (unreliable
with a very dilute urine or urinary sodium >25 meq/L.
[22] If renal potassium excretion is reduced, in the face
13.1.23 Assessment and Investigation of a normal GFR, the patient must then be investigated
of Hyperkalaemia for hypoaldosteronism or aldosterone resistance.
Gordon’s syndrome pseudohypoaldosteronism (type II)
A thorough clinical assessment, including drug and is a rare inherited mutation of WNK1 or WNK4 genes
dietetic history as well as volume status, is essential, resulting in gain of function and increased inhibition or
but an ECG takes precedence in the setting of severe the thiazide-sensitive sodium chloride co-transporter. This
hyperkalaemia as this will establish whether the patient results in excess sodium and chloride retention, hyperka-
is at imminent risk of life-threatening bradycardia, asys- laemia, hyperchloraemic metabolic acidosis and low renin
tole and death (see Appendix 1). “Regular Really Wide hypertension which can become severe by the third decade.
Complex Tachycardia” (. Fig. 13.6) with QRS >200 ms Aldosterone levels are high not low due to impaired feed-
and an only moderate elevation in heart rate should back. It may be associated with short stature, dental abnor-
raise the concern of a metabolic cause and suggest malities and reduced intelligence. The diagnosis is usually
the use of IV calcium and sodium bicarbonate rather made by paediatricians but renin/aldosterone levels and
than antiarrhythmic drugs [21]. Pseudohyperkalaemia fractional excretion of sodium or TTKG (low). Treatment
13 should be excluded in unexpectedly hyperkalaemic is with a low-salt diet and thiazide diuretics.
Reduced renal loss Drugs: Angiotensin converting enzyme inhibitors (ACEi), angiotensin receptor antagonists (ARBs), beta-
(low urinary blockers, aldosterone receptor antagonists (spironolactone, eplerenone? Sp), potassium-sparing diuretics
potassium) (amiloride, triamterene), calcineurin inhibitors (CNIs), trimethoprim, non-steroidal anti-inflammatories
(NSAIDs), heparin
Endocrine: Addison’s disease (aldosterone/mineralocorticoid deficiency), some forms of congenital adrenal
hyperplasia
Renal: Most causes of reduced GFR, type I renal tubular acidosis and type IV renal tubular acidosis, Gordon’s
syndrome (pseudohypoaldosteronism)
Excessive production Rhabdomyolysis, intravascular haemolysis, massive transfusion (especially incompatible transfusion), tumour
lysis syndrome, significant tissue infarction (especially if impaired renal function), severe exercise
Redistributive Acidosis, beta-blockade, insulin deficiency, digoxin toxicity, suxamethonium muscle relaxant, hyperkalaemic
periodic paralysis
Reduced non-renal Rarely clinically relevant, but constipation can worsen hyperkalaemia in patients with reduced GFR
losses
Excessive intake Only usually relevant in context of reduced renal excretion (but becomes a common, and avoidable, cause in
patients with ESRD or supplemented patients with AKI), the notable exception being lethal injection. Lo-salt
condiment has high levels of potassium and not suitable for patients with reduced GFR
Pseudohyperkalaemia See . Table 13.10
Common Electrolyte Abnormalities
283 13
. Fig. 13.6 ECG changes in patient with severe hyperkalaemia (8.2 mmol/L). Standard 12-lead ECG (25 mm/s, 10 mm:1 mV). Ventricular
rate 100 bpm, QRS 208 ms
13.1.24 Management of Hyperkalaemia tions. A recent retrospective cohort study by Noel et al.
showed a twofold higher 30-day risk of gastrointestinal
The management of hyperkalaemia (. Table 13.12, events for SPS users with an absolute risk of 1 in 1000.
. Fig. 13.7) depends on the severity of the disorder and The commonest gastrointestinal events was intestinal
the presence of ECG changes. Acutely reducing plasma ischemia and thrombosis, followed by ulceration and
potassium by redistribution is just a temporary mea- perforation. Nevertheless, due to limitations of this
sure, and initiating treatment that will reduce total body study (no dose-dependent information, no investiga-
potassium is crucial. It is not unusual for patients to be tions on chronic SPS administration, no SDS-sorbitol
given repeated doses of insulin and dextrose without association evaluation), the safety characteristics of SPS
appropriate measures to resolve the underlying problem. remain unclear [24].
Moreover, it needs to be made clear that in an oliguric, New potassium binders have been recently approved,
hyperkalaemic patient with AKI or ESRD, early plans such as patiromer and sodium zirconium cyclosilicate
need to be made for renal replacement therapy unless (. Table 13.13). They showed promising results in
there is a rapidly reversible element. studies on their long-term efficacy and safety in chronic
Sodium polystyrene sulfonate (SPS) is an oral resin hyperkalaemia with less adverse events compared to
which binds potassium in the large intestine approved by SPS. Furthermore, these drugs may prevent the dis-
FDA in 1958 for chronic hyperkalaemia. One gram of continuation of renin-angiotensin-aldosterone system
SPS exchanges 0.5–1 mEq of potassium. Although his blockers, often limited by hyperkalaemia in people with
role in acute settings is less clear, its use is widespread advanced CKD [25].
after cardiac membrane stabilisation and administration
of drugs to increase intracellular shift of potassium. Its
main side effects are electrolyte disturbances (e.g. hypo- 13.1.25 Calcium Disorders
kalaemia, hypomagnesaemia, hypocalcaemia) and gas-
trointestinal symptoms (nausea, vomiting, constipation Calcium is the most abundant mineral in the body. The
and diarrhoea up to gastrointestinal bleeding, ulcer- majority of total body calcium is stored in the skeleton
ation, perforation and ischemic colitis). The association with the remainder overwhelmingly intracellular, where
with sorbitol is reported at increased risk of complica- its effects are regulated by calmodulin. Extracellular cal-
284 A. Petrosino et al.
Cardiac stabilisation If ECG changes, then IV calcium gluconate 10 ml of 10% instant effect can be repeated
Redistribution Insulin and dextrose: 50 ml of 50% dextrose with 10 units of insulin IV effect with 15 minutes effect lasting for
(combination about 4 hours
treatment more
Beta2-agonists: Nebulised but high dose required, e.g. salbutamol 10–20 mg (drop in K+ 0.6 and 0.85 mmol/L)
effective)
Correction of acidosis: With bicarbonate both redistributes potassium and can lead to sustained reduction in
the setting of CKD with chronic acidosis
Reduce/stop intake Stop supplements and dietary excess (consider dietary review)
Stop/suspend/reduce ACEI, ARB, aldosterone antagonists, NSAID, trimethoprim, heparin, CNIs
potassium-sparing
medication
Lowering total body potassium:
1. Renal losses Diuresis: Loop diuretics (plus or minus thiazides if poor renal function) thiazides for CNI-induced hyperkalaemia
Mineralocorticoid: Fludrocortisone, for patients with adrenal insufficiency supplementing hydrocortisone and
fludrocortisone
Gastrointestinal losses Binders: e.g. calcium resonium very limited evidence (should be given with laxatives which may be more
effective than resins)
Laxatives: An important and under-used method of reducing total body potassium in a tight corner (NB
ensure laxative does not contain potassium)
2. Renal replacement Haemofiltration, haemodialysis or acute peritoneal dialysis highly effective at reducing total body potassium
therapy
13
. Fig. 13.7 Suggested algorithm for hyperkalaemia. *In case of ESKD end-stage kidney disease, AKI acute kidney injury, CKD
Digitalis intoxication or hypercalcemia. (**Sodium zirconium cyclo- chronic kidney disease, RRT renal replacement therapy [23])
silicate and patiromer when available, kayexalate if not available.
Common Electrolyte Abnormalities
285 13
. Table 13.13 Characteristics of potassium-binding agents for their treatment of hyperkalaemia (Adapted from Bianchi S and
Regolisti G, 2019) [26]
cium is either protein bound, ionised (the active form) hypercalcaemia (≥3.5 mmol/L) and life-threateningly
or complexed with phosphate, citrate, bicarbonate or high levels, sometimes precipitating AKI.
sulphate. The total body calcium is closely regulated
and determined by the balance of gut uptake and renal
excretion with bones being a large reservoir. Regulation 13.1.27 Causes of Hypercalcaemia
is via the parathyroid glands (via the calcium-sensing
receptor (CaSR; see 7 Chap. 50). [27] Most calcium The causes of hypercalcaemia are shown in . Table 13.14
assays measure total (bound and unbound) calcium with malignancy and primary hyperparathyroidism
correcting for albumin levels using the following for- accounting for more than 90% of cases. Malignancy can
mula: cause hypercalcaemia in a variety of ways in part through
Adjusted Calcium (mmol/L) = measured serum cal- the production of PTH-related protein (PTHrP), typi-
cium (mmol/L) + 0.02 × [40-serum albumin (g/L)] cally through solid malignancies with metastases, clas-
This becomes inaccurate if the patient is very aci- sically breast and squamous cell carcinoma. Alternative
dotic, with paraproteinaemia and at extremes of albu- mechanisms include malignancy-associated cytokine
min. Changes in ionised calcium are significant clinically release (IL-6, IL-1, TGF-β, RANK), direct bones involve-
and can be obtained via blood gas analysers although in ment, prolonged immobility and increased macrophage
practical terms most diagnosis and decisions are made production of 1,25 (OH)2 vitamin D with some haema-
on the corrected calcium. tological malignancies. More than 40% of all hypercalce-
mia cases presenting to the Emergency Department may
be secondary to cancer, and these patients have a 50%
13.1.26 Hypercalcaemia 30-day mortality.
Malignancy PTHrP (squamous cell carcinoma, breast malignancy), pro-inflammatory cytokine release,
immobilisation, direct bone involvement (multiple myeloma), increased synthesis of 1,25 (OH)2
vitamin D (lymphoma)
Hyperparathyroidism
Primary 85% single adenoma> primary hyperplasia, multiple endocrine neoplasia (MEN), parathyroid
carcinoma
Tertiary Exacerbated by high doses of vitamin D, aluminium intoxication and adynamic bone disease
Granulomatous diseases Classically TB and sarcoidosis but potentially any chronic inflammatory process involving
accumulation of macrophages (sometimes unmasked by vitamin D supplementation)
Vitamin D intoxication Hypervitaminosis D, food faddists but not uncommon iatrogenic cause in patients with CKD on
large doses of supplements
Vitamin A intoxication
Aluminium intoxication
Medication Thiazides, lithium, excess antacid ingestions (milk-alkali syndrome)
Endocrine causes Addison’s disease, acromegaly, hyperthyroidism, phaechromocytoma
Familial hypocalciuric hypercalcaemia Secondary to calcium-sensing receptor mutations
Prolonged immobilisation Unusual as a sole cause; Paget’s disease only causes hypercalcaemia in the immobile patient
Recovery phase of rhabdomyolysis Hypercalcaemia 1–2 weeks post AKI may be the only clue as to the aetiology of missed
rhabdomyolysis
hyperparathyroidism. Renal effects include polyuria, hypercalcaemia may mimic neoplasia). Rarely there
thirst, renal failure, nephrocalcinosis and kidney stones may be a family history of MEN or familial hypocal-
(most commonly associated with primary hyperpara- ciuric hypercalcaemia. Examination may reveal signs
13 thyroidism as chronic). Bone pain is common but often of malignancy, granulomatous conditions, an underly-
non-specific; however, worsening bone pain in known ing endocrine cause or very rarely (but very satisfyingly)
malignancy should provoke a calcium check. Pruritus corneal calcification. As with all electrolyte disorders,
and conjunctivitis may also occur. Neurological com- volume status needs to be assessed. Blood tests should
plications include depression, inability to concentrate, include PTH level, alkaline phosphatase, phosphate,
confusion, reduced neural excitability resulting in neu- albumin, total proteins and renal function (magnesium
rological depression, ataxia, upper motor neurone signs and potassium will be important for subsequent man-
and (in severe cases) coma as well as reduced smooth agement). In general hyperparathyroid patients have
and striated muscle movement. Constipation is a com- inappropriately high PTH and a low phosphate. In such
mon feature in part due to reduced smooth muscle cases parathyroid ultrasound and radioisotope scan-
activity. Hypercalcaemia induces increased gastrin ning may be performed. If the PTH is not suppressed
secretion, and peptic ulcers can occur as can pancreati- in the face of hypercalcaemia, then the patient has pri-
tis. Cardiotoxicity may also occur in severe hypercalcae- mary or tertiary hyperparathyroidism (the caveat being
mia with ECG changes including short QT interval and that some patients have this and a secondary cause such
ST changes mimicking acute coronary syndrome (see as malignancy). If the PTH is suppressed, then a more
Appendix 1). detailed assessment of secondary causes is warranted,
e.g. serum ACE (unhelpful if on ACEI), 25(OH) vita-
min D, paraproteins, Bence Jones proteinuria, protein
13.1.29 Assessment and Investigation electrophoresis and immunofixation, chest X-ray and
of Hypercalcaemia where appropriate further imaging with mammogram,
CT scanning or gallium. An ECG is necessary to exclude
A history of long-standing symptoms especially stones any electrophysiological changes.
is suggestive of primary hyperparathyroidism, whereas Of note, in some occasions, total calcium level may
constitutional symptoms of malignancy may sug- be very high in the context of a normal ionised calcium
gest this as a primary cause (although symptoms of and usually no manifestations of hypercalcaemia. This
Common Electrolyte Abnormalities
287 13
is defined as pseudohypercalcaemia and usually arises Is less common than hypercalcaemia but familiar to
in the presence of a circulating factor that can bind nephrologists in the setting of CKD and nutritional
calcium (such as additional albumin, paraproteins or deficiency and very common among hospital inpatients.
additional immunoglobulins like in Waldenstrom mac- Severe hypocalcaemia (<1.75 mmol/L) can have life-
roglobulinaemia, or citrate in case of citrate overload threatening consequences in terms of seizures and car-
during CRRT regional citrate anticoagulation). diac arrhythmias.
The treatment of hypercalcaemia is directed at restoring The commonest cause of hypocalcaemia is artifactual
intravascular volume and treating the underlying cause. and relates to a low serum albumin, and the corrected
Severe and symptomatic hypercalcaemia requires urgent calcium and ionised calcium should be normal if no defi-
corrective therapy with most agreeing that a calcium ciencies. Parathyroid hormone level (PTH) can be use-
above 3.4 mmol/L requires admission and urgent cor- ful in dividing possible aetiologies especially if chronic
rection. Cessation of contributing medication (antacids, but may be less discriminatory in acute illnesses such as
thiazides, lithium, vitamin D supplements) is appropri- burns or pancreatitis. Beyond renal disease as a cause
ate. Volume expansion with normal saline promotes a of hypocalcaemia, vitamin D deficiency is epidemic and
diuresis and is calciuric; in fact anything promoting a may be a contributing factor with other causes of hypo-
natriuresis promotes calciuresis. Once euvolaemia has calcaemia (. Table 13.14). “Hungry bone syndrome”
been achieved, saline may be given in tandem with intra- is worth special mention as it occurs in renal practice
venous or oral loop diuretics, promoting renal losses following parathyroidectomy in patients with tertiary
further. In hypercalcaemia due to sarcoidosis, other hyperparathyroidism and can result in life-threatening
granulomatous disease, vitamin D intoxication and hypocalcaemia. It results from reduced bone resorption,
some malignancies, prednisolone therapy is effective a marked influx of calcium into calcium-depleted bones
and of course is part of the treatment of adrenal insuf- and reduced calcium absorption from the gut second-
ficiency. Bisphosphonates (pamidronate and etidronate) ary to a fall in PTH. Advanced age, hypomagnesaemia,
can be given to inhibit bone resorption although are rel- vitamin D deficiency and size of gland removed are risk
atively contraindicated in patients with GFR <30 mL/ factors, but it is largely dependent on how severe the
min, and a judgment call needs to be made on the risk/ parathyroid bone disease is and occurs in 25–90% of
benefit in patients with severe hypercalcaemia and low those patients with radiological evidence of hyperpara-
GFR. Subcutaneous calcitonin also blocks bone resorp- thyroidism compared to only 0–6% of those without
tion and increases urinary calcium excretion by inhib- radiological change [28] (. Table 13.15).
iting calcium reabsorption and can be useful in severe
acute hypercalcaemia.
The calcimimetic agent cinacalcet has been shown to 13.1.33 Clinical Features of Hypocalcaemia
lower calcium in hyperparathyroidism related to reduced
GFR, although surgical parathyroidectomy remains the Perioral paraesthesia and numbness, dystonia, bron-
standard UK approach in the absence of contraindica- chospasm, laryngospasm, seizures, tetany and respira-
tions to surgery and occasionally should be considered tory arrest are well-known neuromuscular features of
as an urgent procedure. Finally, severe hypercalcaemia severe hypocalcaemia. Prolonged QTc, heart block and
around 4 mmol/L or above (lower if ECG changes) may flat T waves, reduced PR interval and U waves, heart
be better treated by acute renal replacement therapy, block, Torsades de Pointes and ventricular fibrillation
especially if the patient has significant AKI or CKD, are cardiovascular sequelae (see Appendix 1). Chronic
which is highly effective at temporarily reducing calcium hypocalcaemia may be associated with rickets and/or
levels. osteodystrophy, basal ganglia calcification, poor denti-
tion and cataracts. More moderate hypocalcaemia may
also be associated with more subtle symptoms chroni-
13.1.31 Hypocalcaemia cally such as depression, irritability, muscle cramps and
dementia. Chvostek’s sign (ipsilateral facial muscle con-
traction on tapping of the facial nerve) and Trousseau’s
sign (hand and wrist flexion on inflating a blood pres-
Hypocalcaemia (corrected calcium <2.1 mmol/L) sure cuff above systolic blood pressure) may confirm a
clinical suspicion of significant hypocalcaemia.
288 A. Petrosino et al.
High PTH Renal failure (falling 1α (OH) vitamin D and rising phosphate)
25 (OH) vitamin D deficiency (UV exposure, short-bowel syndromes, malabsorption, liver disease)
Pseudohypoparathyroidism resistance to PTH (Albright hereditary osteodystrophy (type 1a) short fourth and
fifth metacarpals and round facies)
Low/normal PTH Magnesium deficiency (severe) (lowers PTH secretion and end-organ resistance)
Hypoparathyroidism: Post-operative parathyroidectomy (acute “Hungrey bones”) (chronic PTH deficiency with
removal of all four glands), post-operative thyroidectomy/neck trauma, infiltrative malignancy, autoimmune
(including part of polyglandular syndrome-1, haemochromatosis, DiGeorge syndrome (thymic aplasia and
absent parathyroid glands), Barakat (HDR) syndrome (hypoparathyroidism, sensorineural deafness and renal
disease (dysplasia, reflux, cystic)), idiopathic hypoparathyroidism
Hyperphosphataemia Rhabdomyolysis (acutely), tumour lysis syndrome, phosphate supplements (IV, oral, rarely phosphate enema’s
in patients with CKD)
Medication Cinacalcet, bisphosphonates, loop diuretics, proton pump inhibitors, cisplatin, phenobarbital, phenytoin
Miscellaneous Acute pancreatitis, burns, sepsis, massive transfusion
Artifactual Low albumin (correction for serum albumin or ionised calcium give true status)
Redistributive Alkalosis (e.g. hyperventilation)
Causes of hypophosphataemia are shown in . Table 13.12 The majority of hypophosphataemia is asymptomatic
and can broadly be separated into renal causes (increased with perhaps non-specific weakness, paraesthesia and
excretion), gastrointestinal causes (decreased absorption) fatigue. Severe hypophosphataemia can result in proxi-
and redistributive. Renal causes can be further subdivided mal myopathy, rhabdomyolysis and respiratory failure
290 A. Petrosino et al.
Renal
Inherited phosphate-wasting disorders Autosomal dominant hypophosphataemic rickets (via impaired
metabolism of FGF-23) (variable age of presentation may appear
in early adulthood), autosomal recessive hypophosphataemic
rickets (dentin matrix protein-1 (DMP1) via impaired inhibition
of FGF-23), X-linked hypophosphataemic rickets (phosphate
regulating endopeptidase (PHEX) mutation via FGF-23),
childhood rickets and inappropriately low or normal vitamin D,
X-linked dominant.
Hereditary hypophosphataemic rickets with hypercalciuria (defect
of NaPi2 co-transporter, increased vitamin D levels and risk of
stones)
Proximal tubular disorders Fanconi syndrome (see . Table 13.6), Dent’s disease, cystinosis
Medication/drugs Diuretics (acetazolamide, loop and thiazide diuretics), cisplatin,
ifosfamide, tetracyclines, aminoglycosides, tenofovir, adefovir,
imatinib, streptozocin, toluene, mannitol (pseudohypophospha-
taemia), IV iron maltose
Post-transplant FGF-23 mediated usually short term
Tumour-induced osteomalacia (TIO) Mostly benign mesenchymal tumours via FGF-23
Fibrodysplasia May be associated with endocrine abnormalities and café au lait
spots in McCune-Albright syndrome (facial or long bone
asymmetry)
Hyperparathyroidism/vitamin D deficiency Reduced sodium/phosphate co-transporter expression
Gastrointestinal Malnutrition from any cause, chronic alcoholism (common),
eating disorders, short-bowel syndrome, chronic phosphate
binders (especially in context of improving renal function)
as well as acute cardiomyopathy. Intravascular hae- the patient’s nutritional status and clinical features of
molysis, depressed white cell function and neurotoxicity tubular disorders as well as signs of osteomalacia, rick-
in the form of neuropathy, metabolic encephalopathy ets and proximal myopathy (. Table 13.17).
and seizures can also occur in very advnaced deficiency. Unless the cause of hypophosphataemia is obvi-
More chronic cases in adults and those often occur- ous, then renal excretion of phosphate is helpful in
ring with milder levels of hypophosphataemia result in distinguishing between renal and extra-renal. If renal,
osteomalacia with diffuse bone pain and fracture risk. then further tests for diffuse proximal tubular disease
On the other hand, in children with inherited forms of such as Fanconi syndrome are warranted. Family his-
hypophosphataemia, rickets and growth retardation are tory is essential in children and young adults with iso-
common. lated phosphate wasting who should be offered genetic
screening.
Hypophosphataemia is often a surrogate marker for The underlying cause of hypophosphataemia should be
malnutrition, or renal proximal tubular disease, and established and, where possible this, treated (e.g. vita-
investigations should include an overall assessment of min D supplementation, cessation of tubular toxins
Common Electrolyte Abnormalities
291 13
such as tenofovir if feasible, resolution of malabsorp- If there is associated vitamin D deficiency, then sup-
tion). Acute mild-to-moderate hypophosphataemia can plementation is essential (patients with malabsorption,
usually be managed with high-phosphate foods with or starvation or alcoholism, sufficient to cause hypophos-
without oral phosphate supplements (although diar- phataemia, are likely to have multiple vitamin and other
rhoea is a common and frequently limiting side effect nutritional deficiencies as well). Resection of the caus-
of phosphate supplements). The evidence base for dos- ative tumour is curative in tumour-induced osteomala-
ing in acute moderate-to-severe hypophosphataemia is cia (TIO) and induced hypophosphataemia [33].
somewhat limited [32]; anticipation, close monitoring
and common sense are probably the best guides. IV
phosphate should be considered in patients with severe 13.1.42 Hyperphosphataemia
(<0.32 mmol/L) acute hypophosphataemia particularly
if they already have cardiorespiratory compromise (e.g.
ventilated patients), those with a predisposition to sei-
zures or those unable to take enteral feed. As always, Hyperphosphataemia, serum phosphate >1.5 mmol/l
with electrolyte abnormalities, the response depends on
the stability of the deficit and the direction of travel: for
example, those with hypophosphataemia with ongoing Is uncommon in the general population but omnipresent
losses such as continuous renal replacement therapy in advanced CKD (in the absence of phosphate lowering
or anticipated re-feeding syndrome in a sick patient measures) (see 7 Chap. 50). Acute hyperphosphataemia
are likely to need IV supplements (or phosphate addi- can occur, usually in the setting of significant cell death
tion to the dialysate/reinfusate for patients on CRRT), or inappropriate supplementation. In both scenarios,
whereas a healthy post-transplant patient with a level this is much more likely to occur with impaired renal
of 0.30 mmol/L, who is able to take a high-phosphate function (. Table 13.18).
diet, vitamin D and oral supplements, may not need
to be given IV phosphate, particularly if it is clear that
level has reached a nadir and is no longer falling. An 13.1.43 Clinical Features
important caveat with supplementation, especially intra- of Hyperphosphataemia
venous, is that it can worsen hypocalcaemia and hypo-
magnesaemia, both of which must be corrected and The major clinical consequence of hyperphosphataemia
monitored, and over-aggressive poorly monitor supple- is related to the presence of calcium-phosphate deposits
mentation may result in phosphate-induced AKI (which in target organs which may manifest as conjunctivitis or
does not look good for a nephrologist). tenosynovitis. It is usually asymptomatic but if chronic
292 A. Petrosino et al.
Reduced renal AKI and CKD, hypoparathyroidism, pseudohypoparathyroidism (PTH promotes phosphate excretion), acromegaly
excretiona (increased tubular reabsorption)
Cell lysis Tumour lysis syndrome (TLS), rhabdomyolysis, significant infarction, intravascular haemolysis and extravascular
haemolysis (e.g. extensive haematoma). High LDH, lactate, urate, potassium and creatine kinase may be raised
depending on cause
Excess intake Inappropriate supplementation (especially IV phosphate) and phosphate enemas can cause an acute rise in phosphate
and thus can be hazardous in patients with significant renal impairment especially those with pre-existing vascular
calcification. Intake of phosphate-rich foods (see 7 chap. 54) is rarely an issue in patients with normal renal function
but commonplace in patients with advanced CKD
Vitamin D Rare cause of hyperphosphataemia in the general population but contributory in patients with CKD (vitamin D (25
intoxication (OH) and 1, 25 (OH) levels may be helpful
Redistributive Acidosis promotes shift from extracellular to intracellular location
will lead to calcium-phosphate deposition in multiple low-phosphate diet and the purpose and importance of
tissues, the most significant being vascular and with phosphate binders (see 7 Chaps. 50 and 54).
important cardiovascular consequences including calci-
phylaxis (see 7 Chap. 51). Occasionally and particularly
in dialysis patients, a large hard mass may develop in the 13.1.45 Magnesium Disorders
soft tissue (Teutschlander’s disease) sometimes second-
ary to calcification of a haematoma. This is often pain- Magnesium is the second intracellular cation after
ful and may ulcerate, but X-ray imaging usually makes potassium and is a co-factor of several enzymatic reac-
the diagnosis fairly evident and rules out more sinister tions, and it is involved in the regulation of ion mem-
causes. Sudden acute hyperphosphataemia may lead to brane transport (e.g. for K and Ca), having a critical
acute tissue calcification, hypocalcaemia and acute kid- role in a series of biological processes including mito-
13 ney injury. chondrial function, inflammation, neuromuscular and
cardiac electrical activity and blood pressure regulation.
Of the total body content of magnesium (around
13.1.44 Treatment 26 g), nearly 99% are located in the bones (60%), 20%
of Hyperphosphataemia skeletal muscle and 19% soft tissues, leaving only 1% in
the extracellular fluid. Serum magnesium (0.3% of total)
Treatment needs to be directed at the underlying cause is ionised for nearly two thirds, and only in a smaller
and in the case of CKD covered in 7 Chaps. 50 and 54. proportion is bound to proteins and other anions.
Management of acute and severe hyperphosphataemia Magnesium balance is maintained by dietary intake and
involves prevention in the setting of TLS (see 7 Chap. absorption (small intestine via TRPM6 channel, influ-
30) and volume expansion to promote renal excretion enced by calcium steroids and PTH) and renal excretion
(if good renal function), with the possible addition of with limited shift between the intra- and extracellular
loop diuretic to promote renal excretion (with monitor- pools and the bone.
ing of calcium). Although the evidence base is weak, Good sources of Mg are green leafy vegetables,
there is at least a good theoretical argument for acute such as spinach, nuts, brown rice, wholegrain bread and
haemodialysis or haemofiltration in the setting of cocoa. Proton pump inhibitors can decrease Mg absorp-
tumour lysis syndrome or rhabdomyolysis associated tion. Magnesium is passively reabsorbed mainly in the
with hyperphosphataemia in the context of AKI and is thick ascending limb of the loop of Henle but also in the
worth considering, especially if potassium is becoming distal convoluted tubule via an active mechanism. Renal
bothersome. excretion has a primary role in finely tuning the balance,
In patients with CKD, management relies on patient and it is influenced by extracellular fluid volume, GFR,
engagement with the issue, excellent and clear edu- magnesium, calcium and phosphate levels, acid-base
cation on how to have a good and culturally relevant status, PTH and glucagon.
Common Electrolyte Abnormalities
293 13
13.1.46 Hypomagnesaemia . Table 13.19 Causes of hypomagnesaemia
The current reference range for plasmatic magnesium is Gastrointestinal Acute or chronic diarrhoea, prolonged
0.70–1.05 mmol/L. losses vomiting, nasogastric drainage, short bowel
syndrome of any cause, malabsorption of
any cause acute or chronic pancreatitis,
non-magnesium containing laxative abuse
Hypomagnesaemia (Mg <0.7 mmol/l)
Renal losses
Acquired renal Drugs: Loop or thiazide diuretics
causes especially in combination, drugs causing
Appears to be quite common in hospitalised patient tubular injury, especially aminoglycosides,
with an incidence of up to 10%. cisplatin, foscarnet, amphotericin B
These reference values have been put in question
Others proton pump inhibitors, calcineurin
lately for two main reasons. First, they were assumed inhibitors
from a healthy population of the NHANES I cohort
Endocrine: Hyperthyroidism, hyperaldoste-
(1974) rather than based on clinical outcomes (and
ronism, hypoparathyroidism (particular risk
with all the limits of a “historical” control). Second, post-parathyroidism with “hungry bone
significant evidence now supports the idea of subclini- syndrome”)
cal magnesium deficiency and of advantages of higher
High urine output: Osmotic diuresis,
magnesium levels beyond those target values. Available post-obstructive diuresis any polyuric state
evidence suggests 0.85 mmol/l as new cutoff for hypo-
Genetic renal Gitelman syndrome, Barrter syndrome,
magnesaemia [34].
causes congenital magnesium wasting (TRPM6-
Mg2+ channel), familial hypomagnesaemia
with hypercalciuria and nephrocalcinosis,
13.1.47 Causes of Hypomagnesaemia isolated dominant hypomagnesaemia with
hypocalciuria.
Hypomagnesaemia is most commonly related to gut Redistributive Movement from ECF to ICF occurs in
losses followed by renal losses or a combination of the refeeding and insulin treatment of diabetic
two, and dietary deficiency is relatively rare except in ketoacidosis
alcoholics, the malnourished and the hospital setting Inadequate Chronic malnutrition (especially if
(. Table 13.19). intake associated with diarrhoea), alcoholism,
parentral fluids/feed without magnesium
sium wasting (. Table 13.19). Bloods including urea, 13.1.51 Clinical Features
creatinine and electrolytes, calcium, phosphate, liver of Hypermagnesaemia
function, pancreatic enzymes, alcohol, glucose, albumin
and total proteins should be performed. Protein levels These relate principally to neuro- and cardiotoxicity
will influence the measurement of total plasma magne- (bradycardia, prolonged QT, widening of QRS com-
sium, so as with calcium a low serum albumin requires plex) (see Appendix 1). Paraesthesia and hyporeflexia
correction of magnesium upwards. If hypomagnesaemia occur as an early feature, as well as flushing nausea and
is confirmed, it is useful to assess the fractional excretion vomiting. In very severe cases, hypotension, hypocalcae-
of magnesium in a spot urine with simultaneous plasma mia, paralysis, ileus, urine retention, coma, heart block
level using the following equation: and ventricular fibrillation may occur.
Perhaps the most important aspect of investigation
FEMg ! # UMg " PCr $ / # PMg " UCr " 0.7 $ " 100
is the index of suspicion, i.e. checking the magnesium
In hypomagnesaemia, daily excretion of more than level particularly in patients with CKD and those likely
1 mmol (on 24-hour collection) or a fractional excretion to be chronically consuming high levels of magnesium-
>2% represents renal wasting [23, 36]. containing products. Fractional excretion of magne-
Treatment of acute severe hypomagnesaemia is via sium in the face of hypermagnesaemia may indicate
intravenous magnesium sulphate bolus and/or infusion whether there is failure of excretion or excessive intake/
but also correction of any associated hypocalcaemia production. However, in renal impairment, it is likely
and hypokalaemia, both of which are very commonly to be a combination of factors, and it is necessary to
associated electrolyte abnormalities. More chronic get a careful history of prescribed and non-prescribed
therapy involves treating the underlying cause, where medication, illicit use of laxatives and exclusion of other
possible, and supplementing with oral magnesium secondary causes (see . Table 13.20).
salts such as magnesium glycerophosphate, magnesium
oxide and magnesium carbonate although diarrhoea
is a common side effect. Lesser maintenance doses are 13.2 Treatment of Hypermagnesaemia
required for patients with CKD, and levels need to be
monitored. Treatment consists of removing any oral or IV intake and
treating secondary causes, which is usually sufficient if no
neurological signs or ECG changes. IV calcium will coun-
13 13.1.50 Hypermagnesaemia teract acute cardiac and neurotoxicity thereafter IV fluids
with or without loop diuretics (supplemented calcium
and potassium as necessary). Dialysis is highly effective
at acutely reducing magnesium and rarely necessary out-
Hypermagnesaemia is defined as a serum magnesium side significant renal impairment but worth considering
of greater than 0.9 mmol/l. for patients with treacherously high levels or CKD.
Case Studies
Case 1 sistent sickness for which the patient had been unable to
A 50-year-old patient underwent cardiac surgery for mitral eat hardly anything. ECG showed a moderate and wide
valve replacement due to severe mitral regurgitation sec- complex tachycardia. Laboratory tests were still pending;
ondary to myocardial infarction. Lab tests showed a sub- when on a blood gas, the following results were noted:
stantially normal biochemistry. After an uneventful valve Na + 130 mEq/L, K+ 8.2 mEq/L, creatinine 4 mg/dL,
replacement, he was admitted to the post-surgical ITU, bicarbonate 18 mmol/L and ionised calcium 1.0 mmol/L.
where he received IV hydration, opioids and paracetamol Despite concomitant hyponatraemia, the key element
for pain. Three days after, the patient was referred to the to address is severe hyperkalaemia which would require
renal team due to a significantly decreased urinary output urgent treatment especially in the context of ECG changes
(from 2500 to 700 ml/24 h) with dark-orange urine in suspected for metabolic toxicity. When seen by the emer-
absence of haematuria or proteinuria on the urine dip. On gency physician, the patient was prescribed with 10 ml of
examination, the patient was neurologically appropriate calcium gluconate IV in rapid infusion and with 500 ml of
and showing no features of haemodynamic instability. He sodium bicarbonate over 4 hours.
looked to be in an overall good clinical condition apart ECG changes recovered few seconds after IV calcium
from moderate peripheral oedema but with preserved cap- administration.
illary refill time; the repeated laboratory tests were as fol- Which is the other relevant question to ask in order to
lows: plan any further management of hyperkalaemia? A key
5 FBC: Hb 13,4 g/dL, WBC 4700/mcL, RBC 5 mln/mcL, element would be to know if the patient is passing urine as
HCT 43%, PLT 300000/mcL. this would be the only reliable way to decrease the total
5 Biochemistry: P-osmolality 275 mOsm/Kg, BUN body content of potassium apart from renal replacement
10 mg/dL, Na + 124 mEq/L, K+ 3.5 mEq/L, glucose therapies.
109 mg/dL, bicarbonates 24 mEq/L.
5 Urine: U-osmolality 250 mOsm/Kg, Na + 35 mEq/L, Case 3
SG 1025. A 65-year-old man was admitted to the Emergency
Department for fatigue and widespread body pain worsen-
In this case, the patient developed hyponatraemia in the ing over the last 4 months. No other symptoms where
contest of a reduction in the urinary output and with a reported apart from some constipation. There was no sig-
urine osmolality lower then plasma osmolality (inadequate nificant past medical history. Observations were in the nor-
response to a hypo-osmolar state). The first step in the mal range. Lab tests showed as follows: Hb 8.0 g/dL, WCC
clinical assessment of hyponatraemia should be the identi- 2000/ul, Plts 99,000/ul, ESR 47 mm/h, creatinine 2 mg/dL,
fication of clinical emergencies: is there any new neuro- Na and K in normal range, Ca 16.5 mg/dL, albumin 3.8 g/
logical symptom requiring urgent treatment? Second, we dL, phosphate 2.2 mg/dL, iPTH 3 pg/mL and 25 (OH)Vit
should aim to identify the causes of the disorder: in this D3 4 nmol/L.
case hyponatraemia could be a combination of post-oper- The emergency physician after noticing severe derange-
ative fluid intake and a clear over-production of ADH, ment in calcium levels requested for ECG which showed
possibly due to chest surgery and pain. no significant changes. After further discussion with his
senior colleague, a blood gas was requested, and this
Case 2 showed a normal ionised calcium. As a result, the senior
A 68-year-old woman presented to A&E complaining of physician requested for a haematological opinion.
chest tightness and severe fatigue. She was brought in by Why was the total calcium so high? The likely explana-
the ambulance crew on a wheelchair as unable to stand due tion is the presence of calcium-binding substances in the
to leg weakness over the previous few days. The daughter bloodstream. In this case it is mandatory to look for para-
reported also a history of significant weight loss and per- proteins, and myeloma becomes the main working diagnosis.
296 A. Petrosino et al.
Tips and Tricks of Electrolyte Disorders a relatively uncommon but serious adverse effect
of parathyroidectomy. Treatment relies on intra-
5 Relative urinary electrolyte concentrations are venous calcium supplementation (with following
often very helpful in swiftly distinguishing between shift to oral calcium), correction of hypomagne-
renal and extra-renal loss of electrolytes. saemia. Vitamin D is also essential after para-
5 Acute electrolyte abnormalities tend to be more thyroidectomy, but it can also be administered
dangerous than those that develop over time, and pre-operatively, together with bisphosphonates.
establishing the rate and direction of travel is of 4. Rapid correction of hyponatraemia can cause a
critical clinical relevance in determining speed and rapid rise in serum osmolality and subsequent
vigour of correction. osmotic dehydration of neural cells with central
5 Establishing close and frequent monitoring of seri- pontine myelinolysis. This is a serious condition
ous electrolyte abnormalities is vital to avoid fail- which manifests with seizure and altered state of
ure to correct or over-rapid correction; hence consciousness, up to spastic quadriparesis and
patients with significant electrolyte abnormalities reduction of respiratory function.
need to be in a place of safety. Suggested correction rates are <8–10 mEq/L
5 Artificial intelligence or just slick IT reporting of in the first 24 hours and <18 mEq/L in the first
results with early intervention by wise and experi- 48 hours.
enced experts is likely to improve patient care, and 5. Bartter syndrome is caused by mutations of a
nephrologists should have a role in developing a number of transporters necessary for the proper
safe service. functioning of the sodium potassium chloride
5 Patients with long-term predisposition to electrolyte co-transporter in the thick ascending limb of the
abnormalities may need MedicAlert bracelets or loop of Henle. Disruption of the normal water-
equivalent as well as clear instructions and stream- reabsorbing function of the loop causes severe
lined access to medical review if they become unwell. salt and water loss with the activation of renin-
angiotensin-aldosterone system and thus hyperal-
dosteronism, resulting in metabolic alkalosis and
hypokalaemia.
? Questions
1. Which are the complications of chronic hyper-
phosphataemia?
13 2. What is the therapeutic approach for a patient References
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299 14
Acid-Base Disorders
Elizabeth R. Wan and Stephen B. Walsh
Contents
References – 312
n Learning Objectives maintain the bicarbonate/ PCO2 ratio) and thus to mini-
This chapter aims to teach: mise the effect on the blood pH. This is achieved by
1. An understanding of the physiological principles increasing or decreasing the respiratory rate and is
of acid-base homeostasis therefore a rapid compensation, starting as soon as
2. An approach that is clinically useful to approach- 30 minutes after the serum bicarbonate falls.
ing a patient with a disorder of acid-base balance On the other hand, when a respiratory disorder
3. An understanding of the principles of treating causes the PCO2 to rise (respiratory acidosis) or fall
patients with disturbances of acid-base physiology (respiratory alkalosis), there is a similar compensatory
rise or fall in the serum bicarbonate. This is achieved by
either an increase or decrease in the rate of acid secre-
14.1 Introduction tion by the renal tubule (which generates bicarbonate
for the circulation). This is a much slower response than
Disorders of acid base homeostasis and their treatment respiratory compensation, taking 3–5 days to complete;
are often a source of confusion in clinical practice; this this means that the degree of compensation can be
is not helped by the varied nomenclature, the different taken as a guide to the chronicity of the respiratory dis-
ways of measuring and classifying acid base disorders order; acute disorders will have little or no metabolic
and the rationale for treating them. compensation; chronic ones will have full metabolic
This chapter outlines the methods of classifying and compensation.
diagnosing different acid base disorders and their treat- It is important to note that in simple acid base disor-
ment. Included at the end is a section detailing the man- ders, compensatory respiratory or metabolic responses
agement of some individual disorders that merit special do not return the blood pH to normal, with the possible
consideration. exception of mild chronic respiratory acidosis or alkalo-
sis, which may be fully compensated, to give a low nor-
mal or high normal blood pH, respectively. Thus, a
14.2 Determination of Respiratory/ normal blood pH in the presence of significantly altered
Metabolic Acidosis/Alkalosis serum bicarbonate and PCO2 may well indicate a mixed
acid-base disorder.
The Henderson-Hasselbalch equation (. Fig. 14.1) dic-
tates that the blood pH is determined by the ratio of the
serum bicarbonate and the PCO2. If either of these val- 14.4 Respiratory Acid-Base Disorders
ues are lowered or raised, then the blood pH will be
These are caused by ventilatory disturbances, which
14 altered; if the pH is altered by the serum bicarbonate
alter the PCO2 and thus the blood pH.
concentration, the process is a metabolic acidosis or
alkalosis; if the PCO2 change alters the pH, then it is a
respiratory acidosis or alkalosis (see Side Bar).
14.5 Respiratory Acidosis
14.3 Compensation (Respiratory/ As stated before, respiratory acidosis can be divided into
acute and chronic by the degree of metabolic compensa-
Metabolic)
tion that accompanies them.
Acute respiratory acidosis will have little or no meta-
As the pH is affected by both bicarbonate and PCO2, a
bolic compensation and will occur when an abrupt inter-
simple alteration in one of these variables is usually
ruption in ventilation occurs; this can be either due to
compensated by a change in the other in order to miti-
decreased central nervous stimulation (e.g. sedative
gate the effect on the blood pH.
drugs), neuromuscular failure of ventilatory effort (e.g.
When a metabolic disorder causes the bicarbonate to
myasthenia crisis, Guillain-Barré, flail chest) or acute
fall (metabolic acidosis) or rise (metabolic alkalosis),
airway obstruction (e.g. acute asthma, inhaled foreign
there is a compensatory respiratory response to change
object) (see 7 Box 14.1).
the PCO2 in the same direction as the bicarbonate (i.e. to
Chronic respiratory acidosis will have a much more
pronounced metabolic compensation, in some cases,
pH = 6.1 + log ([HCO3-] /(0.03 x pCO2)) enough to normalise the blood pH. Conditions which
cause it are more likely to be long-standing and ongo-
. Fig. 14.1 The modified Henderson-Hasselbalch equation ing, in the same categories as above: central nervous (e.g.
Acid-Base Disorders
301 14
cerebral disease), neuromuscular (e.g. amyotrophic lat- stimulation of ventilation (e.g. psychiatric/anxiety,
eral sclerosis, muscular dystrophy), structural/mechani- drugs, subarachnoid haemorrhage) or mechanical over-
cal (e.g. severe obesity, thoracic deformities) and chronic ventilation (e.g. over-ventilating an intubated patient).
airway obstruction (e.g. chronic obstructive pulmonary Chronic respiratory alkalosis will be more fully com-
disease) (see 7 Box 14.1). pensated metabolically and may be due to central ner-
vous system disease (e.g. stroke) or increased hypoxic
drive (e.g. high altitude, conditions with decreased alve-
Box 14.1 Causes of Respiratory Acid-Base olar gas exchange) (see 7 Box 14.1).
Disturbances
5 Acute respiratory acidosis
– Decreased CNS stimulation 14.7 Metabolic Acidosis
– Sedative drugs
– Neuromuscular ventilatory failure Metabolic acidosis can be caused by one of three main
– Guillain-Barre mechanisms: increased acid production, increased bicar-
– Myasthenic crisis bonate loss and decreased renal excretion of acid (see
– Structural/mechanical ventilatory failure 7 Box 14.2).
– Flail chest Increased acid production/ingestion:
– Tension pneumothorax 1. Lactic acidosis (e.g. hypoperfusion, metformin, alco-
– Airway obstruction hol, malignancy)
– Acute asthma 2. Ketoacidosis (e.g. diabetic ketoacidosis, alcohol,
– Inhaled foreign object fasting)
5 Chronic respiratory acidosis 3. Ingested acid (e.g. Salicylate poisoning, ethylene gly-
– Decreased CNS stimulation col ingestion, toluene)
– Cerebral disease
– Neuromuscular ventilatory failure Increased Bicarbonate Losses
– Amyotrophic lateral sclerosis 1. Bicarbonate loss through diarrhoea or ureteric diver-
– Muscular dystrophy sion, or any other cause of loss of pancreatic, biliary
– Structural/mechanical ventilatory failure or intestinal secretions
– Severe obesity 2. Renal bicarbonate loss in the proximal tubule in
– Thoracic deformities proximal renal tubular acidosis
– Chronic airway obstruction
– Tracheal stenosis Decreased Renal Acid Excretion
– Chronic obstructive pulmonary disease 1. A specific failure of acid secretion in the distal renal
5 Acute respiratory alkalosis tubule (distal renal tubular acidosis)
– Increased CNS stimulation 2. Reduced acid excretion in generalised renal failure
– Anxiety/psychiatric causes
– Drugs (e.g. aspirin)
– Subarachnoid haemorrhage Box 14.2 Causes of Metabolic Acidosis
– Increased ventilation 5 Increased acid production/ingestion
– Mechanical overventilation of an intu- – Lactic acidosis
bated patient – Hypoperfusion (secondary to any cause,
5 Chronic respiratory alkalosis e.g. hypovolaemia, cardiac failure, sepsis)
– Increased CNS stimulation – Alcohol
– Stroke – Malignancy
– Increased hypoxic drive (e.g. high altitude) – Metformin
– Nucleoside reverse transcriptase inhibitors
(e.g. stavudine, didanosine)
– Ketoacidosis
14.6 Respiratory Alkalosis – Diabetic ketoacidosis
– Alcohol
This will be caused by hyperventilation and the resultant – Fasting
excessive fall in the PCO2. – Ingested acid
Acute respiratory alkalosis will have little or no meta- – Methanol
bolic compensation and can be due to central nervous
302 E. R. Wan and S. B. Walsh
Anion gap ! # Na " K $ – # Cl " HCO3 $ " # 0.25 % # normal albumin & observed albumin $ $
14 The causes of a high anion gap metabolic acidosis 5. Much more rarely, some inherited and acquired met-
are summarised in 7 Box 14.3. An anion gap of abolic conditions may cause a high anion gap acido-
25 mmol/L or over is strongly suggestive of one of these sis (see 7 Box 14.3).
disorders.
The main causes are:
1. Lactic acidosis with increased lactate in shock, sepsis Box 14.3 Causes of a High Anion Gap Acidosis
or malignancy. 5 Lactic acidosis
2. Diabetic ketoacidosis with increased beta- 5 Ketoacidosis
hydroxybuyrate. – Diabetic ketoacidosis
3. Ingestion of acids: – Alcoholic ketoacidosis
1. Methanol with formate as the principal unmea- – Starvation ketoacidosis
sured anion 5 Ingestion of acid
2. Ethylene glycol with glycolate and oxalate com- – Ethylene glycol (also propylene glycol and
prising the unmeasured anions diethylene glycol)
3. Aspirin with ketones and lactate as the unmea- – Salicylate
sured anions – Methanol
5 Renal failure
And less commonly: 5 Toxins
4. Renal failure, which may cause a normal or increased – Iron
anion gap acidosis, the latter through the retention – Isoniazid
of sulphate, phosphate and urate.
Acid-Base Disorders
303 14
as well as the pCO2 and the presence of non-volatile
– Toluene weak acids.
5 Inherited causes This approach uses three primary variables, the
– Glutathione synthetase deficiency strong ion difference (SID), the total concentration of
5 Other acquired causes weak acids (Atot which includes proteins and phosphate)
– Pyroglutamic acid accumulation (rarely with and the pCO2.
glutathione depletion following paracetamol The SID is the sum of the strong cations (Na+, K+,
ingestion) Ca and Mg2+) minus the sum of the strong anions
2+
Also, the classification of metabolic acid-base disor- ent will increase in a variable manner as the serum pH
ders is overly complex (e.g. metabolic acidosis can be falls; in metabolic acid base disturbances, the increment
associated with normal SIDa, low SIDa, normal SIG, may be as great as 0.83 mmol/L ionised calcium per 0.03
high SIG or high Atot). pH [10].
Whilst the classical and base excess methodologies
keep a clear distinction between diagnosis and cause, the
Stewart approach tries to do both at once which can be 14.12 Metabolic Alkalosis
misleading; the concept of Atot acidosis and alkalosis is
largely groundless [7]; in vivo, there is no evidence that Metabolic alkalosis can be caused by loss of bicarbon-
changes in serum albumin correlate with changes in ate, either from the GI tract or renally, by inappropriate
pCO2 or pH [8]. The assertion that SID and Atot mecha- secretion of renal acid or by ingestion of exogenous base.
nistically determine [HCO3−] is based on mathematics,
not biology and as such does not satisfactorily establish
cause and effect, and experimental evidence for just such 14.12.1 GI Acid Loss
cause and effect is lacking [8].
The stomach secretes HCl and to a lesser extent, KCl.
Production of HCl in the stomach does not cause alka-
14.11 Treatment of Metabolic Acidosis losis as it is matched by bicarbonate secretion by the
pancreas, which is stimulated by acid reaching the duo-
The general principles of treating metabolic acidosis is denum [11]. This stimulus is missing in the case of vom-
the treatment of the underlying disorder and the resto- iting or NG tube drainage, and so alkalosis can occur.
ration of the normal extracellular pH. Urinary chloride conservation will occur in this setting,
In the acute setting, the extracellular pH can be nor- and so the urinary chloride concentration will be very
malised with alkali therapy, usually sodium bicarbon- low (<25 mmol/L); this can be an important clue if the
ate; with an aim to increase the serum pH to greater vomiting is surreptitious.
than 7.2, the point at which the serious and acute conse-
quences of acidosis should not occur.
However, this guideline does not apply in all cases, 14.12.2 Renal Acid Loss
especially where the anion will be metabolised to bicar-
bonate during recovery (see special cases, lactic acidosis Inappropriate renal acid secretion sufficient to cause a
and ketoacidosis, below). metabolic acidosis requires aldosterone excess and/or
In adequately ventilated patients with acute severe increased sodium and chloride delivery to the cortical
14 acidaemia, an appropriate replacement regime would be collecting duct. Aldosterone increases the amount of
1–2 mmol/kg sodium bicarbonate as an intravenous ENaC present in the collecting duct increasing the
bolus with a repeat dose after 30–60 minutes if the pH is absorption of sodium as well as the activity of the acid
still less than 7.1. secreting vH+ATPase. Rapid absorption of sodium and
In chronic acidosis, oral alkali treatment, usually the slow absorption of chloride generate lumen electro-
with sodium bicarbonate, is given with the aim of negativity, increasing the amount of H+ (and K+)
raising the serum bicarbonate to 22–24 mmol/L with secreted.
the aim of bone protection and often volume expan-
sion.
In the setting of metabolic acidosis, a major site for 14.12.3 Mineralocorticoid Excess
the buffering of the excess hydrogen ions is in the intra-
cellular compartment. This will tend to cause an efflux Therefore, any primary cause of mineralocorticoid
of potassium in order to maintain electroneutrality. The excess will tend to lead to a metabolic alkalosis, usually
plasma potassium concentration will rise by an average with hypertension.
of 0.6 mmol/L for every reduction in pH of 0.1. However,
this average is of a wide range (0.2–1.7 mmol/L) [9], so
the response of the plasma potassium cannot be reliably 14.12.4 Increased Sodium Delivery
predicted, and therefore calculation is no substitute for
vigilant monitoring. Diuretic use, surreptitious or otherwise will lead to meta-
As calcium binds with albumin in competition with bolic alkalosis. These patients will tend to be volume con-
hydrogen ions, pH changes can alter the amount of ion- tracted and thus also have a high aldosterone
ised calcium ions. The amount of ionised calcium pres- concentration. Urinary chloride concentration will be
Acid-Base Disorders
305 14
high during the duration of action of the drug and there- unwell, and will also depress the respiratory drive, which
after will be very low as the kidney appropriately retains is challenging for those with pulmonary disease.
chloride. The treatment of a metabolic alkalosis will aim for
A similar picture will occur with either Bartter or three goals:
Gitelman syndromes, which are caused by genetic inac- 5 Correction of chloride loss. Chloride is exchanged for
tivation of the loop of Henle sodium potassium and bicarbonate in the distal tubule and is required for
chloride cotransporter (NKCC2) and the distal convo- bicarbonate secretion. Increasing chloride delivery
luted tubule sodium and chloride cotransporter (NCC), to the distal tubule will therefore facilitate the renal
respectively. NKCC2 is the target of loop diuretics, and elimination of bicarbonate.
NCC is the target of thiazide diuretics, which is the rea- 5 Correction of hypovolaemia. This will remove the
son that loop diuretics cause the same biochemical pic- stimulus for sodium conservation that causes more
ture as Bartter and thiazides mimic Gitelman. bicarbonate to be resorbed in the proximal tubule.
Therefore, volume replacement with intravenous
sodium chloride is very effective.
14.12.5 Exogenous Base 5 Correction of hypokalaemia. Potassium will displace
intracellular hydrogen ions which move into the
Metabolic alkalosis may occur with the ingestion of extracellular space in order to maintain electroneu-
large amounts of bicarbonate (or any anion that is trality. These hydrogen ions will then buffer excess
metabolised to HCO3−, e.g. acetate or citrate). bicarbonate, ameliorating the alkalaemia.
Thus, alkalosis can occur after ingestion of large
amounts of bicarbonate or citrate and large blood trans- In oedematous patients, it may not be safe to give IV
fusions (when anticoagulated with acid citrate dextran), sodium chloride, in which case, potassium chloride may
after FFP administration after plasmapheresis or with be helpful if the patient is hypokalaemic. Alternatively,
crack cocaine (which is mainly comprised of alkaline renal bicarbonate wasting can be facilitated by giving
‘free base’). acetazolamide, which will also act as a weak diuretic.
Finally, in critically ill patients who prove resistant to
acetazolamide, intravenous hydrochloric acid can be used
14.12.6 Contraction Alkalosis via a central vein. This requires very careful monitoring,
and should not be attempted without senior and experi-
The term contraction alkalosis is still used occasionally enced supervision.
and therefore deserves some explanation; it theoretically
occurs after the loss of relatively large volumes of bicar-
bonate free fluid, which raises the plasma bicarbonate 14.14 Special Cases
concentration as there is contraction of the extracellular
fluid whilst the quantity of extracellular bicarbonate in 5 Renal Tubular Acidosis
solution remains constant. Chronic Metabolic Acidosis AG/N
Examples include rapid fluid removal with diuretics Distal renal tubular acidosis (dRTA or type 1
in oedematous patients, sweat losses in patients with cys- RTA) is caused by failure of the acid secreting alpha
tic fibrosis and congenital chloride diarrhoea. intercalated cell of the CCD to secrete acid. This
The difficulty with this concept is that other mecha- failure is most often caused by autoimmune disease
nisms to account for the alkalosis can be invoked in all (typically Sjögren syndrome, but also SLE, RA or
of these cases, increased sodium delivery to the CCD hypergammaglobulinaemia from any cause) or
with diuretics, increased aldosterone concentrations in genetic disease (mutations of the basolateral anion
volume contraction with cystic fibrosis and chloride exchanger 1 (AE1), carbonic anhydrase 2 (CA2) or
depletion in congenital chloride diarrhoea (bicarbonate the apical proton pump (inactivating mutation of
excretion depends on chloride reabsorbtion in the the A4 or B1 subunit of vH+ATPase, the forkhead
CCD). trranscription factor FOXI1 and the WD repeat-
containing protein WDR72). Genetic dRTA is rare,
with the possible exception of dRTA causing AE1
14.13 Treatment of Metabolic Alkalosis mutations in Southeast Asia, where they are some-
what more common [12]. Acquired causes are a little
Metabolic alkalosis is surprisingly common and well more common, the commonest being Sjögren syn-
tolerated, however as a persistent alkalosis will promote drome: dRTA is reported in up to 25% of Sjögren
hypokalaemia, which may be problematic in the acutely series [13].
306 E. R. Wan and S. B. Walsh
This failure to secrete acid into the urine results in from osteopenia; it will diminish the stone forma-
an alkaline urine despite a possible metabolic acido- tion/nephrocalcinosis risk and also reduce urinary
sis, osteomalacia/low bone mineral density from potassium wasting. This may be achieved with oral
chronic acidosis, (which may cause growth retarda- sodium bicarbonate (typically 1–3 g/day in divided
tion and rickets in children), hypercalciuria, nephro- doses). If hypokalaemia is a problem, oral potas-
calcinosis and kidney stone formation (calcium sium citrate (9 g/day as solution in divided doses)
phosphate stones, as CaPO4 precipitates at an alka- may be used.
line pH) and renal potassium losses leading to hypo- Proximal renal tubular acidosis (pRTA or type 2
kalaemia. The severity of the clinical features varies RTA) is caused by a failure of bicarbonate reabsorp-
greatly, even in the same families with hereditary dis- tion in the proximal tubular cell. It is usually accom-
ease. Patients can be asymptomatic and have prob- panied by generalised transport failure of that cell;
lems with recurrent kidney stones, through to the resulting glycosuria, phosphaturia, uricosuria,
life-threatening hypokalaemia or end-stage renal dis- aminoaciduria and tubular proteinuria are known as
ease from nephrocalcinosis. (See . Fig. 14.2) the renal Fanconi syndrome. It is usually caused by
An alkaline urine pH (>5.3) in the presence of a proximal tubular toxicity (e.g. tenofovir, lead),
metabolic acidosis is diagnostic of dRTA; however, myeloma or Wilson disease (see 7 Box 14.4). Two
the acidification defect may not be enough to pro- hereditary forms have been described. Although the
voke a systemic acidosis (termed incomplete dRTA); acidosis is usually milder than in dRTA due to the
in this case, a urinary acidification test can be used to acidaemia being self-limiting (due to bicarbonate
make the diagnosis, either by testing urinary acidifi- being absorbed in the loop of Henle and collecting
cation in response to a furosemide and fludrocorti- duct when the serum concentration falls below
sone challenge [14] or to ammonium chloride [15], approximately 14 mmol/L), administration of oral
which directly provokes systemic acidaemia. bicarbonate provokes an immediate bicarbonate
Correction of the acidaemia will correct the diuresis, so that the amount of oral bicarbonate
growth retardation seen in children and protect bone required to stay ahead of the increased urinary losses
is typically much higher than that needed in dRTA
and may be as high as 10–15 g bicarbonate a day.
This also enhances urinary potassium losses, so
increased potassium supplementation may be needed
when commencing bicarbonate replacement, replac-
ing up to half of the alkali as potassium citrate is a
good strategy. Serum bicarbonate and potassium
14 concentrations must be monitored and doses titrated
to achieve target levels.
of the acidosis. In both cases, this is achieved by infu- occult ethylene glycol substitution in illegally pro-
sion of dextrose to increase insulin and decrease glu- duced spirits).
cagon secretion and saline to volume expand the Unlike ketoacidosis and lactic acidosis, the inor-
patient. In alcoholics, it is important to give intrave- ganic anions generated in methanol or ethylene gly-
nous (or intramuscular) thiamine before IV dextrose col poisoning are not metabolised to bicarbonate;
to prevent precipitating Wernicke encephalopathy or they are toxic and must be removed. Therefore, treat-
Korsakoff psychosis. ment is much more active in these cases.
5 Lactic Acidosis Both methanol and ethylene glycol are both rela-
Acute Metabolic Acidosis AG: High tively harmless alcohols (both can cause sedation),
Like ketoacidosis, in lactic acidosis, the lactate but they both form very toxic metabolites when oxi-
replaces bicarbonate. Once the stimulus for lactic dised by alcohol dehydrogenase and (to a lesser
acid production is removed, lactate is metabolised to extent) aldehyde dehydrogenase.
bicarbonate, ending the acidaemia. Methanol is metabolised to formate. Formate tox-
This means that the role of alkali therapy in lactic icity causes visual impairment from optic disc
acidosis is limited to control of acute acidosis. There oedema and direct retinal damage, leading eventually
is some evidence [21, 22] that acidosis impairs car- to permanent blindness, as well as injury to the basal
diac contractility, and in severe acidosis, acute ther- ganglia, probably via mitochondrial toxicity [27].
apy with intravenous bicarbonate may improve tissue Ethylene glycol is metabolised to glycolate, glyox-
perfusion. alate and oxalate. These metabolites cause acute kid-
However, there a number of reasons to be cau- ney injury, mainly from tubular injury caused by
tious with bicarbonate replacement in lactic acidosis: glycolate, but also via oxalate precipitation in the
– Fluid overload and post-treatment metabolic kidney. The kidney injury will further delay the elim-
alkalosis when the excess lactate is converted to ination of the ethylene glycol. Hypocalcaemia may
bicarbonate, as with ketoacidosis. occur due to calcium oxalate precipitation.
– CO2 retention may be a problem in patients with Inhibition of alcohol dehydrogenase is an impor-
compromised cardiac and pulmonary function, as tant strategy, to prevent metabolism of the parent
bicarbonate buffers excess hydrogen ions, CO2 is alcohols to their toxic metabolites. Fomepizole is an
formed, and normally this would be eliminated alcohol dehydrogenase inhibitor, which is superior to
via the lungs; if the pulmonary circulation is inad- ethanol therapy, is safe and easy to administer.
equate to vent the CO2, it will be retained [23], Alternatively, alcohol dehydrogenase can be com-
adding an additional acid burden. petitively inhibited by ethanol which has a higher
– It has been proposed that intravenous bicarbonate affinity for alcohol dehydrogenase than either meth-
14 could cause a paradoxical drop in intracellular pH anol or ethylene glycol. However, it is vastly inferior
[24], worsening hepatic lactate metabolism and to fomepizole, as it is difficult to administer, monitor
cardiac contractility [22]. This was based on iso- and adjust; it is irritant to veins and most impor-
lated cell experiments, and several lines of evi- tantly causes central sedation, possibly leading to
dence show that this is probably not the case obtundation and airway compromise. Although this
in vivo [25]. is only effective if done early, co-ingestion with etha-
– Bicarbonate therapy may cause a fall in serum nol is very common and will delay the appearance of
ionised calcium by increasing calcium binding to the toxic metabolites, so it is worth attempting inhi-
albumin [26]; this could potentially worsen car- bition even hours after ingestion.
diac contractility. Alkalinisation: both formate and glycolate and/or
oxalate are more likely to penetrate their target cell
Thus, much like in ketoacidosis, the role for bicar- membranes when they are protonated (and therefore
bonate therapy is probably only for the acute control uncharged), and this is more likely to occur when the
of severe acidaemia (~pH 7.1). patient is acidaemic. There is thus a clear rationale
5 Ingestion of Methanol or Ethylene Glycol for alkalinisation with bicarbonate in these patients,
Acute Metabolic Acidosis AG: High especially as the metabolic acidosis in these cases is
Both methanol and ethylene glycol poisoning often severe (bicarbonate often as low as 8 mmol/L).
tend to occur in the setting of ethanol substitution, Intravenous bicarbonate should be given with an aim
either deliberate (i.e. drinking methylated spirits or for an arterial pH of 7.35.
deliberate self-harm) or accidental (i.e. methanol Haemodialysis is the best way to rapidly clear
contamination of domestically distilled alcohol or both the parent alcohols and their toxic metabolites.
Acid-Base Disorders
309 14
It should be started rapidly in a case of suspected about a GFR of 40–50 mls/min. After this, there will
methanol or ethylene glycol poisoning, and the be a net retention of acid, which may progress to a
patient has evidence of acidaemia, and end organ significant metabolic acidaemia.
damage (renal failure or visual impairment) confir- Even in salt- and water-retaining patients with
matory levels of methanol or ethylene glycol should advanced chronic renal failure, oral sodium bicar-
not delay treatment. Repeated courses of haemodi- bonate is well tolerated [28], and treatment of the
alysis may be necessary in massive overdoses or in acidosis has three main aims:
those whom renal failure results from ethylene glycol Retardation of the progression of renal impair-
poisoning. Haemodialysis may also shorten the ment. Oral bicarbonate supplementation has been
course of alcohol dehydrogenase inhibitor therapy. shown to retard the progression of CKD in acidotic
Haemodialysis may not be necessary in ethylene gly- CKD patients compared to patients receiving no
col ingestion if fomepizole has been given, there is no bicarbonate supplementation [29]. The mechanism
acidaemia (i.e. there is little or no glycolate circulat- for this effect is not clear.
ing), and renal function remains normal. Bone protection. As a chronic acidosis, the acido-
5 Aspirin Overdose sis of CKD causes calcium and phosphate leeching
Acute (Rarely Chronic) Respiratory Alkalosis/ from the bone in order to buffer the extra hydrogen
Metabolic Acidosis AG: High ions. Preventing this by bicarbonate supplementa-
Aspirin (and other salicylates, such as salicylic tion may delay the onset of osteopenia, in dialysis
acid and methyl salicylate) is common and can cause patients at least [30].
multiple toxic effects (tinnitus, nausea and vomiting, Improved nutritional status. Acidosis in CKD can
altered mental state and seizures, tachyarrhythmias, cause muscle wasting and weakness, probably by a
acute lung and liver injury), including a complex direct effect of the acidaemia in stimulating genes
acid-base disturbance. that promote muscle proteolysis, an effect amelio-
Salicylates directly stimulate the respiratory cen- rated by bicarbonate [31]. Bicarbonate is also benefi-
tre causing hyperventilation and respiratory alkalo- cial in preventing the growth retardation caused by
sis. This is followed by a high anion gap metabolic chronic acidosis in children with CKD.
acidosis, caused by accumulation of organic anions, 5 Surreptitious Vomiting
including lactate and ketoacids. Approximately a Chronic Metabolic Alkalosis AG: N
third of salicylate overdoses are a part of mixed The urinary sodium concentration is often used
overdoses, often with respiratory depressants, so the as an indicator of volume status. However, it should
respiratory alkalosis may be ameliorated, or a respi- be borne in mind that in acute metabolic alkalosis,
ratory acidosis may be present in these cases. the urine concentration of both sodium and potas-
Salicylate is also uncharged when protonated and sium is high, even if there is volume depletion. In
able to cross cell membranes; thus, acidaemia will fact, the urinary losses of potassium are the main
increase its delivery to target tissues. cause of hypokalaemia in vomiting, and the potas-
Alkalinisation of serum and urine is therefore sium loss in vomitus itself is minimal.
desirable, not just to reduce tissue penetration but In this setting a much better indicator of volume
also to enhance the renal elimination of the salicy- depletion is the urinary chloride concentration,
late. Intravenous bicarbonate should be given, even which will be low as the kidney appropriately retains
if there is a mild respiratory alkalosis. chloride, both for volume expansion and due to the
Haemodialysis removes salicylate and should be hypochloraemia due to chloride loss in the vomitus.
considered in patients with cerebral or pulmonary In protracted vomiting, the reabsorbative capac-
oedema, renal failure, depressed level of consciousness, ity of the nephron is increased in order to deal with
a very high salicylate level (>700 mg/dL) and clinical the increased filtered load of bicarbonate; at this
deterioration despite good supportive treatment. point, the urinary concentrations of sodium and
5 Chronic Renal Failure potassium will become very low, and the urine pH
Chronic Metabolic Acidosis AG: N will fall.
Excess acid consumed in the diet is excreted 5 Surreptitious Diuretic Abuse
renally, mainly as ammonium. In chronic kidney dis- Chronic Metabolic Alkalosis AG: N/high
ease, as the GFR falls, the ammonium production As mentioned above, the biochemical profile of a
per nephron increases to maintain normal acid excre- patient taking a loop diuretic is identical to that of
tion; however, this compensation starts to fail at Bartter syndrome, and the profile of someone tak-
310 E. R. Wan and S. B. Walsh
ing a thiazide is the same as that of Gitelman syn- 14.15 Worked Case Example
drome. If a patient is taking either of these drugs
surreptitiously, they may present as either of these A 60-year-old woman was visiting family in the UK. She
conditions. had been unwell with vomiting and fever for 2 weeks
The only biochemical clue may come from the and saw a GP who gave her antibiotics for a urinary
urine; patients with either Bartter or Gitelman tract infection.
have constant inappropriate urinary losses of chlo- She had a background of previous renal stones, high
ride. Patients on loop or thiazide diuretics will also blood pressure, recurrent urine infections and a bladder
have inappropriately high urinary chloride losses, operation 20 years before. She would normally intermit-
but only during the duration of action of the tently self-catheterise, but had not done so since arriving
diuretic, during which time, the diuretic should be in the UK. She took sodium docusate, omeprazole and
detectable in the urine. After this time, the urinary lisinopril.
chloride will fall precipitously, as the kidney tries On assessment, she was unwell with a temperature of
to conserve chloride, and the diuretic will be 37.2 °C. She was obese with BMI 41, drowsy and
undetectable. confused. Her vital signs showed pulse 85, BP 150/80,
5 Sudden Relief of Hypercapnoea JVP -1 cm, oxygen saturations 99% on room air and
Acute Metabolic Alkalosis AG: N respiratory rate 32. Her heart sounds were normal, chest
Chronic hypercapnoea will cause an appropriate was clear and abdomen was soft, with a lower abdomi-
compensatory metabolic increase in renal hydrogen nal scar. She had been catheterised with a residual vol-
ion secretion. Sudden correction of the hypercap- ume of 1300 ml and was now passing 100 ml/hr urine.
noea (e.g. by mechanical ventilation) can cause meta- Her blood results are shown in . Table 14.1.
bolic alkalosis due to the sustained high serum What is the acid-base disturbance?
concentration of HCO3−. This may be enough to She has a primary metabolic acidosis with incomplete
increase cerebral pH and cause a neurological deficit respiratory compensation.
or even death [32]. As chloride is exchanged for What are the likely causes?
bicarbonate in the cortical collecting duct, and We can narrow down the potential causes of a meta-
hypercapnoeic patients may have a chloride deficit bolic acidosis by calculating the anion gap. Note that the
[33], it is often necessary to administer IV sodium albumin is normal, and does not therefore need to be cor-
chloride to allow the excess bicarbonate to be rected for. In practice, the potassium is often excluded
excreted. from the equation because it is too small to be significant.
14
. Table 14.1 Blood results for worked case
v Answers
. Fig. 14.3 Cystogram demonstrating colo-vesical fistula
1. Although there have been a number of potential
problems posited to be associated with a chronic
Anion Gap !148" # !126 $ 4 " % 18 and well-tolerated metabolic acidosis (negative
inotropic effects, decreased protein synthesis),
This is normal, suggesting that there is NOT a large these are mainly based on animal data. Patients
increase in unmeasured anions. Causes of a normal anion with chronic, well-tolerated metabolic acidosis
gap metabolic acidosis include gastrointestinal bicarbon- (e.g. with dRTA) get bone demineralisation
ate losses, renal tubular acidosis (1, 2 and 4), ureteric (osteomalacia in adults, rickets in children) as the
diversion, post-treatment of ketoacidosis and carbonic only obvious negative effect.
anhydrase inhibition. 2. This is the most common acid-base disturbance in
Review the cystogram (. Fig. 14.3). Why has she hospitalised patients, due to problems such as
deteriorated? prolonged vomiting, diuretic use and hypokalae-
This image shows a colovesical fistula, with abnormal mia. Extremely severe cases can cause agitation,
flow of urine from the bladder into the bowel. This would delirium, seizures and coma, but this is uncom-
explain her symptoms of recurrent UTIs and loose stool. mon; it is almost never serious enough to cause
This could be a long-term complication from her previous clinical consequences outside of those with pre-
bladder surgery. existing respiratory depression.
In this scenario, the acidosis is equivalent to that 3. Absorption of bicarbonate occurs mainly in the
caused by ureteric diversion (e.g. with an ileal conduit). proximal convoluted tubule; this is therefore dis-
The degree of acidosis is determined by the length of con- rupted in the renal Fanconi syndrome. However,
tact between the bowel and the urine, in this case prolonged the disturbance can be compensated by reabsorp-
due to failure to self-catheterise, and the segment of bowel tion of bicarbonate later on in the tubule, includ-
involved. In health, the bowel secretes sodium in exchange ing in the loop of Henle and collecting duct
for hydrogen and bicarbonate in exchange for chloride. (beta-intercalated cells), which together can reab-
312 E. R. Wan and S. B. Walsh
sorb ~15 mmol/L of bicarbonate from the filtrate. Definitions (Side Bar)
This ensures the serum concentration will not fall
Acidemia An arterial pH below the normal range
lower than that in Fanconi syndrome.
(<7.36)
Supplementing patients with oral bicarbonate
delivers more bicarbonate to the filtrate and urine. Alkalaemia An arterial pH above the normal range
(>7.44)
However, large doses are needed (e.g. more than
16 g/24 hours). Also, once the reabsorption mech- Acidosis A process that tends to lower the
anism is saturated, the additional bicarbonate extracellular fluid pH. This can be
caused by a fall in the serum bicarbon-
anions in the tubules create a lumen electronega-
ate (HCO3) concentration or a rise in
tive potential which can only be equalised by CO2
P
secreting a cation, in this case potassium. Thus,
Metabolic A disorder that causes a reduction in
bicarbonate supplementation can cause hypoka-
acidosis the serum HCO3 concentration and pH
laemia.
4. Methanol and ethylene glycol are both alcohols Respira- A disorder that causes an elevation in
tory arterial PCO2 and a reduction in pH
whose metabolites are poisonous. They are both
acidosis
metabolised by alcohol dehydrogenase. The first
goal of therapy is to inhibit alcohol dehydroge- Alkalosis A process that tends to raise the
extracellular fluid pH. This can be
nase and cause a lower rate of generation of
caused by an elevation in the serum
those metabolites. This should be done with non- HCO3 concentration and/or a fall in
competitive inhibitors like fomepizole rather P
CO2
than with competitive inhibitors like ethanol, as
Metabolic A disorder that causes an elevation in
dosing is safer, and patients will already have alkalosis the serum HCO3 concentration and pH
alcohol intoxication from their poisoning.
Respira- A disorder that causes a reduction in
Second, the toxic metabolites (formate and oxa-
tory arterial PCO2 and an increase in pH
late, respectively) cross cell membranes best when alkalosis
they are chargeless (i.e. they are proton bound),
Simple One of the four acid-base disorders
so increasing the systemic pH of the patients will
acid-base with or without the appropriate
help reduce the cell toxicity of the metabolites. disorders compensatory response
Lastly, the parent alcohols and their toxic metab-
Mixed Having two (or more) of the above
olites are all small molecules that will cross a
acid-base disorders at the same time
dialyser membrane and can therefore be dialysed disorder
out. Poisoning with ethylene glycol or methanol
14 is therefore an indication for emergency haemo-
dialysis.
5. Classical acid base theory has been well validated
and accepted in clinical correlation, whereas the References
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betic ketoacidosis. Am J Med. 1983;75(2):263–8. intake. J Clin Invest. 1961;40:1238–49.
315 IV
Hypertension and
Renovascular Diseases
Contents
Approach to Hypertension:
Diagnosis and Investigation
Roohi Chhabra, Reecha Sofat, Aroon Hingorani, and Jennifer Cross
Contents
References – 332
Approach to Hypertension: Diagnosis and Investigation
319 15
Hypertension is one of the most common chronic medi- indication of the strength of the relationship, for those
cal conditions and the single most important prevent- between 40 and 69 years for every 20/10 mmHg rise in
able cause of premature death in developed countries. BP above 115/70 mmHg, cardiovascular risks roughly
It presents a significant burden of disease to society as double [2] (. Fig. 15.1). The converse is also true; reduc-
persistent uncontrolled hypertension is associated with tion of blood pressure by 20/10 mmHg approximately
coronary artery disease, cerebrovascular disease and halves the risk of cardiovascular events. BP also shows a
renal impairment. The prevalence of hypertension rises continuous, independent relationship with CKD, heart
with age, affecting 60% of the population over the age of failure and peripheral artery disease. According to the
60. Among young adults (18–39 years), approximately Global Burden of Disease 2000 study, approximately
20% of men and 15% of women have been diagnosed 50% of strokes and MIs can be attributed to hyperten-
with hypertension in the USA. Forty-five percent of sion and an estimated 7.6 million deaths per year (13.5%
the adult population worldwide has hypertension, and of all deaths worldwide) [3].
recent estimates suggest that this number may increase The relationship between CKD and hypertension is
by as much as 15–20% by 2025 [1]. complex, given the kidney’s role in regulation of body
Most cases of hypertension are idiopathic or essen- fluid volumes and BP homeostasis. More than 80% of
tial with no identifiable underlying cause. In 5–10% of CKD patients are hypertensive and teasing out whether
cases, hypertension is related to an underlying disorder the hypertension is primary, and the cause of the CKD
or secondary; this is termed secondary hypertension can be a challenge. However, data from cohort studies in
which is most commonly related to diseases of the kid- patients with hypertension and no baseline renal disease
ney such as diabetic nephropathy but also vascular and demonstrate a graded relationship between increasing
endocrine disorders. Given the magnitude and impor- BP and the development of CKD [4] suggesting that it
tance of hypertension as a risk factor for cardiovascular relates to BP control.
and renal disease, this chapter will discuss the approach
to defining and diagnosing hypertension before discuss-
ing the approach to investigation of patients with sus- 15.2 Defining Hypertension and Setting
pected resistant and secondary hypertension. Treatment Thresholds
Definition BP has a well-recognised skewed normal distribution in
Hypertension is arbitrarily defined as a persistently the population, and given the continuous log linear rela-
elevated arterial blood pressure with a current thresh- tionship with cardiovascular and renal disease, down to
old exceeding 140/90 mmHg in adults. at least a level of 115/70 mmHg [2], the BP cut-off that
Accelerated hypertension (also known as malig- defines ‘hypertension’ is arbitrary.
nant hypertension) is a severe increase in blood pres- Definitions of hypertension and treatment thresholds
sure ≥180/120 mmHg associated with new or and targets have been issued by more than 100 organ-
progressive end-organ damage such as retinopathy. isations worldwide including the National Institute of
Clinical Excellence (NICE) in the UK [5], the American
Heart Association (AHA) [6], European Societies of
Hypertension (ESH) and Cardiology (ESC) [7, 8],
n Learning Objectives Japanese Society of Hypertension (JSH) [9] and the
The aims of this chapter are to explore the causes of World Health Association (WHO) [10].
complex or difficult to manage hypertension and to . Table 15.1 summarises the definitions of hyper-
understand the diagnostic approach to patients with tension used in these particular guidelines. All of these
complex or multi-agent hypertension. sample guidelines agree that the term hypertension be
applied to a patient with a clinic BP of ≥140/90 mmHg.
However, BP is further subdivided using a variety of
15.1 Introduction terms such as optimal, normal, high-normal, pre-
hypertension and grades (or stages) 1–3.
Hypertension is the most prevalent, modifiable risk fac- Treatment thresholds and targets differ between guide-
tor for cardiovascular disease (CVD), stroke, chronic lines, but there is clear consensus in all guidelines delin-
kidney disease (CKD), heart failure and peripheral arte- eating between low- and higher-risk groups. High-risk
rial disease. groups are those with additional cardiovascular risk fac-
The risk of death, myocardial infarction (MI) and tors, including diabetes mellitus (DM), established CKD,
stroke has a continuous relationship on a log scale with pre-existing cardiovascular disease (including cerebrovas-
both systolic and diastolic blood pressure (BP), though cular, heart disease and peripheral arterial disease), sub-
the relationship is steeper for stroke than MI. As an clinical end-organ damage (. Table 15.2) or a ‘10 year
320 R. Chhabra et al.
IHD mortality
16 16
40–49
40–49
years
years
8 8
4 4
2 2
1 1
. Fig. 15.1 Association between blood pressure and ischaemic heart disease
Heart
Left ventricular hypertrophy ECG Sokolow-Lyon >38 mm Havranek EP et al.
(15)
Echocardiogram LVMI M ≥ 125 g/m2, Milani RV et al. (16)
W ≥ 110 g/m2
Arteries
Carotid intima-media thickening (IMT) Ultrasound Doppler IMT >0.9 mm Zanchetti A et al. (17)
carotid
Renal
Low estimated glomerular filtration rate Serum eGFR <60 ml/min/1.73 m2 Tsioufis C et al. (18)
(eGFR) (MDRD formula)
Microalbuminuria Urine dip 1+ protein
(proceed to measure of
quantity)
Random urine: albumin/ M > 22 W > 31 mg/g Cirillo M et al. (19)
creatinine ratio creatinine
24-hour urine collection 30–300 mg/24 h
Cerebrovascular
Small vessel ischaemia MRI Presence of cerebrovascular Kearney-Schwartz A
lesions et al. (20)
Retinal
Hypertensive retinopathy Fundoscopy ≥Grade 2 changes Kim GH et al. (21)
aInvestigationsin bold are first-line and should be performed in all patients; others may have a role in selected patients
bThresholds (other than fundoscopy) taken from 2007 ESH guidelines [12]
cReference provided is an example of a study demonstrating an association between the end-organ damage in question and cardiovas-
cular end-points
culated 10-year cardiovascular risk. In general, such treatment (to a nadir of 110 mmHg systolic). This is in
patients are underrepresented in clinical trials, as the keeping with evidence from prospective observational
selection of high-risk patients maximises event rate and studies that predict lowering BP by this degree confers a
thus the power of trials. Furthermore, most trials are of similar magnitude of protection [2]. The authors of this
a short duration (4–5 years), whereas the additional life review suggested that their results indicated the impor-
expectancy for middle-aged hypertensives is 20–30 years. tance of lowering blood pressure in everyone over a cer-
Consequently, there is a lack of high-quality evidence tain age (55 years old), rather than in just those with
and therefore consensus regarding treatment thresholds higher-risk profile.
in this cohort. Despite this data, guidelines differ in their recom-
In the largest overview of blood pressure treat- mendations for low-risk individuals.
ment trials conducted by Law et al. [11], all patients All guidelines agree that treatment should be com-
who achieved a sustained BP reduction over 5 years menced when the clinic BP is >160/100 mmHg. However,
of 5–6 mmHg in systolic BP recorded a reduction in there is variance. The guidelines produced by NICE,
coronary events by approximately 20% and strokes by WHO and JSH do not recommend treatment in this
40% [11]. The percentage reductions in CVD events group when BP is between 140 and 160 mmHg [5, 9, 10].
and stroke were similar in people with or without car- However, the ESH and the AHA [6, 7] do recommend
diovascular disease regardless of blood pressure before treatment if BP is uncontrolled by lifestyle measures.
322 R. Chhabra et al.
15.4 Measuring Blood Pressure emphasis is being put on the value of ambulatory blood
and Diagnosing Hypertension pressure measurement (ABPM) in diagnosing hyperten-
15 sion.
The extremely large evidence base on which the treat-
ment for hypertension is based, including cohort stud-
ies with approximately one million participants and 15.5 Ambulatory Blood Pressure
randomised studies in over 500,000 individuals [11], is Measurement (ABPM) in the Diagnosis
based on using clinic BP measurements. Such measure- of Hypertension
ments are cheap and readily available and require no
specialised training or equipment over and above what is ABPM requires a patient wearing a cuff and bladder con-
usually available in a clinic setting, and treatment based nected to electronic sensors which measures BP by the
on these measurements is cost-effective, worldwide. oscillometric technique. Serial BP measurements are per-
However, BP can be highly variable and is influenced formed (usually every 30–60 minutes), while going about
by multiple factors including the time of day, posture, their daily routine, over a period of time (usually 24 hours).
stress, pain, room temperature, etc. Indeed, even with This allows their diastolic and systolic blood pressures to
serial back-to-back measurement, BP reproducibly falls. be plotted over time and allows calculation of various
Thus, one-off clinic readings, even performed under measures, including mean ambulatory BP over 24 hours,
ideal conditions, may give limited information about diurnal variation (by comparing mean BP at night with the
a patient’s BP and thus cardiovascular risk. In order daytime mean) and the overall range and variability of BP.
to overcome this limitation, multiple measurements Of nine cohort studies identified by the NICE 2011
over time are required to make a diagnosis, and this is clinical guideline, eight (including over 25,000 patients)
advocated in multiple guidelines. However, increasing found that mean 24-hour blood pressure values derived
Approach to Hypertension: Diagnosis and Investigation
323 15
from ABPM were more strongly associated with and first reading and repeating at 2-minute intervals while
therefore more accurately predict cardiovascular events the BP is above target and once achieving target to
than standard clinic measurements [5]. reduce the frequency of monitoring to weekly or even
The authors of the NICE guideline were persuaded monthly. Recording BP at home may be regarded as a
to recommend (somewhat contentiously) that ABPM healthy lifestyle choice to confirm control and monitor
be used in all patients with a clinic BP greater than treatment efficacy and provides patients with control
140/90 mmHg to confirm the diagnosis of hypertension recording results in smart phone apps and is an effec-
[5], but not to use ABPM in monitoring the response tive way of communicating results over time to primary
to treatment. At present, of the major hypertension and secondary care. Various apps exist that will in future
guidelines, only NICE have recommended using ABPM allow us to download this data set to healthcare systems.
to make the diagnosis of hypertension in all patients.
Other international guidelines recommend its use in
a more targeted fashion. Other indications for its use 15.7 Resistant Hypertension
include investigating patients with suspected resistant,
white coat or masked hypertension and monitoring Resistant hypertension is defined as hypertension (clinic
response to treatment, particularly when there is a con- BP >140/90 mmHg) despite treatment with a rational
cern regarding iatrogenic hypotension. combination of at least three antihypertensive agents,
Although the predictive value of ABPM is well estab- or controlled hypertension on four agents including a
lished, there is no randomised evidence to guide the diuretic. It excludes non-adherence. Cohort studies sug-
selection of an average BP threshold at which treatment gest a prevalence of 10–15% among those diagnosed
would be indicated. In an effort to address this, Head et al. with hypertension [14]. Apparent resistant hyperten-
[13] compared mean 24-hour BP and mean daytime BP sion may be due to white coat hypertension (WCH) and
(n = 8575) with clinic BP in a different cohort (n = 1693), poor adherence with prescribed medication, which may
and using least product regression analysis established that be as common as 50% of cases or due to a secondary
clinic BP was 6/3 mmHg higher than daytime mean ambu- cause. Careful clinical evaluation of patients with sus-
latory BP and 10/5 mmHg higher than 24-hour mean pected resistant or secondary hypertension is critical as
ambulatory BP. The differences were more marked at the diagnosis may significantly alter treatment. A list of
higher BPs. On the basis of this data, the ABPM daytime suggested first-line investigations in patients with resis-
equivalent to 140/90 mmHg in guidelines is 135/85 [10]. tant hypertension is presented in . Table 15.4.
The overall impact of utilising ABPM more fre-
quently in clinical practice is yet to be fully appreciated.
. Table 15.4 Suggested first-line investigations in resistant
hypertension
WCH or ‘isolated clinic hypertension’ is a condition in Masked hypertension or isolated ambulatory hyperten-
which BP measured in clinic is hypertensive, but that sion is the inverse of WCH, in which clinic BP mea-
measured out of the clinic is normal where the intro- surements are <140/90 mmHg, whereas the mean BP
duction of routine ABPM or home monitors allows its on ABPM is elevated (>135/85 mmHg). This occurs in
identification. This phenomenon is observed in approxi- approximately 15% of the population [17], and since the
mately 30% of patients with a clinic BP >140/90 mmHg associated cardiovascular risk is similar to that of sus-
[15], and the prognosis of these patients is good com- tained hypertension, it represents a significant diagnos-
pared with those with sustained hypertension. However, tic challenge. A high index of suspicion is warranted in
whether or not the patients with WCH should be treated patients with a normal clinic BP who have multiple car-
with antihypertensives is controversial. diovascular risk factors and evidence of organ damage.
Several studies have linked WCH with subclinical
end-organ damage including left ventricular hypertro-
phy and proteinuria; however, these findings have not 15.10 Adherence
been reproduced across all studies. Multiple longitudi-
nal studies suggest that WCH increases the long-term Poor adherence is a major cause of lack of blood pres-
risk of stroke, cardiovascular events and all-cause sure control and, along with WCH, accounts for the
mortality but to a significantly lesser degree than sus- majority of patients who appear to have resistant hyper-
tained hypertension. The relative risk of WCH versus tension. Retrospective analyses indicate that up to 40%
sustained hypertension is nicely demonstrated in the of patients with newly diagnosed hypertension will dis-
Kaplan-Meier curves derived from the PAMELA study continue their medication the first year of treatment [18]
(. Fig. 15.2) [16]. and over 5–10 years this figure may rise to over 60 [19].
Thus, patients with WCH appear to have an interme- Adherence or compliance with medication is complex
diate risk of cardiovascular events, compared with nor- and is commonly not deliberate. Assessing adherence
motensives and hypertensives. Several reasons for this is difficult. Patients rarely report it and often wish to
increased risk have been proposed, most notably that comply but cannot comply. Several strategies have been
BP variation (inherently higher in those with white coat developed to overcome this, including directly observed
hypertension) is itself an independent risk factor for therapy and measurement of urinary or serum antihy-
cardiovascular events and that over time, a significant pertensive levels. Directly observed therapy may neces-
proportion of patients with WCH develop sustained sitate an admission to a day ward or overnight inpatient
hypertension. stay and should be conducted with caution – giving
ABPM is the investigation of choice to investigate multiple prescribed antihypertensives to a patient who
whether a patient has WCH. has not been taking them in the community may cause
15 profound and life-threatening hypotension; thus giving
only 1–2 agents initially is advised.
100
Once this diagnosis is established, management can
be a challenge, but focusing on patient’s motivations and
95 considering side-effect profiles of available antihyperten-
sives should both form part of the strategy. Educating
the patient about the condition as well as using patient-
Survival (%)
90
centred techniques such as motivational interviewing is
likely to increase adherence [20].
85 It is important to explore and determine possible
Normal blood pressure non-intentional (e.g. forgetfulness) and intentional (e.g.
80 White-coat hypertension unhelpful beliefs about medication-taking) lapses in
Sustained hypertension medication-taking behaviours. In one study conducted
at the Royal Free Hospital, renal unit, the Medication
0
Adherence Report Scale (MARS) [21] demonstrated
. Fig. 15.2 Kaplan-Meier curves depicting the survival of patients discrepancies between patients’ reported antihyperten-
with normal BP (red), WCH (light grey) and sustained hypertension sive treatment adherence and their corresponding urine
(dark grey) analysis with approximately one-fifth of the patients
Approach to Hypertension: Diagnosis and Investigation
325 15
under-reporting their non-adherence. Furthermore, con-
. Table 15.5 Causes of secondary hypertension
flict between patients’ concerns and worries about taking
medication and their beliefs about its necessity in manag- Condition Symptom/sign
ing their blood pressures was shown in the beliefs about
medicines questionnaire (BMQ) with this ‘conflict’ being Renal
greater than that found in similar studies of medication- Renal parenchy- Mostly asymptomatic
taking in other long-term conditions [22]. mal disease
Renal artery Renal bruit, rise in serum creatinine
stenosis >30% after initiation of angiotensin-
15.11 Secondary Hypertension converting enzyme inhibitor
Distal tubular Mostly asymptomatic
Secondary hypertension is hypertension in which there
disorders
is an identifiable cause. It is thought to account for up
to 10% of patients with hypertension although this fig- Endocrine
ure is likely to increase with the increasing prevalence Primary Mostly asymptomatic
of chronic kidney disease and obesity. In addition to aldosteronism
patients with apparently resistant hypertension, second- Pheochromocy- Episodic headaches, sweating, palpita-
ary causes should be considered in those who present: toma tions, flushing
1. Young (<40 years)
Cushing’s Moon faces, central obesity, easy bruising
2. With accelerated hypertension/hypertensive emer- syndrome
gencies
Hypothyroidism/ Symptoms of hypothyroidism or
3. Have suddenly worsening hypertension
hyperthyroidism hyperthyroidism, e.g. gain/loss of weight,
4. Severe end-organ damage cold/heat intolerance
5. Family history of early onset hypertension/stroke
Hyperparathy- Bone pain, stones, abdominal pain,
roidism constipation
Secondary causes of hypertension may be split into four
broad groups: (i) renal, (ii) endocrine, (iii) drugs (see Acromegaly Headache, visual field defects, macro-
glossia
7 Box 15.2) and (iv) ‘other causes’. A comprehensive
summary of these is presented in . Table 15.5. The Carcinoid Cutaneous flushing, venous telangiecta-
most important of these will now be discussed. syndrome sia, diarrhoea, bronchospasm
Other
Coarctation of Radio-femoral delay
Box 15.2 Drugs Which Increase BP aorta
5 Oestrogens (e.g. in contraceptives) Obstructive sleep Daytime somnolence, fatigue, obesity
5 Non-steroidal anti-inflammatory drugs apnoea
5 COX-2 inhibitors
Obesity Mostly asymptomatic
5 Weight-loss agents (amphetamine-related)
5 Stimulants (e.g. cocaine) Pregnancy Headache. Blurring of vision, fluid
(pre-eclampsia) retention
5 Mineral and glucocorticoids
5 Antiparkinsonian agents (serotoninergic) Medication See 7 Box 15.2
5 Monoamine oxidase inhibitors (serotoninergic) Familial Sensorimotor neuropathy, sympathetic
5 Anabolic steroids dysautonomia storm
5 Sympathomimetics including decongestants
5 Migraine treatments (triptans – serotoninergic)
5 Calcineurin inhibitors
15.12.1 Renal Parenchymal Disease
15.12 Renal Causes of Secondary Renal parenchymal disease is the most common cause
Hypertension (50–75%) of secondary hypertension. Hypertension
may occur in the course of glomerulonephritis, vas-
These can be broadly divided into (a) diseases of renal culitis and almost any cause of reduced GFR. The
parenchyma, (b) renovascular hypertension and (c) dis- mechanisms leading to hypertension in kidney disease
tal tubular disorders. includes impaired urinary sodium and water excretion
326 R. Chhabra et al.
resulting in volume overload, excessive release of vaso- The gold-standard diagnostic test is intravenous
constrictors (renin, angiotensin II) and sympathetic contrast-enhanced digital subtraction angiography.
activation. However, non-invasive tests are often sufficient in con-
CKD itself is associated with a marked escalation of firming the diagnosis. Due to its wide availability and
cardiovascular risk increase; thus, all patients with newly low cost, ultrasonography and colour Doppler stud-
diagnosed hypertension should have serum urea, creati- ies are often the first imaging study used to investigate
nine and electrolytes measured and an estimation of glo- RAS; however, results are operator-dependent, and
merular filtration rate (eGFR) as well as a urine dip for stenotic lesions are often missed. Preferable imaging
protein, erythrocytes and leucocytes. There should be a modalities are computed tomography (CT) and mag-
robust referral pathway for patients with renal impair- netic resonance (MR) angiography. Both have sensitivi-
ment or an abnormal urine sediment. ties over 90%, and the choice of modality may be guided
by factors such as renal function and the presence of
implanted devices. MRI tends to overestimate RAS par-
15.12.2 Renovascular Hypertension ticularly if there is generalised vascular calcification.
(See Chap. 17 on Renal Vasculature) Rarer causes of renovascular hypertension include
middle-aortic syndrome, Takayasu’s arteritis, which
Renal artery stenosis (RAS) is a common cause of sec- primarily affects women in 80–90% of cases and may
ondary hypertension. The vast majority is atheromatous be expected in case of absent or diminished peripheral
in origin and risk factors include long-standing hyper- pulses, most commonly at the level of radial arteries.
tension, diabetes, smoking and dyslipidaemia. Other rare causes include page kidney (acute hyper-
Its prevalence in the general hypertension population tension secondary to intra capsular haematoma) and
is approximately 2–5% and is more than 30% in patients suprarenal coarctation of the aorta.
undergoing cardiac catheterisation and may account for
up to 14% of patients with end-stage renal failure. The
culprit stenoses are of the conduit renal arteries and are 15.12.3 Coarctation of the Aorta
most commonly caused by atherosclerotic plaques but
may also be the result of vasculitis, neurofibromatosis, Coarctation is a rare but important cause, representing
congenital bands and extrinsic compression. about 6–8% of all congenital heart disease and 1 in 2500
In a young patient with RAS, it is important to con- births [30]. It is seven times more common in white than
sider fibromuscular dysplasia (FMD) as a potential Asian children. Patients may present as children or adoles-
cause. FMD is a noninflammatory, non-atherosclerotic cents with symptoms of dyspnea, leg cramps on exercise,
disorder that leads to arterial stenosis, and most fre- chest pain, fainting and shortness of breath but are increas-
quently involved are the renal and carotid arteries. It is ingly identified earlier because of other congenital heart dis-
more common in young women in the third and fourth ease or as investigation of mid-systolic murmur (radiating
15 decade, and its aetiology remains unknown, although to the back). Making the diagnosis is critical as untreated
various hormonal, mechanical and genetic factors have there is 80% mortality by 50 years. Cool feet and poor
been suggested. The angiographic appearance of FMD lower limb pulses are a strong clue; radio-femoral delay and
is classified as multifocal FMD, where the classic ‘string- unequal blood pressure in limbs are non-invasive and useful
of-beads’ appearance is seen typically in the middle and simple clinical examinations (. Figs. 15.3 and 15.4).
distal two-thirds of the main renal artery (unlike athero-
matous RAS which is usually ostial), and focal FMD,
where a concentric, smooth, band-like focal stenosis 15.12.4 Distal Tubular Disorders
is seen. FMD is highly responsive to revascularisation
with angioplasty and should be attempted in those with Rare, inherited dysfunctions of the distal renal tubule
evidence of symptomatic disease (renovascular hyper- can cause increase sodium absorption and hypertension.
tension and renal atrophy). The most important of these is Liddle’s syndrome.
Classically, RAS is suggested by the presence of Liddle’s syndrome is the result of mutations in the
hypertension, fluid overload, an abdominal bruit though genes which encode the amiloride-sensitive epithelial
this is very poor at discerning, progressive deterioration sodium channel (ENaC) in the distal nephron which
of renal function, acutely worsening renal function after increases both the numbers and activity of the channels.
the introduction of an angiotensin-converting enzyme This results in increased sodium and water retention and
(ACE) inhibitor (poor sensitivity and specificity) and therefore hypertension. It is inherited in an autosomal
episodes of unexplained flash pulmonary oedema or dominant fashion and is probably the most common
angina. type of monogenic hypertension. It usually presents in
Approach to Hypertension: Diagnosis and Investigation
327 15
Another, familial autosomal disease of the distal
nephron is Gordon’s syndrome (pseudohypoaldoste-
ronism type II). Gain-of-function mutations in the
thiazide-sensitive sodium chloride co-transporter result
in excessive sodium and chloride reabsorption, hyper-
tension and hyperkalaemia.
A good initial screening test is measurement of Confirmatory functional tests involve aldosterone
plasma renin levels, with or without the addition of suppression utilising oral or intravenous salt loading,
plasma aldosterone levels and calculation of a renin/ fludrocortisone or captopril, although these are seldom
aldosterone (R/A) ratio. used in practice. The ARR criterion is highly sugges-
A suppressed renin and elevated aldosterone – result- tive of primary aldosteronism, but in equivocal cases,
ing in an elevated ratio (>800) is suggestive of primary a saline suppression or captopril challenge test is more
aldosteronism; however, a ratio >2000 with aldosterone discerning. CT or MR imaging is required to identify
>250 pmol/L makes the diagnosis almost certain in the the presence of an adenoma. The absence of adenoma
absence of polluting drugs which must be omitted prior does not exclude the diagnosis, and in a small minority
to testing as the results may be uninterpretable. of cases, visible adenomas are not the source of aldo-
However, this test must be interpreted with caution sterone.
in the elderly or black patients who tend to have lower Subsequently, adrenal vein sampling (AVS) allows
renin levels and those on drugs which interfere with the for confirmation and localisation of the primary aldo-
renin-angiotensin-aldosterone pathway (. Table 15.6). steronism to one or both adrenals. The success rate of
15 This is clearly a common problem in patients with resis- this procedure depends on accurate cannulation of both
tant hypertension that may be on several of these agents. adrenal veins. The adequacy of AVS is determined by
Ideally, the antihypertensives are stopped between 2 and the ratio of cortisol concentration in the adrenal vein
6 weeks prior to the measurement of serum renin and and in the inferior vena cava. AVS is a technically chal-
aldosterone levels. Beta blockers have the biggest impact lenging procedure that should be carried out by an expe-
and make the ratio uninterpretable as they prevent renin rienced practitioner.
release. Alpha-blockers, diltiazem, or hydralazine can AVS is particularly important as identified adeno-
be used to treat the hypertension during this period. mas may be non-functioning or may in fact be the result
Calcium channel blockers have unpredictable effects of nodular hyperplasia.
on renin and aldosterone but are nonetheless com- More recently, positron emission tomography (PET)
monly used to control blood pressure in such patients. CT, utilising the radiotracer (11) C-metomidate, a
Spironolactone has a long-acting effect and should be potent inhibitor of adrenal steroidogenic enzymes, has
omitted for 6 weeks prior to testing. Time of day, pos- been developed as a non-invasive alternative to adrenal
ture and serum potassium levels are other important vein sampling [27].
factors which may affect renin. Ideally potassium should Rarer causes of mineralocorticoid excess include the
be corrected into the normal range, and R/A ratio fol- following:
lowing normal saline infusion is said to be more specific. 1. Congenital adrenal hyperplasia – Defects in
Test is positive if aldosterone (pmol/L)/Renin (mcg/L/ 11-hydroxylase and 17-hydroxylase (key enzymes in
hr) (ARR) >550 and aldosterone >416 pmol/L. the production of adrenal steroids) result in excessive
Approach to Hypertension: Diagnosis and Investigation
329 15
accumulation of intermediate products with miner- abdomen, urinary bladder or mediastinum. They can be
alocorticoid activity. In addition to hypertension, inherited, often as part of a multiple endocrine neopla-
patients have genital ambiguity. sia syndrome or acquired.
2. Glucocorticoid-remediable aldosteronism – A rare The diagnosis should be suspected in patients who
autosomal dominant disorder in which a fusion of report episodic headaches, palpitations (64%) and
two genes results in aldosterone production being sweating (70%) in addition to hypertension. Episodic
stimulated by adrenocorticotropic hormone (ACTH). pallor, tremor, flushing, epigastric pain, dyspnea, syn-
3. Apparent mineralocorticoid excess – A rare autoso- cope and hypotension are also important though less
mal recessive disorder in which an inactivating muta- common findings. It can also present with hypokalae-
tion of the 11 B-hydroxysteroid dehydrogenase type mia. Of note, previous cohort studies have suggested
II enzyme allows cortisol to activate the mineralo- that up to 70% of such patients are hypertensive, but
corticoid receptor. since many are now picked up incidentally, hypertension
4. Exogenous mineralocorticoid excess – May be the is only a feature in approximately half. Screening tests
result of fludrocortisone administration or excess (in order of sensitivity) include plasma-free metaneph-
licorice ingestion. rines (99%), urinary fractionated metanephrines (97%),
urinary and plasma catecholamines (85%), urinary total
metanephrines (77%) and vanillylmandelic acid (VMA)
15.13.2 Cushing’s Syndrome (64%) (. Fig. 15.6).
Confirmatory tests include glucagon stimulation
Cushing’s syndrome is caused by excess glucocorticoids, and clonidine suppression tests, and cross-sectional
which is most commonly iatrogenic. It may also be due imaging is required to localise the tumour. In the case
to over production of ACTH by the pituitary gland of extra-adrenal tumours, isotopic scanning with meta-
(Cushing’s disease) or by production of cortisol by a iodobenzylguanidine (MIBG) can be of use.
tumour of the adrenal gland or rarely by ectopic release
from another organ or gland. The syndrome affects
<0.1% of the total population but causes hypertension 15.14 Other Causes of Secondary
in approximately 80% of those affected [28]. Hypertension
Screening tests include 24-hour urinary cortisol
excretion (sensitivity 76–100%, specificity 95–98%) There are several other secondary causes of hyperten-
and the single-dose (1 mg) dexamethasone suppression sion which are listed in . Table 15.5. Obstructive sleep
test (sensitivity 95%, specificity 86%) where a normal apnoea and obesity are particularly important causes
response is suppression of serum cortisol to less than which will now be discussed further.
50 nmol/L. Positive results should be confirmed by per-
forming at least one other tests or midnight cortisol.
Prednisolone should be stopped at least 24 hours prior 15.14.1 Obstructive Sleep Apnoea
to the test as it cross reacts with assays and has a half-life
of 3.5 hours and so takes 16–18 hours to be adequately There is a strong association between obstructive sleep
cleared from the circulation. apnoea (OSA) and hypertension (present in 50–90%
Subsequent localising tests include plasma ACTH, of patients with OSA and with increasing severity, the
long dexamethasone suppression tests and the cortico- associated hypertension is more difficult to control). The
trophin-releasing hormone stimulation test. proposed mechanism to explain this association is that
intermittent hypoxaemia induces a sustained increase
in sympathetic nervous system activity, which intern
15.13.3 Pheochromocytoma raises blood pressure by well-described mechanisms.
The cardiovascular risk of OSA is a significant and an
Pheochromocytoma is a rare cause of secondary hyper- important cause of hypertension not to miss. Loss or
tension accounting for <0.5% of patients with hyperten- reversal of nocturnal dipping (the usual 10% drop in BP
sion (M/F 2:1), but some case series have reported an at night) may be prominent, and a clue but history or
incidence of 4% in patients with resistant hypertension body habitus of OSA should prompt exclusion of OSA
[29]. Approximately 85% arise from the adrenal glands, as a contributor to hypertension as correction can some-
with the remainder, termed ‘paragangliomas’ arising times have a marked effect on hypertension and cardio-
from extra-adrenal chromaffin tissue, typically in the vascular risk.
330 R. Chhabra et al.
Case Study
Case 1
A 45-year-old male with no past medical history presented
15 with a 4-month history of headaches and generalised weak-
ness. On examination, physical examination was unremark-
able apart from a BP of 190/105 mmHg, which was initially
treated with a calcium channel blocker. Initial investigation
revealed Na 132 mmol/L, K 3.3 mmol/L, urea 4 mmol/L, Cr
100 μmol/L and bicarbonate 36 mmol/L. In view of hyper-
tension and hypokalaemic alkalosis, an aldosterone to renin
ratio was checked and was found to be consistent with the
suspected diagnosis of primary hyperaldosteronism. An
abdominal CT showed slight enlargement of the left adrenal
gland (. Fig. 15.5). This was followed by adrenal vein sam-
pling which confirmed left-sided lateralisation of plasma
aldosterone concentration. A left adrenalectomy was per-
formed which had a good clinical and biochemical response.
Treatment includes medical therapy with mineralocorticoid
receptor antagonist for bilateral disease and adrenalectomy
for unilateral aldosterone producing adenoma.
Contents
References – 350
Management of High Blood Pressure
337 16
n Learning Objectives 16.2 Non-pharmacological Management
1. To explore the treatment of high blood pres- of Hypertension
sure with lifestyle modifications and various drug
classes to prevent end-organ damage and identifi- Many patients, particularly those age group under 40
cation of the indications and contraindications of and some patients from BAME groups, find the concept
specific drug groups when making decisions about of committing to lifelong antihypertensive agents daunt-
treatment initiation and escalation. ing and would prefer a more natural solution. In general
2. To describe the management of hypertensive crises this is adequate in only the minority, but supporting this
and its aim to reduce end-organ damage. avenue of treatment initially goes a long way to creating
3. To appreciate that achieving BP targets in a sub- a cooperative therapeutic relationship between clinician
stantial proportion of patients is difficult because and patient to support engagement in self-testing and
it is usually asymptomatic, no gain is immedi- ownership of this long-term condition which in turn
ately discernible to patients for decades and com- increases compliance when and if pharmacological
mencing treatment usually commits the patient to interventions are required. A number of non-
lifelong daily medication in the majority often in pharmacological interventions have been shown to be
youth when there is likely to be the greatest gain. effective in randomised controlled trials, producing sus-
Its management is akin to convincing patients to tained reductions in blood pressure. These measures can
invest in a health pension. Pay now to protect your- therefore be a useful first strategy for lowering BP in
self from the unknown later with no guarantee that individuals, particularly where no end-organ damage
it will be effective. has been identified. Lifestyle modifications offer the
potential to lower BP in a simple, inexpensive, effective
manner and also improve a range of other health-related
16.1 Introduction outcomes (e.g. alteration in lipid profile resulting from
diet and exercise and liver function through moderation of
Treatment of blood pressure in the context of renal dis- alcohol intake).
ease is important for several reasons. If unchecked it is a Such measures include:
common cause of end-stage kidney disease (EKD); high 1. Salt (reducing sodium intake from 10 g/d to 5 g/d
BP is a consequence of renal disease and impacts upon leads to a ~5/3 mm Hg reduction in BP) [3, 4]:
many other organ systems; and finally hypertension is a Recommendation is for lowering salt intake
major modifiable risk factor for CVD which in turn is to <90 mmol (<2 g) per day of sodium (correspond-
the main cause of mortality and morbidity in individu- ing to 5 g of sodium chloride), unless contraindi-
als with EKD. The approach to treatment of BP should cated. Salt retention is associated with high BP in
be similar in those with and without established renal patients with CKD. The vast majority of salt is not
disease. For the most part, antihypertensives that are added to food but instead found in everyday food. In
efficacious and reduce risk in groups without renal fail- a typical western diet, a lunch of a ham and cheese
ure, often excluded from major cardiovascular trials, sandwich and a packet of crisps constitutes the
broadly seem to benefit at least as much and possibly majority of your daily salt intake.
more in groups with renal failure as the event rate in 2. Alcohol (reduction is dependent upon initial con-
these individuals is considerably higher. sumption) [5]: Recommended alcohol intake to no
Randomised controlled trials (RCTs) demonstrate more than two standard drinks, units, per day for
BP reduction, whether achieved by diet, lifestyle or men and no more than one unit for women.
drug therapy, and reduce the risk of CHD, stroke and 3. Weight: Recommend healthy weight corresponds to
EKD. Review of RCTs of drugs that demonstrate effec- BMI 20–25. On average you can expect a 1–2 mm Hg
tive BP lowering demonstrates that a 5-year sustained BP for every kg above an ideal BMI [6]. In CKD
reduction of 5–6 mm Hg reduces coronary events by patients, weight reduction also confers other health
20% and stroke by 40% [1]. This is in keeping with evi- benefits including reduction in urine albumin or pro-
dence from prospective observational studies that pre- tein levels, an independent negative prognosticator,
dict lowering BP confers the same magnitude of improved lipid profile and increased insulin sensitiv-
protection [2]. There has been much discussion about ity and reduction in hepatic steatosis which is a com-
specific drugs and their efficacy in reducing cardiovas- mon incidental finding in hypertension. The impact
cular risk, but the overall signal from the evidence of weight control in the management of hyperten-
appears to be that it is more important to achieve blood sion is demonstrated in a meta-analysis of 57 studies
pressure lowering than to focus on which drug is used to that showed improvement and resolution of hyper-
achieve it. tension after bariatric surgery in morbidly obese
338 M. Umaid Rauf and J. Cross
patients, defined as BMI >40 kg/m2 or BMI >35 kg/ are perceived as safe, holistic and inexpensive and pro-
m2 with significant comorbidities [7]. vide a sense of authority and control over health, inde-
4. Exercise: Thrice weekly aerobic exercise results in an pendent of conventional medicine and the sickness role.
average reduction of ~3/4 mm Hg [8]. The KDIGO Several clinical trials have demonstrated efficacy of nat-
2012 guidelines recommend undertaking exercise for ural herbs in BP lowering. The mechanisms of action
at least 30 minutes five times per week to optimise are attributed primarily to their effect on vascular
cardiovascular health and reduce blood pressure. smooth muscle generating a variety of intermediaries
5. Diet: A diet rich in fresh fruit and vegetables, whole including nitric oxide (NO). They also combat patho-
grains and low-fat dairy products, with reduced con- logical damage to vessels by reversing endothelial dys-
tent of total and saturated fat, is effective in blood function resulting from imbalance between vasodilators
pressure lowering by approximately 11 mm Hg. (NO, PGI2) and vasoconstrictors (Enthothelin-1,
Dietary potassium supplementation (~ 3500– thromboxane, PDGF) and also by modifying ROS
5000 mg/d) through consumption of high-potassium (reactive oxygen species) generated by various patho-
foods reduces BP by 4/5 mm Hg. This is limited in logical states [14].
advanced renal impairment because of the risks of Some widely used herbs in the treatment of hyper-
potassium supplementation resulting in accumula- tension and CVD, validated by randomised control tri-
tion in renal impairment below a GFR of 25 ms/ min als, include:
[9]. The Dietary Approaches to Stop Hypertension 1. Garlic
(DASH) eating pattern is well established to reduce 2. Beetroot
BP, by 6.7/3.5 mm Hg [10]. 3. Tea (black and green)
6. [11–13] Fish oil supplementation is similarly effective 4. Berberine
although the mechanism is unclear. 5. Hawthorns
7. A variety of psychosocial stressors (e.g. occupational 6. Saffron
stress, poor social support); negative personality 7. Roselle
traits like anxiety, anger and depression; and reduced 8. Black cumin
sleep duration/quality, in association with sleep 9. Ginseng
apnoea, have also been associated with high BP.
8. A number of environmental exposures, including Some of the most scientifically persuasive evidence
loud noises (e.g. traffic), colder temperatures (e.g. exists for beetroot and other food stuffs high in nitrates
winter), higher altitudes and air pollutants, exacer- such as celery, cabbage and other leafy green vegetables
bate high BP. including spinach and some lettuce. Dietary inorganic
9. Although nicotine in cigarette smoke is a vasodilator nitrates eaten enter the circulation rapidly; some of them
initially, in the medium term it is associated with are absorbed and then resecreted in a concentrated form
rebound vasoconstriction, and although precise in saliva, a process known as the enterosalivary nitrate
mechanisms are unclear, the same applies to many circulation. Bacteria in the mouth convert inorganic
recreational substances such as marijuana and nitrate to nitrite [15] which is swallowed and then
cocaine, in particular, that both result in vasocon- absorbed into the circulation where it acts as a substrate
16 striction, especially cocaine which can be associated for conversion to NO resulting in vasodilation and car-
with hypertensive crises and severe acute renal fail- diovascular protection [16]. Professor Ahluwalia’s group
ure. Cigarette and recreational substance use effect demonstrated that supplementation of dietary nitrate
on overall cardiovascular risk is multiplicative and is (6.4 mmol nitrate daily equivalent to a glass of beetroot
eminently modifiable as a risk factor making advice juice daily) for 4 weeks was associated with robust, sus-
on cessation a routine part of care. tained and clinically meaningful reductions in BP (mea-
sured by clinic, ambulatory and home methods) of
~8/4 mm Hg, an effect magnitude broadly in line with a
16.2.1 Role of Evidenced Natural Therapies single antihypertensive agent at full dose [17].
as Antihypertensive Agents
The increasing role of Complementary and Alternative 16.3 Drugs Used to Lower Blood Pressure
Medicine (CAM) in treatment of various health condi-
tions including hypertension relates to a number of fac- There are seven broad classes of antihypertensive drugs
tors including de-medicalising long-term conditions, although the British National Formulary lists ~50 BP
health belief systems held by patients who need to inte- agents. Four drug classes dominate prescribing in the
grate management into their lifestyle. Natural remedies UK: angiotensin-converting enzyme (ACEi) inhibitors
Management of High Blood Pressure
339 16
and angiotensin receptor blockers (ARBs) (A-class tage in reducing recurrent CHD events in patients who
drugs), β-blockers (B-class drugs), calcium channel have suffered an MI, and dihydropyridine calcium
blockers (CCBs) (C-class drugs) and diuretics (D-class channel blockers may have an advantage over other
drugs). Each class has a differing mechanism of action classes in the prevention of stroke. The number of
[18], but all classes have been shown in RCTs to be effec- patients with kidney disease in these trials is small, but
tive in reducing the risk of cardiovascular and renal it seems reasonable to extrapolate the findings to
pathological outcomes. patients with kidney disease.
Evidence from review of short-term trials (with
blood pressure as the outcome) indicate that all classes
of blood pressure-lowering drugs at either standard, 16.4 Controversies in Blood Pressure
half or quarter standard doses result in broadly compa- Management
rable reductions in BP [19]. Combinations of drugs from
different classes at low dose may provide a way of Despite this evidence there continue to be controversies
achieving additive or in some combinations multiplica- in the pharmacological management of BP. Until 2006,
tive reductions in blood pressure with the possible international guidance on BP management was largely
advantage of a reduction in dose-related mechanism- uniform. The message was clear, and the recommenda-
based adverse effects, which are important causes of dis- tion was that the overarching benefit of antihypertensive
continuation of therapy [19]. medication is in lowering BP rather than the specific fea-
Generic drugs are available for all the major drug tures of the drug used to achieve it. Subsequent to the
classes. Reduced acquisition costs of drugs translate publication of influential trials and meta-analysis [21,
into cost savings to health providers, provided branded 22], guidance in England and Wales has evolved. As a
medications are avoided (from within these major consequence pharmacological updates of joint guidance
classes). Newer agents available currently (e.g. aliskiren) issued by the National Institute for Health and Care
or in the future can only be rationally prescribed if there Excellence (NICE) and the British Hypertension Society
are persuasive reasons to think that they are superior to (BHS) have led to recommendation of A-class drugs as
existing generic drugs for which there is little evidence initial treatment in those <55 years and C-class drugs in
currently. those >55 years of age, while B-class drugs have been
The evidence base for the efficacy of BP-lowering relegated to being a third- or fourth-line option. In the
drugs from all the major classes reducing not just blood most recent NICE/BHS guidelines (7 http://www.nice.
pressure itself but cardiovascular and renal outcomes is org.uk/CG127), D-class drugs were relegated to a third-
large, numbering ~150 RCTs over four decades. Broadly line option because they were considered to be less
there are three types of trials conducted. Those that effective in reducing BP variability than C-class drugs.
test active treatments versus placebo were the first trial The rationale for the emphasis of updated guidelines on
to be performed in the 1940s to 1960s (long-term trials drug choice rather than BP reduction can be summarised
are no longer ethical because of the established benefits as follows:
of BP-lowering), then those that test a more versus a 1. BP-lowering drugs differ in their BP-lowering effi-
less intensive BP-lowering regime and, lastly, trials of cacy in younger and older patients: drugs that target
one active drug versus another so-called head-to-head the renin-angiotensin system (A-/B-class drugs) are
trials. The first two categories of trial answer questions considered to be more effective in lowering BP in
about the efficacy of BP lowering on outcome. However, younger patients (aged under 55 years) than in older
differences between classes might be inferred by explor- patients where renin concentration tends to be lower
ing evidence for heterogeneity in effect sizes across tri- and C-/D-class drugs are considered more effective.
als of different agents. The third category of trial 2. Differences exist in the efficacy and safety of differ-
investigates class- or drug-specific differences in effi- ent BP-lowering drug classes in different age and dis-
cacy. To ensure a fair test in a head-to-head trial of this ease groups. Specifically:
type, the achieved BP in the two arms of such a trial 5 B-class (β-blockers) and D-class (thiazide diuretics)
must be similar, to allow that differences in outcome/ increase the risk of type 2 diabetes.
event rates are not simply due to BP differences between 5 B-class (β-blockers) in general and atenolol in par-
the two arms. Two recent overviews [1, 20] have both ticular confer less protection from stroke than other
interpreted the evidence in the context of achieved BP drug classes but greater protection post-myocardial
reductions and emphasised the similarity in effective- infarction.
ness of different BP-lowering drugs in the prevention 5 A-class drugs confer a specific advantage, over and
of cardiovascular outcomes with two possible excep- above BP-lowering, in protection from renal disease
tions: beta-blockers may have a class-specific advan- thought to relate to the reduction in transglomerular
340 M. Umaid Rauf and J. Cross
pressure and the concomitant proteinuria which is an early on the advice of the data safety monitoring
independent negative prognosticator. committee because of a significant treatment differ-
3. Apparent differences in cardiovascular outcomes ence in favour of patients randomised to the C-class-
between the different drug classes may arise as a based regimen for two secondary endpoints (stroke
result of differences in their effect on diabetes risk, and total cardiovascular events). There was no evi-
their effect on central (aortic) compared to periph- dence of a difference in the primary endpoint of
eral (brachial artery) BP and their effect on BP vari- non-fatal myocardial infarction or fatal coronary
ability. heart disease. BP after intervention was lower in the
group randomised to amlodipine compared to aten-
However, the extent to which these proposals are sup- olol by on average 2/3 mm Hg throughout the trial.
ported by the evidence is debatable. The European and The trialists’ analysis suggested the BP difference
US guidelines on the treatment of hypertension remain was insufficient to explain the disparity in event
largely similar to the pre-2006 UK guidance unswayed rates, but others have reached the opposite conclu-
by the preceding arguments. sion [29].
a. Age as a Determinant of BP-Lowering Response to A subsequent meta-analysis examined trials com-
Different Drug Classes paring B-class drugs with other BP-lowering drugs
Recommendations that BP is best lowered with [22]. Stroke risk was 16% higher (95% CI 4–30%)
A-class drugs in patients aged under 55 years (in among patients randomised to B-class drugs than in
whom an activated renin-angiotensin system may be those taking other drug classes. A number of other
an important mechanism) and D-class diuretics or meta-analyses reached similar conclusions [27, 28].
C-class calcium channel blockers in older patients However, they are all sensitive to the requirement to
(because sodium retention, with suppression of the include only including RCT and did not take full
renin-angiotensin system, may be more important) account of differences in achieved BP between treat-
were based primarily on the findings of a mechanis- ment arms. These limitations are borne out by a re-
tic study (n = 36) that rotated young patients through analysis [30] suggesting that achieved BP favoured
monthly treatment with each of four main classes of the comparator drug over B-class drugs in all
BP-lowering drugs and assessed the effect on BP [23]. instances, which may explain the apparent benefit of
Since renin declines with age [24], and the major other BP drugs over β-blockers. The BP disparity is
drug classes differ in their effect on the renin- unlikely to be because β-blockers are inherently less
angiotensin system [25], age has been proposed as a effective at lowering BP than other drugs but rather
proxy for stratifying the response of BP medications because achieving a precisely equivalent BP reduc-
on cardiovascular outcomes. However, on the few tion in two arms of a comparator trial is extremely
occasions when potential effect modification by age difficult.
of the effect of BP treatment on cardiovascular out- The pairwise meta-analyses conducted by Law
comes has been evaluated, no major differences have et al. [1] and that by the Blood Pressure Lowering
been observed [20]. Similar analyses using renin con- Treatment Trialists’ Collaboration [17] now super-
centrations (now possible with a rapid, cheap assay sede these studies. They examined the efficacy of all
16 [26]) have yet to be conducted, and this therefore major BP drug classes (not just B-class drugs) in the
remains a hypothesis. context of the achieved reductions in BP. The Blood
b. β-Blockers and Stroke Prevention Pressure Lowering Treatment Trialists’ Collaboration
Two sources of evidence were influential in the incorporated information from 190,606 participants
relegation of B-class β-blockers from first-line treat- across 31 treatment trials and concluded that all
ment of the NICE guidance: the 2005 Anglo- classes of drug were broadly equivalent with respect
Scandinavian Cardiovascular Outcomes Trial to protection from major cardiovascular events if
(ASCOT) [21] and three meta-analyses examining achieved BP was taken into account. The investiga-
the efficacy of β-blockers in prevention of cardio- tors found a log-linear association between BP
vascular events, published in 2005–2006 [22, 27, 28]. reduction and the relative risk of cardiovascular
ASCOT was a randomised trial comparing a C-class events, in keeping with predictions from observa-
drug (amlodipine)-based treatment regimen (with tional studies. A second analysis by Law and col-
addition of perindopril and then doxazosin if leagues, which included information from 147
required) with a B-class drug (atenolol)-based treat- published trials among 464,000 participants, con-
ment regimen (with the addition of bendroflume- cluded that the protective effect of lowering BP on
thiazide and then doxazosin if required) to achieve coronary heart disease was the same for all drug
a BP <140/90 mm Hg. The trial was terminated classes in primary prevention, with the possible
Management of High Blood Pressure
341 16
exception of the effect of C-class drugs on stroke [1]. into doubt by results of recent trials which indicate
The authors considered that this probably accounted that, after 5 years follow-up, tight glucose control
for most of the apparent disadvantage of B-class does not necessarily lead to a reduction in cardiovas-
drugs in stroke protection, because C-class calcium cular event rates [34].
channel blockers had been the most common com- d. A-Class Drugs and Protection from Renal Disease
parator drug in trials of B-class drugs. UK guidance [35, 36] has encouraged the use of
c. BP-Lowering Drugs and the Risk of Type 2 Diabetes drugs that specifically block the renin-angiotensin
Patients receiving B- or D-class drugs rather than system (including ACEi and ARBs) as first-line
A-class drugs are at higher risk of diabetes. But what treatment to reduce proteinuria and slow the pro-
is the magnitude of the blood glucose increase; by gression of renal disease. The recommendation, ini-
how much is the absolute risk of diabetes increased; tially for those with diabetes and evidence of renal
and, importantly, how does this affect the risk of car- impairment, is now more generally applied even to
diovascular events? those without diabetes. These recommendations
In the ASCOT trial, diabetes risk was increased evolved following randomised trials of A-class ACEi
among people randomised to the B-class arm and subsequently ARBs that demonstrated a reno-
(atenolol-bendroflumethiazide) (the hazard ratio protective effect. Implicit in the interpretation of the
comparing C-class (amlodipine) with B-class (ateno- guidance is that inhibition of the renin-angiotensin
lol) was 0.70, 95% CI 0.63–0.78, equating to a risk system with ACEi/ARBs has specific reno-protective
difference of 11 per 1000 people over 5 years). effects beyond lowering BP alone. However the RCTs
However the average absolute difference in blood on which this guidance was based compared ACEi
glucose concentration was only 0.2 mmol/L (SD and ARBs against placebo rather than another
2.08 mmol/L, P < 0.0001). The substantial increase BP-lowering agent. Given that systemic BP is a major
in the risk of diabetes arises because an average determinant of the progression of renal disease [37]
increase in glucose of as little as 0.2 mmol/L leads to and that BP differences are inevitable when compar-
an increase in the proportion of people marginally ing placebo with BP-lowering drugs, the between-
exceeding the diagnostic fasting blood glucose treatment-arm BP differences may confound the
threshold of 7 mmol/L and therefore being classified observed effects on renal outcomes in placebo-
as diabetic. controlled trials of ACEi/ARBs.
The evidence is less than compelling that this A previous systematic review and meta-analysis
small average increase in glucose translates to a net of RCTs investigated the effect of different classes of
reduction in protection from stroke or coronary antihypertensive drugs on the progression of renal
heart disease. Recent overviews of prospective disease [38]. ACEi/AR0Bs, when compared to other
observational studies [31, 32] indicate that BP-lowering drugs, stratified by degree of BP lower-
although the risk of coronary heart disease is lin- ing, yielded a relative risk of 0.74 (95% CI 0.59–0.92),
early and modestly increased above a fasting glu- in the group with greatest degree of BP lowering
cose value of 5 mmol/L, the risk of stroke is (−6.9 mm Hg), and a RR of 0.9 (95% CI 0.72–1.12)
substantially raised only at fasting glucose values in the group with the smallest degree of BP lowering
well above 7 mmol/L [32]. (1.5 mm Hg), reinforcing the major role of BP differ-
In the ALLHAT trial (in which 33,357 patients ences as the mechanism to explain the observed ben-
were randomised to A-class (lisinopril), C-class efits of A-class drugs over other antihypertensive
(amlodipine), or D-class (chlorthalidone)), there was drug classes on renal outcomes. Smaller studies dem-
a difference in blood glucose of 0.16 mmol/L in the onstrated a smaller overall benefit in renal endpoints.
amlodipine group compared with the chlorthalidone There was little evidence of an advantage in the dia-
group with an odds ratio for diabetes of 0.73 (0.58– betic subgroup, in which the relative risk for end-
0.91) [33]. Yet the hazard ratio for stroke after stage renal failure was 0.89 (95% CI 0.74–1.07).
4.9 years of follow-up was 0.93 (0.82–1.06). There Despite these findings, and the lack of large trials,
was a very small BP disparity between the chlortha- the UK (and in this instance other international
lidone and amlodipine arms (mean difference for guidelines) recommends the use of A-class drugs
amlodipine versus chlorthalidone 0.8 mm Hg sys- first line to treat hypertension and retard progression
tolic (P = 0.03)). This suggests that the observed dif- of renal disease [35, 39]. This may be an example of
ferences in the risk of stroke in these trials are more a widely applied drug policy that over-reached its
likely to be explained by between-arm differences in evidence base; it is an academic point given that most
BP rather than glucose level. The relevance of the patients with kidney disease will require combina-
small average increase in glucose is further brought tion antihypertensive treatment.
342 M. Umaid Rauf and J. Cross
. Table 16.1 Summary of hypertensive crises, signs and symptoms associated with their presentation and pharmacological
approach for each
Hypertensive encepha- Headache, altered conscious level, seizures, focal MRI of the brain Labetalol
lopathy neurological signs, haemorrhage/exudates and
papilloedema on fundoscopy
Dissecting aortic Chest and back pain, BP in both arms, palpation of CT or MRI of the Labetalol, GTN (only after
aneurysm all peripheral pulses aorta labetalol to counter reflex
tachycardia)
Acute ventricular Breathlessness, gallop rhythm, raised JVP, third CXR, echo may be GTN
failure with pulmonary heart sound, inspiratory crackles on auscultation useful
oedema
Acute myocardial Chest pain, diaphoresis, breathlessness ECG, cardiac GTN, labetalol, esmolol
ischaemia/infarction enzymes
Eclampsia Visual fields, headaches, altered mental state, acute Labetalol (and delivery)
stroke, abdominal pain, heart failure, oliguria
Acute kidney injury Oliguria, uraemia, electrolyte-associated arrhyth- Urea, creatinine, Labetalol, nicardipine
mias electrolytes,
urinalysis
Sympathetic crisis Labile blood pressure Toxicology screen Verapamil/diltiazem/
(cocaine induced) nicardipine
Catecholamine Labile blood pressure with associated flushing Urine catechol- Phentolamine
associated crisis amines
344 M. Umaid Rauf and J. Cross
Hypertensive crisis most commonly presents as a A key first step is thought to be a rapid increase in sys-
complication of intrinsic or essential hypertension and temic vascular resistance (SVR) precipitated by vaso-
can result from non-adherence with prescribed antihy- constrictor substances (e.g. noradrenalin, angiotensin
pertensive medication, but a larger proportion of this II) or relative hypovolaemia. Like many other biological
group have a secondary underlying cause which should systems, the endothelium attempts to compensate by
be sought. It is important to distinguish hypertensive release of vasodilators to counter increases in
emergencies from severe hypertension without acute SVR. However sustained hypertension overwhelms
end-organ damage. While the latter does involve inten- compensatory mechanisms, leading to further endothe-
sive treatment, it does not require immediate parenteral lial dysfunction, increase in vascular permeability, fibri-
therapy and may be the difference between inpatient and noid necrosis of the vessel wall, activation of platelet
outpatient management. Most hypertensive emergencies aggregation and the coagulation cascade. Activation of
are associated with a systolic blood pressure (SBP) of these systems can promote further inflammation of the
greater than 180 mm Hg or a diastolic blood pressure endothelium, thrombosis and vasoconstriction.
(DBP) of greater than 110 mm Hg. Rarely it presents
with more normal blood pressure readings in the con-
text of specific patient groups who have experienced a 16.10 Determination of Precipitant
rapid acceleration of BP such as the preeclamptic or for Hypertensive Crises Is Crucial
those with thrombotic microangiopathy or conditions to Prevent Recurrence
resulting in renal ischaemia such as dissection or HCV-
related cryoglobulinaemia. Hypertensive crises require Non-adherence to prescribed antihypertensive medica-
rapid introduction of controlled, modest blood pressure tions is the most common precipitating factor, but oth-
reduction over time, ideally with relatively non-potent, ers to look for include use of prescribed,
short-acting, parenteral therapy that can be titrated over-the-counter or illicit drugs (e.g. cocaine, amphet-
minute to minute. A high dependency setting is ideal amines, sympathomimetic agents, nonsteroidal anti-
with a high nursing ratio with arterial blood pressure inflammatory drugs and high-dose steroids). Patients
and cardiac monitoring available. Rapid normalisation with acute glomerulonephritis such as lupus, preeclamp-
of blood pressure can result in end-organ hypoperfusion sia, phaeochromocytoma or scleroderma renal crisis
ischaemia or infarction. In the first 2 hours of manage- may present with hypertensive urgency/emergency.
ment, a reduction in BP of 20% is appropriate; thereaf- Acute stroke or heart failure can be both cause and con-
ter a reduction of 10% magnitude each day until 160/90 sequence of severe hypertension.
is reached, and in general conversion to an oral regime Further testing should be considered for secondary
can be commenced and further escalation can be causes of hypertension if no precipitant is identified,
achieved in the outpatient area with weekly appoint- such as renovascular disease, primary aldosteronism,
ments. In the setting of arterial dissection, more rapid glucocorticoid excess, phaeochromocytoma and, in
control is justified for organ salvage as hypertension is younger patients, coarctation of the aorta [49].
usually the driver for further dissection.
In contrast to the management of chronic hyperten-
16 sion, where there is a mature evidence base, there are no
Assessment and Clinical Evaluation A targeted history
and examination supported by key laboratory and imag-
large randomised trials in the setting of hypertensive ing investigations are essential. Salient features in any
emergencies. This is likely to be due to the small num- evaluation should establish pre-existing hypertension, its
bers of individuals presenting in this way (1% of all treatment, control and adherence to medication, concur-
those with hypertension) and the heterogeneity of the rent clinical conditions that could precipitate a hyperten-
presentation (. Table 16.1). Management is therefore sive crises and drugs including prescribed, over-the-counter
based on consensus rather than evidence. or illicit such as cocaine. Examination should focus on
identifying syndromes where rapid intervention can be
life-saving (aortic dissection, eclampsia, hypertensive
16.9 Pathophysiology encephalopathy, acute renal failure, pulmonary oedema)
as a priority but should not preclude a full examination as
Pathophysiology of hypertensive crises is not well under- other complications may also be present. Assessment
stood. A crisis can develop de novo or can complicate an should be made of BP in both arms, in the supine, seated
underlying primary or secondary cause of hypertension. and standing position if possible, to determine volume
The vast majority of hypertensive crises appear to occur status. Cardiac compromise in particular left ventricular
in patients with background hypertension, the excep- failure can be assessed by examination of the jugular
tions being eclampsia and de novo nephritic syndrome. venous pressure, the presence of a gallop rhythm and/or
Management of High Blood Pressure
345 16
fourth heart sound and presence of inspiratory crackles thrombotic microangiopathies and HIV. Changes associ-
on auscultation of the lungs. Hypertensive encephalopa- ated with PRES as well as hypertensive encephalopathy
thy can be detected by assessment of the conscious level, are potentially reversible with treatment of the underlying
assessment of focal neurology and grades III or IV hyper- cause. Blood tests should include renal function, electro-
tensive retinopathy. Assessment and symmetry of all lytes, LDH and a full blood count/platelet count with a
pulses should also be made and is particularly important peripheral blood film to exclude a thrombotic microangi-
where aortic dissection is suspected. opathic anaemia.
a b
. Fig. 16.1 a CT scan of a patient with CKD who developed bilat- recover her vision. b MRI scan showing extensive white matter
eral cortical blindness with a blood pressure of 165/105 mm Hg. The changes in a 21-year-old with systemic lupus erythematosus and a
scan shows bilateral hypoperfusion consistent with posterior revers- blood pressure of 230/140 mm Hg
ible encephalopathy syndrome (PRES) and patient went on to
346 M. Umaid Rauf and J. Cross
therefore over-zealous or poorly monitored blood pres- tous BP falls. The other disadvantage of nitroprusside is
sure reduction carries a significant risk [49]. In acute the association with cyanate or thiocyanate toxicity and
ischaemic stroke, BP reduction to <185/110 mm Hg is the need to protect from light, if used over days, particu-
warranted if thrombolytic therapy is indicated. If larly in individuals with hepatic or renal dysfunction.
thrombolytic therapy is not indicated and there is no This should be offset by use of the drug over a short
acute end-organ damage other than stroke, no interven- period of time and a dose not exceeding 2 microgram/
tion is indicated for the first 48–72 hours. kg/min. If needed at higher doses, concurrent thiosul-
In cases of acute intra-cerebral haemorrhage in phate infusions can be considered.
known hypertensives and those with underlying vascular Other useful agents include hydralazine, calcium
abnormalities, decrease SBP to 140–150 mm Hg within channel blockers and dopamine-1 receptor agonists.
1 hour if systolic BP is in the range of 150–220 mm Hg. Hydralazine acts by vasodilation but can cause precipi-
Cases of increased intracranial pressure due to mas- tous BP falls and has a 12-hour half-life. Because of this
sive intracranial bleed warrant more liberal approach prolonged and somewhat unpredictable effect on blood
(keep SBP <180 mm Hg). pressure and inability to titrate dose to BP, it is no longer
used first line but can be reserved for more complex
refractory cases with careful administration and moni-
16.12 Pharmacological Agents toring. Parenteral preparations of calcium channel
blockers are available (nicardipine), which act by vasodi-
Agents for the management of hypertensive crises need lation. These are more water soluble than nifedipine,
to be fast acting, rapidly reversible and titratable with whose use in the setting of hypertensive emergencies or
minimal adverse effects. In the absence of one ideal urgencies can cause sharp falls in BP when chewed and
agent, knowledge of the pharmacological properties of swallowed, an effect which can last up to 8 hours, and is
agents that are available can be used to tailor treatments therefore not recommended. In contrast nicardipine
for a given clinical situation. Parenteral preparations of given as an intravenous infusion has a rapid onset of
most drug classes are available with preferred options in action (5–15 minutes) with a duration of 4–6 hours. It
UK-based practice being beta-blockers (labetalol and can therefore be titrated to BP, although the shorter-
esmolol) and nitric oxide donors (glyceryl trinitrate). acting beta-blockers and nitric oxide donors are of
Beta-blockers (esmolol and labetalol) are often the greater use for rapid titration.
preferred drug, as they are short acting (esmolol within The dopamine receptor agonist fenoldopam has
60 seconds and labetalol within 5 minutes) and are the been approved by the Food and Drug Administration
drug of choice where cardiac output, heart rate and (FDA) for hypertensive emergencies. Although similar
blood pressure are all increased. They achieve control of to dopamine in mechanism, fenoldopam is a much more
systemic vascular resistance, lowering this without specific agonist at peripheral dopamine-1 receptors.
reduction in total peripheral blood flow. They are the Like dopamine it increases renal blood flow and pro-
agents of choice in aortic dissection, eclampsia (labet- motes natriuresis. It can be given by the intravenous
alol does not cross the placenta) and myocardial isch- route and has a rapid onset of action (5 minutes), with a
duration of action of 30–60 minutes. It may therefore be
16 aemia (in the absence of left ventricular failure).
Glyceryl trinitrate (GTN) is the nitric oxide donor useful in hypertensive crises with a renal cause, in order
commonly used in the UK. It acts by venodilation with to maintain renal blood flow.
effects on arterial tone only at higher doses. It therefore Prostacyclin has a very short half-life and often used
achieves its therapeutic effect by reducing preload and in the treatment of scleroderma renal crisis.
cardiac output but can cause a reflex tachycardia and Hypertensive emergencies require rapid diagnosis
significant hypotension, which may be disadvantageous and immediate treatment in a place of safety. Recognition
in certain hypertensive crises (myocardial ischemia, aor- of the underlying clinical syndrome is essential to guide
tic dissection). However, given the short duration of both clinical and pharmacological management. BP
action and plasma half-life, the advantage of GTN is lowering in hypertensive emergencies should be carried
that unwanted effects are rapidly reversible. GTN can be out in a high dependency setting where close nursing,
particularly useful in individuals presenting with hyper- cardiac and arterial monitoring are available. Drugs that
tensive crises associated with left ventricular failure. are short acting with a short half-life are preferable so
Sodium nitroprusside, another nitric oxide donor, also that doses can be titrated to BP.
acts by reducing venous tone, with more of an effect on It is important to differentiate between hypertensive
arterial tone, reducing both pre- and post-load. Like emergency and hypertensive urgency (acute severe
GTN it has a rapid onset of action, with a short dura- hypertension without target-organ damage) since these
tion of action and plasma half-life, but like GTN it also patients can be cared for as outpatients. Treatment with
can be associated with reflex tachycardia and precipi- guideline-concordant long-acting medications should
Management of High Blood Pressure
347 16
be started, resumed or adjusted, and follow-up should Educating patients, their families and caregivers
be scheduled within 1–7 days. Intravenous medications about hypertension, the consequences of hypertension
are not advised in this context. and the possible adverse effects of medications is of vital
importance. Robust systems to maintain contact with
patients for ongoing follow-up and monitoring includ-
16.13 Resistant Hypertension ing tele- and e-communication may be helpful. Patients
and Non-adherence should be encouraged to integrate pill taking into their
routine activities of daily living with the use of adher-
to Antihypertensives
ence support tools such as reminders, pillboxes, etc.
Resistant hypertension is defined as failure to achieve 16.15 Role of RDN (Renal Denervation)
a guideline-driven blood pressure of less than in Management of Resistant
140/90 mm Hg in patients who are adherent to maxi-
Hypertension
mally tolerated doses of at least three antihyperten-
sive drugs, including a diuretic appropriate for kidney
The role of sympathetic nervous system is pivotal in the
function [50].
pathogenesis of primary hypertension and had been an
area of interest for potential treatment of drug-resistant
hypertension with emergence of renal sympathetic
denervation therapy.
16.14 Delivery of Hypertension Treatment However, after encouraging results from initial clini-
cal trials, a large randomised control trial (SYMPLICITY
It is worth spending time considering how to deliver not HTN-3) could not meet its primary efficacy endpoint,
just treatment but monitoring and responsive adjust- that is, office BP reduction; hence the use of renal dener-
ments for a patient with hypertension. This is particu- vation for treatment of resistant hypertension is not rec-
larly key in the management of ‘resistant hypertension’ ommended in routine clinical practice [52].
that is usually due to one of two causes (a) poor compli-
ance or (b) undiagnosed secondary cause of hyperten-
sion. 16.15.1 Overview of Treatments of Major
In order to diagnose a secondary cause of resistant Causes of Secondary Hypertension
hypertension, non-adherence to antihypertensive medi-
cations as well as white coat hypertensive effect should 1. Primary Hyperaldosteronism: 20% prevalence in con-
be excluded. Medication non-compliance is highly prev- firmed cases of resistant hypertension. There should be
alent among patients with apparent resistant hyperten- low index of suspicion to investigate for it in any patient
sion, so much that an estimated 50–80% of hypertensive with unexplained high BP and low serum potassium
patients who are prescribed antihypertensive medica- levels. Medical management by aldosterone antago-
tions demonstrate suboptimal adherence [51]. nists (selective preferably, e.g. eplerenone) is preferred
Few factors contributing to non-adherence are large and laparoscopic adrenalectomy for unilateral adeno-
pill burden, dosing complexity, expense, high frequency mas with ~50% complete cure [51].
of adverse reactions with multidrug antihypertensive 2. Phaeochromocytoma: Up to 4% prevalence in resis-
regimens, poor patient-clinician relationship and clini- tant hypertension and should be high index of suspi-
cian inertia with reduced insistence on adherence when cion to investigate. Ninety percent are adrenal
patients are consistently non-adherent. catecholamine-secreting tumours. Laparoscopic
Exclusion of non-adherence should include frank removal of tumour is the only option after diagnosis.
and non-judgemental clinician-patient discussion, mon- Peri-operative management such as combined α- and
itoring of prescription refills and pill counts and, if β-blockade, a high-sodium diet and fluid hydration is
available, biochemical assay of drugs or their metabo- recommended for at least a week before surgery to pre-
lites in urine or plasma. vent intraoperative BP instability and to reverse vol-
A patient-centred approach in decision-making helps ume contraction. β-Blockade alone can result in
in improving adherence to antihypertensive medications. paradoxical pressor responses. Postoperatively, close
Effective strategies include preference for once daily follow-up is needed for the possibility of recurrence or
dosing and using fixed-dose combination agents when metastasis, especially with the inherited forms.
available, using low-cost and generic antihypertensives 3. Cushing’s Syndrome: RAS blockade with ACEi/
and consolidating refills. ARBs/potassium-sparing diuretics treats 50% of
348 M. Umaid Rauf and J. Cross
Case Study
Case 1 She had her airway secured with Guedel’s airway. Her BP
A 56-year-old man, with past medical history of hyperten- was 232/135 and heart rate 85 bpm. Her GCS was 10/15.
sion and active smoker, presented to A&E with dizziness Auscultation of heart revealed fourth heart sound.
and moderate central chest pain radiating through the Fundoscopy revealed arteriolar narrowing, cotton wool
back for the last 6 hours. He reported recent bouts of self- spots and papilloedema. Rest of physical examination was
resolving chest pains over the last week. ECG with para- unremarkable. Initial bloods including electrolytes were
medics showed ST depressions in lateral leads. His BP was normal. ECG showed LV strain pattern and CXR was
230/125 mm Hg and pulse 80 beats/min. Physical exam normal. Her emergency CT head showed heterogeneous
revealed a fourth heart sound, a diastolic murmur and areas of low attenuation in posterior parieto-occipital
inter-arm BP difference of >20 mm Hg. IV access was regions bilaterally with no acute haemorrhage or infarc-
obtained and initial blood sent. He was started with IV tion. These findings were consistent with PRES (posterior
labetalol with aggressive management target of BP. reversible encephalopathy syndrome), precipitated by non-
Troponins were elevated to 60 ng/L (normal: <14). Other adherence to antihypertensive medications. She was started
laboratory tests were normal. CXR showed slight widen- on IV labetalol infusion with target reduction of BP by
ing of mediastinum, and patient was moved to ITU for 20–25% during first hour and was transferred to high
invasive monitoring. An urgent CT chest confirmed dependency unit for close monitoring.
ascending aortic dissection. Vascular and cardiothoracic
teams were involved, and surgical correction of dissection Case 3
was undertaken. It shows the importance of physical exam A 40-year-old lady, being diagnosed with diffuse systemic
and high index of suspicion for aortic dissection because it sclerosis a year ago, was being referred from rheumatol-
can mimic acute coronary event, management of which ogy clinic to A&E on account of high BP. She was recently
may be highly detrimental for underlying aortic dissection. being started on steroids. She was monitoring her BP at
home over the last week that showed a persistent rise
Case 2 despite being started on antihypertensive. She also
A 63-year-old woman, with known hypertension, on amlo- reported 3-day history of fatigue, decreased urine output
dipine and atenolol, presented to A&E with two episodes and ankle swelling. Her BP upon presentation was
of witnessed generalised tonic conic seizures. She was 185/105 mm Hg. Her physical exam revealed tight perioral
post-ictal, though her son reported a 3-day history of her skin and chronic skin ulceration and induration of digits.
having occipital headaches and blurred vision. Also Auscultation of the lungs revealed bibasal fine crackles.
reported is her spotty adherence with antihypertensives. Her initial blood results showed serum creatinine
350 M. Umaid Rauf and J. Cross
220 umol/L and urea 18 mg/dL. Full blood count revealed ing malignant hypertension and AKI. Thrombotic
Hb of 10 g/dL and platelets of 125 × 10*9/L. LDH was microangiopathic picture was secondary to high BP itself;
slightly raised and there are no fragments observed on however, index of suspicion for other causes of AKI with
peripheral film. Urine showed active sediment. Acute active urine should be high. Prognosis of SRC depends
renal screen was sent. She was immediately started on upon methodical BP control prior to onset of irreversible
ACEI and moved to high dependency unit. Her presenta- kidney damage; hence prompt recognition and treatment
tion was likely due to scleroderma renal crisis (SCR) caus- are critical.
Acknowledgement Special Acknowledgements to Authors analysis of controlled clinical trials. Arch Intern Med.
of First Edition: 1993;153(12):1429–38.
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353 17
Contents
References – 374
n Learning Objectives
1. To learn about non-atheromatous and atheroma-
tous renal artery disease, focusing in more detail on
fibromuscular dysplasia (FMD) and atherosclerotic
renovascular disease (ARVD)
2. The role of renal revascularization in management
of ARVD in light of recent RCT data
17.1.1 Introduction
17.1.2.1 Vasculitis
phosphamide or methotrexate or increasingly with
In Indian and South Asian populations, almost 60% biologicals such as anti-TNF-α monoclonal antibod-
of RAS cases are vasculitic, whereas in Caucasian ies. However, due to limitations in local health care in
populations, this is extremely rare. Takayasu’s arteri- developing countries, the majority of patients present
tis is the most common form of vasculitis in Asia and with secondary hypertension in the chronic pulseless
affects females more than males with ratios of up to 9:1 phase of disease. In this context, revascularization is an
reported. Presentation is typically before the fifth decade appropriate intervention, with combined clinical and
of life. The disease follows two clinically distinct phases. angiographic success rates of over 90% following bal-
The first phase is inflammatory with mononuclear leu- loon angioplasty reported [1].
kocytes and scattered multinucleated giant cells observed
within the vessels on histological examination. The sec- 17.1.2.2 Fibromuscular Disease
ond is described as ‘pulseless disease’ in which progres- Fibromuscular disease (FMD) accounts for approxi-
sive fibrosis results in stenoses. The diagnosis is often mately 10% of diagnosed cases of RAS in Western
17 delayed as symptoms are often non-specific but should populations. Fibromuscular dysplasia (FMD) describes
be considered in young Asian women with constitu- several idiopathic, segmental, non-atherosclerotic, non-
tional symptoms such as fevers, arthralgia, hypertension inflammatory diseases of arterial wall musculature,
and an acute phase response (raised ESR/CRP). In the causing stenosis of small- and medium-sized arteries.
chronic phase, features of end-organ ischaemia predomi-
nate such as claudication and difficult hypertension. If Clinical Features
suspected it is important to check blood pressures in all The commonest presenting symptoms of FMD are
limbs and examine across the vascular tree for bruits, and hypertension and headache. Clinical presentation of
whole-body MRA is helpful in assessing the extent of FMD is diverse depending on the arterial bed involved,
involvement (. Fig. 17.1). The territory of blood vessel and the US FMD registry has also highlighted sex-
affected further describes the disease. Within the Indian related differences in presentation. Women present
population, Takayasu’s disease of the descending tho- with symptoms and signs of carotid or vertebral artery
racic and abdominal aorta is the most common pattern. involvement (e.g. pulsatile tinnitus, neck pain, cervical
This explains the high incidence of associated RAS. bruit) more frequently than men, whereas men are more
In the acute or inflammatory phase of the disease, likely to display symptoms and signs consistent with
Takayasu’s is treated using corticosteroids +/− cyclo- renal artery involvement (e.g. flank or abdominal pain,
Disease of the Renal Vessels
355 17
renal impairment or renal infarction) [2]. Given that that FMD found in any arterial bed should prompt
FMD commonly co-exists in more than one vascular screening for FMD elsewhere.
bed (74% in ≥2 vascular beds), it is recommended that
diagnosis of FMD should prompt screening in other Aetiopathology
vascular beds [3, 4]. The US FMD registry highlighted FMD is neither inflammatory nor atherosclerotic, with
delayed diagnosis with a mean time between clinical the cause(s) poorly elucidated. Although the vast major-
presentation and diagnosis of 3.6 ± 7.4 years. Clinical ity of affected patients are female (at a ratio of 9:1), the
scenarios that should raise the suspicion of FMD are reason is unclear, with no evidence of a link between
shown in . Table 17.3. increased oestrogen exposure (including from use of
oral contraceptives) and development of disease.
Epidemiology Genetic factors almost certainly play a part in the
The true general population prevalence of clinically sig- development of FMD, most likely a dominant trait with
nificant fibromuscular dysplasia (FMD) is not known, variable penetrance. However, limited patient numbers
but estimates are in the order of 0.4%. Asymptomatic make it hard to reach firm conclusions about genetic
FMD is more common. A recent review of 4 angio- linkage. Reports of a familial link in 11% of FMD
graphic studies of 3181 asymptomatic potential kidney patients are not consistently duplicated, and other data
donors found FMD in 139 subjects (4.4%) [5]. have rebutted a potential link with alpha-1-antitrypsin
FMD can present across a wide age range deficiency. Work into other potential genetic factors is
(5–83 years) with peak age of diagnosis at 52 years. Men ongoing as is investigation of a ‘two-hit’ hypothesis,
present at a similar age to women. The overall preva- with some data describing higher rates of disease and
lence of arterial dissections and aneurysms in patients more severe disease in smokers (although again conflict-
with FMD is 20%. ing reports exist) [6].
Extrarenal FMD is more common than previously FMD can lead to a variety of abnormal artery mor-
thought. Renal arteries are most commonly involved in phologies including stenosis, a beaded appearance, aneu-
75–80% of cases. Cranio-cervical arteries (e.g. carotid rysms and dissections. FMD is usually found in the middle
and vertebral arteries) are involved in 75% of cases. and distal parts of the renal artery distinct from athero-
Two-thirds of renal artery FMD have co-existent sclerosis which is most often proximal (. Fig. 17.1). A
cranio-cervical involvement and vice versa. FMD can histological classification is based on the predominantly
be seen in any small- or medium-sized arteries includ- involved arterial layer, but biopsies are rarely warranted,
ing lower extremities (60%), mesentery (26%) and and the American Heart Association recommends an
upper extremities (16%) and rarely in coronary arteries angiographic classification based broadly on multifocal
[3]. Based on these data, guidelines now recommend or focal involvement (. Table 17.1) [4].
. Table 17.1 Histological and angiographic classification of fibromuscular dysplasia (FMD) (adapted from)
Medial 85–100 Heterogenous collagen deposition with ‘String of beads’ with bead Multifocal
fibroplasia fragmented internal elastic lamina resulting in diameter larger than normal
(common) multiple small aneurysms. Interspersed with vessel lumen (Fig.17.2)
localized regions of fibrotic narrowing
Perimedial Collagen deposition in outer half of media but ‘String of beads’ with bead
fibroplasia does not extend beyond external elastic lamina diameter more narrower
(rare) than the normal vessel
lumen
Medial True smooth muscle hyperplasia with no Stenosis without beading Focal
hyperplasia fibrosis appearance
(rarest)
Intimal <10 Intimal concentric collagen deposition Concentric or long smooth
(more stenosis
common in
children)
Adventitial <1 Dense collagen replaces the fibrous adventitia Smooth stenosis or diffuse
and may extend into surrounding tissues attenuation of lumen
356 D. Vassallo et al.
Differential Diagnosis
The angiographic appearance of FMD easily distin- 17.1.3 Atheromatous Renal Artery Disease
guishes it from atheromatous disease, and the non-
inflammatory nature of the condition facilitates the use The umbrella term renal artery stenosis is useful to
of simple blood markers of inflammation (e.g. CRP/ describe physical loss of luminal diameter but fails to dis-
ESR) in distinguishing it from a vasculitic aetiology. tinguish between atheromatous and non-atheromatous
A more challenging differential diagnosis is segmental causes. A more specific term is atheromatous renovascu-
arterial mediolysis. This is a poorly understood condi- lar disease (ARVD).
tion that may actually be a sub-type of FMD. Here, Most clinical studies of ARVD have considered the
17 spontaneous arterial occlusion, aneurysm formation respective roles of revascularization and medical ther-
and dissection can all occur – typically associated with apy. The open surgical techniques pioneered in the 1950s
severe pain from infarction of visceral organs. The acute and 1960s have been almost entirely replaced by percu-
onset pain and presentation in a more elderly popula- taneous approaches. Percutaneous interventions were
tion (50–80 years old) help distinguish segmental arte- introduced in the 1980s and have evolved with improve-
rial mediolysis from FMD. ments in technology from angioplasty alone to angio-
plasty and stenting, or primary stenting, which offer
Treatment higher rates of long-term vessel patency. Despite these
Historically, percutaneous transluminal coronary continued improvements, no RCT has ever demonstrated
angioplasty (PCTA) without stenting has been consid- superiority of an interventional approach over standard
ered as first-line therapy for hypertension secondary to medical therapy for clinical outcomes such as progressive
FMD. However, no form of revascularization (surgical renal dysfunction, cardiovascular or renal events or mor-
or percutaneous) has ever been compared to medical tality. However, many questions remain, as the ARVD
therapy in a randomized controlled trial (RCT). With population cannot be considered a single homogenous
the primary aim of therapy being to control blood pres- group.
Disease of the Renal Vessels
357 17
. Fig. 17.3 Potential manage-
ment algorithm for fibromuscular
disease
Diagnosis of FMD
Medical therapy
unless concerns
PCTA Medical therapy
about renal
function
If deteriorates If deteriorates
consider PCTA consider PCTA
17.1.3.1 Clinical Features restoring patency with a procedure. In this sense, reno-
Subclinical vascular hypertension is a retrospective diagnosis.
ARVD is often diagnosed incidentally during coronary
or peripheral angiography. In these patient groups, car- Ischaemic Nephropathy/Progressive Chronic
diovascular event rates are worse in those with inciden- Kidney Disease
tal ARVD compared to those without [9]. The most common presentation of ARVD is stable
chronic kidney disease (CKD) with hypertension. With
Renovascular and Refractory Hypertension modern anti-atherosclerosis therapy, the average annual
Atherosclerotic RAS accounts for only 2% of all cases decline of eGFR in ARVD is around 1–2 ml/min/1.73m2/
of hypertension, but it is a more common cause of year, similar to most other causes of CKD [10]. However
refractory hypertension (8–14%). Conversely, hyperten- this disguises the 12–22% with rapid renal functional loss
sion is almost universal with 95% prevalence in those in contemporary clinical trials [11]. Risk prediction for
diagnosed with ARVD. Epidemiology studies can only this important minority remains challenging.
show associations and cannot determine causality or
natural history. In individual patients, hypertension Acute Kidney Injury
might be one of several atherosclerotic factors caus- As with all forms of CKD, those with ARVD have
ing the development of the ARVD. On the other hand, increased risks of developing AKI from all causes. This
renovascular hypertension refers to hypertension as a is more likely with a greater severity stenosis to a single
consequence of RAS-induced activation of the renin- functional kidney or bilateral disease. A few specific
angiotensin-aldosterone system that may resolve upon causes worth noting are:
358 D. Vassallo et al.
5 Cholesterol embolization of atheroma after angiog- coronary atherosclerosis are also frequent associations
raphy or revascularization procedures or commenc- with ARVD.
ing anticoagulation
5 Contrast-induced nephropathy 17.1.3.2 Epidemiology
5 Treatment with RAS antagonists in patients with Many cases of ARVD are clinically silent, making
physiologically significant RAS, due to dilatation of it difficult to accurately estimate disease prevalence.
the efferent glomerular arteriole with a greater than Interpretation of available data is complicated both
expected decline in GFR by temporal changes in availability of diagnostic tools
and also by changes in attitudes towards use of these
Use of RAS antagonists such as ACEi and ARBs is com- resources following publication of ‘negative’ RCTs
plex and depends on context. A highly activated RAS can such as the Angioplasty and Stenting for Renal Artery
be both a consequence and cause of RAS that is associ- Lesions (ASTRAL) trial and the Cardiovascular
ated with a more rapid long-term decline in GFR. While Outcomes in Renal Atherosclerotic Lesions (CORAL)
major randomized controlled trials have established that study [22, 23]. With these caveats considered, the most
RAS antagonists help preserve renal function in patients definite statement that can be made is that ARVD is
with diabetic and non-diabetic proteinuric kidney disease not rare in the general population aged older than
[12, 13], the evidence that these agents provide the same 65 years (annual incidence 0.5%; prevalence 7%) and is
benefit in patients with ARVD is less robust [14]. Use of recognized as a primary cause of ESKD in a propor-
RAS antagonists in patients with ARVD has been associ- tion of these patients (annual incidence of ESKD due
ated with concerns related to increased risk of AKI [15]. to ARVD, 1.3–1.7%; prevalence, 0.7–1%) [24]. Ethnicity
However, it is also clear that RAS antagonists can opti- is not a significant factor in the development of ARVD.
mize cardiac status and prevent cardiovascular events in Populations enriched with other vascular disease have
this patient population with cardiovascular disease and higher rates of ARVD. Given the anatomical proximity
cardiac structural abnormalities [16] and can improve of the abdominal aorta and the iliac vessels to the renal
overall survival [17, 18]. On starting RAS antagonists, a arteries, it is unsurprising that 20% and 40% of patients
short-term and stable decline in GFR is hemodynami- with atheromatous disease in these respective areas have
cally and physiologically expected. Diagnosis of AKI ARVD. However, the association extends to more distant
requires a larger than expected decline in GFR. The vascular beds, with high rates of ARVD found in patients
UK National Institute of Healthcare Excellence guid- with carotid (10%) and coronary (40%) disease [25].
ance advice on starting RAS antagonists in CKD rec-
ommends to stop or reduce the drug if creatinine rises 17.1.3.3 Aetiopathology
>30% or eGFR falls >25% from baseline and to exclude Despite the significant associations with other vascu-
hemodynamically stressful risk factors such as volume lar pathologies, the effects of classical risk factors for
depletion and NSAID use [19]. If ARVD is not already development of atherosclerosis are less clear in ARVD
identified, it should be suspected and diagnostic imaging than, e.g. coronary artery disease. Although the associa-
considered. Use of RAS antagonists should be tempo- tions of CKD with smoking and diabetes may skew the
rarily withheld during an intercurrent illness or prior to data, single-centre comparison of patients investigated
administering iodinated contrast agent. for ARVD did not describe a difference in smoking rates
or prevalence of diabetes mellitus between patients with
17 Cardiorenal Syndromes Including Flash normal or abnormal renal angiograms. This is despite
Pulmonary Oedema higher rates of other vascular disease in the patients
Flash pulmonary oedema (FPO) refers to a dramatic found to have ARVD [26]. The surprising lack of effect
form of acute decompensated heart failure. The semi- of smoking is confirmed in other data, but systematic
nal description by Pickering showed a strong association reviews appear to suggest that increased rates of ARVD
with RAS particularly if bilateral or to a single func- are observed in diabetic patients [25].
tioning kidney [20]. Patients with ARVD have chroni- Given that patients with a single kidney can have an
cally elevated left ventricular and atrial pressures due eGFR in the normal range, it is not immediately clear
to chronic hypertension, diastolic dysfunction, left why unilateral RAS should lead to loss of renal func-
ventricular hypertrophy and fluid retention associated tion. Indeed, the renal vasculature is highly adapted for
with highly activated RAAS. This leads to increased filtration, and renal blood flow is in excess of the meta-
ventricular wall stress (afterload) and back reflection of bolic needs of that kidney. Compensatory arteriovenous
the ventricular pressure into the left atrial and pulmo- shunting, tubulo-glomerular feedback and neuro-hor-
nary capillaries [21]. Flash pulmonary oedema remains monal inputs form part of a complex autoregulation
a strong indication for renal revascularization, and such that maintains renal oxygenation across a wide range of
patients have not typically been included in clinical tri- blood flows [27]. Studies using latex casts and hemody-
als as discussed further below. Chronic heart failure and namic measurements indicate measurable hypoxia only
Disease of the Renal Vessels
359 17
occurs when a renal artery stenosis (RAS) is 70–80% by
. Table 17.2 Diagnostic imaging techniques for renovascu-
angiographic assessment [28]. Loss of renal function in lar disease
ARVD is probably twofold: direct hemodynamic conse-
quences of significant reduction in renal perfusion and a Technique Advantages Disadvantages
consequence of an ischemic cascade of neuro-humoral
activation, inflammation, oxidative stress, capillary rar- Duplex Entirely Time-consuming
efaction and fibrosis that might persist despite perfusion ultrasound non-invasive Operator dependent
No contrast or Technical failure
being restored [29]. Thus there is likely a threshold at radiation rate >10% (bowel gas,
which restoring blood flow cannot reverse this vicious Able to monitor obesity, etc.)
cycle of hypoxic consequences, and this may explain the disease
negative results of ASTRAL and CORAL. progression
Thus it is most likely that renal parenchymal damage, Computed Widely available Contrast and
secondary to ‘flow-independent’ effects of the stenosis tomography tool radiation exposure.
(e.g. hypertension/micro-emboli), is the main arbiter of angiography Reproducible Risk of contrast
functional loss. In support of this, there is no correla- results nephropathy
Most sensitive Calcified vessels can
tion between degree of stenosis and level of proteinuria technique limit interpretability
in ARVD, but an inverse relationship between eGFR of images
and proteinuria, where proteinuria acts as a surrogate Can over-estimate
marker of the degree of irreversible renal parenchymal stenosis
damage. Indeed observational studies have shown that Magnetic No risk of Can over-estimate
the level of proteinuria is a possible marker of likelihood resonance contrast stenosis
of improvement in eGFR following revascularization. angiography nephropathy Risk of nephrogenic
Even minor elevations (>0.6 g/24 hours) correspond to No radiation systemic fibrosis
Reproducible
large reductions in the chance of renal functional benefit images
from intervention [30, 31].
a b
. Fig. 17.4 Direct angiography in atherosclerotic renal vascular disease. a – 70% left renal artery stenosis. b – Right renal artery occlusion
and 98% left renal artery stenosis
Cardiac Imaging
In over 95% of patients with ARVD, an abnormality of
either left ventricular function or structure can be dem-
onstrated on transthoracic echocardiography, with risk
of deterioration in all these parameters over time [33].
Baseline cardiac imaging is therefore an appropriate
request. Currently this is of more prognostic than ther-
apeutic benefit. Randomized data comparing cardiac
structural and functional outcomes between medical and
interventional therapy in patients with ARVD have inter-
estingly not shown any significant differences between the
two treatment arms [34, 35]. This is again similar to the
lack of differences in primary outcome measures noted in
the two main RCTs ASTRAL and CORAL. As explained
below, potential explanations include the clinical heteroge-
17 neity of the ARVD patient population and the underrep-
resentation of ‘high-risk’ ARVD patients in these studies.
Author Year Patients (n) Inclusion criteria Follow-up Treatment Primary end-point Key clinical outcomes Comments
in months modality
Weibull 1993 58 Non-diabetic 24 29 – PTRA Technical success, primary Diastolic BP Given the tight inclusion
et al. [62] ≤70 years 29 – surgery and secondary patency and <90 mmHg – criteria and the highly selected
Untreated BP changes in BP and renal secondary results b: population, it was unclear
Disease of the Renal Vessels
≥160/100 mmHg function from baseline PTRA 5/29 (17%), whether the clinical benefit
Significant Surgery 5/29 (17%) observed following both
unilateral RAS Secondary improved/ interventions could be
Serum creatinine stable renal function extrapolated to the general
<300 umol/L b: population of patients with
PTRA 83%, surgery ARVD
72% p = 0.53
Complications:
PTRA 5/29 (17%),
surgery 9/29 (31%)
p = 0.17
Primary patency rate
at 24 months:
PTRA – 75%,
surgery – 96%
Plouin 1998 49 <75 years of age 6 23 – PTRA Blood pressure at 6 months No statistical PTRA resulted in a reduced
et al. [63] Diastolic BP 26 – medical and change from baseline difference between antihypertensive medication
>95 mmHg treatment mean ambulatory BP use at 6 months; however it
CrCl ≥50 ml/min at 6 months and was associated with a higher
Significant average reduction in risk of complications
unilateral RAS BP between the two
groups
Complications:
PTRA 6/23 (26%),
medical 2/25 (8%)
Webster 1998 55 <75 years 3–54 25 – PTRA Blood pressure at 6 months A statistically BP fell significantly following
et al. [64] Diastolic BP 30 – medical and change from baseline significant drop in BP the 4-week run-in period with
≤95 mmHg treatment (p < 0.05) was standardized antihypertensives
≥50% Unilateral/ detected only in in both groups
bilateral stenosis patients with bilateral
sCr <500 umol/L disease randomized
to PTRA
There were no
361
significant differences
in renal function or
survival between
groups
(continued)
17
17
362
Author Year Patients (n) Inclusion criteria Follow-up Treatment Primary end-point Key clinical outcomes Comments
in months modality
Van de Ven 1999 85 ≥50% ostial ARVD 6 42 – PTRA Primary success rate and Primary success rate PTRAS was technically more
et al. [65] BP >160/96 mmHg 43 – PTRAS patency rate at 6 months c: successful than PTRA,
D. Vassallo et al.
30/403 (8%)
intervention group;
31/403 (8%) medical
Rx
CVE:
141/403 (35%)
intervention group,
145/403 (36%)
medical Rx
Deaths:
103/403 (26%)
intervention group;
106/403 (26%)
medical Rx
Marcantoni 2012 84 Unilateral/bilateral 12 41 – Medical Change in echocardiographic Controlleda or LVMI, a surrogate cardiovas-
et al. [34] RAS >50%–≤80% therapy LVMI from baseline improved BP control: cular end-point, decreased by
(RAS-CAD) IHD and elective 43 – Medical 75% - Intervention equivalent amounts in both
coronary therapy + group; 81% - groups
angiography PTRAS medical Rx
(intervention Deaths:
group) 2/43 (4.6%)
Intervention group;
2/41 (4.9%) medical
Rx
CVE:
11/43 (25.6%)
Intervention group;
11/41 (26.8%)
medical Rx
(continued)
17 363
17
364
Author Year Patients (n) Inclusion criteria Follow-up Treatment Primary end-point Key clinical outcomes Comments
in months modality
Cooper et al. 2014 947 Unilateral or 43 480 – medical Composite end-point of Composite primary Revascularization conferred no
[23] bilateral ARAS (median) Rx death from cardiovascular or end-point benefit over optimal medical
D. Vassallo et al.
(CORAL) ≥60% 467 – medical renal causes, myocardial 169/472 (35.8%)- treatment in terms of clinical
Rx + PTRAS infarction, stroke, hospital- medical Rx; 161/459 outcomes
(95%) or ization from congestive heart (35.1%)-
PTRA failure, progressive renal intervention group
(intervention impairment or need for renal (p = 0.58)
group) replacement therapy Deaths:
63/459 (13.7%) –
intervention group
76/472 (16.1%) –
medical Rx (p = 0.2)
ESKD:
16/459 (3.5%) –
intervention group
8/472 (1.7%) –
medical Rx (p = 0.11)
ACEi angiotensin-converting enzyme inhibitor, ARAS atherosclerotic renal artery stenosis, ARVD atherosclerotic renovascular disease, BP blood pressure, ESKD end-stage kidney
disease, IHD ischaemic heart disease, PTRA percutaneous transluminal renal angioplasty, PTRAS percutaneous transluminal renal angioplasty and stenting, RAS renal artery stenosis,
RF renal function, sCr serum creatinine
Disease of the Renal Vessels
365 17
end-points such as death, cardiovascular events and pro- Example clinical
gression to renal replacement therapy have been assessed. scenarios
No trial has shown a conclusive benefit of revasculariza- Scenario Actions
tion over medical therapy for any outcome measure. Patient aged Examine for bruits Good candidate for
The first three trials published between 1998 and 2000 <30 years Indirect angioplasty if
used angioplasty alone. Subsequently, it was established presenting with angiography to angiogram shows
that better long-term angiographic outcomes occurred hypertension investigate for FMD
FMD
when angioplasty was coupled with bare metal stenting
(PTRAS). This technique was therefore adopted for more Patient with Do not expose to Consider admission
recent trials [22, 23, 36]. This difference in interventional eGFR 20 ml/ gadolinium. Image for hydration for
min and renal vessels with CTA
technique limits direct comparison between RCTs. Small asymmetric either DUS or
patient numbers, short follow-up periods and low rates kidneys on CTA
of statin/renin-angiotensin blockade use in early trials ultrasound
further limit their applicability to current practice. The Elderly patient Address lifestyle Prescribe
largest two landmark studies, ASTRAL and CORAL, with chronic factors – e.g. angiotensin
provide the most robust data about the role of revascular- CKD stage 3 smoking, diabetic blockade as
ization and, despite the limitations of both studies, had an and renal artery control first-line blood
important impact on the current management of ARVD: stenosis pressure control.
Commence statin
5 The Angioplasty and Stenting for Renal Artery Lesions and consider
(ASTRAL) trial was based in the UK and Australasia anti-platelet agent
and randomized 806 patients with ARAS to either
Patient Assess left If significant
medical therapy alone or medical therapy with revascu- presenting with ventricular bilateral renal
larization. Patients were included into the study if they recurrent acute function. If systolic artery stenosis,
had significant stenosis in at least one renal artery and onset function is consider referral for
their clinician was uncertain that revascularization pulmonary preserved, perform revascularization
would be of benefit. This inclusion criterion received oedema indirect renal
angiography
significant criticism as criteria for revascularization
were not established and the functional significance of Patient with Doppler imaging Refer for renal
stenosis was not assessed; indeed, out of the entire suspected renal of renal vessels artery angioplasty
artery stenosis and stenting
study population, 40% were found to have low-grade and previously
stenosis (50–70%) at angiography, while 17% of patients preserved renal
randomized to stenting were not revascularized either function
due to non-significant degrees of stenosis at angiogra- presenting
phy (8%) or patient refusal [11]. After a median of acutely dialysis
dependent
34 months follow-up, there was no between-group dif-
ference in the primary outcome of renal function nor Greater than Consider volume If significant
for secondary outcomes of blood pressure control, car- 25% reduction state and stenosis and no
in eGFR concurrent other culprit
diovascular event rates or mortality (secondary end- following nephrotoxic drugs medications,
points) [22]. Safety analysis noted a 6.8% rate of initiation of Indirect renal consider
significant complications in the revascularized arm. angiotensin angiography revascularization
5 The US-based Cardiovascular Outcomes in Renal blockade to
Atherosclerotic Lesions (CORAL) study randomized treat chronic
heart failure
947 patients to stenting and best medical therapy or
best medical therapy alone. The original design of Patient with Review If uncontrolled
CORAL aimed to overcome the shortcomings of uncontrolled echocardiograms symptoms, increased
symptoms of regarding LVMI LVMI and
ASTRAL; only patients with haemodynamically con- CHF and renal significant stenosis,
firmed severe renal artery stenosis and a systolic BP artery stenosis consider
of 155 mmHg or higher despite use of at least two revascularization
antihypertensive agents were intended to be recruited.
The degree of stenosis was standardized by means of FMD fibromuscular disease, DUS duplex ultrasound, CTA
computed tomography angiography, CHF chronic heart fail-
an angiographic ‘core lab’ evaluation and trans-
ure, LVMI left ventricular mass index
lesional gradient measurement, and severe stenosis
was defined as either at least 80% but less than 100%
366 D. Vassallo et al.
angiographic stenosis or 60–80% stenosis with a of patients were compared to those of patients who were
trans-lesional systolic pressure gradient of at least treated exclusively medically. Results showed that revas-
20 mmHg. However, patient recruitment proved to be cularization was associated with improved outcomes in
very slow, and hence these inclusion criteria were patients with either flash pulmonary oedema or with a
relaxed such that by the end of the study average angi- combination of rapidly declining kidney function and
ographic stenosis was 66% (very similar to ASTRAL), uncontrolled hypertension [38].
and only 20% of patients had >80% stenosis [11, 37]. We have published another recent observational
The primary end-point was a composite of major car- study that confirms that revascularization appears
diovascular events, progressive deterioration in renal to be of benefit in a sub-group of high-risk patients
function and death from cardiovascular or renal with rapidly deteriorating renal function either in the
causes. Again, after a median follow-up of 43 months, context of critical stenosis (≥70% bilaterally) or <1 g/
revascularization did not confer any clinical benefit day baseline proteinuria, a surrogate marker of well-
over medical therapy on its own [23]. preserved parenchyma [39] (. Fig. 17.6a). Previous
work from our research group forged the concept of
Both the ASTRAL and CORAL trials received criti- ‘hibernating parenchyma’, that is, viable renal paren-
cism due to selection bias: patients had well-preserved chyma that has not yet undergone the irreversible
renal function at recruitment in CORAL (eGFR 58 ml/ changes associated with ARVD and hence retains the
min/1.73m2), and high-risk patients with uncontrolled possibility to recover function post-revascularization
hypertension, rapidly deteriorating renal function or (. Fig. 17.6b, c). Studies which have related the iso-
recurrent flash pulmonary oedema, more likely rep- topic GFR of the kidney with RAS to its parenchy-
resenting clinically significant stenosis, were under- mal volume (measured by MRI) suggest that selecting
represented in both studies. We have undertaken a organs with the highest volume-GFR ratio can poten-
single-centre observational retrospective study of 237 tially select patients most likely to improve renal
patients with at least 50% RAS and one or more of the function following PTRAS [40]. Although increased
above ‘high-risk features’, 24% of whom were treated mortality is observed in patients with higher degrees
with revascularization. Clinical outcomes for this subset of stenosis, a direct causal link cannot be made, due
a b
17
. Fig. 17.6 a Angiogram of a 41-year-old male smoker who pre- contrast demonstrated marked differential perfusion with significant
sented with severe hypertension, a creatinine of 90 and pulmonary areas of hypoperfusion consistent with ‘hibernating renal paren-
oedema. The angiogram demonstrates bilateral tight proximal chyma’. c MRA also demonstrates differential perfusion of ‘hiber-
renal artery stenosis with post-stenotic dilatation (arrows). Despite nating’ renal parenchyma. Crucially both the CT and MRA show
evidence of good adherence, he had multiple admissions with good sized kidneys with preserved renal cortex. Following bilateral
hypertension (c.220/120 mmHg) and pulmonary oedema on five renal angioplasty and stenting, his blood pressure returned to 140/90
antihypertensives including maximum dose ACEi. b The CT with on ACEi alone
Disease of the Renal Vessels
367 17
to increased co-existent coronary disease in these elderly patients with chronic heart failure (CHF) have
patients. Sub-analyses of patients with >70% RAS in co-existent ARVD [42]. With examples of cardiac struc-
RCT data have not shown any difference in outcome tural benefit described following revascularization, and
following PTRAS than in patients with a lower per- a case series describing improved NYHA status and
centage stenosis. Again, selection bias affects interpre- reduced hospitalization rates following intervention
tations of the RCT data, but RAS severity especially [42], there is interest in the potential role of PTRAS in
when considered in isolation is not considered a reli- the treatment of chronic heart failure [43]. In spite of
able guide to intervention. this, both the cardiac imaging substudies of ASTRAL
It is hoped that recent advances in imaging tech- and the Stenting of Renal Artery Stenosis in Coronary
nology will enable accurate characterization of func- Artery Disease (RAS-CAD) study have not shown any
tional renal tissue in ARVD with the aim of identifying significant cardiac structural or functional improve-
patients who may benefit from revascularization in a ment between revascularized and non-revascularized
timely manner. patients [34, 35]. As explained above, selection of rela-
tively ‘low-risk’ patients is an important limitation for
In Which of the Following Scenarios Is both studies, but to date revascularization is not con-
Revascularization to Be Considered? sidered to play a role in the management of chronic
heart failure.
Stable CKD or Incidentally Diagnosed ARVD Renin-angiotensin blockade is recognized as an
Available evidence does not support revascularization important therapy in treatment of both CHF and
for patients with stable CKD. Real-world experience ARVD with morbidity and mortality benefits. Though
has duplicated trial findings, emphasizing the need to angiotensin-converting enzyme inhibitors and angio-
focus on appropriate medical therapy for these patients. tensin II receptor blockers are well tolerated in
Acceptance of this finding is important to minimize risk ARVD, there remains a small group of patients for
of complications from intervention (discussed below). whom these treatments are associated with a signifi-
While incidentally diagnosed ARVD could be consid- cant decline in renal function. Revascularization can
ered to be the same as ARVD with stable CKD, specific allow safe use of renin-angiotensin blockade in pre-
outcome data exist for patients found to have RAS dur- viously intolerant patients [20]. As such intervention
ing another angiographic procedure. In line with trial can be considered a tool to facilitate optimal medical
data, when incidental cases of ARVD were compared therapy.
between those that were revascularized and those who
were not, no difference was seen in terms of blood pres- Rapid Loss of Renal Function and Refractory
sure or renal function at 12 months. Hypertension
The overall lack of benefit from revascularization Refractory hypertension (defined as a blood pressure
when examining renal dysfunction as a primary out- >160/90 mmHg despite three or more different anti-
come measure is almost certainly due to the slow rate hypertensive agents) is considered by some as a poten-
of loss of renal function seen in ARVD. The annual tial indication to revascularize a patient with RAS. In
eGFR loss associated with ageing is around 0.7 ml/ part, this position is supported by an early RCT pub-
min/1.73 m2/year, with the average rate of loss in ARVD lished by the Dutch Renal Artery Stenosis Intervention
only slightly higher than this. As such, any longitudinal Cooperative Study Group (DRASTIC) [44]. Although
difference in renal function between medical and inter- the study was not powered to examine this end-point,
ventional groups would be subtle and require an RCT patients saw reductions in their blood pressure from an
to be powered to very high patient numbers to identify a average of 190/111 mmHg at 3 months to 169/102 mmHg
statistical difference. at 12 months suggesting that further studies with this
group are warranted. Within ASTRAL, a limited pre-
Acute and Chronic Heart Failure specified analysis of patients with rapidly declining renal
Approximately 5% of patients with ARVD present with function (greater than a 20% or 100 μmol/L increase in
flash pulmonary oedema. Although this patient group serum creatinine in the 12 months before enrolment into
has yet to be investigated in an RCT or case control the study) was performed. For the 96 patients fitting
series, this presentation is accepted as an indication for these criteria, there was a non-significant reduction in
PTRAS [17]. Despite the lack of high-grade evidence, serum creatinine at 12 months in the revascularization
this approach is appropriate based on what data are group compared to the medical group. As described
available – an unmatched series of 39 patients with FPO above, two small retrospective observational analyses
showed a significant reduction in hospitalization rates suggest that patients with rapidly deteriorating renal
following revascularization from 2.4/year to 0.3/year [41]. function and uncontrolled hypertension can gain benefit
As discussed above, significant cardiac structural from revascularization especially if there is evidence of
changes are observed in ARVD, and over 30% of well-preserved renal parenchyma with low levels of pro-
368 D. Vassallo et al.
teinuria. Larger studies or data from an international there is advanced renal dysfunction), with beta-block-
ARVD registry would add clarity. ers and calcium channel blockers as third-line agents.
Although no outcome data support use of diuretics in
17.1.3.7 Complications of Revascularization ARVD, the understanding that resistant hypertension in
Although there is a possibility that minor complications CKD is often due to underuse of diuretics, and espe-
(e.g. discomfort) may be over-reported in RCT data, it cially that salt-water retention is increased by RAAS
is clear that PTRAS has potentially serious side effects overstimulation, makes these agents a logical choice.
and should not be undertaken lightly. Some of the more Support for use of beta-blockade comes from rec-
common complications associated with PTRAS in con- ognition of increased local sympathetic and adrenergic
temporary medical practice include groin haematoma, activity in ARVD. This local increase is associated with
renal artery dissection, cholesterol embolization, renal elevated serum noradrenaline concentrations which have
artery rupture, contrast-induced nephropathy and aor- been linked to both reduced eGFR and the increased
tic dissection. cardiovascular mortality. There are some data which
Meta-analysis of 687 patients represented in data suggest that beta-blockade following revascularization
published between 1991 and 1998 found that 9% of renal leads to improved renal functional outcomes and lower
angioplasty procedures resulted in a serious complica- rates of restenosis. Renal artery denervation, which has
tion (e.g. significant blood loss, renal infarction, loss of been shown (in a non-ARVD population) to reduce
renal function), with an overall 1% mortality rate. The peripheral blood pressure, may be helpful, but as yet
more recent RCT quoted a lower rate of serious adverse there are no data in the ARVD population to support
events (6.8% in ASTRAL and 5.2% in CORAL), its use.
although two deaths were reported in the ASTRAL
trial. The reported rate of the more common complica- Statins
tions mentioned above is between 0.5% and 10%. The evidence supporting statin therapy in ARVD has
a clear narrative. Though early case reports describing
17.1.3.8 Medical Therapy regression of stenosis with statin therapy have not been
Given the overall ‘negative’ findings in trials of revascu- duplicated, it is certain that rate of progression of ste-
larization versus medical therapy in ARVD, an under- nosis is slowed. In addition, statin-treated patients (even
standing of appropriate use of pharmacotherapy is with a normal lipid profile) have been shown to have
vital. Despite this, a lack of concordance between tri- lower rates of death and progression to dialysis [45].
als makes it difficult to define optimal medical therapy. Revascularized patients also benefit from treatment
We would suggest that renin-angiotensin blockade in with statins, with a reduction in risk of death of over 80%.
conjunction with statin therapy should be considered Although the mechanism of benefit is not clear, it is most
first-line treatment for all patients with ARVD, with likely achieved through a composite effect of reduced
anti-platelet agents strongly considered on a case by renal fibrosis, reduced left ventricular hypertrophy and
case basis. These interventions have benefits in excess the wider cardiovascular advantages of these agents.
of blood pressure and proteinuria reduction and should
be complimented by general measures to manage risk in Anti-platelet Therapy
CKD such as smoking cessation advice, good diabetic The historical perspective of anti-platelet therapy in
control and taking exercise. all forms of atheromatous disease makes an objective
17 assessment of the role of these agents in ARVD chal-
Renin-Angiotensin Blockade lenging. With the co-existent burden of vascular dis-
The importance of tight blood pressure control is well ease in ARVD, the use of anti-platelets is easy to justify.
recognized in all-cause CKD, with a widespread appre- Although the DOPPS study did not identify a benefit of
ciation that blockade of the RAAS provides renal ben- aspirin therapy in dialysis-dependent patients, sub-anal-
efits in excess of those delivered solely by the associated ysis of patients with mild to moderate CKD in primary
blood pressure reduction. As explained above, in ARVD prevention studies have shown significant reduction
these agents reduce both blood pressure and risk of in the rate of vascular events, albeit with a significant
mortality to a greater extent than other antihypertensive increase in bleeding risk [46]. Less information is avail-
agents. able regarding alternative agents such as clopidogrel
(which may have reduced pharmacological activity in
Second-Line Treatment of Hypertension CKD).
For ARVD patients with blood pressure not controlled The time point for which there is definitive evidence
by RAAS inhibition, data on second- and third-line for anti-platelet agents in ARVD is at time of inter-
agents is scarce. CORAL has defined thiazide diuretics vention. The amount of micro-emboli released during
as a second-line agent (replaced by loop diuretics where stenting is significantly reduced by clopidogrel loading
Disease of the Renal Vessels
369 17
in combination with aspirin therapy (although the long- As mentioned above, novel functional magnetic reso-
term functional benefits are not yet established). nance imaging (MRI) techniques such as blood oxygen
level-dependent magnetic resonance imaging (BOLD-
17.1.3.9 Future Treatment Options MRI) may play a role in risk stratification by estimat-
The negative findings of RCTs were not predicted due ing the degree of intrarenal hypoxia to identify critically
to a range of case reports and series describing benefit ischaemic kidneys with potentially viable or ‘hibernat-
from intervention. As explained above, it is likely that ing’ parenchyma.
selection bias accounts for the bulk of this discrepancy. Increased understanding of the complex pathogen-
Hence more focused selection of patients and risk strati- esis of renal parenchymal injury in ARVD raises the
fication likely to benefit from revascularization (dis- possibility of novel therapeutic strategies. Cell-based
cussed below) may be an important approach. A simple therapies have been proposed to counteract the inflam-
risk calculator has been designed by our centre and is matory milieu and oxidative stress typically found in the
freely available. Although this requires further valida- post-stenotic kidney, in order to prevent irreversible loss
tion in larger ARVD populations, this risk calculator of renal microvascular architecture and help improve
shows that a small number of easily obtained variables clinical outcomes. Some strategies that are still at an
can help predict clinical outcomes and encourage a experimental stage include targeting mitochondrial
patient-specific therapeutic approach [47]. injury, which appears to play a major role in mediating
In addition to an increased recognition of the need both renal and cardiac remodelling in ARVD and infu-
for accurate clinical phenotyping, there is the potential sion of vascular growth factors, endothelial progenitor
that serum biomarkers could aid selection of patients cells or mesenchymal stem cells to stimulate angiogen-
most likely to benefit. Of a range of markers under esis and modulate the inflammatory milieu [51–54].
investigation, the most promising thus far is brain natri-
uretic peptide (BNP). Studies assessing BNP level in
relation to blood pressure response from revasculariza- 17.2 Renal Artery Embolic Disease
tion have shown that patients with a BNP level >50 pg/
ml (average baseline eGFR 66 ml/min/1.37m2) have a 17.2.1 Cholesterol Emboli
higher likelihood of a blood pressure reduction follow-
ing PTRAS. This finding is more marked in patients Cholesterol embolization occurs when cholesterol crys-
with a >70% stenosis or refractory hypertension [48]. tals are released following the rupture of an atheroma-
A small retrospective observational study performed at tous plaque. These crystals can occlude any small vessel,
our centre showed that only patients with NT-proBNP precipitating a multisystem disorder. Although the true
levels above a standard cut-off (300 pg/ml) gained ben- incidence and prevalence are unknown, cholesterol
efit from revascularization with regard to all adverse embolization is typically described as a disease of the
end-points compared to medically managed patients. over-60s (with a male preponderance) and may account
Novel revascularization techniques have also been for between 5% and 10% of cases of acute kidney injury
explored as a way of improving patient outcomes. The within this demographic.
Sirolimus-Eluting vs. Bare Metal Low Profile Stent for
Renal Artery Treatment trial failed to demonstrated sig- 17.2.1.1 Clinical Features
nificant benefit of drug-eluting stents at 2 years. More As with vasculitis, disease presentation depends entirely
promising is the use of embolic protection devices on the vessels involved. Severe acute kidney injury is
(EPD). Crossing a renal artery lesion with an unde- relatively rare, with only the minority of patients having
ployed stent risks causing disruption of the stenosis and a significant abrupt rise in serum creatinine within a few
release of downstream emboli. These emboli may con- days of an interventional procedure. Mostly there is slow,
tribute to the rapid eGFR losses noted when patients progressive loss of renal function spread over a period in
with CKD stage 1 or 2 undergo revascularization. Dual excess of 4 weeks. This is suggestive of two distinct pathol-
anti-platelet therapy at the time of PRTA can reduce the ogies – the first where a large crystal burden causes acute
proportion of patients with distal embolization from vascular occlusion within the kidney and a second where
50% to 36% [49], but use of downstream EPD to capture there is either slow sustained emboli release or a regional
larger particles is an attractive proposition. In a small inflammatory response to emboli dispersed to the kidney.
pilot RCT where these devices have been deployed in In patients with renal involvement, the two other
conjunction with glycoprotein IIa/IIIb inhibition, signif- most commonly affected organ systems are the skin
icant improvements in eGFR have been seen at 1 month (presenting with livedo reticularis, blue toes, purpura,
(compared with eGFR reductions in other treatment ulceration and gangrene) and the gastrointestinal tract
groups); however further studies are required before (presenting with non-specific abdominal pain, bleeding,
these devices form part of routine clinical practice [50]. ischemic bowel, pancreatitis). Neurological manifesta-
370 D. Vassallo et al.
tions are less common and harder to define, but where no co-existing renal disease cause) may be suggestive.
retinal embolization occurs, this should dramatically A relationship between cholesterol embolization and
raise the index of suspicion for the diagnosis. hypocomplementaemia is not consistently reported, and
the presence of this should perhaps direct more atten-
17.2.1.2 Aetiopathology and Epidemiology tion to the possibility of other diagnoses such as sub-
Given the link between cholesterol embolization and acute bacterial endocarditis. Of more clinical use is the
pre-existing atheromatous disease, it is unsurprising that presence of systemic eosinophilia, which, although tran-
risk factors are common between these conditions (age sient, is commonly seen at high levels where there is cho-
over 60 years, hypertension, diabetes, smoking history, lesterol embolization. This finding, although sensitive,
Caucasian). More clinically relevant are the precipi- is not specific and should also prompt consideration
tants for embolization, which have changed over time. of acute interstitial nephritis if there has been a newly
While 20–30 years ago spontaneous plaque rupture introduced medication.
was almost the sole cause, the greatly increased use of
interventional endovascular techniques has resulted in 17.2.1.4 Treatment
over 75% of contemporary cases being iatrogenic. Coro- There is no definitive treatment for cholesterol emboli-
nary angiography appears to carry the highest risk, with zation, and between 40 and 60% of patients suspected
approximately 20 cases per 1000 procedures. Addition- to have the diagnosis require acute dialysis with a sig-
ally, anticoagulation can precipitate cholesterol emboli, nificant proportion remaining dialysis dependent.
although this is a rare complication [55]. Withdrawal of any clear precipitant is a vital first step.
Thereafter, the mainstay of treatment is statin therapy.
17.2.1.3 Diagnosis Although there is a lack of randomized data or a mech-
It is highly likely that many minor or clinically asymp- anistic explanation, there is good, prospective, evidence
tomatic cases of cholesterol embolization go undetected, that these agents reduce risk for ESKD [56]. There is no
especially following endovascular revascularization ther- large-scale evidence of benefit for corticosteroids, and
apy. However, the presence of acute/subacute renal dys- use is often limited to patients with severe multisystem
function in the context of a clear precipitant and other disease.
signs of peripheral embolization is sufficient to con-
firm the diagnosis of cholesterol embolization. Where
this triad does not exist (and if retinal emboli cannot 17.2.2 Renal Artery Thromboembolism
be demonstrated on fundoscopy), tissue is required to
make a definitive diagnosis and exclude conditions such Renal artery thromboembolism, if not immediately
as small vessel vasculitis. Renal biopsy is the gold stan- treated, leads to irreversible renal parenchymal damage
dard test (providing a positive diagnosis in over 75% of and loss of renal function. Unfortunately, due to the
cases – . Fig. 17.7), but samples from other areas, e.g. non-specific nature of the symptomatology and the rar-
skin, can be valuable if this is contraindicated. ity of the condition, this is often a delayed diagnosis.
Prior to biopsy, there are few serum markers of
diagnostic use, but new-onset proteinuria (assuming 17.2.2.1 Clinical Features and Diagnosis
Most patients are aged over 60 years and present with
severe acute onset flank/abdominal pain, which can be
17 associated with a fever and nausea and vomiting. There
is no gender or racial preponderance.
While the presence of new-onset dipstick haematuria/
proteinuria is supportive of renal thromboembolism,
the key to making the diagnosis is a high index of
clinical suspicion and expedient angiographic imaging
(either direct angiography or CTA, as USS has very
low sensitivity). When reviewing imaging it should be
understood that up to 10% of cases present with bilat-
eral thrombi.
17.2.2.2 Aetiopathology
The primary source of emboli causing renal infarction
is cardiac (typically left atrial clots secondary to atrial
. Fig. 17.7 Renal biopsy showing cholesterol emboli. Renal biopsy fibrillation), although cases linked to sickle cell disease
demonstrating small vessel cholesterol athero-emboli (arrow) and septic emboli are reported.
Disease of the Renal Vessels
371 17
17.2.2.3 Treatment
The rarity of the condition makes treatment recommen-
dations difficult. Prompt initiation of anticoagulation
with i.v. heparin (followed by warfarin when stable) is
the accepted first step, followed by percutaneous throm-
bolysis or thrombectomy as soon as possible. Renal
functional prognosis is highly dependent on speed of
diagnosis and treatment [57].
renal vein between the abdominal aorta and the supe- after walking for approximately 200 m on the level. He
rior mesenteric artery. The presentation can be at any is receiving an angiotensin-converting enzyme inhibi-
age and is classically with left flank pain (which can tor (ACEi), which was commenced about 2 months
extend to the left testicle) with non-visible or visible before referral, and he also receives a diuretic and a
haematuria or orthostatic proteinuria. Diagnosis can calcium antagonist at full dosage to optimize his blood
be made either by ultrasound or computed tomography pressure. On examination he is noted to have bilat-
imaging. eral ilio-femoral bruits but palpable pedal pulses. His
Treatment of the ‘nutcracker syndrome’ is dependent blood pressure remains sub-optimally controlled at
on the severity of symptoms. In the most extreme cases, 170/90 mmHg. He is commenced on an alpha-blocker
renal vein stenting, surgical venous bypass and auto- (Doxazosin).
transplantation have all been used [59]. Following the clinic visit, you review his blood
results and notice that there has been a deterioration in
his renal function with the serum creatinine increasing
17.4 Lymphatic Disease from 120 to 180 μmol/L and estimated glomerular filtra-
tion rate (eGFR) decreasing from 58 to 36 mL/min since
Cystic dilatation of renal lymphatic channels, renal the time of referral.
lymphangiomatosis (also called cystic lymphangioma
or renal lymphangiectasia), is an exceptionally rare con- ? Chapter Review Questions
dition in which the renal lymphatics fail to adequately 1. Which statement(s) support(s) your suspicion that
drain, resulting in structural malformations. The kid- the patient has underlying renovascular disease?
neys can enlarge to such a size that they may mimic A. Longstanding hypertension.
17 polycystic disease or cause an obstructive uropathy. As B. There is difficulty in controlling the blood
pressure with three different antihypertensive
there is minimal effect on renal function, management
is normally conservative. The exception is during preg- drugs.
nancy in which the condition may be exacerbated to the C. There was a relatively rapid deterioration of
point of requiring percutaneous drainage [60]. renal function between the time of referral
and the first clinic visit.
D. He is an arteriopath with symptoms of lower
limb claudication pains.
17.5 Questions and Answers
2. What would be the most appropriate investigation(s)
A 65-year-old male is referred for investigation of to decide whether the hypertension has a renovascu-
lower limb claudication pains. His past medical history lar origin?
includes diabetes, longstanding hypertension, angina A. Direct intra-arterial angiography
and a previous transient ischaemic attack. He is also B. Renography with captopril provocation
a lifelong smoker. His symptomatic claudication arises C. Magnetic resonance angiography (MRA)
Disease of the Renal Vessels
373 17
D. Computerized tomography angiogram (CTA) patient basis [61]. In this situation, the ACEi-I
E. Duplex ultrasound of the renal arteries was withheld given the acute on chronic kidney
injury.
3. What is the most appropriate revascularization
In this patient, magnetic resonance imaging
approach for the renal artery stenosis?
showed diffuse aorto-iliac disease. There was a
A. Aortorenal bypass
90% stenosis with post- stenotic dilatation at the
B. Thromboendarterectomy
ostium of the left renal artery, and the kidney was
C. Percutaneous transluminal angioplasty (PTA)
10 cm in length. On the right hand side, there were
with stent
two renal arteries,; the smaller of these exhibited
D. PTA alone
a 50% renal artery stenosis (RAS). The kidney
E. Nephrectomy
measured 11 cm in length. Given the rapidly dete-
4. Which are the most frequent serious complica- riorating renal function, uncontrolled hyperten-
tions seen after renal artery PTA? sion and anatomically severe stenosis in the left
A. Arterial rupture renal artery, this patient fell into the ‘high-risk’
B. Occlusion category, and it was decided to proceed with inter-
C. Cholesterol microembolization vention.
D. Contrast-related acute kidney injury 3. C. The most appropriate revascularization tech-
E. Groin haematoma nique is percutaneous transluminal angioplasty
F. All of the above (PTA) with stent.
4. F. Renal Aartery PTA is a potentially hazardous
5. Which of the following would be most appropri-
intervention associated with significant compli-
ate for his future management?
cations. The prevalence of these complications
A. Regular clinic review with attention to medi- in contemporary clinical practice is around 0.5 –
cal control of blood pressure and vasculopro- 10%.
tective therapy The patient underwent percutaneous angio-
B. Repeat renal artery imaging with possible plasty with bare- metal stent placement in the
repeat left renal artery stenting left renal artery. The right renal artery was not
C. Right renal artery PTA and stenting amenable to endovascular intervention. The pro-
D. Surgical revascularization of the left kidney cedure progressed without complications, and the
patient was sent home the day after treatment in
v Answers good condition.
1. B and D. Haemodynamically -significant reno- He was reviewed again after 2 weeks at which
vascular disease leads to neurohumoral activation stage his creatinine had improved to 140 μmol/L
and upregulation of the renin- angiotensin system (eGFR 49 mL/min). His blood pressure (165/90)
leading to hypertension that can prove resistant to control had improved to some extent.
medical management. This gentleman has numer- 5. A. The most appropriate long-term management
ous atherosclerotic risk factors, and up to a quar- plan for this gentleman would be aggressive con-
ter of patients with peripheral vascular disease trol of his atherosclerotic risk factors with appro-
have been found to have incidental ARVD. priate vasculoprotective therapy that includes a
2. C and D. Both MRA and CTA are non-invasive statin, aspirin, and, once kidney function is stable,
and have been shown to have an almost equiva- re-introduction of renin- angiotensin blockade.
lent performance to direct intra-arterial angiog- Clinic reviews should focus on optimization of
raphy, with sensitivities and specificities >90%. blood pressure and glycaemic control together with
Given that his eGFR is >30 ml/min, he is not at smoking cessation advice. Further intervention on
high risk of Ccontrast-induced nephropathy or the left renal artery is not warranted; however he
Nnephrogenic systemic fibrosis. Currently there is at risk of developing in-stent restenosis in the
is insufficient evidence to support the routine dis- future especially if his atherosclerotic risk factors
continuation of angiotensin-converting enzyme are not adequately controlled. Open surgical revas-
inhibitors (ACE-Ii) or angiotensin receptor cularization techniques are very rarely performed
blockers (ARBs) in stable outpatients. However in nowadays. Intervention on the right renal artery is
acutely ill patients at an increased risk of develop- not needed given that the degree of stenosis (50%)
ing AKI, it is suggested that withholding ACEi-I is not of any haemodynamic or functional signifi-
and ARBs should be considered on an individual cance.
374 D. Vassallo et al.
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17
377 V
Glomerular Diseases
Contents
Contents
References – 390
a b
. Fig. 18.1 Scanning electron micrograph of external (urinary) strates a normal podocyte. (b) demonstrates a podocyte in nephrotic
aspect of normal human glomerular capillary showing podocyte cell syndrome and the loss of normal architecture with foot process
bodies (*), primary (1°) and secondary (2°) processes. (a) demon- effacement
In adults, primary membranous nephropathy (PMN) Although IgA nephropathy is a common glomerulo-
is the most common cause of nephrotic syndrome, with nephritis, it does not often cause nephrotic syndrome.
some series describing 20–37% of cases of nondiabetic Membranoproliferative (mesangiocapillary) glomerulo-
adults presenting with nephrotic syndrome, with an nephritis is a recognised cause of the nephrotic syn-
increasing incidence in patients aged over 60 years old drome but is relatively rare and is usually is a secondary
[12] the majority of which have autoantibodies to process being driven by a primary cause. It is crucial to
M-type phospholipase A-2 receptor [13]. A proportion make the correct diagnosis of the cause of nephrotic
of patients with membranous nephropathy will have a syndrome, as there are differences in treatment as well as
secondary process, for example, driven by infection, rates of CKD and progression to ESRF.
autoimmune disease such as lupus, as well as drugs and Alternatively, NS may be due to a secondary process
malignancy. such as diabetes mellitus, autoimmune diseases (lupus),
Minimal change disease in adults is responsible for amyloid and the paraproteinaemias; a virally driven
about 10–15% of cases of nephrotic syndrome. This is in process (hepatitis B, hepatitis C or HIV), medication, or
contrast to children greater than 1 year old up to a paraneoplastic process with treatment of these sec-
puberty, in which minimal change disease will account ondary causes focused on the underlying cause. This
for 70–90% of cases of nephrotic syndrome [7]. In older demonstrates the importance of a detailed and thought-
children the incidence does start to decrease and ful assessment.
accounts for about 50% of cases of nephrotic syndrome.
The incidence of FSGS has increased in the 1990s
compared to 1970s (15% increasing to 35% in one 18.4 Inherited Causes
study). There is also an ethnic variation with FSGS,
with an increased incidence in African-American The unifying factor in most genetically mediated podo-
patients compared to Caucasian ethnicity [10]. This is cyte disorders seems to be disruption of the actin cyto-
supported in other renal biopsy studies of patients pre- skeleton: in 85% of cases of steroid-resistant nephrotic
senting with nephrotic-range proteinuria, with African- syndrome (SRNS) presenting by the age of 3 months
American patients having a FSGS incidence of 57% and 66% of cases presenting by the 1st year of life, a
compared to 23% in a Caucasian population [14]. recessive mutation in just four genes has been demon-
African-American patients with FSGS may have muta- strated (NPHS1, NPHS2, LAMB2, WT1) [15]. Nephrin
tions in the apolipoprotein L1 (APOL1) gene, but this is (NPHS1) is a signalling molecule located at the slit dia-
not routinely analysed. phragm that forms an integral part of the glomerular
382 G. Goldet and R. J. Pepper
. Fig. 18.2 Diagram representing the podocyte, glomerular base- transcription factor 1β, (metabolism and cytosol) ALG1 asparagine-
ment membrane (GBM), endothelial cells and common gene muta- linked glycosylation 1, APOL1 apolipoprotein L1, PMM2 phospho-
tions causing nephrotic syndrome mannomutase 2, ZMPSTE24 zinc metalloproteinase STE24,
. The defective gene-resulting mutated protein pairs are as follows: (cytoskeleton and membrane) ACTN4 α-actinin 4, INF2 inverted
(mitochondria) ADCK4 AarF domain containing kinase 4, COQ2 formin 2, (lysosome) SCARB2 lysosomal integral membrane protein
coenzyme Q2, COQ6 Coenzyme Q6, MTTL1 mitochondrial tRNA type 2, (slit diaphragm) NPHSE1 nephrin, NPHSE2 podocin,
1, PDSS2 prenyl diphosphate synthase subunit 2, (nucleus) WTI CD2AP CD2-associated protein, PLCE1 phospholipase C epsilon 1,
Wilms’ tumour protein 1, SMARCL1 SMARCA-like protein, TRPC6 transient receptor potential channel C6, (GBM) LAMB2
WDR73 WD repeat-containing protein 73, LMX1B LIM homeobox laminin β2, ITGA3 integrin α3, ITGB4 integrin β4
18
filtration barrier. Mutations in podocin are associated respond to coenzyme Q10 treatment. Additionally, a high
with steroid-resistant nephrotic syndrome and muta- risk of progression to ESRF has been demonstrated in
tions in the cation channel TRPC6, leading to constitu- genetic SRNS with a lower risk of disease recurrence in
tive activity of the channel and unregulated calcium transplantation [8]. Therefore genetic testing (and
entry into the cell, seem to exert some or all of their appropriate counselling) is crucial for young patients
effects via alterations in the actin cytoskeleton and and their families. Genetic screening is being introduced
therefore in the cell shape [16, 17]. nationally and should be considered for steroid-resistant
A single-gene cause of SRNS presenting before the nephrotic syndrome presenting at any age. Additionally,
age of 25 years has been demonstrated in 29.5% of in those patients with FSGS, screening should be con-
patients [18]. A genetic diagnosis is significant as this sidered if immunosuppression or transplantation is
may result in a specific intervention, for example, SRNS being considered especially in the context of a family
caused by mutations in the Q10 pathway, which may history of syndromic features.
Management of the Nephrotic Patient: The Overall Approach to the Patient with Nephrotic Syndrome
383 18
FSGS 35%
FSGS 12%
MCD 15%
membranous 33%
Other 5%
MPGN 14%
. Fig. 18.3 Pie charts demonstrating relative causes of nephrotic and membranous nephropathy [7, 8]. (ii) FSGS, 35%; membranous
syndrome due to primary glomerulonephritides in both children (i) nephropathy, 33%; MCD, 15%; MPGN, 14%; other, 3%. Other in
and adults (ii). (i) In children MCD, 83%; FSGS, 12%; other 5%. adults includes amyloid nephropathy, IgA, chronic glomerulone-
Other in children includes diffuse mesangial sclerosis (DMS), pro- phritis, nephrosclerosis, C1q nephropathy and fibrillary glomerulo-
gressive mesangial sclerosis (PMS), collapsing glomerulopathy (CG) nephritis [9–11]
18.5 Investigations
. Table 18.1 Table to demonstrate investigations in
nephrotic syndrome
The initial investigations for patients with nephrotic
syndrome (see . Table 18.1) are aimed to (1) confirm
Confirming Urine dipstick, urine protein creatinine ratio,
the presence of nephrotic syndrome, (2) elucidate pri- diagnosis renal function, liver function tests
mary or secondary cause and (3) prepare the patients for
Investigation Full blood count, bone profile, autoanti-
a kidney biopsy to allow a definitive diagnosis. Urine
secondary bodies (ANA, dsDNA, complement C3 and
dipstick with quantification of proteinuria with a urine causes C4), ENA, immunoglobulins, serum-free
protein creatinine ratio (uPCR) along with renal func- light chains, serum and urine electrophore-
tion and albumin will confirm the nephrotic state with a sis, glucose, C-reactive protein, virology
uPCR of 300–350 mg/mmol defining nephrotic-range (HIV, hepatitis B and C)
proteinuria. Investigating Vitamin D, thyroid function tests, lipids
complications Consider CT-PA or V/Q scan if PE
suspected, CXR may show pleural
effusions, Doppler renal vessels if renal vein
18.6 Treatment and General Management thrombosis suspected, Doppler lower legs
exclude DVT
KDIGO (kidney disease improving global outcomes)
Additional Anti-phospholipase A-2 receptor antibody
clinical practice guidelines for glomerulonephritis pro- tests If malignancy suspected: targeted
vides guidance in the treatment of glomerular disease investigations (imaging, endoscopy)
and is used as an aid in decision-making, with clinicians
Preparing for MSU, coagulation screen, renal tract US
taking account individual patient preference and patient renal biopsy scan
factors [19]. The treatment of specific causes of NS are
covered in their respective chapters, but clear and con- Genetic testing Podocyte panel of genes
in SRNS
sistent advice on salt restriction (high-salt diets impair
the impact of RAS blockade, increase oedema and
result in more rapid progression to ESRD in proteinuric
patients), regular monitoring of weight, postural blood
pressure, urine dipstick and urine PCR for inpatient and
Nephrotic syndrome may or may not be associated
outpatient care is critical. A guide dry weight is often
with hypertension. Blood pressure control is important,
helpful to discuss a mechanism with the patient by which
but the benefit is disproportionately so the greater the
diuretics and antihypertensives can be adjusted depend-
amount of proteinuria.
ing on response.
384 G. Goldet and R. J. Pepper
a b
General measures in the nephrotic patient with sig- very useful in the setting of intractable proteinuria but
nificant oedema include salt and fluid intake restriction run the risk of contributing to AKI and progressive
along with diuretic therapy (management of oedema in CKD if not handled with careful monitoring and mod-
NS is covered in the following chapter). . Figure 18.4 est target trough levels. The KDIGO guidelines recom-
demonstrates the significant oedema patients with mend initially tacrolimus doses of 0.05–0.1 mg/kg/day
nephrotic syndrome can suddenly develop, with (i) tak- in two divided doses, with the doses tapering to main-
ing at time of relapse and (ii) at time of remission. tain remission in minimal change disease with a dose of
Renin and angiotensin inhibition, with either ACE-I 0.1–0.2 mg/kg/day in FSGS with an initial target of
or ARB, is important in reducing proteinuria (and 5–10 ng/ml (6–12 nmol/l) with slow tapering once remis-
hypertension) in patients who are not volume deplete sion achieved. For membranous nephropathy, the dose
and who are unlikely to go into rapid remission. In the of tacrolimus recommended is 0.05–0.075 mg/kg/day in
setting of CKD, the greater the proteinuria, the more a two divided doses.
18 patient is likely to benefit from RAS blockade. Due to
the potential adverse effect of reducing GFR especially
in the patient with significant hypoalbuminaemia, care 18.7 Steroid Side Effect Prophylaxis
must be taken to monitor the renal function following
initiation. Non-dihydropyridine calcium channel block- For patients with significant doses of glucocorticoids, as
ers also reduce proteinuria (by up to 30%), and miner- one-off or especially repeated courses, bone prophylaxis
alocorticoid receptor antagonists may have an additive should be considered and ultimately bone density
effect. assessed. Prophylaxis against candida and gastritis also
Calcineurin inhibitors also have an antiproteinuric need to be covered. Patients should be forewarned about
effect beyond any immunomodulatory role, in part increased appetite and weight gain including strategies to
through afferent artery vasoconstriction. They can be reduce this including careful eating and regular exercise.
Management of the Nephrotic Patient: The Overall Approach to the Patient with Nephrotic Syndrome
385 18
This is important for several reasons not least because patients with urine protein sticks (along with daily
patients may be understandably distressed by the weight weight measurement) allowing early identification of a
gain induced by steroids and reluctant to be compliant a relapse and to contact their nephrologist early to pre-
second time around. vent a full-blown relapse and avoid hospital admission.
For those in whom a relapse can be managed with
early institution of treatment, a personal treatment plan
18.8 Personal Treatment Plan (PTP) may avoid an unnecessary admission via the emergency
department and treatment by non-specialists. Agreeing
For patients with recurrent relapses, it is vital to support a PTP with the patient or their family goes some way
patients and their families and encourage their engage- towards self-determination.
ment through education and explanation. Providing An example of a PTP might be:
3+ or 4+ protein on dipstick for 3 consecutive days in a patient known to have frequently relapsing
steroid sensitive nephrotic syndrome
18.9 Causes of Relapse or Treatment aggregation, with platelet activation inversely correlat-
Resistance ing with the level of albumin in the serum [21].
Very low serum levels of antithrombin III have been
A significant proportion of patients with nephrotic syn- demonstrated in children with complications such as
drome, especially minimal change, will continue to have DVT and PE. These thrombotic complications have
frequently relapsing disease. Additionally some patients been demonstrated when the levels are 75% below nor-
with nephrotic syndrome may become steroid-resistant. mal with an albumin of less than 20 g/L [22].
At times of relapses, or of treatment non-response, a Membranous nephropathy is well-recognised to result in
detailed history and further investigations may be a higher thrombotic risk compared to the other causes
appropriate. of nephrotic syndrome. One study has demonstrated the
risk of thrombotic events (DVT, renal vein thrombosis
(RVT) and PE) in membranous was significantly higher
(7.9%) compared to FSGS (3%) and IgA nephropathy
18.10 Complications of Nephrotic
(0.4%) [23]. The risk of thrombosis events is highest in
Syndrome the 1st 6 months of presentation. The highest risk of
RVT is observed in membranous nephropathy (account-
18.10.1 Thrombosis and Nephrotic ing for 37% of cases of a RVT), with a clinically signifi-
Syndrome cant risk in MPGN (occurring in 26% of cases of RVT)
and minimal change (in 24% cases of RVT) [24]. This
Thrombosis is a well-known complication of nephrotic increased risk of DVT and or RVT has been demon-
syndrome. There are several important factors contrib- strated when the albumin level is <20–25 g/l. However,
uting to this hypercoagulable environment. These thromboembolism can still occur with a more mildly
include urinary loss of antithrombin III, protein C, pro- reduced level of albumin [25]. There is no clear consen-
tein S and tissue factor pathway inhibitor as well as sus or randomised trial data of when to initiate prophy-
alterations in procoagulants such as fibrinogen, factor V lactic anticoagulation. Generally, low-molecular-weight
and VIII, von Willebrand factor with increased platelet heparin or warfarin is used in patients with membra-
reactivity and changes in fibrinolysis [20]. Albumin has nous nephropathy with an albumin less than 20–25 g/l.
been demonstrated to play a critical role in platelet Prophylaxis in other causes of nephrotic syndrome due
386 G. Goldet and R. J. Pepper
to the high thrombotic risk is also initiated [26]. In those uncommon during either the presentation or relapse of
patients with a thrombotic event, it seems sensible to nephrotic syndrome, and there are several potential
continue with anticoagulation for the duration of causes (see . Table 18.2). The commonest cause relates
nephrotic syndrome. In those patients with minimal to glomerular hypoperfusion, which is usually second-
change nephropathy in which a response to treatment ary to hypotension, reduced intravascular volume and
may occur in a few weeks, prophylaxis with heparin is blockade of the RAS. Other causes may include the use
more appropriate than warfarin. The dose of warfarin of nephrotoxic drugs (such as calcineurin inhibitors) or
may change depending on albumin levels, and higher contrast which is usually apparent, but renal vein throm-
doses of heparin are likely due to the loss of antithrom- bosis and abdominal compartment syndrome secondary
bin III in the urine. For patients with relapsing NS who to tense ascites need to be excluded. Additionally,
have had previous thromboembolism, then a personal patients treated with ciclosporin or tacrolimus should
treatment plan that involves early anticoagulation is have drug levels carefully monitored due to the known
worth considering. nephrotoxic effects of these drugs.
Proteinuria also has a deleterious effect on the proxi-
mal tubular epithelial cells, with the persistence of pro-
18.10.2 Infection teinuria known to be a poor prognostic factor in
progression of chronic kidney disease. Proteinuria, with
Infection is a well-recognised cause of morbidity and the filtration of macromolecules such as albumin and
mortality in patients with nephrotic syndrome. Low lev- immunoglobulins, can have a direct toxic effect via the
els of IgG from urinary loss and changes in complement dysregulation of signalling pathways of proximal tubu-
are recognised as well as alterations in neutrophil phago- lar epithelial cells with the resultant inflammatory milieu
cytosis and T-cell function [27]. Spontaneous bacterial and stimulation of pro-apoptotic pathways [32].
peritonitis, for example, caused by Streptococcus pneu- For the reason above as well as the risk of thrombo-
moniae, is a recognised and serious complication of embolic disease, it is critical to keep patients with severe
nephrotic syndrome, and in children, administration of NS under close observation by checking for signs of
pneumococcal vaccination is recommended [28]. intravascular depletion such as hypotension, cool
Immunodeficiency is compounded if immunother- peripheries, significant weight loss, cramps and serial
apy is used in an attempt to treat the NS, and patients chemistry results. Critically, patients or their carers need
should be investigated aggressively for infection if to be involved in their management by weighing them-
unwell including blood cultures, ascitic tap (spontane- selves and reporting significant changes in weight as well
ous bacterial peritonitis) and commenced rapidly on as being instructed to suspend ACE-I and/or ARB if, for
antibiotics if febrile. example, they get gastroenteritis.
Patients should be tested for varicella-zoster
immunity as infection in the immunocompromised can
be life-threatening. Vaccination can be considered in
. Table 18.2 Causes of relapse/non-response
patients in remission. Data from children has demon-
strated although this is a live vaccine, it is safe and effec- Steroid-resistant Consider genetic causes especially in
tive in children in remission or on alternate low-dose younger patients, or a positive family
steroids [29]. Following exposure to non-immune history
patients, prophylactic varicella-zoster immune globulin Relapse of a Has the underlying disease reoccurred,
can be given. However, a Cochrane review concluded secondary cause of e.g. malignancy and membranous,
18 there is no strong evidence on the effectiveness of other NS lymphoma and minimal change
prophylactic interventions to prevent infection in Treatment Non-adherence
patients with nephrotic syndrome [30]. resistance
Low drug levels of Drug interactions
ciclosporin or
18.10.3 Acute Kidney Injury tacrolimus
Oedema Poor absorption of diuretics
Risk factors for AKI in patients with nephrotic syn-
drome include older age (e.g. AKI is less common in Vaccinations Well-recognised to be a relapse trigger
children with minimal change disease compared to Viral infections Typically upper respiratory tract
adults), male gender, hypertension and heavy protein- infections known to trigger relapses
uria with a low albumin [31]. An episode of AKI is not
Management of the Nephrotic Patient: The Overall Approach to the Patient with Nephrotic Syndrome
387 18
18.11 Progressive Renal Impairment . Table 18.3 Causes of AKI in nephrotic syndrome
The risk of progressive renal impairment depends on the Prerenal Can occur acutely. Also, when a patient is
underlying cause of nephrotic syndrome as well as the intravascular entering remission and remains on high-dose
burden of drugs such as ciclosporin and tacrolimus. depletion diuretics. Patients on ACE-I or ARB may be
Minimal change disease is not a cause of CKD or ESRF, susceptible
and if this occurs, a diagnosis of FSGS must be consid- Acute Following on from a prerenal insult. Also
ered. Additionally, the long-term use of ciclosporin or tubular may occur secondary to hypotension
tacrolimus, which may have been required to stop recur- injury
rent relapses, is a well-recognised cause of CKD in Renal vein Often clinically silent. More common in
patients with minimal change disease. thrombosis membranous and with albumin less than
With steroid-resistant nephrotic syndrome and heavy 20 g/l. May present with loin pain, haematu-
ria or just a decrease in GFR
proteinuria, a significant proportion of patients will
require renal replacement therapy within 5 years of their Interstitial May be related to medication: PPI, NSAIDs,
diagnosis with about 30–50% of the patients with less nephritis antibiotics, diuretics
severe proteinuria at 10 years surviving without renal Renal Tense ascites increasing intra-abdominal
replacement therapy. Repeated episodes of AKI during vascular pressure and reduced renal perfusion
times of relapse are also a recognised factor for increas- compression
ing the risk of CKD in the future. Progression Rapid progression of the underlying cause
In those patients with CKD, addressing the revers- of renal
ible, modifying factors of CKD known to cause progres- disease
sion is key to their management with the aggressive Calcineurin
control of blood pressure vital. In those proteinuric inhibitor
patients, the benefit of treatment with ACE-I or ARB toxicity
(independent of the blood pressure lowering effects) has
been demonstrated, with clear beneficial effects with
respect to preserving GFR and a lower rate of decline in an increase in production of LDL, with resulting increase
GFR [33]. There is a correlation between the reduction in LDL and cholesterol levels [36]. Loss of lecithin-cho-
in proteinuria with therapy and the decreased progres- lesterol acyltransferase (LCAT) from urinary loss as well
sion of renal disease [34]. Along with these medications, as low albumin and a reduction in hepatic HDL docking
adherence to a low-salt diet is also vital, as a high salt receptor and increased plasma cholesterol ester transfer
intake will additionally impair the anti-proteinuria protein levels lead to increased triglyceride content of
action of ACE-I and ARBs (. Table 18.3). HDL and contribute to the abnormalities in HDL seen
in nephrotic syndrome [37].
Additionally, the treatments used in nephrotic syn-
18.12 Dyslipidaemia drome may also have a deleterious effect on a patient’s
lipid profile. Corticosteroids are used in the treatment
Abnormalities of lipids in nephrotic syndrome increase of nephrotic syndrome and have also been demon-
the risk of atherosclerosis and are a significant risk factor strated to cause hyperlipidaemia through different
for vascular disease. This abnormality in lipids correlates mechanisms. Calcineurin inhibition with drugs such as
with the degree of proteinuria. Cholesterol, triglycerides tacrolimus and ciclosporin, with a higher risk in ciclo-
and apolipoprotein B (ApoB)-containing lipoproteins sporin, treated patients in which there is an increase in
have been demonstrated to be increased in patients with LDL cholesterol [38].
nephrotic syndrome, with changes in the composition as The significance of dyslipidaemia is acceleration of
well as the function of these lipoproteins. The total cho- atherosclerosis as well as dyslipidaemia being a risk fac-
lesterol to HDL cholesterol ratio is increased in patients tor for thrombosis complications [39].
with nephrotic syndrome [35]. There are several different No clear guidelines exist for the treatment of the
mechanisms in the pathogenesis of the dyslipidaemia of lipid abnormalities in nephrotic syndrome, but given
nephrotic syndrome. These include defective lipoprotein accelerated atherosclerosis in patients with very high
lipase activity as well as decreased hepatic lipase activity cholesterol, it is common practice to treat with HMG
and increases in fatty acid biosynthesis due to increased CoA reductase inhibitors unless the patient is likely to
expression of enzymes involved in this process. There is go into rapid remission.
388 G. Goldet and R. J. Pepper
Case Study
Case 3 Case 5
A 20-year-old man with steroid-sensitive, frequently A 60-year-old woman with diabetes mellitus, diabetic reti-
relapsing minimal change had been on tacrolimus therapy nopathy and albuminuria was shown to have a sudden
for many years with unsuccessful cessation of therapy due increase in her proteinuria. Blood tests including virology,
to recurrent relapses requiring high-dose steroids. He was PLA2R-antibody testing and an autoimmune screen were
subsequently treated with rituximab. This enabled tacroli- negative. A biopsy demonstrated membranous nephropa-
mus therapy to be weaned and stopped and allowed a pro- thy. A cause for this glomerulopathy was sought, and a
longed period relapse-free without tacrolimus therapy. lung malignancy was thus found, thus demonstrating how
1 year after rituximab, he was treated again with rituximab an increase in proteinuria in a diabetic patient should not
to ensure a prolonged period of B-cell depletion and dis- simply be attributed to diabetes mellitus, especially if the
ease remission. increase is sudden.
Other indications for genetic testing include a 9. Hull RP, Goldsmith DJ. Nephrotic syndrome in adults. BMJ.
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15. Hinkes BG, et al. Nephrotic syndrome in the first year of life:
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393 19
Management of Extracellular
Fluid Volume in the Nephrotic
Patient
Liam Plant
Contents
References – 399
New cases of NS occur with an estimated annual inci- 19.6.1 What Are the Clinical Goals of
dence of 3 new cases per 100,000 in adults and 2 new Generic Management of NS?
cases per 100,000 in children [1].
The primary objective of generic therapy is to initiate
and sustain an increased natriuresis/saliuresis/diuresis
19.4 Aetiopathology until the patient has returned to clinical euvolaemia.
It should then be easier to maintain homeostasis at
19.4.1 Why Do Nephrotic Patients Become the new desired steady state, particularly if dietary salt
Oedematous? restriction is appropriately introduced.
Whilst the NS persists, total body salt and water will
The traditional explanation has been that proteinuria not decrease unless excretion exceeds intake. Dietary
leads to hypoalbuminaemia, causing a decrease in plasma sodium intake frequently exceeds 100 mmol/day (~6
oncotic pressure. The consequent imbalance in Starling g salt/day). Thus, for example, a patient will need to
forces across the capillary wall causes fluid to ‘leak’ into excrete 300 mmol of sodium over and above that needed
the interstitium. Effective hypovolaemia follows, and this to balance this daily intake if s/he is to lose 2 kg of
triggers activation of the renin-angiotensin-aldosterone, excess ECF volume.
sympathetic nervous and arginine vasopressin systems, Whilst salt avidity persists, this requires the use of
with inhibition of the release of atrial natriuretic pep- (various) natriuretic agents – usually referred to as ‘diuret-
tide. All of this leads to secondary renal salt and water ics’, with specific pharmacokinetic and pharmacody-
retention [3, 11]. namic properties, in different doses and combinations.
However, observations in clinical cases and in experi- Dietary sodium intake also needs to be restricted,
mental models call this ‘underfill’ hypothesis into ques- ideally to <80 mmol/day, but this may be difficult to
tion, and whilst it may play some role, particularly at achieve. Most salt intake is not ‘elective’ but occurs
the onset of NS, opinion now favours a greater role because of addition in food processing. Furthermore,
for a specific renal salt retention process coupled with many patients find diets containing less than 80 mmol/
an alteration in capillary permeability independent of day of sodium to be bland and unpalatable.
changes in oncotic gradients [11, 12]. Unexpected failure to lose weight/ECF volume in a
No compelling and consistent explanation for the patient on a seemingly appropriate diuretic dose should
dysregulation in sodium balance in NS has yet been prompt enquiry into salt intake. Measurement of 24-h
universally accepted, but it is notable that many studies sodium excretion may help. A patient passing 150 mmol/
indicate an upregulation of epithelial sodium channel day or more but not losing weight is likely to have salt
(ENaC) expression in the distal nephron, independent intake in excess of the reduced target.
of aldosterone and other systemic hormones [12].
Recent studies postulate a role for plasminogen and
plasmin, both of which appear in proteinuric urine. It 19.6.2 What Are the Different Classes
is postulated that, in NS, plasminogen enters the urine of Diuretics and How Do They Work?
through more permeable glomerular capillaries; that it is
then activated to plasmin by urokinase; and that plasmin Diuretics are different classes of drugs that inhibit
activates distal nephron epithelial sodium (ENaC) chan- sodium reabsorption at different sites along the neph-
nels [13]. Thus, a prominent aspect of NS is a particu- ron. By increasing natriuresis they achieve clinical
lar salt avidity in the distal nephron, mediated through benefit [2–6]. However, clinical goals may not always be
ENaC and occurring in concert with other mechanisms easily achieved.
(possibly reflecting the ‘underfill’ hypothesis) enhancing Site of action classifies the commonly used agents
salt retention at other sites. (. Table 19.1). Although most (60–70%) filtered
sodium is reabsorbed in the proximal tubule, agents act-
ing at this site (e.g. acetazolamide) are of relatively little
19.5 Diagnosis clinical use in oedematous states because the increased
sodium loss here is offset by increased reabsorption fur-
The diagnosis is made based on the clinical triad of ther down the nephron, especially in the thick ascending
oedema, hypoalbuminaemia and proteinuria. Other loop of Henle. The same principle applies to the proxi-
conditions (e.g. SLE or diabetes mellitus) may co-exist. mal tubular effect of some thiazide diuretics.
396 L. Plant
Loop diuretics Furosemide Thick ascending Organic anion Secretion of loop Proximal
Bumetanide loop of Henle transporter diuretics and convoluted
(TALH) (OAT1) thiazide-type/like tubule
diuretics into
Thiazide-type Hydrochlorothiazide Distal convo-
tubular lumen
diuretics Bendroflumethiazide luted tubule
Thiazide-like Chlorthalidone (DCT) Organic cation Secretion of Proximal
diuretics Metolazone transporter potassium-sparing convoluted
Indapamide diuretics into tubule
tubular lumen
Potassium-spar- Amiloride Cortical
ing diuretics Triamterene collecting duct Sodium- Site of action of Thick ascending
(CCD) potassium-2 loop diuretics loop of Henle
chloride
Selective Spironolactone Cortical
transporter
aldosterone Eplerenone collecting duct
(NKCC2)
receptor (CCD) – Princi-
Solute carrier
antagonists pal cells
family 12 A1
(SARA)
(SCL12A1)
Sodium-chloride Site of action of Distal convo-
cotransporter thiazide/thiazide- luted tubule
Loop diuretics (e.g. furosemide, bumetanide) are (NCC) like diuretics
organic anions, secreted into the tubular lumen by Solute carrier
family 12 A3
the organic anion transporter (OAT1) in the proximal (SCL12A3)
tubule (. Table 19.2). They act on the luminal aspect
of the thick ascending loop of Henle where they exhibit Epithelial sodium Site of action of Cortical
channel (ENaC) amiloride and collecting duct
high affinity for the chloride-binding site of the sodium- triamterene (Principal cells)
potassium-2 chloride (NKCC2) transporter – a mem- Expression
ber (SCL12A1) of the solute carrier family 12 group of influenced by
proteins [2, 4–6] (. Table 19.2). This directly inhibits activation of
sodium and chloride reabsorption and indirectly leads aldosterone
receptor
to decreased reabsorption of calcium and magnesium.
Up to 20% of filtered sodium can be excreted using these
agents.
Thiazides and related compounds (e.g. bendroflu- sodium channel (ENaC) in the cortical collecting duct
methiazide, hydrochlorothiazide, chlorthalidone, meto- [2, 4–6] (. Table 19.2). Spironolactone and eplerenone,
lazone, indapamide) are organic anions also secreted by contrast, enter the principal cells of the cortical col-
by OAT1 in the proximal tubule. They act on the distal lecting duct from the plasma and interfere with the acti-
tubule and connecting segment where they bind to a num- vation of the intracellular aldosterone receptor. This
ber of transporters, principally the chloride-binding site leads to a reduction in the activity of the baso-lateral
of the sodium-chloride cotransporter (NCC) – another sodium-potassium ATPase and a reduction in luminal
member (SCL12A3) of the solute carrier family 12 pro- expression of ENaC (. Table 19.2).
tein group – directly inhibiting sodium reabsorption [2,
19 4–6] (. Table 19.2). This indirectly increases calcium
19.6.3 What Are the Pharmacokinetic
reabsorption. The maximum natriuresis achievable is less
than that achieved with loop diuretics, but a combina- Barriers to Achieving Therapeutic
tion of these classes can be especially potent [14]. Objectives?
The potassium-sparing diuretics include amiloride,
triamterene and spironolactone. These have slightly dif- The primary driver of pharmacological natriuresis
ferent modes of action. Amiloride and triamterene are (other than with SARA drugs) is the rate of excretion of
organic cations secreted into the lumen of the proximal diuretic into the tubular fluid. This relationship exhibits
tubule and acting on the luminal aspect of the epithelial a threshold phenomenon, following which the rate of
Management of Extracellular Fluid Volume in the Nephrotic Patient
397 19
accumulate particularly in the presence of renal failure
. Table 19.3 Pharmacokinetic barriers to achieving
therapeutic goals
and hepatic failure. In such circumstances the expected
dose-response to loop and thiazide diuretics may be less
Problem Response than anticipated. Certain drugs (such as cimetidine) also
compete for excretion. This problem does not occur with
Decreased oral bioavailability Increase drug dose spironolactone, which does not require to be excreted
More likely with gut oedema Uses drug with higher
into the tubular lumen, and its diuretic effect is thus less
oral bioavailability
Administer drug affected by liver failure.
intravenously A fall in GFR, particularly when combined with a
low cardiac output, will decrease diuretic delivery and
Hypoproteinaemia (which increases As above
the volume of distribution of agents also reduce the initial filtered sodium load making a
within the circulation) substantial natriuresis even more difficult to achieve.
More likely with nephrotic syndrome It was previously postulated that urinary protein
Interference with proximal tubule As above bound to diuretic in the tubular lumen decreased its
excretion by organic anions/other effectiveness. This view has not been substantiated by
medications experimental studies [19].
More likely with cirrhosis/CKD Therefore, there are many factors active in NS that
Decreased GFR/cardiac output As above act as additional pharmacokinetic ‘hurdles’ to achiev-
More likely with CKD/CHF ing a degree of diuretic excretion sufficient to initiate
a natriuresis. In most circumstances, increasing the
prescribed dose or otherwise enhancing the bioavail-
ability of that dose is the appropriate strategy. An illogi-
sodium excretion reflects diuretic excretion in a linear cal, but common, error is to repeat the same ineffective
dose-dependent pattern [4–6]. Failure to deliver a suf- dose more frequently. If there is doubt as to whether
ficient dose of diuretic to exceed the natriuretic thresh- or not a natriuresis has been initiated, measurement of
old may be described as ‘diuretic resistance’ but more 24-h sodium excretion (or even 6-h excretion following
usually reflects a failure to appreciate pharmacokinetic diuretic administration) is a rational choice.
principles (. Table 19.3).
Most prescribing choices to address pharmacoki-
netic issues involve administering larger doses of diuretic 19.6.4 What Are the Pharmacodynamic
or enhancing bioavailability.
The first step is to ensure that an adequate dose of
Barriers to Achieving Therapeutic
diuretic enters the bloodstream and is delivered to the Objectives?
kidney for excretion into the tubular lumen. Diuretics
differ in their oral bioavailability. The oral bioavailability Once a natriuresis is initiated, it needs to be sustained
of furosemide ranges from 20% to 70%, decreasing with until the patient has been restored to the desired steady
increased gut oedema. On the other hand, bumetanide state. Once diuretics are administered and natriure-
has an oral bioavailability approaching 80%. When faced sis achieved, there is a rapid functional and structural
with a very oedematous patient, administering a higher response in the nephron that acts to reduce the degree
dose of oral furosemide, switching to oral bumetanide of enhanced natriuresis [2–6]. This can be viewed as
or administering furosemide intravenously are all ratio- ‘diuretic blunting’ and reflects pharmacodynamic prin-
nal therapeutic choices. ciples.
Loop and thiazide diuretics are transported bound Most of the adaptation occurs downstream from the
to albumin and other plasma proteins. In NS, levels of site of action of the initially deployed diuretic. Changes
albumin and other plasma proteins are often extremely in the expression and activity of transporters in the dis-
low, and the consequent increased volume of distri- tal tubule and the cortical collecting duct occur within
bution decreases the amount delivered to the kidney days [3–6]. It is now apparent that allelic variations,
[15]. Increasing the dose administered is the appropri- particularly in the genes encoding for the SLC12A3
ate response to this; coadministration of albumin with protein (NCC) and the β-subunit of the SCNN1 pro-
diuretic has not been consistently demonstrated as being tein (ENaC) (. Table 19.2), may explain variance in
of additional benefit [16–18]. response between patients [20].
Diuretics compete with other anions for excretion In addition, there is evidence that chronic exposure to
by OAT1 into the proximal tubule [3–6]. Such anions both loop and thiazide/thiazide-like diuretics increases
398 L. Plant
the expression of their respective target transporters as Tips, Tricks and Pitfalls
well as of OAT1 [21].
The clinician needs to anticipate these changes. In 1. On clinical examination, first determine the prob-
the first instance, once a natriuresis has been initiated, able extent of ECF volume expansion; express
one can prescribe the effective dose more frequently. this in kg; set a target weight to be achieved at
Although the response to consecutive doses will pro- which one can anticipate that the patient will be
gressively decline, more net natriuresis will be achieved restored to euvolaemia.
with twice daily, thrice daily or a continuous infusion of 2. Initiate dietary sodium restriction to a target of
diuretic. It is unclear if a continuous infusion achieves a 80 mmol/day or less (a trained dietician is very
greater daily natriuresis than the same total dose given helpful for this).
as boluses [5, 22]. 3. Administer a loop diuretic, selecting agent/dose/
However, the most effective strategy to adopt is the mode of administration based on degree of
early initiation of sequential nephron blockade, using a oedema, level of hypoproteinaemia, level of renal
combination of diuretic agents to target multiple sites and cardiac function and presence of liver disease.
down the nephron [2–6]. This blocks the adaptation 4. Progressively increase the dose until a natriuresis
in the distal tubule and cortical collecting duct to the is initiated (either on clinical evidence or with a
increased luminal sodium delivery following inhibition measurement of urinary sodium excretion).
of the NKCC2. Combination of loop diuretics with thi- 5. Once natriuresis is established, administer the
azide/thiazide-like diuretics is effective, even in the pres- same dose more frequently, or as a continuous
ence of advanced renal dysfunction and in advanced infusion.
heart failure [14, 23]. In addition, the early prescription 6. Rapidly (within 2–3 days, or immediately if the
of potassium-sparing diuretics will minimise the kal- patient has already been on loop diuretics for
liuresis/hypokalaemia that will occur with successful some time) initiate sequential nephron blockade
blockade of the NKCC2/NCC systems [2–6]. Given the with thiazide/thiazide-like agents and potassium-
key role of ENaC activation in the aetiopathology of sparing diuretics.
NS, early prescription of amiloride is also a plausible 7. When choosing between thiazide/thiazide-like
strategy. diuretics, consider duration of action when used
There is now also some interest in supplementing in combination with loop diuretics (indapamide/
the use of standard natriuretic agents with human atrial metolazone are longer acting than bendroflume-
natriuretic peptide analogues such as carperitide [24]. thiazide/hydrochlorothiazide).
These are not yet part of the mainstay of therapy.
Case Study
A 39-year-old female patient with Type 1 diabetes and 2 and 6 h after administration of 5 mg of bendroflumethia-
diabetic nephropathy was transferred from the Diabetes zide. A natriuresis was initiated. Two days later she was
service. She was massively oedematous, with a serum also prescribed amiloride 5 mg daily.
albumin of 14 g/dl and a 24-h protein excretion of 16 g/ With this regimen, her weight dropped by 8 kg over 10
day. Serum creatinine concentration was 200umol/l. Her days; she was converted to 3 mg of bumetanide twice daily
weight had continued to rise on a dose of 120 mg p.o. whilst remaining on her other medications. She became
furosemide, which had been increased to twice daily with- clinically euvolaemic despite there being no change in her
out benefit. serum albumin concentration or urinary protein excre-
The renal dietician assisted her with reducing her tion.
19 dietary sodium intake to <100 mmol/day. She was con- This illustrates the ‘classical’ strategy employed to con-
verted to 100 mg twice daily of iv furosemide administered trol ECF volume in NS.
Management of Extracellular Fluid Volume in the Nephrotic Patient
399 19
Conclusion 3. Qavi AH, Kamal R, Schrier RW. Clinical use of diuretics in
heart failure, cirrhosis and nephrotic syndrome. Int J Nephrol.
Failure to control ECF volume in NS usually stems
2015:1–9.
from insufficient dietary sodium restriction, an insuf- 4. Brater DC. Pharmacology of diuretics. Am J Med Sci.
ficient initial dose of loop diuretic to initiate natriure- 2000;319:38–50.
sis and insufficiently rapid introduction of sequential 5. Brater DC. Update in diuretic therapy: clinical pharmacology.
nephron blockade to maintain natriuresis. In some Semin Nephrol. 2011;31:483–94.
6. Sica DA. Diuretic use in renal disease. Nat Rev Nephrol.
cases, patience is needed with frequent adjustments of
2012;8:100–9.
medication doses and timings; fastidiousness usually 7. Acute Dialysis Quality Initiative (ADQI) consensus group.
achieves the desired objective. Cardio-renal syndromes: an executive summary from the
consensus conference of the Acute Dialysis Quality Initiative
(ADQI) Consensus Conference. Contrib Nephrol. 2010;165:54–
? Chapter Review Questions 7.
1. What is the time to onset of effect and duration of 8. Ronco C, Cicoira M, McCullough PA. Cardiorenal syndrome
effect with iv furosemide? type 1: pathophysiological crosstalk leading to combined heart
2. Are there any strategies other than salt restriction and kidney dysfunction in the setting of acutely decompen-
sated heart failure. J Am Coll Cardiol. 2012;60:1031–42.
and sequential nephron blockade that can increase
9. Felker GM, Lee KL, Bull DA, Redfield MM, Stevenson LW,
natriuresis in NS? Goldsmith SR, LeWinter MM, Deswal A, Rouleau JL, Ofili
3. Which diuretic agents limit magnesiuria and EO, Anstrom KA, Hernandez AF, McNulty SE, Velazquez EJ,
hypomagnesaemia? Kfoury AG, Chen HH, Givertz MM, Semigran MJ, Bart BA,
Mascette AM, Braunwald E, O’Connor CM, for the NHLBI
Heart Failure Clinical Research Network. Diuretic strategies in
v Answers
patients with acute decompensated heart failure. N Engl J Med.
1. Onset 5 mins; duration 2 h. This compares with an 2011;364:797–805.
onset of effect after 30–60 mins and a duration of 10. Kidney Disease: Improving Global Outcomes (KDIGO)
onset of 6–8 h with p.o. furosemide. If a patient Glomerulonephritis Work Group. KDIGO clinical
takes p.o. bendroflumethiazide (onset 1–2 h; dura- practice guideline for glomerulonephritis. Kidney Int.
2012;2(Suppl):139–74.
tion 6–12 h) at the same time that iv furosemide is
11. Rondon-Berrios H. New insights into the pathophysiology of
given, the combined effect will not occur in syn- oedema in nephrotic syndrome. Nefrologia. 2011;31:148–514.
chrony. 12. Doucet A, Favre G, Deschenes G. Molecular mechanism of
2. Previous studies suggested that an equivalent dose edema formation in nephrotic syndrome: therapeutic implica-
of diuretic given by intravenous infusion as tions. Pediatr Nephrol. 2007;22:1983–90.
13. Svenningsen P, Bistrup C, Friis UG, Bertog M, Harteis S,
opposed to bolus doses was associated with
Krueger N, Stubbe J, Nørregrad Jensen O, Thiesson HC,
greater natriuresis – it is now felt that it was the Uhrenholt TR, Jespersen B, Jensen BL, Korbmacher C, Skøtt
need to lie recumbent whilst having the infusion O. Plasmin in nephrotic urine activates the epithelial sodium
that led to greater natriuresis. Consideration can channel. J Am Soc Nephrol. 2009;20:299–310.
be given to the beneficial effects of recumbency on 14. Fliser D, Schröter M, Neubeck M, Ritz E. Coadministration of
thiazides increases the efficacy of loop diuretics even in patients
natriuresis.
with advanced renal failure. Kidney Int. 1994;46:482–8.
3. Successful inhibition of the NKCC2 transporter 15. Pichette V, Geadah D, du Souich P. Role of plasma protein
will lead to increased magnesiuria; however, binding on renal metabolism and dynamics of furosemide in
increased sodium delivery to the distal nephron the rabbit. Drug Metab Dispos. 1999;27:81–5.
consequent to inhibition of the NCC transporter 16. Akcicek F, Yalniz T, Basci A, Ok E, Mees EJ. Diuretic effect of
furosemide in patients with nephrotic syndrome: is it potenti-
typically leads to more hypomagnesaemia. This
ated by intravenous albumin? BMJ. 1995;310:162–3.
effect is mitigated by amiloride, but not by spi- 17. Fliser D, Zurbrüggen I, Mutschler E, Bischoff I, Nussburger
ronolactone. J, Franek E, Ritz E. Coadministration of albumin and furose-
mide in the nephrotic syndrome. Kidney Int. 1999;55:629–34.
18. Chalasani N, Gorski JC, Horlander JC, Craven R, Hoen H,
Maya J, Brater DC. Effects of albumin/furosemide mixtures on
References responses to furosemide in hypoalbuminemic patients. J Am
Soc Nephrol. 2001;12:1010–6.
1. Hull RP, Goldsmith DJA. Nephrotic syndrome in adults. BMJ. 19. Agarwal R, Gorski JC, Sundblad K, Brater DC. Urinary pro-
2008;336:1185–9. tein binding does not affect response to furosemide in patients
2. Plant L. Clinical use of diuretics. In: Barratt J, Harris K, with nephrotic syndrome. J Am Soc Nephrol. 2000;11:1100–5.
Topham P, editors. Oxford desk reference nephrology, Chap 20. Vormfelde SV, Sehrt D, Toliat MR, Schirmer M, Meineke I,
18.3. Oxford: Oxford University Press; 2009. p. 708–12. Tzvetlov M, Nürnberg P, Brockmöller J. Genetic variation in
400 L. Plant
the renal sodium transporters NKCC2, NCC, and ENaC in 23. Channer KS, McLean KA, Lawson-Matthew P, Richardson
relation to the effects of loop diuretic drugs. Clin Pharmacol M. Combination diuretic treatment in severe heart failure: a
Ther. 2007;82:300–9. randomized controlled trial. Br Heart J. 1994;71:146–50.
21. Jim JH. Long-term adaptation of renal ion transporters to 24. Kanzaki M, Wada J, Kikumoto Y, Akagi S, Nakao K, Sugiyama
chronic diuretic treatment. Am J Nephrol. 2004;24:595–605. H, Makino H. The therapeutic potential of synthetic human
22. Salvador DR, Rey NR, Ramos GC, Punzalan FE. Continuous atrial natriuretic peptide in nephrotic syndrome: a randomized
infusion versus bolus injection of loop diuretics in congestive controlled trial. Int J Nephrol Renovasc Dis. 2012;5:91–6.
heart failure. Cochrane Database Syst Rev. 2005;(3):CD003178.
19
401 20
Contents
References – 410
n Learning Objectives
. Table 20.1 Factors associated with the onset of
1. Minimal change disease is a common cause of nephrotic syndrome in minimal change disease
nephrotic syndrome in children and adults.
2. Biopsy of patients with nephrotic syndrome is indi- Drugs
cated for adults but only for children who do not
Nonsteroidal anti-inflammatory drugs
respond to steroids.
3. Understand the initial treatment and management Lithium: rare (usually causes chronic interstitial nephritis)
of relapsing disease. Interferon-α
Gold: rare (usually associated with membranous nephropathy)
16
14
12
N = 100
Mean ± 1 sd
Duration of disease, years
10
12 2 3 34 45 56 67 78 8 9 9 10 10 11 11 12 12 13 13 14 >14
Age of onset of MCD, years
. Fig. 20.1 Long-term outcome in childhood-onset minimal change disease. The duration of disease is inversely related to the age of pre-
sentation. (Reproduced with permission from Trompeter et al. [8])
404 P. D. Mason
5 Relapse occurs in >2/3 of children and about half 5 Other clinical features include white nails, sometimes
relapse more than four times, usually following ste- in bands (Muehrcke’s bands) correlating with peri-
roid cessation or reduction. If relapse occurs during ods of clinical relapse. Rarely xanthomata are associ-
steroid reduction, the patient is described as steroid- ated with gross hyperlipidaemia.
dependent. 5 Microscopic haematuria is rare.
5 <5% of children with MCD enter adulthood still 5 Hypertension is present in 30–43% of adults [8] and
relapsing, although the younger the onset of the first in 14–21% of children, when compared with age-
attack, the longer the child is likely to continue hav- and sex-matched blood pressure reference ranges [9].
ing relapses [7]. This usually resolves during remission, especially in
5 In general, increasing time since last relapse reduces children. Hypertension is sometimes associated with
the risk of further relapse, but occasionally adults expansion of the intravascular volume but may para-
relapse after an interval of >10 years. doxically be secondary to hypovolaemia and activa-
5 MCD does not progress to renal failure, although a tion of the renin–angiotensin axis.
number of patients with this diagnosis are found to 5 AKI is present or develops in ~18% of patients.
have FSGS on subsequent biopsies. It is unclear 5 Other complications, as for any cause of nephrotic
whether the focal nature of the disease resulted in the syndrome, include thromboembolism, infection and
correct diagnosis being missed on the initial biopsy hyperlipidaemia.
or whether evolution from MCD to FSGS occurs.
20.4 Clinical Features and Complications 20.5 Diagnosis and Differential Diagnosis
The symptoms and clinical signs are the same as those The clinical diagnosis of nephrotic syndrome is usually
for the nephrotic syndrome from any cause, but it is obvious, with oedema and heavy proteinuria, usually
worth noting: without microscopic haematuria on urine dipstick test-
ing. The differential diagnosis is that of nephrotic syn-
5 A fairly rapid onset of oedema is common with drome and requires a renal biopsy to make a definitive
increased risks of hypovolaemia (especially in chil- diagnosis. In patients with conditions that may be asso-
dren). ciated with the nephrotic syndrome (e.g. diabetes or
5 Severe fluid retention exceeding 3% of the body amyloidosis), the decision to biopsy needs to be care-
weight and often much more. fully considered.
5 60% of presentations and relapses follow an infec-
tion (most often upper respiratory tract); however,
minor infections are common in children, and fol- 20.6 Investigations
lowing remission most infections do not trigger a
relapse, so it is uncertain whether or not these are of 20.6.1 Routine Investigations
causative significance.
5 Children commonly present with pleural effusions, Hyaline and sometimes lipid casts may be seen on urine
ascites and hepatomegaly and may present with microscopy. There is nephrotic-range proteinuria
abdominal pain. (>3.5 g/24 h in adults or >40 mg/h per m2 in children or
5 Pericardial effusions may occur, but pulmonary a protein/creatinine ratio >350 mg/mmol).
oedema is uncommon except following treatment Routine blood biochemistry confirms hypoalbumi-
with albumin or with coexisting cardiac disease. naemia and hyperlipidaemia. Hyponatraemia may be
5 Oedema is gravitational, but a puffy face is common present even before treatment, and elevated urea and
and genital swelling may be very uncomfortable, creatinine are more common in adults.
especially in men. Gross oedema may result in ulcer- Usually the IgG level is low, IgM is normal or raised
20 ation, and infection of dependent skin and lacera- and serum complement levels are normal. In children,
tions and needlestick punctures may weep fluid steroid-responsive MCD is usually associated with
profusely. ‘selective’ proteinuria of smaller molecules including
5 Striae commonly appear even without steroids. albumin and transferrin but not of larger molecules
5 Bowel oedema may cause diarrhoea, and increased such as immunoglobulins and ferritin. A selectivity
capillary leak has been suggested as a mechanism for index can be derived from the ratio of IgG to albumin
losing protein via the gut. clearance:
Minimal Change Disease
405 20
$IgG %U $ Albumin %S
Selectivity index ! SI " #
$IgG %S $ Albumin %U
followed by a switch to alternate-day dosing at 1.5 ating agents (cyclophosphamide and chlorambucil),
mg/kg (maximum 40 mg per day) for 6 weeks, but subse- levamisole, ciclosporin or tacrolimus and, more recently,
quent tapering is no longer recommended [11, 12]. rituximab.
Children should remain on steroids for 3–4 months, Alkylating agents were originally first-line, although
which is associated with a lower 1-year relapse rate com- increasingly other agents are now being tried first,
pared with those receiving steroids ≤2 months (19% v. mainly because of the potential side effects of alkylating
64%, respectively) based on several studies and a meta- agents (immediately infection and alopecia, and subse-
analysis [13, 14]. The 2-year sustained remission rate is quently sterility [17], haemorrhagic cystitis and longer-
49% with a 29% frequent relapse rate although this is term risks of hematologic malignancy). Although these
higher in younger children. The KDIGO recommenda- are small for a 3-month course, they need to be balanced
tions published in 2021 now recommend a shorter against the fact that MCD is usually self-limiting and
course of high dose steroids (8–12 weeks), which are the permanent remission rate is not very high. On the
noninferior to longer courses [15, 16]. basis of one but not all studies, cyclophosphamide
For children still proteinuric after 4 weeks on ste- (2–2.5 mg/kg daily) for 12 weeks is more effective than
roids, there is anecdotal evidence that either increasing an 8-week course, giving a 2-year remission rate of 60%
the steroid dose or giving an intravenous pulse of meth- versus 30% [18]. Younger children are less likely to have
ylprednisolone (1 g/1.73 m2) improves the probability of a sustained response to cyclophosphamide (. Fig. 20.3).
inducing a remission. However, it is important to con- Chlorambucil (0.2 mg/kg daily) for 2 months appears to
sider reasons for treatment failure including noncompli- have a similar effect to cyclophosphamide and, apart
ance and poor absorption from an oedematous bowel, from not provoking haemorrhagic cystitis, has similar
especially in the presence of diarrhoea, both of which adverse effects. Frequent relapsers are more likely to
would make intravenous steroids logical. Even in the have a long-term remission following an 8-week course
absence of diarrhoea, prescription of non-enteric-coated of cyclophosphamide or chlorambucil than steroid-
steroid formulations is recommended, since occasionally dependent children (75% versus 35%). Second courses
enteric-coated tablets are poorly or not absorbed. are not recommended as they are less effective, and the
cumulative dose of 150–250 mg/kg [17] is likely to be
exceeded.
20.11 Diagnosis and Treatment of Initial During treatment with cyclophosphamide or chlo-
and Infrequent Relapses rambucil, blood counts should be checked weekly and
dose reductions made to avoid cytopenias. Herpes zoster
Daily urine testing should continue after remission in infection is potentially catastrophic, serostatus must be
order to detect and treat relapses early. Relapse should
be diagnosed on the basis of dipstick 3+ proteinuria for 100
3 consecutive days. The first relapse is treated with a 2nd
induction course of steroids but of shorter duration, for
Cumulative sustained remission (%)
Urinary remission
100
Complete remission
80
urinary and completed remission
Cumulative % of patients with
60
0 10 20 30 40 50 60 90 294
Days of prednisone therapy
. Fig. 20.4 Corticosteroid responses in children and adults. (Adapted from [13, 26])
more rapid tapering after urinary remission is achieved falls, a biopsy is indicated to distinguish between calci-
(e.g. halving dose every 5 days until 10–15 mg/day and neurin inhibitor toxicity or the development of
then reduce by 5 mg/day every 5 days until stopped). FSGS. Tacrolimus is similarly effective and useful for
Second-line treatments are given to frequently relaps- patients with side effects from ciclosporin.
ing patients and those who are steroid-dependent (who Reports of the use of mycophenolate and rituximab
relapse as the steroid dose is reduced but remain in are, as for children, anecdotal and need to await further
remission as long as a ‘threshold’ dose is maintained). studies. The largest published study of rituximab in
As in children, cyclophosphamide or calcineurin inhibi- adult steroid-dependent or frequently relapsing MCN
tors are used. A permanent remission is achieved with suggests that a significant proportion of patients (65%)
cyclophosphamide more often than in children (75 and maintained a remission for >2 years, and it appeared to
66% at 2 and 5 years, respectively) [26], and based on the be more effective when given in remission [29]. However,
paediatric data, a 12-week course (2 mg/kg of ideal body the study was retrospective, and although patients were
weight up to 175 mg/day) may be more effective than adults, 12/17 had developed NS as children. Evidence
8 weeks. Adults may be less susceptible to gonadal dam- remains anecdotal [30, 31] and controlled prospective
age, and men can be given the opportunity to bank trials are needed.
sperm prior to treatment. IV cyclophosphamide has not A small proportion of patients with repeated
been adequately evaluated in MCN (one study in chil- relapses, even if they remain steroid-dependent, but
dren concluded 6 monthly pulses was less effective the more often if they become steroid-dependent or resis-
historical 3-month oral cyclophosphamide). tant are shown to have FSGS of repeat biopsy. These
Ciclosporin (4–6 mg/kg/day, aiming for 50–150 ng/ml) patients then develop progressive chronic kidney disease
and tacrolimus (target levels 4–6 ng/ml) are alternatives and, eventually, renal failure.
(and may be preferred in younger adults) or can be used
if cyclophosphamide fails. Relapse usually follows dose
reduction or withdrawal, but since immunosuppression-
free remission eventually occurs in up to 75% of patients, 20.15 ‘Minimal Change’ Appearance
20 it is an effective strategy to maintain patients non- with Non-nephrotic Proteinuria
nephrotic. There are no controlled studies to inform the and Normal Albumin
best length of time on ciclosporin. My practice is to treat
for 1 year and then taper the dose gradually to stop over Steroid treatment is not indicated, but hypertension
4–6 months. Relapse would indicate a longer course of should be treated with an ACE inhibitor or angiotensin
treatment. Since nephrotoxicity is more common after II receptor antagonist. Proteinuria and renal function
>1-year treatment [28], careful monitoring of renal func- should be monitored with re-biopsy in case of increased
tion and ciclosporin levels is essential, and if the GFR proteinuria of reduced renal function.
Minimal Change Disease
409 20
Case Study
Focal Segmental
Glomerulosclerosis
Philip David Mason
Contents
References – 421
21 sensitive MCD developing into FSGS after many years cMost common cause of adult familial FSGS—usually non-
nephrotic
of relapses. dMutations confer resistance to Trypanosoma brucei but pre-
Nephrotic FSGS is sometimes found in association dispose (uncertain aetiology) to FSGS
with a wide range of other conditions and genetic muta-
Focal Segmental Glomerulosclerosis
415 21
adaptive changes in response to glomerular loss from 21.3 Natural History and Complications
scarring resulting in hyperfiltration [5].
Nephrotic FSGS may also be a consequence of 5 The incidence of progressive renal failure in primary
genetic mutations, which usually present in childhood FSGS is often quoted as around 50%, although there
and mostly encode podocyte proteins involved with the may be variation in the exact diagnostic criteria.
actin cytoskeleton and integrity of the slit diaphragm 5 The prognosis is clearly related to the level of pro-
[6]. At least 38 genes have now been identified [7]. teinuria and the response to treatment [19]
Sadowski et al. reported nearly 30% children had an (. Figs. 21.1 and 21.4).
identified gene mutation and was more common in the 5 Non-nephrotic patients with normal plasma albu-
younger patients (69% of those presenting younger than min and proteinuria of <3 g/day have a 10-year inci-
3 months and 50% presenting at 4–12 months of age) dence of renal failure of just 10–15%, but many of
[8]. Mutations are also increasingly being discovered in these will have secondary FSGS.
adults onset FSGS [9].
Evidence for a circulating factor in FSGS is more The complications of FSGS are generally the same as
substantial than in MCD, mainly based on the high for any cause of nephrotic syndrome and include infec-
incidence of recurrence following transplantation, tion (especially with encapsulated bacteria and includ-
with heavy proteinuria developing sometimes within ing spontaneous bacterial peritonitis particularly in
hours (with resolution reported in one case report of children), life-threatening venous or arterial thrombosis,
an affected transplant after retransplantation into a AKI (especially adults).
second recipient [10]). In another case report, trans-
mission of heavy proteinuria to the foetus of a mother
with FSGS resolved rapidly after delivery [11]. 21.4 Clinical Features
Following transplantation the histologic picture is ini-
tially MCD later developing into FSGS. Plasma The symptoms and clinical signs are the same as those
exchange and elution with protein A or anti-IgG col- for the nephrotic syndrome from any cause, but it is
umns can lead to temporary remission in transplant worth noting:
recurrence of FSGS, and eluates from the columns
may induce proteinuria [12]. A soluble factor that 5 Severe fluid retention exceeding 3% of the body
causes increased protein permeability in cultured weight and often much more.
human glomeruli has also been described [13]. 5 As in MCD, oedema is gravitational, but a puffy face
Although not definitively characterised, cardiotrophin- is common, and genital swelling may be very uncom-
like cytokine-1 (structurally similar to interleukin-16) fortable, especially in men. Gross oedema may result
is a potential candidate, and upregulated receptors in ulceration and infection of dependent skin and
have been demonstrated on the podocytes of patients lacerations, and needlestick punctures may weep
with recurrent disease [14]. Upregulated expression of fluid profusely.
transforming growth factor-β (TGF-β), a pro-fibrotic 5 Striae commonly appear even without steroids.
cytokine, has been described in patients with FSGS, 5 Bowel oedema may cause diarrhoea, and increased
but it is unclear whether this is a primary or secondary capillary leak has been suggested as a mechanism for
phenomenon. Yu et al. reported CD80 may be upregu- losing protein via the gut.
lated in some patients and abatacept (CTLA4-Ig which 5 Other clinical features include white nails, sometimes
binds CD80 and blocks T-cell activation) induced in bands (Muehrcke’s bands) correlating with peri-
remission [15], but further studies have resulted in ods of clinical relapse. Rarely xanthomata are associ-
contradictory findings [16]. ated with gross hyperlipidaemia.
In 2013 it was reported that soluble urokinase-type 5 Microscopic haematuria is more common in FSGS
plasminogen activator receptors (suPAR) were present in than MCD.
two-thirds of patients with FSGS and high levels seem to 5 Hypertension is more common, especially with
be predictive of recurrence following transplantation impaired function [20].
[17]. It is believed that the suPAR activates β3 integrin, 5 AKI is present or develops in ~18% of patients with
which plays a major role in anchoring the podocyte to MCD.
the GBM, resulting in dysregulation. However, further 5 Other complications, as for any cause of nephrotic
studies have cast doubt on suPAR as the underlying syndrome, include thromboembolism, infection and
causative factor and may be merely a biomarker [18]. hyperlipidaemia.
416 P. D. Mason
100 %
90 %
Non-nephrotic
80 %
70 %
% Survival
60 %
Nephrotic
50 %
40 %
30 %
0 1 2 3 4 5 6 7 8 9 10 11
Non-nephrotic 21 20 16 16 13 12 10 9 8 8 8 6
Nephrotic 60 46 32 26 21 19 13 11 11 11 11 9
. Fig. 21.1 Prognosis in primary focal segmental glomerulosclero- likely to develop renal failure than those with low-grade proteinuria.
sis. The risk of developing renal failure is related to the extent of The figures indicate the number of at-risk patients at different time
proteinuria. Those with nephrotic-range proteinuria are much more points. (Reproduced with permission from Rydel et al. [19])
. Fig. 21.2 Light microscopic appearances in focal segmental glo- . Fig. 21.3 The glomerular ‘tip’ lesion. A glomerulus in a renal
merulosclerosis. Segmental scars with capsular adhesions in other- biopsy from an adult with steroid-responsive nephrotic syndrome.
wise normal glomeruli [periodic acid—Schiff, ×300]. (Courtesy of The glomerular tuft is normal away from the tubular origin, but at
Prof Ian Roberts, Oxford University Hospitals NHS Trust) the tubular origin, there is adhesion to Bowman’s capsule with pro-
trusion into the tubular lumen (methenamine silver stain ×300).
(Courtesy of Prof Ian Roberts, Oxford University Hospitals NHS
21.8 Immunofluorescence Trust)
5 Sclerotic segments are often positive for IgM and C3 5 Glomerular ‘tip’ lesion: segmental scars are described
complement (thought to be a nonspecific conse- as ‘hilar’ when related to the vascular pole, ‘periph-
quence of the injury, possibly caused by passive trap- eral’ when opposite the tubular pole or ‘intermedi-
ping of large molecules in damaged capillary loops). ate’. The ‘tip’ lesion refers to peripheral segmental
sclerosis adjacent to the tubular pole of Bowman’s
capsule, often with adhesions or synechiae to Bow-
21.9 Electron Microscopy man’s capsule and may prolapse into the proximal
tubular lumen (. Fig. 21.3). The glomerular capil-
5 Foot process fusion of non-sclerotic segments and lary loops adjacent to the proximal tubule may be
unaffected glomeruli may be indistinguishable from dilated, with accumulation of foamy cells. ‘Tip’
that seen in MCD, but diffuse foot process fusion lesions are seen in other proteinuric conditions
predominates in the sclerotic segments, with partial including normal glomeruli consistent with MCD
effacement in surrounding apparently normal lob- (more often in adults than children), which may
ules. explain why they have been reported to be more
likely to be steroid-responsive with a better long-
term prognosis. However, most series do not support
21.10 Histologic Variants of Primary FSGS an association with a better prognosis, possibly
reflecting a more widespread use of the term ‘tip’
There is considerable overlap in the descriptions of his- lesion when glomerular changes at the tubular origin
tologic variants of FSGS and uncertainty as to whether occur in other glomerular disorders with proteinuria,
they should be regarded as distinct entities. including membranoproliferative glomerulonephri-
tis and IgA nephropathy (and renal transplants).
5 Collapsing variant (best defined histologically vari-
ant): segmental sclerotic lesions are associated with The most important reason to recognise the lesion is to
glomerular tuft collapse and clinically associated prevent a misdiagnosis of a proliferative glomerulone-
with nephrotic syndrome and rapidly progressive phritis.
AKI similar to HIV and bisphosphonate-associated
FSGS. The prognosis is significantly worse with 5 The cellular variant: characterised by podocyte
resistance to treatment and usually rapid decline in hyperplasia and proliferation, often overlying seg-
renal function. mental scars or areas of collapsed capillary loops,
418 P. D. Mason
sometimes with endocapillary hypercellularity, foam (used less often in children because of the greater risk of
cells, leukocytes and nuclear debris, mimicking pro- hypovolaemia). Consideration should be given to pro-
liferative glomerulonephritis. Clinicopathologic cor- phylaxis against thrombosis and infection and, in nonre-
relates of this variant are variable. sponders, control of hyperlipidaemia.
5 Mesangial hypercellular variant: there are contradic- Traditionally, FSGS has been thought to have a poor
tory data regarding the significance of this, but many prognosis, with a low rate of response to steroid treat-
consider mesangial hypercellularity to be an inter- ment and about 50% of patients progressing to ESRD in
mediate step in the evolution (progression) of MCD 10 years [22] although only those who are nephrotic
to FSGS. seem to be at particular risk (. Fig. 21.1). However,
5 IgM nephropathy: Patients with mesangial deposits since up to 40% of nephrotic patients (adults and chil-
of IgM, usually with minor mesangial hypercellular- dren alike) respond to steroids with complete remission
ity, are more likely to be associated with haematuria and, in those who respond, the 5-year actuarial renal
(usually microscopic) and less likely to respond to survival exceeds 95% [19], treatment is definitely indi-
steroids (50% compared with 90% for MCD). How- cated (. Fig. 21.4).
ever, since IgM deposits are seen in MCD, FSGS and Currently there is no way of identifying those
mesangial proliferative glomerulonephritis in a simi- patients who will respond. The only (retrospective) fac-
lar proportion of patients, it may not be a specific tor identified in published studies seems to be the dura-
entity in its own right. Similar arguments apply to tion of steroid treatment, but recommended protocols
the rarer finding of mesangial complement C1q vary widely. For example, one study showed that 87% of
deposition, sometimes labelled as C1q nephropathy. responders received 60 mg prednisolone for 1 month
and 67% for 2 months and that the median response
time was 3.7 ± 2 months [23].
21.11 Management A pragmatic approach is to treat nephrotic adults
with FSGS with prednisolone, 1 mg/kg daily for at least
As described in the chapter on the general management 3 months (2 months in children) after considering
of nephrotic syndrome, all patients should receive gen- patient comorbidities and possible contraindications
eral management of the nephrotic syndrome to control and after discussion with the patient. Responders, in
oedema with fluid and salt restriction and diuretics whom the proteinuria reduces or remits, are treated with
100 %
Responder
90 %
80 %
70 %
60 %
% Survival
Untreated
50 %
40 %
30 %
Non-responder
20 %
10 %
0%
0 1 2 3 4 5 6 7 8 9 10 11
Responder 15 14 10 9 7 7 5 5 5 5 5 5
21 Non-responder 15 13 10 7 5 5 3 3 3 3 3 2
Untreated 30 21 14 12 11 9 8 5 5 5 5 4
Years
. Fig. 21.4 Renal survival is good in patients with FSGS who respond to steroids. (Reproduced with permission from Rydel et al. [19])
Focal Segmental Glomerulosclerosis
419 21
reducing doses for about 6 months, whilst the steroids steroids and chlorambucil, similar to that introduced by
are tapered and stopped within 4 weeks in nonre- Ponticelli for the treatment of membranous nephropa-
sponders. Steroid treatment should be combined with thy. More recently mycophenolate and rituximab have
gastric protection (an H2 blocker or proton pump inhib- been reported by several groups to be effective, but no
itor) and bone protection with a bisphosphonate. controlled trials are available, and the risks of potentially
Patients should be monitored for steroid side effects and toxic treatments need to be carefully weighed against
decisions to abandon treatment need to be made on an likelihood of success and alternatives, even if these
individual basis. include progression to ESRD with medical or surgical
Frequent relapsers and those who become steroid- nephrectomy for intractable and debilitating nephrotic
dependent may benefit from a 3-month course of cyclo- syndrome. All patients, whilst proteinuric, especially
phosphamide [24], but steroid-unresponsive patients those who are steroid-resistant should receive angioten-
rarely, if ever, obtain a sustained remission [24, 25], and sin-converting enzyme (ACE) inhibitors or ARBs to
so the risks outweigh the benefits. reduce proteinuria and treatment for hyperlipidaemia.
Ciclosporin is sometimes effective, especially in the
steroid-dependent patients, and although, as in the
MCD patients, relapse usually follows withdrawal of the
21.12 Focal Segmental Glomerulosclerosis
drug [22], it may have a role in those patients with refrac-
tory nephrotic syndrome. There are several randomised with Non-nephrotic Proteinuria
controlled trials of ciclosporin, including patients with
steroid-resistant FSGS [22]. Treated patients received Careful evaluation is required to exclude secondary
ciclosporin for 6 months, followed by gradual with- FSGS in those with non-nephrotic proteinuria. There
drawal. Only 20% of patients achieved complete remis- is no convincing evidence that these patients are
sion, but a further 60% had a partial remission, although steroid-responsive and the risks of treatment outweigh
there were many relapses following dose reduction. the benefits.
There have been anecdotal reports that patients kept in
remission for 12 months can then have ciclosporin suc-
cessfully withdrawn without relapse [26]. 21.13 Transplant Recurrence
Currently the largest randomised trial of ciclosporin
includes only 49 adults: all patients were steroid-resistant Recurrence is common after transplantation, but
(and 40% had also received cyclophosphamide) and because the label FSGS may often include non-nephrotic
received prednisolone (0.15 mg/kg/day) and 6 months of native renal disease, an accurate proportion is difficult to
either ciclosporin (3.5 mg/kg/day adjusted to trough lev- assess. It is often reported to be 20% but is probably
els 125–225 ng/ml) or placebo. Complete (12%) or par- higher (~40%) for patients with true nephrotic
tial (58%) remission followed in the ciclosporin arm FSGS. Recurrence is more likely with rapid progression
compared with 4% (combined) in the placebo group. in native kidneys, previous recurrence following trans-
Although 60% of responders relapsed within a year fol- plantation (up to 80%) and paediatric recipients [28].
lowing the end of the trial medication, the remainder Recurrence may be evident early, even within hours,
was still in remission at last follow-up (up to 4 years), although the median time to appearance is 14 days and
and the treated cohort had a significantly lower rate of acute renal failure and acute rejection are common.
progression of renal failure [27]. Because of the evidence that a circulating agent is patho-
Based on these limited data, I treat steroid nonre- genic in FSGS, patients with recurrent disease following
sponders with ciclosporin (aiming for trough levels of transplantation have been managed with plasma
150–200 ng/ml) for 6 months if remission is not achieved exchange. There is no doubt that plasma exchange can
but continue for 1 year with tapering over 3–6 months if reduce proteinuria, although the response is not abso-
remission does occur. This takes advantage of the lutely reliable but has been reported in many case reports
proven long-term beneficial effects of 6 months of ciclo- and small series [29] and a systematic review and meta-
sporin with control of nephrotic syndrome. Ciclosporin analysis [30]. The best chance of a lasting response
is restarted in patients who subsequently relapse again occurs when plasma exchange is initiated as soon as pos-
but with careful monitoring of renal function. sible after the appearance of proteinuria and in those
Other approaches that have been tried include tacro- whose recurrence is in the first few weeks after trans-
limus and very aggressive regimens such as prolonged plantation [30]. The effect can be dramatic and long-
courses of daily cyclophosphamide (up to 2 years), lasting, but unfortunately the nephrotic syndrome
extended therapy with pulse steroids and intravenous frequently recurs within a few months of discontinuing
cyclophosphamide or cyclical treatments with cortico- plasma exchange, and there is much less evidence that a
420 P. D. Mason
further course of plasma exchange is useful. Some have I generally treat with daily plasma exchange for
suggested that pre-emptive plasma exchange is logical, 7 days; if improvement occurs continue with reducing
especially for those with a rapid course in native kidneys, frequency depending on response, but sometimes treat-
but others have found no benefit [31]. High-dose ciclo- ments are continued for weeks with plasma exchange
sporin and rituximab (and more recently ofatumumab) associated with reduction in proteinuria and improve-
have been tried anecdotally with mixed results. ment or preservation of renal function.
Case Study
Case 1 rent FSGS are more than 80% likely to have recurrence in
A 37-year-old male presented with nephrotic syndrome the second transplant but do not always lose the transplant
with a creatinine of 102 μmol/L (eGFR 66 ml/min), serum in a short space of time, and so transplantation is usually
albumin 14 g/L and a urinary PCR of 780 mg/mmol. His offered with appropriate counselling.
blood pressure was 138/78. A renal biopsy demonstrated
FSGS. He was treated with high-dose steroids and made a Case 2
partial response with a serum albumin increasing to A 58-year-old female presented with sudden onset of
28 g/L with a urinary PCR of 115 mg/mmol. He was nephrotic syndrome with normal renal function with a cre-
maintained on a tapering dose of steroids for 4 months. atinine of 88 μmol/L and serum albumin 17 g/L with heavy
After withdrawal of steroids, his proteinuria continued at proteinuria (urinary PCR at 950 mg/mmol). She was
a similar level for about 2 years, after which it increased hypertensive with a blood pressure of 159/94. Renal biopsy
with worsening of his nephrotic syndrome symptoms. He demonstrated FSGS, and she was given a trial of high-
was tried on ciclosporin, but this only resulted in a small dose steroids (60 mg/day of prednisolone). After 8 weeks
reduction in proteinuria, but his creatinine increased to of treatment, there was little change in her condition with
154 μmol/L (eGFR 43 ml/min) and so was discontinued. an albumin of 20 g/L urinary PCR 480 mg/mmol. Since a
Over the next 6 years, kidney function gradually deterio- nephrotic syndrome was difficult to control despite maxi-
rated until he started dialysis and then received a living mal ACE inhibition and high-dose diuretics, she was tried
donor kidney transplant from his wife. He developed on ciclosporin which she did not tolerate because of side
heavy proteinuria on day 6 post-transplant, and the cre- effects and was changed to tacrolimus, but these treat-
atinine increased from 116 μmol/L to 145 μmol/L over the ments had little or no effect on the proteinuria, but her
next 2 days. At the onset of heavy proteinuria, plasma renal function was declining with a creatinine of
exchange was started, and he had seven treatments over 239 μmol/L (eGFR 19 ml/min). She was re-biopsied, and
the next 10 days. Proteinuria initially reduced but this showed extensive FSGS with more than 30% intersti-
increased again and after a second course of plasma tial fibrosis and tubular atrophy. There were some changes
exchange proteinuria settled but remained significant with consistent with calcineurin inhibitor toxicity, but there was
a urinary PCR of 200 mg/mmol, but his renal function no improvement in function when the tacrolimus was with-
improved with a creatinine falling to 119 μmol/L. He is drawn. She had a progressive further decline in renal func-
now 2 years post-transplant and continues to have the tion and started dialysis 3 months later.
same level of proteinuria but with stable renal function This picture is seen in up to one-half of patients with
and he has minimal oedema. this diagnosis although this rapid progression is seen less
About 50% of patients who get recurrent FSGS in a often. However, since there is some circumstantial evidence
transplant do respond to plasma exchange. A minority end that patients with very rapid decline (less than 1 year from
up with little or no proteinuria. Those that do not respond diagnosis to dialysis) are more likely to have rapid recur-
at all to not always lose their transplant from recurrent dis- rence following transplantation, she has been advised to
ease in a short space of time in the transplant may last delay transplantation (she has willing potential living
several years. Patients who have had graft loss from recur- donors) for at least a year.
21
Focal Segmental Glomerulosclerosis
421 21
Tips and Tricks 2. No, the limited evidence (only case reports and
small series) suggests this isn’t effective, and so the
1. Make sure the diagnosis of FSGS is associated risks probably out way the potential benefits. In
with the nephrotic syndrome rather than a sec- this situation it is worth a trial of ciclosporin,
ondary FSGS. Childhood FSGS, especially especially if the nephrotic syndrome is difficult to
<2 year is likely to have a genetic cause and should control with ACEI/ARB and diuretics.
not be treated with steroids. 3. This pattern is usually associated with a second-
2. The progression of chronic kidney disease in ary cause, most commonly HIVAN and pamidro-
FSGS (as in most kidney diseases) is related to the nate treatment (see . Table 21.1). It is also seen
level of proteinuria, and so it is important to more often without an identified secondary cause
reduce this if possible. Even a partial response to in patients of African origin. It is usually resistant
steroids or a calcineurin inhibitor will reduce the to treatment and progresses rapidly to renal fail-
rate of decline of kidney function. Always remem- ure, but a trial of steroids is recommended, and
ber to also maximise ACEI/ARB treatment to there are case reports of complete remission. It is
reduce proteinuria. also seen occasionally after parvovirus infection
3. Calcineurin inhibitors are effective in some when the prognosis is better.
patients, but careful monitoring of renal function 4. Yes, although the evidence is not very strong so
is important, and a decline should lead to consid- needs to be discussed with the patient regarding
eration of a further biopsy to determine if disease potential side effects. The alternative would be a
progression or CNI toxicity is to blame. trial of ciclosporin or tacrolimus. Obviously it is
4. Patients who progress rapidly to kidney failure also important to always maximise ACEI/ARB
(especially in <1 year) should be counselled about treatment and manage hypercholesterolaemia.
the risk of recurrence in a transplant, and most
clinicians would recommend waiting at least a
year before transplanting, although the evidence
is anecdotal. References
1. Schena FP. Survey of the Italian Registry of Renal Biopsies.
Frequency of the renal diseases for 7 consecutive years. The
? Chapter Review Questions Italian Group of Renal Immunopathology. Nephrol Dial
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having low-level proteinuria with better long-term ologies of unexplained adult nephrotic syndrome: a compari-
outcomes? son of renal biopsy findings from 1976–1979 and 1995–1997.
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showing a collapsing FSGS pattern. What clinical JF. Minimal change disease and idiopathic FSGS: manifesta-
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scarring as a result of another pathology such as a S, et al. A single-gene cause in 29.5% of cases of steroid-
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ney disease. N Engl J Med. 2013;369(25):2416–23. nephrotic syndrome. Collaborative Group of the Societe de
16. Novelli R, Benigni A, Remuzzi G. The role of B7-1 in pro- Nephrologie. Kidney Int. 1994;45(5):1446–56.
teinuria of glomerular origin. Nat Rev Nephrol. 27. Cattran DC, Appel GB, Hebert LA, Hunsicker LG, Pohl MA,
2018;14(9):589–96. Hoy WE, et al. A randomized trial of cyclosporine in patients
17. Wei C, El Hindi S, Li J, Fornoni A, Goes N, Sageshima J, et al. with steroid-resistant focal segmental glomerulosclerosis.
Circulating urokinase receptor as a cause of focal segmental North America Nephrotic Syndrome Study Group. Kidney Int.
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18. Saleem MA. What is the role of soluble urokinase-type plas- 28. Keith DS. Therapeutic apheresis rescue mission: recurrent focal
minogen activator in renal disease? Nephron. 2018;139(4):334– segmental glomerulosclerosis in renal allografts. Semin Dial.
41. 2012;25(2):190–2.
19. Rydel JJ, Korbet SM, Borok RZ, Schwartz MM. Focal segmen- 29. Artero ML, Sharma R, Savin VJ, Vincenti F. Plasmapheresis
tal glomerular sclerosis in adults: presentation, course, and reduces proteinuria and serum capacity to injure glomeruli in
response to treatment. Am J Kidney Dis. 1995;25(4):534–42. patients with recurrent focal glomerulosclerosis. Am J Kidney
20. Nephrotic syndrome in children: prediction of histopathology Dis. 1994;23(4):574–81.
from clinical and laboratory characteristics at time of diagno- 30. Kashgary A, Sontrop JM, Li L, Al-Jaishi AA, Habibullah ZN,
sis. A report of the International Study of Kidney Disease in Alsolaimani R, Clark WF. The role of plasma exchange in
Children. Kidney Int. 1978;13(2):159–65. treating post-transplant focal segmental glomerulosclerosis: a
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et al. Serial morphometric analysis of sclerotic lesions in pri- case-series. BMC Nephrol. 2016;17(1):104.
mary “focal” segmental glomerulosclerosis. J Am Soc Nephrol. 31. Gonzalez E, Ettenger R, Rianthavorn P, Tsai E, Malekzadeh
1996;7(1):49–55. M. Preemptive plasmapheresis and recurrence of focal segmen-
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21
423 22
Membranous Nephropathy
Sanjana Gupta and Alan D. Salama
Contents
References – 430
Anti-PLA2R antibody levels correlate with disease risk greatest in the first 6 months of diagnosis and cor-
activity and with response to treatment [13]. Testing for relation with serum albumin levels, being greatest in
anti-PLA2R antibody has now become routine in many those with albumin levels below 28 g/L [17]. The pub-
hospitals and can be measured serially. Utilised in this lished rates vary, but approximately 20% of patients will
way, it can be used to guide treatment duration. PLA2R1 have a deep vein thrombosis, 11% pulmonary embolism
is expressed by podocytes, but it is not yet clear how the and 35% renal vein thrombosis [18].
immune response develops against podocyte PLA2R1.
Renal tissue anti-PLA2R immunostaining can predate
serological detection of the anti-PLA2R antibody, sug- 22.5 Histopathology
gesting that renal binding occurs first, with subsequent
overspill of anti-PLA2R antibody into the circulation. MN is a discrete pathological entity (. Fig. 22.1) which
This may also explain some cases of anti-PLA2R anti- can only be identified by renal biopsy and histological
body negativity in patients with AMN. Podocytes are analysis including electron microscopy. The glomerular
targeted by the anti-PLA2R antibodies and injured capillary wall is expanded, but the cellularity of the
through complement activation, via the classical and glomerulus is not typically increased (. Fig. 22.1a).
lectin pathways. Immune deposits including IgG and complement are
The genetic basis of AMN was demonstrated by a found in a granular distribution along the glomerular
genome-wide association study using three European capillary wall (. Fig. 22.1b). Anti-PLA2R antibody
populations [14]. The genetic regions associated with immunostaining has the same pattern as the immune
disease encoded PLA2R1 on chromosome 2 and genes deposits and is present in up to 70% of all AMN patients.
in the human leucocyte antigen locus on chromosome 6, Anti-PLA2R immunostaining is more sensitive than
specifically, HLA-DQA1. These regions and nearby antibody titres and can be utilised to assist differentia-
genes have been replicated as susceptibility markers in tion between primary and secondary MN [19]. THSD7A
other ethnicities. The strength of the association was immunohistochemistry has also very recently proven to
greatest with HLA-DQA1 with an odds ratio of 20.2; be of clinically significant use in identifying a subset of
however, if both variants (HLA-DQA1 and PLA2R1) AMN [20] (. Fig. 22.1c). Electron microscopy shows
were present, the odds ratio increased to 78.5. To date electron dense deposits in the sup-epithelial space adja-
there is no research to demonstrate the direct causation cent to the foot processes of the podocytes (. Fig. 22.1d),
with these variants. (see also separate chapter on podocytopathies).
a b
c d
. Fig. 22.1 Renal biopsy appearances of membranous nephropa- staining for THSD7A by immunofluorescence. (Courtesy of Dr
thy. (a) Light microscopy (haematoxylin and eosin stain). (b) Immu- Shree Sharma, Arkana Laboratories, USA). (d) Electron micros-
nofluorescence, in this case for IgG but similar appearances typically copy: electron dense deposits are shown by asterisks
seen for C3 and anti-PLA2R. (c) Global granular capillary wall
428 S. Gupta and A. D. Salama
demonstrated that risk criteria have not changed signifi- risk with alkylating agents remains infections, increased
cantly [22]. The most recent addition to risk stratifica- risk of malignancy and infertility. Male patients should
tion has been anti-PLA2R antibody status. be sperm banked if possible prior to therapy and ovar-
ian protection strategies offered to women of child
22.7.2.1 Low Risk bearing age.
Low-risk patients are aged less than 50 years, with nor- Calcineurin inhibitors (ciclosporin 3.5–5 mg/kg/day
mal renal function, without fibrosis on histology, with or tacrolimus 0.05–0.075 mg/kg/day) with low-dose ste-
lower levels of proteinuria (less than 4 g per day) and roids (prednisolone 0.15 mg/kg/day) reduce proteinuria
have low serum anti-PLA2R antibody levels. For these and induce remission. They should be reserved for
patients, non-immunosuppressive anti-proteinuric treat- patients who are not suitable for or fail alkylating agents.
ment (NIAT) is recommended, in addition to the treat- A minimum treatment duration of 6 months is advo-
ment measures discussed above. cated, and often longer treatment durations are required.
It is important to the monitor therapeutic drug levels in
22.7.2.2 Medium to High Risk the initial phase when starting treatment. As there is a
Patients with a medium to higher risk are older and have very high risk of relapse when calcineurin inhibitors are
abnormal renal function with fibrosis on their histology, stopped, it is recommended that they are continued for a
declining renal function, proteinuria (greater than minimum of 1 year after remission. A small decline in
8 g per day) or persistent proteinuria greater than 4 g per renal function should be expected, but more severe
day after 6 months of treatment and/or severe symp- impairment should prompt treatment cessation.
toms or complications. These patients should be treated There is no evidence that steroids alone, or mycophe-
with NIAT, and in most instances clinicians would wait nolate mofetil has any role in the treatment of AMN, yet
for 6 months for signs of remission, prior to initiating they are still used in instances when neither an alkylating
immunosuppressive treatment. agent or a calcineurin inhibitor is suitable.
Adrenocorticotrophic hormone therapy is hypothesised
to have an additional beneficial direct action on podo-
22.7.3 Immunosuppressive Treatment cytes, but clinical studies using this agent have been on
small cohorts with unconvincing results [25].
The goal of immunosuppression is to induce remission, Rituximab is currently of interest in AMN as a result
but immunosuppressive treatment is not without risk, of studies that have demonstrated efficacy; however, no
and patients should be counselled about the risks and studies have yet shown superiority over other treat-
benefits so they can make an informed decision. The ments. Rituximab depletes B-cell lymphocytes, which
gold-standard regimen for treatment of AMN remains are involved in disease pathogenesis through autoanti-
the KDIGO guidelines due to a lack of an alternative body production, antigen presentation to T cells and
proven superior regime [24]; see links for clinical trials production of pro-inflammatory cytokines. There are
below. different dosage regimens in use in studies – either 1 g
The KDIGO guidelines advocate use of the given twice, 2 weeks apart, or 375 mg/m2 weekly for four
‘Ponticelli regimen’ for high-risk patients. This com- doses. Follow-up doses are sometimes required at
prises a 6-month course of treatment alternating 6 months, as niches of B cells can persist following ritux-
30-day cycles starting with intravenous methylpredniso- imab therapy [26]. There is increasing evidence for the
lone (1 g) daily for 3 days followed by oral prednisolone safety profile of rituximab, especially compared to alkyl-
(0.5 mg/kg/day) for the remainder of the month. In the ating agents. The recent MENTOR trial compared cal-
second month, patients receive an alkylating agent cineurin inhibitors versus rituximab and demonstrated
(either cyclophosphamide 0.5 mg/kg/day or chlorambu- non-inferiority with a safer side effect profile [27].
cil 0.15–0.2 mg/kg/day) orally and then repeat the cycle However, there has not been a randomised controlled
by returning to the steroid regimen. trial of cyclophosphamide versus rituximab. A recent
Alternative regimes exist, such as the ‘modified study comparing the use of rituximab against a histori-
restrictive Ponticelli’ regimen that is more practical and cal cohort of patients treated with cyclophosphamide
continuous with an option of excluding the intrave- demonstrated no difference in remission rates but a bet-
nous methylprednisolone thereby making it easier to ter side effect profile with rituximab. Patients in both
administer orally and exclusively at home. Prednisolone groups were not matched as the cyclophosphamide
is administered (1 mg/kg/day, maximum 60 mg, taper- group had higher risk disease [28]. Another comparative
22 ing per clinical response) with cyclophosphamide study of cohorts treated with rituximab compared with
(1.5–2 mg/kg/day) for a maximum of 6 months. The a separate cohort treated with cyclophosphamide
Membranous Nephropathy
429 22
demonstrated that complete immunological remission PLA2R antibodies were not routinely measured until
was more common in the cyclophosphamide group and recently, and so the current paradigm is that antibody
that RTX was less able to induce disappearance of anti- titres should be undetectable at the time of transplanta-
PLA2R antibodies in those patients with higher (than tion, to avoid the risk of disease recurrence. De novo
152 RU/ml) anti-PLA2R starting levels [29]. Further AMN in a transplanted kidney is apparent in up to 2%
direct evidence is required to prove rituximab superior- of all transplants. The reason for this is not clear but
ity to current cheaper and effective treatments. A trial may be associated with donor-specific antibodies (HLA
directly comparing rituximab to cyclophosphamide or non-HLA).
should be informative [30].
Novel agents such as anti-CD38 monoclonal anti-
bodies (daratumumab) or proteasome inhibitors (bort- 22.9 AMN and Other Autoimmune Diseases
ezomib) are possible alternatives as they deplete plasma
cells, the producers of autoantibodies [26]. Another AMN may be found in association with other autoim-
treatment currently being investigated in phase II trials mune conditions such as anti-GBM disease, ANCA-
is immunoadsorption. The extracorporeal removal of associated vasculitis, thyroid disease and of course SLE.
immunoglobulins including the pathogenic anti-PLA2R
antibodies is proposed to prevent patients’ exposure to
toxic non-specific immunosuppressive treatment [31].
22.10 Summary
22.8 Recurrent and De Novo MN Following MN is a common cause of nephrotic syndrome in adults
and associated with significant morbidity. Distinguishing
Transplantation AMN from secondary MN is critical, and anti-PLA2R
antibodies and PLA2R histology immunostaining help
Recurrent AMN is found in the renal allografts with
identify AMN. Meaningful clinical studies are required
recurrence rates of 10% at 5 years and 16% at 10 years
to determine best and safest treatment strategies to pre-
[32]. After disease recurrence, the 5-year allograft sur-
vent side effects from toxic treatment as well as improv-
vival rate is significantly reduced to 59% [32]. Anti-
ing outcomes to reduce rates of end stage kidney disease.
Case Study
Membranoproliferative
Glomerulonephritis and C3
Glomerulopathy
Daniel Gale and Mared Owen-Casey
Contents
References – 449
. Table 23.1 Traditional classification of membranoproliferative glomerulonephritis (MPGN) by location of electron dense
deposits
1 Discrete electron dense material in IgG ± IgA ± IgM + C3 + C1q Normal ± Infections, autoimmune
mesangium and subendothelial reduced C4 and disease, cryoglobulinaemia
GBM C3
2 Dense transformation of GBM C3 only Reduced C3, C3NeF
lamina densa normal C4
3 Subendothelial and subepithelial IgG ± IgA ± IgM + C3 + C1q Normal ± Infections, autoimmune
GBM electron dense deposits reduced C4 and disease, cryoglobulinaemia
23 C3
Membranoproliferative Glomerulonephritis and C3 Glomerulopathy
435 23
pathway is frequently present [3]. The third observation ses suggested by biopsy appearances are summarised in
was that dense transformation of the GBM (regarded as . Fig. 23.1, and the patterns associated with specific
pathognomonic of ‘type 2 MPGN’) is more often seen diseases are shown in . Table 23.2.
without the accompanying light microscopic changes of In addition to immune-mediated proliferative glo-
MPGN, leading to the unsatisfactory diagnosis of ‘type merulonephritis and C3 glomerulopathies, light micro-
2 MPGN without MPGN’ in a number of cases [4]. scopic appearances resembling MPGN are sometimes
These considerations have led to the introduction seen in patients with chronic thrombotic microangiop-
of the term ‘C3 glomerulopathy’ which encompasses athies (TMAs). In this situation there is no deposition
the disorders in which complement C3 accumulates in of immunoglobulin or complement in the glomeruli –
the kidney in the absence of significant immunoglobu- rather there is accumulation of electron-lucent, floc-
lin deposition there. This is the hallmark of comple- culent material (thought to be composed of fibrin and
ment alternative pathway dysregulation and represents its breakdown products) beneath the endothelial cells).
pathophysiology, prognosis and underlying aetiology This can result in capillary wall thickening and other
which are distinct from those cases of proliferative GN light microscopic features resembling MPGN. Electron
in which strong immunostaining for immunoglobulin is microscopy easily distinguishes this from the dense,
seen in the glomerulus, whatever the morphology may osmiophilic basement membrane deposits seen in
be by light or electron microscopy. Differential diagno- immune complex GN or C3 glomerulopathies. Causes
. Fig. 23.1 Histological categorisation and commoner causes of proliferative glomerulonephritis (GN); GBM glomerular basement mem-
brane, CFHR5 Complement Factor H-related 5, TMA thrombotic microangiopathy
436 D. Gale and M. Owen-Casey
. Table 23.2 Histological characteristics of different diseases causing MPGN pattern. Diagnosis, light microscopy, immunofluo-
rescence and electron microscopy. The term ‘C3 glomerulopathy’ encompasses both DDD and C3 glomerulonephritis
Immune Global and diffuse mesangial proliferation and IgG and C3 +/− IgM on the Subendothelial deposits and
complex glomerular hypercellularity, doubled GBMs inside of glomerular capillary occasional mesangial
membranopro- with mesangial interposition. The glomerulus walls with occasional mesangial deposits
liferative may have a distinct lobular/nodular appear- deposits
glomerulone- ance
phritis
(IC-MPGN)
Acute postinfec- Global and diffuse increase in mesangial Coarse C3 and IgG on the Irregular and variably sized
tious glomerulo- matrix and cellularity with an infiltrate of outside of glomerular capillary electron dense subepithelial
nephritis neutrophils within capillary loops loops deposits that appear as
humps
Dense deposit Normal, mild or variable mesangial prolifera- Coarse, granular C3 deposition in Intramembranous electron
disease (DDD) tion with thickened GBMs without spikes. glomerular capillary walls, with dense deposits often with
Often the GBM does not stain strongly with scant or no immunoglobulins. ring-like mesangial
silver and has a more characteristically brown Sometimes complement can also deposits and correspond-
colour with no doubling of the GBM. The be seen within mesangium, ing deposits within
main differential diagnosis to consider on Bowman’s capsule and within Bowman’s capsule and
H&E is membranous nephropathy tubular basement membranes tubular basement
membranes
C3 glomerulo- Variable increase in mesangial matrix and Complement C3 deposited in Discrete subendothelial,
nephritis cellularity GBMs and mesangium with subepithelial and/or
(C3GN) minimal immunoglobulins mesangial electron dense
deposits
Cryoglobulinae- Global and diffuse mesangial proliferation, Intraluminal glomerular capillary Organised subendothelial
mic glomerulo- mesangial hypercellularity, doubled basement IgM +/− IgG, kappa/lambda deposits often with a
nephritis membranes with acellular eosinophilic recognisable substructure
material in capillary loops, possibly represent-
ing cryoprecipitate, occasionally vasculitic
changes are seen in glomeruli
of TMAs which may result in these kidney biopsy 23.4 Aetiology and Pathophysiology
appearances are summarised in . Table 23.3.
Excessive or prolonged immunological stimulation and
antibody production (whether as a consequence of
infection, autoimmunity or blood cell dyscrasias) can
23.3 Epidemiology
result in proliferative glomerulonephritides, including
MPGN. In this context, immunostaining of the kidney
The incidence of MPGN varies significantly across the
biopsy reveals evidence of activation of the classical
world with higher rates in developing countries. MPGN
complement pathway (i.e. C1q deposition) alongside
is diagnosed in approximately 2% patients undergoing
C3 in the kidney and in addition to the immunoglobu-
renal biopsy in the UK and is the underlying primary
lins themselves. The recognition that isolated activation
glomerulopathy in 5–10% patients with nephrotic syn-
of the alternative pathway (see . Fig. 23.2) is sufficient
drome. However, up to 29% of biopsies in countries such
to cause proliferative GN with deposition of comple-
as Romania or Nigeria show MPGN [5, 6]. While com-
ment C3 (in the absence of immunoglobulin or C1q)
parisons between different countries are difficult since
reinforces the view that renal complement activation per
reporting of, indications for and access to renal biopsy
se is sufficient to cause disease. Furthermore, abnormal-
can vary markedly, longitudinal data suggest that rates
ities of Complement Factor H (CFH, a central regulator
are falling over time [6–8] probably related to reduction
of complement alternative pathway activity) are suffi-
in chronic infection-related MPGN.
cient to dysregulate C3 and can result in MPGN.
23
Membranoproliferative Glomerulonephritis and C3 Glomerulopathy
437 23
which patients develop renal inflammation in this con-
. Table 23.3 Causes of thrombotic microangiopathy
text is unknown (. Figs. 23.3 and 23.4).
Disease Investigations
. Fig. 23.2 The complement system tickover. In the alternative pathway, C3b binds Factor B which is
The complement system is a cascade of circulating proteases which cleaved by factor D to result in the non-covalently bound C3bBb
plays a pivotal role in defence against infection. In humans, comple- complex – a C3 convertase that is able to catalyse the cleavage of C3
ment has a number of functions, including innate recognition and to form more C3b. This completes a positive feedback loop which
destruction of invading micro-organisms; opsonisation (labelling of amplifies generation of C3b and which is further amplified by the
foreign material for phagocytosis); activation of cellular immunity; presence of an appropriate biological surface (such as a cell mem-
and as an effector system for the destruction of antibody-coated brane). In addition to catalysing C3 cleavage, the C3b also acts as an
micro-organisms. Complement therefore bridges innate and adaptive opsonin (labelling the cell to which it is bound for phagocytosis) and
mechanisms of immune defence. Activation of complement occurs forms part of the complex which cleaves circulating C5 to activate
via three pathways, termed the classical, mannose-binding lectin the terminal complement pathway.
(MBL) and alternative (AP) pathways. All result in the cleavage of The Terminal Pathway
the abundant circulating protein C3 to form the active C3b. The binding of C3b to either of the C3 convertases (C4b2a or
The Classical Pathway C3bBb) produces a C5 convertase which catalyses the cleavage of the
Antibody-antigen complexes are recognised by the circulating pro- circulating protein C5 to release C5a (an anaphylatoxin) and C5b
teins C1q, r and s to form the C1qrs complex which recruits and which initiates the terminal pathway, leading to the recruitment of
cleaves the circulating complement proteins C4 and C2 (releasing the the tubular membrane attack complex (MAC) which lyses the cell by
small C4a anaphylatoxin fragment that causes enhanced vascular forming a pore (composed of C6–9) in its surface.
permeability, histamine release and recruitment of immune cells) to Alternative Pathway Regulation
result in the C4b2a complex bound to the cell surface. C4b2a is a C3 In order to prevent runaway activation of its positive feedback loop,
convertase which is able to cleave C3 to form C3a (an anaphylatoxin) the AP requires tight regulation. This is achieved in by a number of
and the active C3b. mechanisms, including cleavage of C3b and acceleration of decay of
The Mannose-Binding Lectin (MBL) Pathway the C3bBb complex, and effected by a range of regulators, including
Mannose groups on bacterial cell surfaces are recognised by circulat- Factor I and Factor H, which prevent over-activation of the pathway
ing mannose-binding lectin (MBL) proteins which bind to form a both in the circulation and at host surfaces. The Complement Factor
complex which, similar to the C1qrs complex, is able to recruit and H (CFH) gene is situated immediately upstream from its 5 homo-
cleave C4 and C2, producing the C4b2a C3 convertase. logues, the CFH-related genes 1–5. The proteins encoded by these
The Alternative Pathway (AP) genes (FHR1–5) are also present in the circulation (although are
C3b is continuously generated by low-grade cleavage of the abun- much less abundant than Factor H), and some have complement
dant plasma protein C3 by water hydrolysis – a process known as AP deregulating activity.
is common. However, because some bacterial antigens tion and large, hump-like deposits on the subepithelial
(or antibodies directed against them) may stabilise the side of the GBM on electron microscopy. Glomerular
alternative pathway C3 convertase, low serum C3 is not immunostaining is usually positive for IgG, IgM, C1q
always accompanied by low serum C4 in this condition. and C3 although occasionally immunostain positivity
23 Kidney biopsy typically shows diffuse proliferation for C3 alone is seen. The pathophysiology of postinfec-
of mesangial cells with prominent neutrophil infiltra- tious glomerulonephritis is not completely understood,
Membranoproliferative Glomerulonephritis and C3 Glomerulopathy
439 23
Chronic infections Viral – Hepatitis B, hepatitis C, Viral serology; RF; cryoglobulins; C3/C4
HIV ± cryoglobulinaemia type 2
Bacterial – Endocarditis, infected shunt Blood cultures; imaging; transoesophageal echo
or prosthesis, abscess
Protozoal – Malaria, schistosomiasis Blood film; serology
Other – Mycoplasma, mycobacterial Cultures; imaging
Autoimmune diseases Systemic lupus erythematosus (SLE) ANAs: Anti-dsDNA; C3/C4
Sjögren’s syndrome ± cryoglobulinaemia ANAs: Anti-Ro/La
Rheumatoid arthritis Rheumatoid factor (RF)
Scleroderma ANAs: Anti-Scl-70/RNP
Coeliac disease Endoscopy; anti-endomysial abs
Paraprotein Cryoglobulinaemia type 1 Serum protein electrophoresis; serum free light chain assay/
deposition diseases immunofixation; bone marrow biopsy; imaging
Waldenström’s macroglobulinaemia
Immunotactoid glomerulopathy
Lymphoproliferative disease
Leukaemia
Malignant neoplasms
Inherited comple- C2 deficiency leading to bacterial CH50, C3/C4
ment deficiency infections and SLE
Chronic liver disease Cirrhosis and alpha1-antitrypsin Liver biopsy, A1AT levels
deficiency
Renal allograft Donor-specific antibodies
rejection
Unknown (formerly Fibrillary glomerulonephritis
‘idiopathic’)
but it has been postulated that some bacterial antigens polyclonal (usually IgG) immunoglobulins and is most
become deposited in the GBM, perhaps as a conse- commonly found in people with serological evidence
quence of their physico-chemical properties, and it is the of hepatitis C virus infection and/or lymphoprolifera-
aggressive immunological response to these antigens, tive disorders. In type 3 cryoglobulinaemia, there is a
including local complement activation, which causes the complex of polyclonal immunoglobulins and can also
renal inflammation. be seen in the context of hepatitis C infection, other
infections, autoimmune disorders and paraneoplastic
syndromes. In type 2 and type 3 cryoglobulinaemia (col-
23.5.3 Cryoglobulinaemic GN lectively referred to as mixed cryoglobulinaemias), tests
for rheumatoid factor are positive, since the IgM anti-
Cryoglobulins are immunoglobulins which reversibly body (whether monoclonal or polyclonal) binds to the
precipitate at a temperature of 4 °C. Cryoglobulinaemia Fc region of IgG.
is subdivided into three types, based on clonality (see The association of cryoglobulins with viral infec-
. Table 23.5): type 1 arises as a result of an aberrant, tions is well-recognised, with detectable mixed cryo-
usually IgM-producing, plasma cell clone (e.g. in mul- globulinaemia reported in 15–20% of people infected
tiple myeloma or Waldenstrom’s macroglobulinaemia). with HIV and as many as 50% of those infected with
Type 2 comprises monoclonal (usually IgM) bound to hepatitis C (HCV) [9, 10]. In addition to lymphoprolif-
440 D. Gale and M. Owen-Casey
process are likely to be the most effective strategy in had stable function vs 12% of controls) leading to the
preventing renal damage in antibody-associated prolif- recommendation that steroids should be tried in this
erative glomerulonephritis. In patients with MPGN and group [14]. However, there have been no subsequent
no identified cause, median time to end-stage renal dis- RCTs. In the 1980s antiplatelet agents in the form of
ease is around 8 years, with 50% patients needing renal aspirin and dipyridamole were thought to be beneficial,
replacement therapy at 10 years. There is some evidence but this has not been supported by clinical trials and
that extent of interstitial fibrosis, glomerular crescent has not gained widespread acceptance. Antiproliferative
formation and degree of mesangial proliferation pro- agents have been reported to have some success in small
vide prognostic information. Importantly, neither age, observational studies with limited follow-up but have
gender, severity of proteinuria, histomorphological type never been tested in RCTs. In the face of this paucity of
nor even renal function at presentation seems to predict data, the KDIGO guidelines suggest that in idiopathic
renal outcomes. MPGN in the context of frank nephrotic syndrome
The evidence base for any treatment in MPGN and declining function, it is reasonable to give a trial of
where a cause is not identified is extremely limited in corticosteroids and either cyclophosphamide or myco-
part because of its rarity and partly because most stud- phenolate mofetil for no more than 6 months initially.
ies failed to differentiate between the underlying diseases It may be that immunosuppressive therapy ameliorates
causing the MPGN [13]. Alternate day corticosteroids some of the glomerular damage caused by macro-
have been advocated on the basis of small observational phage and neutrophil infiltration in severe disease and
studies. One of the few randomised controlled trials a closely monitored trial of immunosuppressive therapy
(RCTs) investigated the use of steroids in children with in unexplained MPGN where the kidney biopsy shows
MPGN type 1 and showed some evidence of a benefi- substantial glomerular infiltration by immune cells and
23 cial effect of alternate day prednisolone (40 mg/m2) in
those with heavy proteinuria and good function (61%
interstitial fibrosis is not too advanced can often be jus-
tified.
Membranoproliferative Glomerulonephritis and C3 Glomerulopathy
443 23
23.5.6 Recurrence Post-Transplantation
23.5.7 C3 Glomerulopathies
Box 23.1 Causes of dense deposit disease (DDD) DDD is associated with the accumulation of retinal
Causes of DDD deposits (also containing C3) in Bruch’s membrane
C3NeF (80%) (which separates the retinal pigment epithelium from
Homozygous CFH mutations (very rare) the choroid) which manifest clinically as drusen. Visual
Activating C3 mutation (case reports) loss may occur (typically over two to three decades) usu-
ally as a consequence of retinal atrophy and sometimes
Other associations with DDD associated with subretinal neovascular membrane for-
Factor B autoantibodies mation. Consequently, ophthalmological assessment
Complement factor H autoantibodies and review are recommended for patients diagnosed
Monoclonal gammopathy with DDD.
446 D. Gale and M. Owen-Casey
23.5.11 C3 Glomerulonephritis
. Table 23.6 C3 glomerulopathies: clinical and laboratory features. Nephrotic syndrome, NS; C3 nephritic factor, C3NeF
Typical features Proteinuria and renal impairment Variable proteinuria ± Haematuria and renal impairment
haematuria
Other features Haematuria and NS Occasional NS or renal Synpharyngitic macroscopic
impairment haematuria
Inheritance Usually sporadic. Rare familial cases Sporadic Autosomal dominant
reported
Gender distribution More common in females – More severe disease in males
Serum C3 Low Low or normal Normal
Serum C4 Normal or transiently low Normal or transiently low Normal
Autoantibody C3NeF (80%) C3NeF (20–40%) Antibodies absent
Extra-renal manifes- Ocular drusen None reported None reported
tations Partial lipodystrophy
Diagnostic finding Dense transformation of GBM – CFHR5 mutation
Post-transplant Typical, with 50% graft loss at 5 years Variable Universal – But rarely causes graft
recurrence loss
reported in other rare families with C3 glomerulopathy, occurrence of the conditions in the same families and
implying that these proteins can play an important role suggesting that, in nonfamilial cases at least, autoim-
in complement regulation in the kidney. munity (i.e. the generation of a C3NeF) plays the key
An important clinical observation which is shared role in the aetiologies of all these disorders [16]. This
by many disorders of complement alternative pathway contrasts with the monogenic complement regulation
regulation (including DDD, C3GN and aHUS) is that defects (such as CFHR5 nephropathy) in familial cases,
otherwise trivial stimulation of the immune system (for in which a primary defect of the complement system is
instance, by a minor infection) can trigger overt flares of responsible.
disease and significant kidney damage.
23.5.14 Investigation of C3
23.5.13 Genetics of MPGN and C3 Glomerulopathies
Glomerulopathy
Diagnosis of a C3 glomerulopathy (i.e. DDD or C3GN)
Although rare variants in the range of complement in a patient should prompt investigation of alterna-
genes implicated in aHUS have been reported in small, tive pathway regulation. Tests for paraproteinaemia,
uncontrolled cohorts of patients with nonfamilial complement C3, complement C4 and C3 nephritic fac-
C3GN, DDD and immune complex MPGN, convincing tor are widely available and should be performed in all
evidence that the frequency of such variants is increased such patients. In patients with a C3 glomerulopathy
compared with the general population is lacking. In addi- who may have Cypriot ancestry, a genetic test for the
tion, a monogenic cause would be inconsistent with the Cypriot mutation should be performed since CFHR5
usually nonfamilial nature of the disease, the increased nephropathy is common in this population (available at
prevalence of DM1 among relatives of those with DDD the Institute of Child Health in London, 7 http://www.
and of course the presence of a C3NeF in many patients labs. gosh. nhs. uk/laboratory- services/genetics/tests/
with these disorders. A recent genome-wide associa- cfhr5-nephropathy). Additional tests such as serum
tion study identified association of all of DDD, C3GN Complement Factor H and Factor I levels and tests for
and antibody-associated MPGN (including those with autoantibodies against Factor B and Factor H should
and without a documented C3NeF) with a particular be considered if a C3NeF is not identified. Given the
HLA haplotype (incorporating alleles DQA1*05:01, high frequency of rare complement gene variants in
DQB1*02:01 and DRB1*03:01) that is also associated healthy populations (estimated at around 6%), the clini-
with DM1 and coeliac disease, likely explaining the co- cal significance of rare missense variants in these genes
448 D. Gale and M. Owen-Casey
in patients with C3G is not understood, so genetic test- Eculizumab, a humanised monoclonal antibody
ing (including analyses to detect copy number variation) directed against C5, blocks the terminal complement
of CFH, CFHR1-5 and C3 should usually be performed pathway. The drug is effective and licenced for use in
only where there is a family history of the disease. aHUS, but reports of its use in C3G (in very small num-
bers of patients) have shown a mixed response, and this
treatment is not widely used for this indication.
23.5.15 Treatment of C3 Glomerulopathies Recurrence of C3G following transplantation is a
well-recognised complication with estimates of the risk
Although it is generally presumed that blood pres- of graft loss to recurrent disease ranging between 30%
sure control and angiotensin system blockade should and 80%, with the risk likely higher in younger people.
be introduced to delay progression of renal damage, Loss of an allograft to recurrent disease does not guar-
there is currently no proven therapy for DDD, C3GN antee that future transplants will have the same fate,
or CFHR5 nephropathy. Since the diseases are rare but such patients should be regarded as being at higher
and rather slowly progressive, robust clinical trial data risk of subsequent allograft loss and counselled accord-
in humans are lacking. Strategies aimed at supressing ingly. Unlike aHUS, no cases of de novo MPGN or
the immune system (e.g. using steroids or antiprolifera- C3G following living-related kidney donation have been
tive agents such as mycophenolate mofetil) may have described, so there is no clear rationale for genetic test-
some beneficial effects on renal inflammation. Where a ing prior to living donor transplantation in nonfamilial
C3NeF is detected, plasma exchange, immunosuppres- cases.
sion, cytotoxic therapy or B-cell depletion (for instance,
using the chimeric anti-CD20 monoclonal antibody
rituximab) may reduce its levels, but trials have not been 23.6 Summary
published showing a clinical benefit of these approaches.
It is important to recognise that the C3NeF is playing a Activation of complement can lead to kidney damage
different role from that played by circulating antibod- with histological appearances ranging from mild prolif-
ies in most autoimmune diseases – only tiny quantities erative changes to membranoproliferative glomerulone-
of C3NeF are needed to stabilise the C3 convertase and phritis. Complement may be activated via the classical
activate the positive feedback loop of the alternative pathway (as a consequence of antibody-antigen com-
pathway: thus strategies to deplete C3NeF must be very plex formation) or by defects in the regulation of the
efficacious indeed if they are to normalise complement alternative pathway. Excessive complement dysregula-
regulation in the circulation. tion in the circulation is associated with dense deposit
In patients with a genetic cause for C3G (e.g. in indi- disease, whereas complement dysregulation at endothe-
viduals with deficiency of CFH or a CFHR5 lengthen- lial surfaces typically leads to atypical haemolytic urae-
ing mutation), plasma infusion or exchange is sometimes mic syndrome. For reasons which are not yet completely
thought to be beneficial, presumably by removal of the understood, some defects which result in complement
mutant FHR protein or supplementation of missing dysregulation at surfaces can result in C3 glomerulone-
Factor H. Interventions which minimise the frequency phritis instead.
of intercurrent infections (such as tonsillectomy in Treatment of these kidney diseases relies on identifi-
children) have also been reported to provide benefit in cation and correction of the aetiological factor(s). It is
CFHR5 nephropathy, which is consistent with the role hoped that development of novel drugs that allow the
that infection plays in precipitating acute deterioration modulation of complement activity directly may pro-
of renal function in the disease. vide completely new ways to treat these disorders.
Case Study
A 24-year-old woman was found to have abruptly increased treated for rheumatoid arthritis, but there was no addi-
proteinuria (>1.5 g/day) and renal impairment (creatinine tional family history of renal or autoimmune disease that
160) during routine monitoring for her type 1 diabetes mel- she was aware of.
litus, which had been diagnosed aged 5. Blood pressure Investigations showed reduced complement C3 at
was low-normal on an angiotensin 2 receptor blocker, and 0.57 g/L (normal range 0.8–1.6) but normal C4, auto-
blood sugar control using insulin had been excellent for immune and virology screens. A kidney biopsy showed
many years, without previous evidence of diabetic multisegmental glomerular capillary wall thickening
23 nephropathy, retinopathy or other complications. There and wrinkling with marked multisegmental mesan-
was no other past medical history. Her mother had been gial expansion associated with moderate hypercellular-
Membranoproliferative Glomerulonephritis and C3 Glomerulopathy
449 23
ity. Immunostains were negative for immunoglobulins as well as subendothelial and mesangial, electron dense
but showed discrete, variably sized C3-positive granules deposits and a diagnosis of C3G (likely dense deposit
(including ‘hump-like’ structures) on capillary walls and disease), was made. Assays for C3 nephritic factor were
granules within mesangial regions, and electron micros- initially negative, but subsequent immunological testing
copy revealed diabetic-type glomerular basement thicken- over a 6-year period showed the presence of a C3NeF on
ing as well as numerous intramembranous (. Fig. 23.15), 3 out of the 12 occasions it was tested and C3 levels that
varied from just below to just within the normal range.
Proteinuria and serum creatinine fluctuated over this time
period without any trend or correlation with C3/C3NeFs
being appreciable.
This case illustrates (1) the coincidence of C3G with
autoimmune (type 1) diabetes mellitus in the same patient
(2) that it is not always possible to distinguish C3GN and
DDD with complete certainty; (3) the C3NeF assay may
be negative initially, but subsequent assays may reveal its
. Fig. 23.15 C3 glomerulopathy case – electron microscopy
presence, and (4) disease progression may be too slow to be
Electron micrograph showing smudgy electron dense patches detectable, even over prolonged follow-up, in the absence
(arrows) within the glomerular basement membrane of immunomodulatory therapy.
3. Servais A, Fremeaux-Bacchi V, et al. Primary glomerulonephri- 13. Levin A. Management of membranoproliferative glomerulo-
tis with isolated C3 deposits: a new entity which shares com- nephritis: evidence-based recommendations. Kidney Int Suppl.
mon genetic risk factors with haemolytic uraemic syndrome. J 1999;70:S41–6.
Med Genet. 2007;44(3):193–9. 14. Tarshish P, Bernstein J, et al. Treatment of mesangiocapillary
4. Walker PD, Ferrario F, et al. Dense deposit disease is not a glomerulonephritis with alternate-day prednisone--a report of
membranoproliferative glomerulonephritis. Mod Pathol. the International Study of Kidney Disease in Children. Pediatr
2007;20(6):605–16. Nephrol. 1992;6(2):123–30.
5. Abdurrahman MB, Aikhionbare HA, et al. Clinicopathological 15. Servais A, Noël LH, et al. Acquired and genetic complement
features of childhood nephrotic syndrome in northern Nigeria. abnormalities play a critical role in dense deposit disease and
Q J Med. 1990;75(278):563–76. other C3 glomerulopathies. Kidney Int. 2012;82(4):454–64.
6. Covic A, Schiller A, et al. Epidemiology of renal disease in 16. Levine AP, Chan MMY, et al. Large-scale whole-genome
Romania: a 10 year review of two regional renal biopsy data- sequencing reveals the genetic architecture of primary mem-
bases. Nephrol Dial Transplant. 2006;21(2):419–24. branoproliferative GN and C3 glomerulopathy. J Am Soc
7. Hanko JB, Mullan RN, et al. The changing pattern of adult Nephrol. 2020;31(2):365–73.
primary glomerular disease. Nephrol Dial Transplant. 17. Martínez-Barricarte R, Heurich M, et al. Human C3 mutation
2009;24(10):3050–4. reveals a mechanism of dense deposit disease pathogenesis and
8. Woo KT, Chan CM, et al. The changing pattern of primary provides insights into complement activation and regulation. J
glomerulonephritis in Singapore and other countries over the Clin Invest. 2010;120(10):3702–12.
past 3 decades. Clin Nephrol. 2010;74(5):372–83. 18. Gale DP, et al. Identification of a mutation in complement fac-
9. Cicardi M, Cesana B, et al. Prevalence and risk factors for the tor H-related protein 5 in patients of Cypriot origin with glo-
presence of serum cryoglobulins in patients with chronic hepa- merulonephritis. Lancet. 2010;376(9743):794–801.
titis C. J Viral Hepat. 2000;7(2):138–43.
10. Bonnet F, Pineau JJ, et al. Prevalence of cryoglobulinemia and Further Reading
serological markers of autoimmunity in human immunodefi-
Goodship THJ, et al. Atypical hemolytic uremic syndrome and C3
ciency virus infected individuals: a cross-sectional study of 97
glomerulopathy: conclusions from a "Kidney Disease: Improving
patients. J Rheumatol. 2003;30(9):2005–10.
Global Outcomes" (KDIGO) Controversies Conference. Kidney
11. Matignon M, Cacoub P, et al. Clinical and morphologic
Int. 2017;91(3):539–51.
spectrum of renal involvement in patients with mixed cryo-
Sethi S, Fervenza FC. Membranoproliferative glomerulonephritis:
globulinemia without evidence of hepatitis C virus infection.
pathogenetic heterogeneity and proposal for a new classification.
Medicine. 2009;88(6):341–8.
Semin Nephrol. 2011;31(4):341–8.
12. D’Amico G. Renal involvement in hepatitis C infection: cryo-
globulinemic glomerulonephritis. Kidney Int. 1998;54(2):
650–71.
23
451 24
Contents
References – 464
24
IgA Nephropathy and IgA Vasculitis
453 24
extremely uncommon in people of African origin. The 24.2.3 Aetiopathology
cause of this variation is likely to be multifactorial but
may in part simply be due to differences in screening The defining feature of IgAN is mesangial deposition of
policies for asymptomatic urinary abnormalities and IgA. Human IgA exists in two isoforms, IgA1 and IgA2,
variations in biopsy practice [1]. Japan, for instance, has which can each exist as monomers (single molecules) or
an annual school screening program, which may con- polymers (most commonly dimers; two IgA molecules
tribute to higher incidences resulting from a detection of linked by a peptide ‘J-chain’). It is predominantly poly-
cases that may have otherwise been subclinical. meric IgA1 that is found in the mesangium of IgAN
Subclinical IgAN is estimated to occur in 2–3% of patients. IgA1 contains a hinge region, which is rich in
Caucasians but up to 16% of the general Asian popula- serine, proline and threonine residues. These amino
tion [2]. acids can be variably glycosylated giving rise to a range
Patients can present at any age, although incidence of IgA1 O-glycoforms in the serum (. Fig. 24.1).
peaks in the second and third decades. There is a 2:1 Unusual for a serum protein, the IgA1 hinge region car-
male to female predominance in North American and ries O-linked oligosaccharides in addition to the more
Western European populations, which is not observed in commonly seen N-linked sugars which are present on
Asian populations. virtually all serum proteins.
Pro
Val
Pro
A
Ser O GalNAC
Thr
Pro
Pro
Thr O GalNAC Gal B
Pro
Ser
Pro
Ser
O GalNAC Gal Sialic acid C
Thr
Hinge
Pro
region
Pro
IgA1 Thr
Pro
Ser
Pro
O GalNAC Sialic acid D
Ser
Cys
. Fig. 24.1 The IgA1 molecule showing the position of the hinge whether it is the same amino acids for all O-glycoforms of IgA1. The
region O-glycans. Serine (Ser) and threonine (Thr) residues in the IgA1 O-glycans are all based on N-acetylgalactosamine (GalNAC)
hinge region provide nine potential O-linked glycosylation sites; units in O-linkage with serine or threonine (a). GalNAC which may be
although to date only six are known to be occupied by O-glycans. It is extended either with galactose (Gal) alone (b) or with Gal and sialic
still not known which amino acids are occupied by O-glycans and acid (c). Alternatively, the GalNAC may simply carry a sialic acid (d)
454 H. Selvaskandan et al.
Changes in the composition of the O-linked sugars When to Consider Doing a Renal Biopsy
at the IgA1 hinge region are the most consistent finding in Suspected IgAN?
in patients with IgAN across the world, with changes Most clinicians would consider performing a renal
having been seen in patient cohorts from North America, biopsy in the context of normal renal imaging and the
Europe and Asia [3]. The key change is an increase in following:
the serum of IgA1 O-glycoforms that contain less galac-
tose. This increase in poorly galactosylated IgA1 5 Proteinuria >1 g/24 h ± haematuria without impaired
O-glycoforms is believed to play a central role in the renal function
pathogenesis of IgAN. It is believed poorly galactosyl- 5 Impaired renal function with or without haematuria
ated IgA1 O-glycoforms form high-molecular-weight ± proteinuria (any level)
circulating immune complexes, either through self- 5 Acute kidney injury
aggregation or through generation of IgG and IgA
hinge region specific autoantibodies. These high- Occasionally, patients with IgAN develop acute on
molecular-weight immune complexes are prone to chronic renal failure, and a renal biopsy may be neces-
mesangial deposition resulting ultimately in mesangial sary to distinguish acute tubular necrosis (due to red cell
cell proliferation, release of pro-inflammatory media- cast tubular obstruction secondary to massive haematu-
tors and glomerular injury [4]. Why there should be an ria) from a crescentic transformation of IgAN.
increase in the levels of poorly galactosylated IgA1
O-glycoforms in IgAN is currently not known, although Renal Biopsy Features
there is increasing focus on dysregulation of the muco- The hallmark of IgAN is mesangial IgA deposition,
sal immune system as a potential source for these neph- often accompanied by C3 and less frequently IgG and
ritogenic O-glycoforms of IgA1. IgM. Deposition of IgA occurs in a diffuse and global
pattern.
Light microscopy:
24.2.4 Diagnosis
5 May appear normal, even with heavy mesangial IgA
24.2.4.1 General Investigations deposition.
Assessment of renal function, urinary protein excretion 5 Commonly shows mesangial hypercellularity in a
and renal size should be undertaken in all patients under focal or diffuse pattern and matrix expansion
investigation for glomerulonephritis, as should an (. Fig. 24.2).
assessment of cardiovascular risk. 5 Crescentic change may be superimposed on mesan-
Raised serum IgA levels are found in 30–50% of gial hypercellularity.
adult patients with IgAN. Serum IgA levels do not cor- 5 Crescents are more common in biopsies performed
relate with disease activity or severity. Complement during episodes of visible haematuria.
components C3, C4, and CH50 are usually normal.
Serum autoantibodies, IgA-rheumatoid factor and IgA-
containing immune complexes may be found, but none
appear to be disease-specific. Likewise, measurement of
poorly galactosylated IgA1 O-glycoform levels are not
sensitive or specific enough to be used as a diagnostic
test in IgAN although there is emerging evidence that P
high levels of poorly galactosylated IgA1 O-glycoforms
may correlate with a worse prognosis.
Laboratory tests for liver function and hepatitis B M
are sufficient to exclude the most common causes of sec-
ondary IgAN.
24
IgA Nephropathy and IgA Vasculitis
455 24
FP
CL
. Table 24.1 The Oxford Classification of IgA nephropathy. Scoring should be assessed on periodic acid-Schiff-stained sections.
For a precise definition of each parameter, see [7, 9]
5 Mesangial hypercellularity Features that may help distinguish between these dis-
5 Endocapillary hypercellularity orders include:
5 Segmental glomerulosclerosis
5 Tubular atrophy/interstitial fibrosis 5 Episodes of visible haematuria – this may occur in
5 Crescents IgAN or Alport syndrome but is uncommon in thin
basement membrane disease.
The predictive value of these biopsy features is similar in 5 Family history
both adults and children [8]. This classification system – Alport syndrome is associated with a family his-
now forms an integral part of the evaluation of a renal tory of end-stage renal disease and deafness. It is
biopsy in IgAN [9]. most commonly X-linked (80%) but may be auto-
somal recessive (15%) and rarely autosomal domi-
nant (5%).
– Thin basement nephropathy is commonly inher-
24.2.5 Differential Diagnosis ited in an autosomal dominant manner.
– A family history of IgAN is uncommon.
24.2.5.1 Differentiating Between Causes
of Isolated Non-visible Haematuria Differentiation between these three disorders does how-
Urine microscopy in non-visible haematuria due to glo- ever ultimately require a renal biopsy. As the likelihood
merular disease will typically show dysmorphic red cells, of the biopsy altering the clinical management of a
and there may also be red cell casts. Non-visible haema- patient with isolated non-visible haematuria is low,
turia in glomerulonephritis is often also accompanied many nephrologists would elect not to biopsy this
by proteinuria, and there may also be pre-existing evi- patient group. The prognosis for most patients with iso-
dence of renal disease with a reduced GFR and develop- lated non-visible haematuria is good, although patients
ment of hypertension. with IgAN and Alport syndrome may later develop pro-
The three main differential diagnoses of persistent gressive kidney disease, heralded by the development of
isolated non-visible haematuria due to glomerular dis- proteinuria and renal impairment. Therefore, these
ease are: patients require long-term follow-up. Thin basement
membrane disease typically has a more benign course;
1. IgA nephropathy however, patients with a COL4A3 or COL4A4 mutation
2. Alport syndrome will have a disease course similar to patients with hered-
3. Thin basement nephropathy itary nephritis.
24
IgA Nephropathy and IgA Vasculitis
457 24
24.2.5.2 Other Causes of Recurrent Visible 24.2.6 Treatment
Haematuria
Recurrent visible haematuria in the over 40s should Despite advances in the understanding of the pathogen-
always raise the suspicion of a urinary tract malignancy, esis of IgAN, there is still no intervention available to
and it is essential initial investigations exclude this as a prevent production of nephritogenic IgA, its glomerular
cause of the haematuria. In terms of IgA nephropathy, deposition or progression of the disease. Current treat-
visible haematuria classically occurs around 1–3 days ment strategies therefore centre on modulating down-
after an upper respiratory tract infection, whereas in stream immune and inflammatory events and can be
post-streptococcal glomerulonephritis it classically thought of as generic strategies applicable to all chronic
occurs around 2 weeks after streptococcal infection. glomerulonephritides. These generic strategies include:
ESRD. However, data from clinical trials is conflicting, period [22]. However, the high-dose corticosteroid regi-
and larger studies are needed before any conclusion can men used ‘pulsed’ methylprednisolone (1 g daily for
be drawn regarding the role of tonsillectomy in preserv- 3 days at induction and at the beginning of months 2
ing long-term renal function in IgAN [17–19]. and 4), and alternate day prednisolone (0.5 mg/kg) for
6 months is felt by many clinicians to carry unacceptable
24.2.6.3 The Patient with >0.5 g/Day toxicity, although only minor side effects were reported
Proteinuria and Slowly in this study. Additionally, renin-angiotensin blockade
Progressive IgAN was only used in a minority of patients, although usage
The risk of progressive IgAN correlates with the degree was evenly distributed between both treatment groups.
of proteinuria. Patients with less proteinuria have Studies by Manno et al. and Lv et al. evaluated the
improved renal survival, and reducing proteinuria effect of corticosteroids plus renin-angiotensin blockade
improves prognosis, according to registry data [20]. versus renin-angiotensin blockade alone in patients with
There are a number of patients who will continue to preserved renal function (mean eGFR around 100 ml/
have proteinuria in excess of 0.5 g/day and declining min/1.73m2) and proteinuria (>1 g/day) [23, 24]. In the
renal function despite maximal tolerated doses of ACEi study by Manno et al., a combination of an ACEi and
and/or ARB. In these patients, current evidence regard- 6 months oral prednisolone led to fewer patients reach-
ing additional therapy is controversial. The 2012 ing the combined end point of doubling of serum cre-
KDIGO guidelines for management of IgAN state that atinine or ESRD compared to those treated with ACEi
the following should not be offered to treat IgAN: alone. Lv et al. demonstrated a reduction of patients
reaching the primary endpoint of a 50% increase in
5 Tonsillectomy serum creatinine in the combination ACEi and cortico-
5 Mycophenolate mofetil steroid arm compared to ACEi alone (3% versus 24%).
5 Cyclophosphamide These studies have, however, been criticised as they
5 Azathioprine required ACEi and ARBs to be stopped prior to com-
5 Anticoagulation or antiplatelet agents mencement in the trial, and therefore there was a lack of
a suitable run-in period to allow for optimisation of sup-
Mycophenolate mofetil (MMF) has been studied in a portive treatment prior to administration of corticoste-
number of small RCTs, but results have been inconsis- roids. Patients entering into the corticosteroid treatment
tent, and a recent meta-analysis of these trials concluded arm may therefore have benefited from optimised sup-
that there is no significant benefit of MMF in reducing portive care alone. The STOP-IgAN trial was designed
proteinuria in IgAN [21]. There does appear to be a dis- to address this [14]. Patients with persistent proteinuria
parity between the effect of MMF in Caucasian (no >0.75 g/d despite optimised supportive management for
effect) and Asian (some renoprotection reported) IgAN, 6 months were randomised to either continue supportive
and further studies are needed to evaluate this further. therapy or receive additional immunosuppressive ther-
In Asia MMF is often used as a steroid-sparing agent in apy (corticosteroids if eGFR ≥60 mL/min, corticoste-
situations where corticosteroids are planned to be used. roids plus cyclophosphamide/azathioprine if eGFR
Based on low-quality evidence, the 2012 KDIGO <60 ml/min). The STOP-IgAN study demonstrated:
guidelines suggest the following may be considered:
5 A third of patients in the run-in phase with ‘persis-
5 Corticosteroids tent proteinuria’ responded to rigorous application
5 Fish oil of supportive management alone, demonstrating the
value of this strategy.
The KDIGO guidelines for the management of glomer- 5 While corticosteroids induced remission of urine
ulonephritis are currently being reviewed, and new abnormalities in more patients than those receiving
guidelines are expected in 2020–2021. supportive therapy alone (17% vs 5%), this did not
translate into renoprotection as there was no differ-
Corticosteroids ence in eGFR at the end of the study between the
A 6-month course of corticosteroids in patients with groups.
persistent proteinuria >1 g/day despite renin-angiotensin 5 Immunosuppressive therapies were associated with
blockade and preserved renal function (eGFR > 50 more adverse effects, including weight gain and
ml/min) may slow progression of renal decline. infections.
Pozzi et al. showed that treatment of patients with
IgAN with a course of corticosteroids reduced protein- In parallel, results from the TESTING study that com-
uria and prevented progression to ESRD over a 10-year pared methylprednisolone against placebo highlighted
24
IgA Nephropathy and IgA Vasculitis
459 24
the significant side effects associated with immunosup- The Patient with Acute Kidney Injury
pression in IgAN [25]. In this study recruitment was IgAN patients who develop AKI and fail to respond to
halted because of the high levels of opportunistic infec- simple supportive measures should have a renal biopsy
tions in the treatment arm. Intriguingly, there did appear to differentiate between the two most common causes of
to be a renoprotective effect of methylprednisolone, AKI in IgAN:
albeit at a dose that was shown to be toxic. A low-dose
TESTING study is currently recruiting. Acute Tubular Necrosis with Intratubular Erythrocyte
The STOP-IgAN and TESTING studies highlight Casts
the importance of having a full and frank discussion This requires supportive care only. Recovery to baseline
with the patient before embarking on immunomodula- GFR is usual; however, some patients may be left with
tory therapy, particularly corticosteroids. irreversible tubulointerstitial scarring.
Fish Oil Crescentic IgAN
Conflicting data exists regarding the use of prescription Patients with rapidly progressive loss of renal function,
strength fish oil. Fish oil is widely prescribed for IgAN active glomerular inflammation and crescents on renal
in certain centres and appears to be safe, although toler- biopsy and no significant chronic damage may be treated
ability is a major issue due to a fishy odour to the breath in a similar way to other forms of crescentic GN, i.e.
and perspiration and increased flatulence. In one RCT high-dose corticosteroids, cyclophosphamide and
patients randomised to receive fish oil (compared to pla- plasma exchange. Evidence for treatment of crescentic
cebo) had better preservation of renal function over a IgAN is derived from small case series and retrospective
median of 6-year follow-up [26]. However, this finding data [30]. Response to treatment is worse in crescentic
has not been reproduced in other RCTs, and a meta- IgAN than in other forms of crescentic glomerulone-
analysis concluded that the available evidence is incon- phritis, and renal survival is estimated to be only 50% at
clusive [27]. Further studies in this area are required 1 year and 20% at 5 years. This may be the consequence
before a definitive recommendation can be made. of significant pre-existing chronic damage at the time of
a crescentic transformation, thereby reducing the
Experimental and Future Therapies chances of a response to immunosuppression.
There has been a welcome rise in the number of clinical
trials being undertaken to evaluate the safety and effi- 24.2.6.4 The Patient with Nephrotic
cacy of novel and repurposed therapeutic agents in Syndrome
IgAN [28]. Agents currently being evaluated include: Nephrotic syndrome in association with mesangial IgA
deposition may be due to advanced glomerular scarring
5 Mucosal targeted corticosteroid: targeted release as a consequence of longstanding IgAN and therefore
formulation (TRF)-budesonide reflect established CKD or an acute podocyte injury
5 B cell-directed therapies: blisibimod, atacicept, beli- indistinguishable from minimal change disease, occur-
mumab ring in a patient with coincidental IgAN. A renal biopsy
5 Spleen tyrosine kinase inhibition: fostamatinib is clearly the key to distinguishing between these two
5 Complement inhibitors: Lectin pathway (OMS721), extremes, and in particular electron microscopy should
alternative pathway (LNP023), final common path- be performed. Patients with IgAN, nephrotic syndrome,
way (avacopan) minimal glomerular scarring and podocyte effacement
typical of minimal change disease should be treated as
Perhaps the most well advanced of these in 2018 is TRF- minimal change disease [31].
budesonide which was evaluated in the phase 2 NEFI-
GAN trial which investigated the efficacy and safety of
TRF-budesonide in 150 patients with IgAN. Treatment 24.2.7 Follow- up
with TRF-budesonide significantly reduced proteinuria
above that achieved with supportive management and Patients with IgAN and CKD1-3 may be followed up in
reported no statistically significant differences in adverse primary care. On discharge from nephrology services,
effects between the treatment and placebo group. How- clear guidance should be provided to the primary care
ever, the stringency with which supportive measures physician regarding frequency of renal function, urine
were optimised in this study was unclear, as the decline dipstick and blood pressure monitoring. This will be
in eGFR observed in the placebo group was greater than dictated by local guidelines; however, we would suggest
what would otherwise be expected [29]. this should be performed at least annually.
460 H. Selvaskandan et al.
24.3.1 Introduction
24
IgA Nephropathy and IgA Vasculitis
461 24
to occur early in the course of the disease. The long-
term outlook of patients who have transient IgAV is
generally very good. However, up to 10% of patients
with IgAV will develop ESRD [36].
24.3.3 Epidemiology
24.3.4 Aetiopathology
24.3.5 Diagnosis
do not correlate with disease activity or severity. 24.3.8 Special Circumstances in IgAV
Similarly, changes in the levels of poorly galactosylated
IgA1 O-glycoform levels are not sensitive or specific 24.3.8.1 Transplantation
enough to be used as a diagnostic test in IgAV. Renal transplantation is the treatment of choice in
Confirmation of the clinical diagnosis requires histo- patients with ESRD due to IgAV. As with IgAN recur-
logical evidence of IgA deposition in affected tissue, rence of mesangial IgA deposition may occur, while loss
often the skin or kidney. of the graft due to recurrence is less common and tends
to occur in patients who had an aggressive original dis-
Skin Biopsy
ease [43, 44]. Renal transplantation should be delayed
Biopsy of the skin rash typically shows a leukocytoclas- for 12 months from date of presentation.
tic vasculitis. IgA immune complex deposition can be
seen by immunofluorescent staining; however, detection 24.3.8.2 Pregnancy
of IgA is unreliable, and if a tissue diagnosis is required, Evidence from cohort studies of children with IgAV
then a renal biopsy should be performed if there is clear suggest that all women with a history of IgAV should be
evidence of nephritis. carefully monitored during pregnancy, even if they had
no evidence of renal disease at the time of diagnosis as
Renal Biopsy
they are increased risk of developing hypertension and
Renal biopsy is usually reserved for adult cases of diag- proteinuria [45].
nostic uncertainty, or when a child presents with more
severe renal involvement. Histological features are the
same as those for IgAN; however, in IgAV there will also Tips, Tricks and Pitfalls
be extra-renal manifestations of disease [38].
1. IgAN incidence varies geographically and among
races, being most common in those from East Asia.
2. Patients over the age of 40 with persistent hae-
24.3.6 Treatment maturia should be investigated for urinary tract
malignancy.
There is little evidence to guide the treatment of IgAV, 3. Familial IgAN is very rare, and therefore a family
and what is available is derived from small retrospective history of haematuria should trigger investiga-
case series [36]. tion for a type IV collagen disorder (Alport or
Patients with haematuria, proteinuria and mild renal thin membrane disease).
impairment do not require any specific treatment, and 4. IgAN is a slowly progressive disease, and long-
the nephritis usually resolves spontaneously. term follow-up is essential to detect development
In patients with crescentic IgAV, typified by a rap- of hypertension, decline in renal function or devel-
idly progressive loss of renal function, and systemic opment/worsening of proteinuria. Follow-up can
manifestations of small-vessel vasculitis, there is lim- take place in primary care.
ited evidence that high-dose corticosteroids may be 5. The priority for management is to control the
beneficial. Regimes include pulsed methylpredniso- blood pressure and ensure the patient is on maxi-
lone followed by a 3-month course of oral predniso- mally tolerated RAS blockade. The antiprotein-
lone [39, 40]. Although there is some evidence that uric effect of RAS blockade can be enhanced with
mycophenolate mofetil may act as a possible steroid- dietary sodium restriction.
sparing agent [41], there is currently no conclusive evi- 6. Immunosuppressant treatment should only be
dence that other immunosuppressive agents, including considered if the patient has persistent protein-
cyclophosphamide or azathioprine, or other interven- uria>1 g/24 h despite measures outlined in [5] and
tions such as plasmapheresis have any beneficial effect has preserved renal function (eGFR>20 ml/
on outcome. min/1.73m2)
7. There is no evidence for the use of azathioprine,
mycophenolate mofetil or cyclophosphamide in
24.3.7 Follow- up IgAN patients.
8. The evidence for efficacy of corticosteroids is very
Patients should be monitored as for IgAN. As with other weak, while the frequency of adverse events is pre-
forms of glomerular disease, those patients with persis- dictable and high. Any decision to start corticoste-
tent proteinuria are at highest risk of developing pro- roids in IgAN MUST involve a full and frank
gressive CKD [42].
24
IgA Nephropathy and IgA Vasculitis
463 24
discussion with the patient describing the risks and IgAV, it is not a marker of disease activity or
and benefits of such a treatment strategy, accept- severity.
ing that adverse events are much higher when the 10. Most cases of IgAV are self-limiting, and
eGFR is 20–50 ml/min/1,73m2. immunosuppression should be reserved for
9. Although serum immunoglobulin A levels are patients with rapidly deteriorating renal
increased in up to 50% of patients with IgAN function.
Case Study
24
IgA Nephropathy and IgA Vasculitis
465 24
18. Wang Y, Chen J, Wang Y, Chen Y, Wang L, Lv Y. A meta- 31. Lai KN, Lai FM, Ho CP, Chan KW. Corticosteroid therapy in
analysis of the clinical remission rate and long-term efficacy of IgA nephropathy with nephrotic syndrome: a long-term con-
tonsillectomy in patients with IgA nephropathy. Nephrol Dial trolled trial. Clin Nephrol. 1986;26(4):174–80.
Transplant. 2011;26(6):1923–31. 32. Floege J. Recurrent IgA nephropathy after renal transplanta-
19. Feehally J, Coppo R, Troyanov S, Bellur SS, Cattran D, Cook tion. Semin Nephrol. 2004;24(3):287–91.
T, et al. Tonsillectomy in a European cohort of 1,147 patients 33. Clayton P, McDonald S, Chadban S. Steroids and recurrent
with IgA nephropathy. Nephron. 2016;132(1):15–24. IgA nephropathy after kidney transplantation. Am J
20. Reich HN, Troyanov S, Scholey JW, Cattran DC. Remission of Transplant. 2011;11(8):1645–9.
proteinuria improves prognosis in IgA nephropathy. J Am Soc 34. Courtney AE, McNamee PT, Nelson WE, Maxwell AP. Does
Nephrol. 2007;18(12):3177–83. angiotensin blockade influence graft outcome in renal trans-
21. Xu G, Tu W, Jiang D, Xu C. Mycophenolate mofetil treatment plant recipients with IgA nephropathy? Nephrol Dial
for IgA nephropathy: a meta-analysis. Am J Nephrol. Transplant. 2006;21(12):3550–4.
2008;29(5):362–7. 35. Saulsbury FT. Henoch-Schönlein purpura in children. Report
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467 25
ANCA-Associated Systemic
Small-Vessel Vasculitis
Jennifer Scott and Mark A. Little
Contents
References – 486
Yes
No
Histology compatible 2b
Yes with CHCC WG
WG No
No
No
MPA No
No
No
Unclassifiable 5
. Fig. 25.1 EMEA algorithm for pragmatic classification of systemic small-vessel vasculitis. (Adapted from Watts et al. [6])
ANCA-Associated Systemic Small-Vessel Vasculitis
471 25
. Fig. 25.2 Leukocytoclastic skin vasculitis typical of small-vessel vasculitis; in the context of AAV, this would be pauci-immune, differen-
tiating it from Henoch-Schönlein purpura
Granulomatosis + − +
Eosinophilia − − +
Asthma − − +
a b
25
. Fig. 25.4 Indirect immunofluorescence staining of neutrophils staining pattern and (b) anti-proteinase-3 antibody positive GPA,
by antibodies contained within the serum of patients with (a) anti- displaying a c-ANCA-staining pattern
myeloperoxidase antibody-positive MPA displaying a p-ANCA-
Clinical indications
Test finding Potential pitfalls
Glomerulonephritis
Positive In addition to anti-MPO antibodies,
p-ANCA p-ANCA may be observed in the presence of Pulmonary haemorrhage, especially pulmonary-renal syndrome
antibodies to lactoferrin, elastase, cathepsin Cutaneous vasculitis with systemic features
G, catalase, bactericidal permeability
inhibitor, lysozyme and beta-glucuronidase Multiple lung nodules
Positive May be confused with a positive ANA Chronic destructive upper airway disease
p-ANCA
Chronic sinusitis/otitis
Positive Associated with non-vasculitic conditions,
Subglottic tracheal stenosis
p-ANCA e.g. inflammatory bowel disease, cystic
fibrosis, autoimmune hepatitis Mononeuritis multiplex or other peripheral neuropathy
Negative Relatively common with ENT-limited Retro-orbital mass
ANCA with disease; 10% of multisystem disease is also
clinical ANCA-negative Scleritis
vasculitis
Positive Usually indicative of systemic vasculitis but
c-ANCA may be seen in chronic cocaine use with nasal
inflammatory bowel disease, primary sclerosing cholan-
septum destruction
gitis and inflammatory liver diseases) and, most notably,
(4) exposure to certain drugs (e.g. cocaine, hydralazine,
propylthiouracil and minocycline). Therefore, decisions
patients with EGPA [8], and in 20–35% of patients with about treatment should be based on clinical, pathologi-
anti-GBM disease [19], the majority of which are spe- cal and radiological features, in addition to serological
cific for MPO. testing, rather than relying on the ANCA results alone.
False-positive ANCA results can occur in patients Of particular concern is the exclusion of infections
with (1) chronic infection (e.g. tuberculosis, hepatitis C noted above prior to commencement of treatment, due
and infective endocarditis), (2) malignancies (e.g. non- to the harmful consequences of immunosuppression in
Hodgkin lymphoma), (3) gastrointestinal disease (e.g. this cohort.
ANCA-Associated Systemic Small-Vessel Vasculitis
475 25
ANCA + ANCA -
Second Assay
Indirect Immunofluorescence
. Fig. 25.5 Recommended diagnostic algorithm. (Adapted from Bossuyt et al. [17])
25.4.1.3 Renal Biopsy tion therapy. The EULAR recommendations [20] on the
A positive MPO- or PR3-ANCA result, in the context management of AAV suggest that disease severity
of clinical evidence of RPGN with active urinary sedi- should be assessed at diagnosis. This has recently been
ment, provides sufficient evidence to diagnose probable simplified into three categories ‘non-organ-threatening
AAV and initiate treatment in a timely fashion. However, disease’, ‘organ or life-threatening disease’ and ‘rapidly
renal biopsy is the gold standard for diagnosis and is progressive renal failure or pulmonary haemorrhage’.
useful to: Immunosuppression regimens for induction and main-
1. Confirm the diagnosis of pauci-immune focal necro- tenance of remission, in patients with AAV, are depen-
tising glomerulonephritis (i.e. associated with the dent on the degree of disease severity. Refractory disease
paucity of immune deposits on immunofluorescence is defined as progressive disease, unresponsive to initial
and/or electron microscopy). therapy – there are particular management recommen-
2. Establish the activity and extent of glomerulonephri- dations with regard to this disease subgroup (see man-
tis. agement section).
3. Assess the degree of chronic irreversible glomerular, During follow-up it is important that patients’ symp-
interstitial and tubular damage, all of which will toms are attributed correctly to either current disease
influence management with respect to the choice and activity or organ damage in order to guide appropriate
intensity of induction immunosuppressive therapy. treatment. Given the rarity of AAV, patients should ide-
ally receive expert assessment from specialists in dedi-
cated vasculitis centres using standardised assessment
25.5 Classification of Disease Severity tools to assess disease activity and damage, i.e. The
Birmingham Vasculitis Activity Score (BVAS) and the
At presentation, patients should have a clear assessment Vasculitis Damage Index (VDI), respectively. (7 http://
of disease severity in order to guide appropriate induc- golem.ndorms.ox.ac.uk/calculators/bvas.html)
476 J. Scott and M. A. Little
a b
c d
. Fig. 25.6 (a) Focal necrotising glomerulonephritis with bridging focal necrotising glomerulonephritis (×600, PAS); (d) crescentic glo-
interstitial scarring (×200, PAS-silver stain); (b) typical red cell tubu- merulonephritis (×600, PAS)
lar cast with associated inflammatory infiltrate (×200, H&E); (c)
ANCA-Associated Systemic Small-Vessel Vasculitis
477 25
haemorrhage, inflammation of dermal venules in the and worst prognosis associated with the focal and
skin causes palpable purpura and involvement of epi- sclerotic class, respectively [22]. Prognosis of the cres-
neural arteries causes mononeuritis multiplex. The peri- centic and mixed forms varies across studies.
vascular inflammatory infiltrate comprises neutrophils,
macrophages and T cells; an infiltrate composed primar-
ily of eosinophils (‘eosinophilic vasculitis’) is diagnostic 25.7 Pathogenesis
of EGPA.
Patients with GPA and EGPA also display necrotis- The aetiology of AAV is not fully understood. Evidence
ing granulomatous inflammation. This is characterised suggests a complex interaction of polygenic susceptibil-
by zones of tissue necrosis surrounded by a mixed ity, epigenetic influences and environmental triggers. It
inflammatory infiltrate consisting of neutrophils, lym- is considered an autoimmune disease given the specific
phocytes, monocytes, macrophages and multinucleated association with ANCA: autoantibodies directed
giant cells. This inflammatory process causes tissue against enzymes (PR3 and MPO) stored in the granules
destruction in the upper respiratory tract in patients and lysosomes of neutrophils and monocytes.
with GPA, resulting in sinusitis, conductive hearing loss
and nasal deformity due to destruction of the cartilagi-
nous nasal septum. Eosinophils may also be seen in the 25.7.1 Genetic Factors
inflammatory infiltrate in these granulomatous lesions
in both GPA and EGPA but are usually more prominent A genome-wide association study (GWAS) demon-
in the latter. strated a strong genetic association with ANCA subtype
In 2010, the Berden histopathological classifica- (PR3/MPO), rather than the clinical syndrome [23] sug-
tion system [21] was introduced to categorise glomer- gesting that they could potentially be distinct autoim-
ular lesions, in an effort to predict renal prognosis in mune syndromes. There is a tight association between
a standardised fashion. Three categories of glomeru- polymorphisms in the HLA-DPB01 allele, as well as
lar lesions – focal, crescentic and sclerotic – are deter- associations with the serpina1, prtn3 and ptpn22 genes,
mined by the percentage of normal glomeruli, cellular all of which are only seen within the PR3-ANCA-
crescents and globally sclerotic glomeruli, respec- positive cohort [24].
tively. The fourth category, mixed, comprises biopsies
without a predominant glomerular phenotype. Tissue
should be assessed under light microscopy and scored 25.7.2 Environmental Factors
for glomerular lesions in the following order: ≥50%
globally sclerotic, ≥50% normal, ≥50% cellular cres- Epidemiological data supports a strong environmental
cents (. Fig. 25.7). Consensus exists with the best impact, although the exact nature of these triggers is
unknown. Variables include seasonality, latitude (as dis-
cussed in epidemiology), infections and environmental
Worst renal prognosis
dusts (e.g. silica).
³ 50% globally Yes
sclerotic flomeruli Sclerotic class
25.7.2.1 Silica Exposure
No Exposure to silica dust has been associated with sev-
eral autoimmune disorders, including AAV. Case-
³ 50% normal Best renal prognosis control studies suggest that 22–46% of patients with
Yes
glomeruli Focal class AAV have previously been exposed to silica and there
is an association between AAV with jobs such as
No farming, sandblasting, textile work and drilling,
which are associated with high exposure to crystalline
³ 50% crescentic silica dust [25, 26]. Interestingly, there was a signifi-
Yes Crescentic class
glomeruli cant rise in the incidence of AAV in the aftermath of
the Kobe earthquake in 1996, and this has been attrib-
No uted to the release of large quantities of silica and
other industrial dusts.
Mixed class The mechanism by which silica triggers AAV is not
known. It induces apoptosis of neutrophils in a dose-
dependent manner [27], and silica may trigger an
. Fig. 25.7 Histopathological classification. (Adapted from [21]) inflammatory reaction through accelerated apoptosis
478 J. Scott and M. A. Little
of neutrophils and alveolar macrophages. MPO 25.7.3 Role of ANCA in the Pathogenesis
25 released by neutrophils can be taken up by activated of AAV
alveolar macrophages and may be presented to T- and
B-lymphocytes resulting in the development of anti- There is increasing evidence from clinical, in vitro and
MPO antibodies and, hence AAV [28]. in vivo studies that ANCA have a pathogenic role in the
development of AAV. Numerous studies have demon-
25.7.2.2 Bacterial Infections strated that ANCA activate neutrophils inappropriately
Bacterial infections, particularly with Staphylococcus and animal model work has proven that anti-MPO anti-
aureus, have been associated with disease relapse in bodies can cause systemic vasculitis in mice and rats.
GPA. Patients with chronic nasal carriage of S. aureus Perhaps the most convincing evidence comes from a
are more likely to have disease relapses [29], and there is case report describing the development of pulmonary
evidence that maintenance treatment with co- haemorrhage and glomerulonephritis associated with
trimoxazole can reduce the frequency of disease relapse elevated MPO-ANCA titres in a neonate, thought to be
by 60% in patients with GPA and granulomatous inflam- caused by transplacental transfer of IgG MPO-ANCA
mation of the upper respiratory tract [30]. from a mother with active MPA [34].
There is some evidence that patients with PR3- Disease activity correlates well with ANCA titres in
ANCA vasculitis have antibodies to complementary some patients with AAV [35] with some longitudinal
PR3 (cPR3, the peptide translated from the antisense observational studies suggesting that clinical remission
DNA strand of the PR3 gene), as well as to the autoan- is associated with falling ANCA titres, and increasing
tigen PR3, found in the granules of neutrophils [31], ANCA titres predict clinical relapse with a sensitivity
although these findings have not been reproduced in of 79% and a specificity of 68% [28]. This may provide
other studies [32]. Peptides from cPR3 share homology supportive evidence of the pathogenic role of these
with peptides from S. aureus and other infectious patho- antibodies, although much controversy exists in this
gens. It has therefore been proposed that infection with area [28, 36–38]. At present, there is insufficient evi-
S. aureus may induce cPR3 antibodies and, subse- dence to support the use of ANCA titre alone as a
quently, PR3-ANCAs by means of an antibody- guide to therapy but rather as an adjunct to the clinical
idiotypic network [28, 33]. picture. Indeed, some patients can attain full clinical
Additional evidence for the role for infection and remission in the face of persistently elevated ANCA
molecular mimicry with microbial peptides in the levels. Conversely, some patients may have significantly
pathogenesis of AAV comes from the observation that raised ANCA titres, with no clinical disease – this
90% of patients with active focal necrotising glomeru- should trigger close observation for the onset of symp-
lonephritis (FNGN) have intermittent autoantibodies toms. ANCA titres are also useful in assessing possible
to lysosomal membrane protein-2 (LAMP-2). These relapse. Multiple studies demonstrate that disease
antibodies cross-react with FimH, a bacterial adhesin relapse, in patients who are ANCA-positive at diagno-
which shares 100% homology with an epitope of sis, is associated with a persistent or renewed positive
human LAMP-2. Infections with fimbriated patho- ANCA, in 80–100% of cases [39]. This is particularly
gens (e.g. E. coli and K. pneumoniae) may therefore the case in those with capillaritis (i.e. glomerulonephri-
induce production of autoantibodies to LAMP-2 tis or alveolar haemorrhage); the RAVE trial demon-
through molecular mimicry. There are numerous other strated a rise in PR3-ANCA is associated with an
case reports describing a multitude of potential infec- increased risk of relapse in this patient group [40]. In
tious triggers, such as Enterococcus and Epstein-Barr addition, it is widely agreed that PR3-AAV is associ-
virus [9]; however, further evidence is required to ated with a higher rate of relapse [39, 41]. However,
assess causation. ANCA titres must be interpreted in the context of other
clinical, biochemical and histological parameters and
25.7.2.3 Drugs therefore can be viewed as an ‘alert signal’. Therefore,
Several drugs have been associated with the develop- at present, the use of rising ANCA titres to guide treat-
ment of ANCA and subsequent AAV, most notably pro- ment remains experimental [41].
pylthiouracil. Others include hydralazine, There is evidence from randomised trials that plasma
D-penicillamine, minocycline and cocaine. Most of exchange (which removes circulating IgG ANCA) and
these have potent epigenetic effects, which is likely to be rituximab (monoclonal anti-CD20 antibody which
the mechanism by which they increase risk of autoim- depletes peripheral B cells) are effective in treating severe
munity. AAV. Treatment with rituximab is associated with a
ANCA-Associated Systemic Small-Vessel Vasculitis
479 25
decline in ANCA titres, and observational studies sug- 5 Maintenance of remission with lower-intensity
gest that reconstitution of peripheral B cells may pre- immunosuppression to prevent disease flares while
cede clinical relapse. The efficacy of these treatments, minimising adverse effects of the treatment itself
which are targeted at antibody removal, provides indi-
rect evidence of the pathogenic role of ANCA in AAV. Evidence-based management of AAV is summarised in
an algorithm in . Fig. 25.8 [20] and general approaches
described in the following sections. Details of immu-
25.8 Management nosuppressive regimens, which are similar to those
used for anti-GBM disease and SLE, are provided in
Morbidity and mortality is a result of both the destruc- Chaps. 27, 28 and summarised in Chap. 29.
tive, inflammatory disease process itself and of the high-
intensity immunosuppression required to induce and
maintain remission of this disease. AAV, particularly 25.8.1 Induction Therapy
GPA, is characteristically a relapsing disease with each
relapse causing cumulative destructive inflammation Conventional treatment of active AAV with renal
and organ damage. Hence most patients with AAV involvement, aiming to induce disease remission, is
require long-term immunosuppression to maintain comprised of high-dose corticosteroids and cyclophos-
remission, although the optimal duration of treatment phamide (CYC). This regimen induces remission in up
is unknown. to 80% of patients but is associated with significant
Treatment of AAV is divided into two phases: toxicity and infectious complications. Therefore sev-
eral clinical trials have been performed to establish
5 Induction with high-intensity immunosuppression to effective treatment regimens using other immunosup-
induce remission as quickly as possible and avoid pressive agents, with the aim of reducing treatment-
irreversible organ damage related toxicity.
methotrexate or
cyclophosphamide or rituximab
mycophenolate mofetil Consider plasma exchange
with glucocorticoid
with glucocorticoid
Refractory
• Seek expert opinion
Remission • Re-evaluate diagnosis
• Optimise treatment
• Consider other drugs
After 2 years
taper azathiprine or methotrexate
stop rituximab
. Fig. 25.8 EULAR algorithm for disease management. (Adapted from [20])
480 J. Scott and M. A. Little
25.8.1.1 Organ- or Life-Threatening Disease The choice between RTX and CYC is guided by
25 Glucocorticoid AND
the desire to protect fertility, the presence of contra-
indications to CYC, perceived patient frailty or
(a) Cyclophosphamide (CYC) OR injured bone marrow. Those at high risk of adverse
(b) Rituximab (RTX) events may do better not receiving cyclophosphamide,
although clinical trials of rituximab have disappoint-
Patients with AAV presenting with organ- or life- ingly failed to provide robust evidence in favour of
threatening disease should receive induction therapy this presumed safety benefit. The main limitation to
with corticosteroids combined with CYC or RTX [42]. RTX use is cost and therefore access, as well as the
The intensity and duration of induction therapy are unknown long-term efficacy and safety outcomes. It
important factors in determining the risk of subsequent is also important to remember that experience with
relapse. For example, pulsed intravenous (IV) cyclo- RTX alone (i.e. without combined CYC) in severe dis-
phosphamide regimens employ approximately half the ease is limited.
dose of oral regimens (CYCLOPS) [43]; this is associ- Various glucocorticoid dosing schedules exist.
ated with equivalent rates of remission and survival but EULAR recommends 1 mg/kg/day, with maximum of
higher long-term relapse rates [44]. The lower cumula- 80 mg/day [20]. The PEXIVAS trial (Plasma Exchange
tive dose in the CYCLOPS protocol is associated with and Glucocorticoids for Treatment of Anti-neutrophil
reduced rates of infertility, leucopenia and bladder- Cytoplasm Antibody-Associated Vasculitis) [47] recently
related complications. It is probable that most patients revealed preliminary data demonstrating that a reduced
will do well with lower cumulative dose pulsed CYC, glucocorticoid dose (target of 5–7.5 mg by week 16) is
although those at high risk of frequent relapses non-inferior to a ‘standard’ regime (target of 10–15 mg
(anti-PR3-positive and/or large granulomatous disease by week 16), with fewer serious infections.
burden) may benefit from a daily oral induction CYC
regimen. The standard dosing for oral CYC is 2 mg/kg/ 25.8.1.2 Rapidly Progressive Renal Failure or
day (maximum 200 mg/day), and IV CYC is 15 mg/kg Pulmonary Haemorrhage
(maximum 1.2 g/pulse), given three times 2 weeks apart, Patients presenting with dialysis-dependent renal fail-
and then once every 3 weeks for 3–6 months (CYCLOPS). ure, Cr > 500 μmol/L or pulmonary haemorrhage may
CYCAZAREM demonstrated that the majority (77%) benefit from adjunctive therapy in addition to standard
of patients develop remission within 3 months, while treatment with CYC or rituximab and oral corticoste-
almost all (93%) are in remission within 6 months – roids, including:
again supporting the reduced cumulative CYC dose [45].
Dosing adjustments should also incorporate age and 5 High-dose IV methylprednisolone (three daily doses
renal function. Anti-emetic therapy should be a routine at 10–15 mg/kg)
adjuvant to CYC, as well as oral or IV fluids on the day 5 Plasma exchange (60 ml/kg × 7 exchanges)
of infusion to dilute CYC metabolites in the urine, and
hence limit injury to the urothelium [20]. The use of The rationale for plasma exchange and rituximab is par-
MESNA, to reduce bladder complications, is controver- tially based on their antibody-depleting properties,
sial but should be considered. which makes theoretical sense given the evidence for the
RTX has entered guidelines as an alternative first- pathogenic role of circulating ANCA. Very few patients
line treatment to CYC, since the recent publication of with such severe disease were included in trials examin-
two randomised controlled trials. RITUXVAS com- ing the efficacy of rituximab, so most clinicians would
pared CYCLOPS regimen to RTX plus low-dose IV default to use of cyclophosphamide in these settings. In
CYC and GCC, in severe renal disease [42, 46]. RAVE, the RITUXVAS trial (the only such trial to include
on the other hand, compared RTX with PO CYC and patients with severe disease), each dose of rituximab was
GCC [42], in patients with more preserved renal func- accompanied by a dose of intravenous cyclophospha-
tion. Remission rates, degree of renal impairment and mide. The full benefit, however, is clearly due to addi-
adverse events were equivalent between RTX and CYC, tional, more complex mechanisms. The MEPEX trial
except in relapsing disease, where RTX was superior. supported a benefit of plasma exchange over high-dose
Dosing in these trials was 375 mg/m2 weekly for 4 weeks. methylprednisolone [48], although this clear benefit dis-
An alternative regimen is two infusions of 1 g a fortnight appears on long-term follow-up [49]. Of note, the global
apart. The most common side effect of RTX is hypo- PEXIVAS trial (Plasma Exchange and Glucocorticoids
gammaglobulinaemia, which may require IV immuno- for Treatment of Anti-neutrophil Cytoplasm Antibody-
globulin therapy. Associated Vasculitis) [47], has just released preliminary
ANCA-Associated Systemic Small-Vessel Vasculitis
481 25
data. It demonstrated, in severe AAV, that plasma 5 Hepatitis B, annual influenza and 5-yearly pneumo-
exchange does not improve composite end point of coccal vaccination (twice in lifetime) vaccination are
death or end-stage renal disease. There is still potential recommended.
benefit of plasma exchange in patients with combined 5 Gastric protection agent, e.g. proton-pump inhibitor
positive ANCA and anti-glomerular basement mem- (PPI).
brane (GBM) antibodies and therefore should still be 5 Calcium/vitamin D supplementation.
used in this circumstance.
Unlike those with anti-GBM disease, patients pre- These medications should be administered as part of the
senting with dialysis-dependent renal failure often induction therapy regimen in all patients. For female
achieve renal recovery and independence from dialysis patients receiving CYC, who wish to maximise subse-
with appropriate high-intensity immunosuppression. quent fertility, ovarian protection with a GnRH agonist
However, there is a clear need to balance the risk of such as goserelin is employed by some centres, although
treatment-related toxicity with the potential benefit of without strong evidence to support the practice. Simi-
organ recovery; histology on renal biopsy is useful in larly, sperm banking can be used in younger men, if this
assessing this risk/benefit ratio [50]. Severe tubular can be arranged without delaying the induction therapy.
atrophy and a low percentage of normal glomeruli on Guidelines addressing infection prophylaxis varies,
renal biopsy should prompt caution in administering and therefore each clinician should seek out local guid-
high-intensity immunosuppression as treatment for ance. Some guidelines recommend measuring HIV,
renal vasculitis as the risk of treatment-related mor- HBV and syphilis serology (Brazilian Society of
tality likely exceeds the potential benefit in these Rheumatology), as well as tuberculosis screening, before
patients. immunosuppression (British Society for Rheumatology,
BSR). Varicella zoster vaccine, or indeed any live vac-
25.8.1.3 Non-organ-Threatening Disease cine, should not be given while a patient is immunosup-
Methotrexate (MTX) or mycophenolate mofetil pressed, but titres should be measured and
(MMF), in combination with glucocorticoids, is rec- immunoglobulin given if exposure risk is significant
ommended for remission-induction of non-organ- (BSR). Female patients should be considered for cervi-
threatening AAV. MTX may be used with similar cal intraepithelial neoplasia (CIN) screening and HPV
efficacy to CYC in this circumstance. The NORAM vaccination according to age-specific local guidance.
trial [51] demonstrated reduced treatment-related tox-
icity with MTX but higher relapse rates and increased
time to remission, compared to CYC. Patients should 25.8.2 Maintenance Therapy
receive concomitant therapy with folic acid to mini-
mise MTX toxicity. MTX 20–25 mg/week, oral or par- Up to 50% of patients with AAV will relapse despite
enteral, is recommended [20]. Dose adjustments for appropriate high-intensity induction therapy [53].
renal impairment should be made, which often limits Maintenance therapy aims to reduce the risk of disease
its use. relapse while minimising the adverse events associated
Mycophenolate mofetil (MMF) is another alterna- with long-term immunosuppression. Therapy generally
tive to CYC, in non-organ-threatening disease [52], consists of low-dose glucocorticoids with a second
although there is no published trial data to guide its steroid-sparing agent:
use.
5 Azathioprine (2 mg/kg/day)
25.8.1.4 Standard Prophylaxis 5 Methotrexate (0.3 mg/kg/wk increasing to 25 mg
All patients receiving induction immunosuppression for weekly), if tolerated
AAV should receive standard prophylaxis to minimise 5 Mycophenolate mofetil (2 g/day)
infections complications, gastric ulceration and bone 5 Rituximab (500 mg every 6 months)
resorption including:
The optimum duration of maintenance immunosup-
5 Trimethoprim/sulphamethoxazole (Septrin): pression remains unclear. In general, given the relaps-
800/1600 mg alternate days or 400/80 mg daily. ing nature of AAV, it should be continued for at least
5 Systemic antifungal prophylaxis therapy should be 2 years, although some centres stop after 6 months,
considered in patients receiving intense immunosup- and it may be required indefinitely in patients with fre-
pression. Patients should perform daily self- quent relapses. Consideration should be given to
inspection of the mouth to detect mucosal candidiasis extending maintenance to 5 years in patients with high-
early. risk of relapse (. Table 25.5) [54]. The REMAIN trial
482 J. Scott and M. A. Little
investigating the rate of relapse associated with 2- or is crucial to ensure the correct diagnosis has been made,
25 4-year maintenance therapy provided a clear signal of that treatment has been optimised and that infection,
increased relapse with the shorter maintenance therapy comorbidities, malignancy and chronic damage have
duration [55]. been ruled out as potential causes of ‘refractory dis-
Azathioprine (AZA) is now widely used for mainte- ease’. Once confirmed, the alternative to the initial
nance therapy. It is as effective as CYC at maintaining induction regime should be trialled (i.e. if CYC used at
remission and is a less toxic drug (CYCAZAREM) [45]. initial induction, now use RTX) [20]. In cases where
Methotrexate is as effective as azathioprine at main- RTX is not an option and IV pulsed CYC was used ini-
taining disease remission and associated with a similar tially, daily oral CYC can be used [61]. In patients with
rate of adverse events (WEGENT) [56]. It is contraindi- persistent low-level disease activity, who fail to achieve
cated in patients with significant renal impairment and remission, IV immunoglobulin may be of benefit [20].
is therefore more frequently used as maintenance ther-
apy in non-organ-threatening disease.
Mycophenolate mofetil (MMF) has been used in 25.8.4 Relapsed Disease
AAV as maintenance therapy, but data from the
IMPROVE trial [57] suggests it is less effective (as well Due to meticulous follow-up, disease relapse is often
as being much more expensive) than AZA in maintain- diagnosed earlier in the course than the initial disease
ing disease remission. It is recommended as second-line presentation. Major relapses can be treated the same as
maintenance therapy in relapsing disease or patients standard induction treatment. It is worth noting that
intolerant of AZA. RTX was more effecting than CYC in treating relapsed
Rituximab is emerging as an important remission disease in the RAVE trial [42]. One should also be cogni-
maintenance agent, particularly for those with anti-PR3- sant of the CYC cumulative dose, especially if used as
positive disease. The MAINRITSAN trial compared part of the initial induction regime – it should not exceed
low-dose RTX in GPA/MPA to AZA for remission 25 g (and ideally <15 g) [62]. Minor relapses can be
maintenance after induction with pulsed CYC and found treated by increasing the dose of maintenance immuno-
more sustained remission in the RTX arm, with no dif- suppression (i.e. GCC and/or AZA/MTX).
ference in adverse events [58]. MAINRITSAN2 is under-
way in an effort to establish dosing frequency and
indication for treatment guided by ANCA titre or B-cell 25.8.5 Future Therapy
reconstitution. The RITAZAREM trial is also underway
to compare RTX 1 g maintenance with AZA in patients Significant research into optimisation of treatment
who received RTX induction; a preliminary report con- strategy in AAV continues. Specifically, the current focus
firms the effectiveness of rituximab at inducing remis- is on the personalisation of immunosuppression therapy
sion in relapsing AAV [59]. The maintenance component to the individual, in an attempt to maximise disease con-
of this trial has not yet reported. There are concerns trol and minimise toxic complications associated with
regarding repeated use of rituximab, notably progressive treatment. Various strategies are being explored, includ-
hypogammaglobulinaemia and a possible increased risk ing steroid minimisation and the use of avacopan
of progressive multifocal leukoencephalopathy. (CLEAR trial [63]: investigating the use of oral C5a
Patients with GPA with localised upper respiratory receptor inhibitor to replace high-dose glucocorticoids
tract disease should receive trimethoprim/sulpha- in induction therapy) and the use of belimumab as add-
methoxazole (Septrin) in addition to other maintenance on treatment to AZA/MTX and GCC in maintenance
therapy as there is evidence this decreases the frequency therapy (BREVAS trial).
of disease relapse [30]. Treatment guidelines and links to
current active trials are maintained on the EUVAS web-
site (7 http://www.vasculitis.org). 25.8.6 Monitoring and Follow-up
frequent reassessment of the vasculitis activity and Therefore, there is a strong rationale for development of
25 spread of infection. If a suspicion lingers that the epi- regional centres of excellence linked to local units (‘hub
sode of vasculitis was secondary to infection, it may and spoke’ model) at which a patient can attend for a
be possible to carefully withdraw immunosuppression ‘one-stop shop’ assessment with access to a multidisci-
early after the infection has been cured, with very plinary team. This includes:
close monitoring of vasculitis activity. In those who
are overtly septic, intense immunosuppression is likely 5 Ready access to ENT assessment with nasendoscopy
to lead to patient death from overwhelming sepsis. In 5 An infusional therapy unit for administering CYC
these cases intravenous immunoglobulin therapy (with appropriate governance to ensure this is deliv-
(1–2 g/kg) may suppress vasculitis activity without ered safely)
compromising the immune response to the infection. 5 Respiratory team input with ability to provide rapid
RTX has been shown to be safe in the context of access to bronchoscopy
severe infection [65]. 5 Dermatology team input with facilities for diagnos-
tic skin biopsy
5 Ready access to neurology and facilities for sural
25.10 The Vasculitis Unit nerve biopsy
5 Excellent immunology services, with rapid turn-
AAV is a complex multisystem rare disease and conse- around of serological tests
quently falls prey to many of the factors that hamper
care in other rare diseases: The key person in coordinating such a clinical service
efficiently and acting as a first port of call for patients is
5 Lack of awareness among clinicians leading to a the clinical nurse specialist, who, with the assistance of
delay in diagnosis carefully designed algorithmic protocols, would be able
5 Lack of access to the most recently developed thera- to manage immunotherapy, provide initial clinical
pies and diagnostic tools assessments and coordinate multispecialist input.
5 Poorly coordinated care with inadequate communi- Procedures should be in place for recording the amount
cation and integration between the specialties that a and type of immunosuppression delivered to an indi-
patient with vasculitis will encounter vidual patient. This provides the capability to calculate
5 Requirement for the patient to travel to numerous cumulative CYC dose received and to audit the use of
clinics at different times expensive biologic agents. The principal factor in deter-
5 Lack of ancillary support, such as clinical psychol- mining treatment of relapsing vasculitis is the cumula-
ogy and social work tive dose of CYC received previously.
Case Study
A patient presenting with fever, Look very carefully for endocarditis and tuberculosis: multiple blood cultures and echocar-
systemic illness and positive anti-MPO diography
serology
Intensive induction therapy of a patient Once the GFR drops below 15 ml/min, the risk of adverse event risk rises rapidly. If adverse
with dialysis requiring renal failure events start accumulating, pull back on therapy rapidly
Young woman with dialysis requiring Consider using rituximab in place of CYC, but do not compromise on therapy intensity; the
renal vasculitis who wants to maintain priority is to recover renal function
fertility
Very scarred kidney in a patient Early withdrawal of immunosuppression, but beware extra-renal disease
requiring dialysis
Rapidly progressive renal vasculitis with Measure anti-GBM antibodies as well as ANCA, up to 30% of anti-MPO patients are also
lung disease anti-GBM positive. Treat as ‘rapidly progressive renal failure’
ENT clinic Introduce routine urine dipstick testing for patients with sino-nasal disease to pick up
glomerulonephritis in a timely fashion
(continued)
486 J. Scott and M. A. Little
Multidisciplinary clinics AAV affects many organs and patients probably have improved outcomes if cared for in a
clinic setting that attempts to join up various services, such as rheumatology, nephrology,
ENT, clinical psychology and immunology. This may involve running a joint clinic
Pulsed intravenous CYC This is logistically more difficult to deliver than daily oral CYC but has several advantages:
lower cumulative dose with equivalent remission-induction efficacy and improved compli-
ance (you know the patient has received it). It is worth setting up the infrastructure required
Want to use pulsed therapy but Oral pulses (given over 3 days) are probably as effective as intravenous pulses
logistically difficult in a given unit
Dialysis-dependent, when to trans- Consider after 12 months of clinical remission. Persistent ANCA positivity is not a
plant? contraindication
Rising ANCA in an asymptomatic Increase vigilance to look for any evidence of new organ dysfunction; treat the clinical
patient features, not the blood test
37. Kerr GS, Fleisher TA, Hallahan CW, Leavitt RY, Fauci AS, 52. Jones R, Harper L, Ballarin J, Blockmans D, Brogan P,
25 Hoffman GS. Limited prognostic value of changes in antineu-
trophil cytoplasmic antibody titer in patients with Wegener’s
Bruchfeld A. A randomized trial of mycophenolate mofetil
versus cyclophosphamide for remission induction of ANCA-
granulomatosis. Arthritis Rheum. 1993;36(3):365–71. associated vasculitis. Presse Med. 2013;42(4):678–9.
38. Stegeman CA. Anti-neutrophil cytoplasmic antibody (ANCA) 53. de Joode AAE, Sanders JSF, Rutgers A, Stegeman
levels directed against proteinase-3 and myeloperoxidase are CA. Maintenance therapy in antineutrophil cytoplasmic anti-
helpful in predicting disease relapse in ANCA-associated body-associated vasculitis: who needs what and for how long?
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2002;17(12):2077–80. 54. Ntatsaki E, Carruthers D, Chakravarty K, D’Cruz D, Harper
39. Staegeman CA. Anti-neutrophil cytoplasmic antibody (ANCA) L, Jayne D, et al. BSR and BHPR guideline for the manage-
levels directed against proteinase-3 and myeloperoxidase are ment of adults with ANCA-associated vasculitis. Rheumatology
helpful in predicting disease relapse in ANCA-associated (Oxford). 2014;53(12):2306–9.
small-vessel vasculitis. Nephrol Dial Transplant. 55. Karras A, Pagnoux C, Haubitz M, Groot K, Puechal X,
2002;17(12):2077–80. Tervaert JWC, et al. Randomised controlled trial of prolonged
40. Fussner LA, Hummel AM, Schroeder DR, Silva F, Cartin- treatment in the remission phase of ANCA-associated vasculi-
Ceba R, Snyder MR, et al. Factors determining the clinical util- tis. Ann Rheum Dis. 2017;76(10):1662–8.
ity of serial measurements of antineutrophil cytoplasmic 56. Pagnoux C, Mahr A, Hamidou MA, Boffa JJ, Ruivard M,
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489 26
Contents
References – 503
n Learning Objectives
. Table 26.1 Chapel Hill Consensus Conference Nomen-
1. Medium and large-vessel vasculitis typically clature of Vasculitides. (Modified from [1])
present with constitutional symptoms, systemic
26 inflammatory responses and features of vascular Large vessel Giant cell arteritis
insufficiency in the territory of affected vessels.
Takayasu arteritis
There are no validated diagnostic criteria, and
diagnosis is usually made on a combination of Medium vessel Polyarteritis nodosa
clinical, laboratory, histopathological and, increas- Kawasaki disease
ingly, non-invasive imaging findings.
Small ANCA- Microscopic polyangiitis
2. Hypertension and renal insufficiency may arise as vessel associated
a complication of aortic and renal artery involve- Granulomatosis with
polyangiitis
ment, particularly in Takayasu arteritis and polyar-
teritis nodosa. Eosinophilic granulomato-
3. Aneurysm formation and rupture may present with sis with polyangiitis
haematuria, loin pain and life-threatening bleeding Immune-complex Anti-GBM disease
in polyarteritis nodosa. SVV
Cryoglobulinaemic
4. In addition to medical therapy, endovascular or vasculitis
surgical intervention may be required for signifi-
IgA vasculitis
cant steno-occlusive or aneurysmal lesions, includ-
ing those of the renal artery. Hypocomplementaemic
5. Significant glomerular disease is uncommon in urticarial vasculitis
large- and medium-vessel vasculitis and should
Abbreviations: ANCA anti-neutrophil cytoplasm antibody,
alert physicians to the possibility of alternative
SVV small-vessel vasculitis, GBM glomerular basement mem-
diagnoses. brane
Abbreviations: CDU colour Doppler ultrasonography, MRI magnetic resonance imaging, MRA magnetic resonance angiography,
CTA computerised tomography angiography, FDG 18F-fluorodeoxyglucose, PET positron emission tomography
ranges from 18 to 29 per 100,000 people over the age of with endothelial function (e.g. ICAM1, VEGF) and
50, with peak incidence in the 8th decade [5]. Females regulators of innate immunity (e.g. TLR4, MPO) have
are more commonly affected than males, at a ratio of also been described. Reports of seasonal variation in
approximately 3:1. There is particular predilection disease onset and epidemiological associations with
amongst those of Scandinavian ancestry, suggesting a some infections, such as Mycoplasma pneumonia and
genetic predisposition to disease. There has been con- parvovirus B19, suggest that infectious or environmen-
sistent association with the inheritance of class II MHC tal factors may act to incite disease in genetically sus-
molecules, in particular with HLA-DRB1*04 alleles [6]. ceptible individuals, though there is no consistent
Associations with genes encoding cytokines and their evidence of any particular micro-organism as a direct
receptors (e.g. TNF, IFNG, IL6), molecules associated trigger [7].
Renal Involvement in Large- and Medium-Vessel Vasculitis
493 26
. Table 26.3 1990 American College of Rheumatology Classification Criteria for Systemic Vasculitides
Giant cell arteritis [48] Age at disease onset >50 years 3 of 5 93.5 91.2
New headache
Temporal artery abnormality
Elevated ESR
Abnormal artery biopsy
Takayasu arteritis [49] Age at disease onset <40 years 3 of 6 90.5 97.8
Claudication of the extremities
Decreased brachial artery pulse
BP difference < 10 mmHg
Bruit over subclavian arteries or aorta
Arteriogram abnormality
Polyarteritis nodosa [50] Weight loss >4 kg 3 of 10 82.2% 86.6%
Livedo reticularis
Testicular pain or tenderness
Myalgias, weakness or leg tenderness
Mononeuropathy or polyneuropathy
Diastolic BP >90 mmHg
Elevated BUN or creatinine
Hepatitis B virus
Arteriographic abnormality
Biopsy of small or medium-sized artery containing PMN
Abbreviations: ESR erythrocyte sedimentation rate, BP blood pressure, BUN blood urea nitrogen, PMN polymorphonuclear neutro-
phils
aSensitivity and specificity refer to ability to discriminate a given form of vasculitis from patients with other forms of vasculitis, rather
than unselected populations. These criteria are used for classification rather than diagnostic purposes
Prior to the uptake of advanced non-invasive imaging Prompt initiation of therapy in confirmed or suspected
26 techniques, temporal artery biopsy was regarded as an GCA is essential, given that the majority of adverse
essential gold standard for diagnosis of GCA, partic- ischaemic complications, such as visual loss, occur prior
ularly in those with symptoms of cranial arteritis. In to receiving treatment. Corticosteroids have been the
acute disease, focal granulomatous panarteritis, typi- mainstay of treatment for several decades, usually initi-
cally with multinucleate giant cells, intimal hyperpla- ated at high dose (0.75–1 mg/kg.day) for a period of
sia and rarely luminal thrombosis, may be observed. 4 weeks, followed by gradual taper over 1–2 years. The
These lesions may be scattered irregularly (‘skip majority of patients demonstrate prompt resolution of
lesions’) in affected vessels, and thus adequate sam- clinical symptoms and inflammatory response following
pling (segments >1 cm) is required to avoid false-neg- corticosteroid treatment, though it should be noted that
ative results. In the chronic phase of disease, steroid-related adverse events are very common (occur-
inflammatory lesions may evolve to fibrosis with resul- ring in almost 90% of cases [9]) and appear to be related
tant vessel narrowing. to both cumulative exposure and patient age. In addi-
In patients with LV-GCA without symptoms of cra- tion, relapses or steroid dependency is frequently
nial arteritis, temporal artery biopsy is reported to have observed, occurring in 40–60% of patients. In these
lower sensitivity than in patients with cranial manifesta- cases, there is limited evidence to support the use of con-
tions, though a systematic, prospective study of tempo- ventional alternative immunosuppressives such as meth-
ral artery biopsy in LV-GCA has not been conducted. otrexate (or azathioprine where methotrexate is
Given the arterial distribution of vessel involvement in contraindicated or not tolerated) [10].
LV-GCA, targeted tissue sampling is often not possible, A number of biologic therapies have been studied in
and diagnosis relies on the use of appropriate imaging the treatment of GCA [11]. Tocilizumab, an IL6 recep-
methods. tor alpha antagonist, has shown clinical efficacy and a
corticosteroid-sparing effect in a large randomised con-
trol trial [12] and is now licensed for treatment of GCA
26.3.4 Imaging in the USA and Europe. Other biologic therapies under-
going investigation in GCA include ustekinumab (an
Recent EULAR guidelines suggest use of colour IL12/IL23 blocking monoclonal antibody) and abata-
Doppler ultrasound (CDU) of the temporal artery as cept (a selective T-cell co-stimulation blocker). Clinical
the first-line imaging modality in patients with sus- studies have failed to show benefit of anti-TNFα ther-
pected cranial GCA, assuming adequate expertise and apy in GCA.
prompt availability of testing [2]. The typical finding is
of homogenous, hypoechoic, circumferential wall
thickening (the ‘halo’ sign), and vessel stenosis or occlu- 26.3.6 Renal Involvement in GCA
sion may also be seen. High-resolution MRI of the cra-
nial vessels may identify mural inflammation and is an Significant renal involvement is thought to be uncom-
alternative imaging modality where CDU is not readily mon in GCA. A pooled analysis of historical post-
available or inconclusive. In patients where there is high mortem series found that arteritis of the main renal
clinical suspicion of cranial GCA and compatible imag- artery was present in 32% of cases [13], though reports
ing findings, diagnostic temporal artery biopsy may not of clinically apparent renovascular involvement are
be necessary. uncommon [14]. Renal artery involvement has not been
In patients with suspected LV-GCA, a variety of specifically addressed in the more recent imaging studies
imaging modalities may be used to identify mural [15]. These patients usually receive conventional treat-
inflammation or luminal changes in extra-cranial arter- ment as for LV-GCA, and percutaneous revascularisa-
ies, which may support the diagnosis. These include tion may be considered in cases where main renal artery
MRI, CT and FDG-PET (. Table 26.2). CDU may be disease is associated with resistant hypertension or pro-
less useful, given its limited access to the thoracic aorta. gressive renal impairment [16].
Some guidelines recommend baseline CTA or MRA Asymptomatic microscopic haematuria is not
imaging in all patients with newly diagnosed GCA [8], uncommon in GCA, being reported in 33–48% of
given the frequency of aortic involvement, though the patients in retrospective series [17, 18]. The largest of
use of this screening approach has not been evaluated these series reported low rates of concomitant protein-
prospectively. uria, preserved renal function and resolution of
Renal Involvement in Large- and Medium-Vessel Vasculitis
495 26
haematuria in 71% of cases after corticosteroid treat- 26.4.1 Epidemiology and Aetiology
ment. In the small number of cases in whom urinary red
cell morphology was assessed (n = 7), dysmorphic cells Takayasu arteritis was first described in Japanese popu-
were seen in all. However, it is unclear whether the lations, where it currently has an estimated incidence of
microscopic haematuria in these cases was related to one to two per million per year, though it is now recog-
indolent intra-renal vasculitis, glomerulonephritis or nised to occur worldwide. The annual incidence of
other pathology, as renal biopsy was not performed. Takayasu arteritis in the UK, for example, is estimated
In this regard, there are rare case reports and small to be 0.8 per million [27]. It is more common in women
series of severe glomerulonephritis in patients with (80–90% of cases), and age of onset is usually between
GCA [19–22]. Histopathological lesions include fibri- 10 and 40 years, the major epidemiological feature that
noid glomerular necrosis, crescent formation and vas- distinguishes it from GCA. Disease susceptibility and
culitis of the renal arterioles and small arteries, lesions severity are consistently associated with inheritance of
more typical of ANCA-associated small-vessel vasculi- the HLA-B*52:01 allele in populations of multiple eth-
tis. Conversely, temporal artery involvement had been nicities (in contrast to the class II association observed
documented in patients diagnosed with granulomato- in GCA). Additional associations with polymorphisms
sis with polyangiitis [23, 24]. Many of these reports, in other class I HLA genes and genes encoding pro-
however, predate the routine use of ANCA testing, and inflammatory (e.g. IL6, IL12B) and regulatory immune
the pathological lesion of granulomatous vessel wall responses (e.g. LILRB, IL38) have been reported [28].
inflammation may be indistinguishable in the two dis- Of note, polymorphisms in KDM4C (a gene encoding a
eases, so whether these cases of glomerulonephritis histone demethylase involved in the epigenetic control
represent true manifestations of GCA, possible ‘over- of gene expression) were recently associated with sus-
lap’ syndromes, or a casual association of disease enti- ceptibility to a number of large and small-vessel vasculi-
ties, remains unclear. Renal biopsy is recommended in tides, including Takayasu arteritis [29]. A number of
patients with GCA demonstrating persistent urinary putative bacterial and viral infectious triggers have been
abnormalities, and when severe pauci-immune glomer- suggested for Takayasu arteritis, though no
ulonephritis is confirmed, induction treatment with micro-organism has been robustly implicated in disease
cytotoxic therapy in addition to corticosteroids should onset.
be considered, in order to prevent long-term renal
morbidity.
Finally, there are rare reports of AA-type amyloi- 26.4.2 Clinical and Laboratory Features
dosis in GCA, with both renal and systemic involve-
ment. A systematic review identified 11 cases in the Takayasu arteritis tends to have indolent presentation,
literature and suggests that the development of amyloi- and its detection is often delayed, such that stenotic
dosis confers adverse renal outcomes and poor overall vascular abnormalities may be well established at first
survival [25]. diagnosis. Constitutional symptoms are common in the
initial phase. Symptoms of arterial insufficiency will
depend on the territories affected; common manifesta-
26.4 Takayasu Arteritis tions include limb claudication (30–80%); hyperten-
sion, and where the cranial arteries are affected,
Definition headache (50–70%); syncope (4–19%); visual distur-
bance (15–35%); and potentially stroke (3–22%).
Takaysu arteritis is defined as arteritis, often granulo-
Angina and gastro-intestinal and respiratory symp-
matous, predominantly affecting the aorta and/or its
toms may be present when the coronary, mesenteric
major branches, usually with onset in patients younger
and pulmonary vasculatures are involved, respectively.
than 50 years.
Carotidynia (tenderness of the carotid artery) is pres-
ent in up to 30% of cases. Absent or weak peripheral
pulses, discrepant blood pressure measurements and
The disease shares some epidemiological, clinical and vascular bruits may also be evident on clinical exami-
histopathological features with GCA, which has led nation. The presence of an acute phase response may
some authors to suggest that the two conditions repre- support a clinical diagnosis of Takayasu arteritis; how-
sent spectrums of the same disease [26]. There are, how- ever, these tests do not reliably reflect disease activity
ever, important differences, emphasised below, such that and are frequently normal in the presence of active
most regard these diseases as distinct entities. arterial inflammation.
496 S. P. McAdoo
26.4.3 Pathology
As in GCA, corticosteroids are the mainstay of therapy, 26.4.6 Renal Involvement in Takayasu
with a suggested initial prednisolone dosage of Arteritis
0.5–1 mg/kg daily. Relapses and corticosteroid depen-
dence are, however, common, and between 46% and Hypertension is common in Takayasu arteritis (occur-
84% of patients will require a second immunosuppres- ring in >50% of cases), and it may be the initial clinical
sive agent in order to achieve sustained remission with manifestation in a significant proportion. The aetiology
acceptable corticosteroid doses. There are no ran- of hypertension is multifactorial, arising as a complica-
domised trial data regarding the use of conventional tion of aortic or renal artery disease driving hyper-
steroid-sparing agents in Takayasu arteritis, though reninism, carotid baroreceptor hyposensitivity, loss of
uncontrolled studies suggest that methotrexate, azathio- vessel wall elasticity, vascular endothelial dysfunction
Renal Involvement in Large- and Medium-Vessel Vasculitis
497 26
and/or of corticosteroid treatment. Somewhat paradox- keeping with this suggestion, an autopsy-based study of
ically, the diagnosis of hypertension in Takaysu’s arteri- 25 cases found histopathological features of long-
tis may be overlooked in the presence of bilateral standing arterial hypertension or renal ischaemia in all
subclavian artery involvement. Indeed, a recent Chinese [36]. In addition, however, specific features of glomeru-
study found that previously unrecognised hypertension lonephritis were found in 14. The most common pattern
was detected at intraarterial angiography in 16% of such was mild diffuse mesangial proliferative GN, occurring
cases [31]. The same study found that renal artery lesions in ten patients, and this associated with a larger extent
were present in 70% of hypertensive Takayasu patients, of vascular inflammatory cell infiltrate, suggesting a
thoracic aortic lesions in 26%, abdominal aortic lesions possible relationship between these phenomena. The
in 21% and mixed pathology in 26%. frequency of specific glomerular lesions in this report is
In unselected Takayasu arteritis cohorts, renal artery perhaps higher than expected, though it is possible that
involvement remains common, with reported incidences findings in these post-mortem cases are not representa-
between 10% and 60%, and it appears to be more fre- tive of a general Takayasu arteritis population.
quent in Asian populations compared to those of There are case reports of a variety of other primary
European descent [32]. Disease is often ostial and proxi- glomerular disorders, such as IgA nephropathy, crescen-
mal, frequently with co-existent involvement of the peri- tic glomerulonephritis and membranous glomerulone-
renal aorta. Bilateral renal artery involvement may phropathy, occurring in patients with Takayasu arteritis,
occur in approximately 50% of cases. The severity of though these likely reflect coincidental rather than
renal artery stenosis correlates with the frequency of causal relationships. As reported in GCA, cases of sec-
hypertension, and inversely with estimated glomerular ondary AA amyloidosis have been described in patients
filtration rate, somewhat in contrast to atherosclerotic with Takayasu arteritis.
renovascular disease (ARVD).
The optimum treatment for hypertension resistant to
medical therapy secondary to renal artery involvement 26.5 Polyarteritis Nodosa
in Takayasu arteritis is unclear, owing to the rarity of
the disease and a lack of controlled, prospective studies;
data derived from studies in ARVD are likely not appli- Definition
cable, given differences in patient demographics and dis- Polyarteritis nodosa (PAN) is a systemic necrotising
ease pathogenesis. A recent meta-analysis of studies that vasculitis of medium or small arteries without glomer-
compared conventional balloon angioplasty to endovas- ulonephritis or vasculitis in arterioles, capillaries or
cular stenting suggested that these approaches were venules. It is not associated with ANCA.
equally efficacious for improving renovascular hyperten-
sion but that the risk of restenosis was significantly
higher following stenting compared to balloon angio-
plasty [33]. The main limitation of percutaneous It should be noted that historical descriptions of PAN,
approaches includes suboptimal correction of long, prior to the introduction of ANCA testing in the 1990s
irregular, potentially fibrotic lesions and recoiling of and the widespread recognition of microscopic polyan-
ostial lesions. A further meta-analysis of retrospective giitis (MPA) as a distinct clinical entity, may have
observational studies (giving low-moderate quality evi- included a significant proportion of patients with other
dence) suggested that restenosis is less common with vasculitides, and they should be interpreted accordingly.
surgical rather than percutaneous interventions, though
the former carry a higher risk of complications [34]. A
number of surgical approaches have been described, 26.5.1 Epidemiology and Aetiology
including aorto-renal bypass, aortic reimplantation,
arterioplasty and autotransplantation to the iliac vessels The annual incidence of PAN is estimated to be 0–1.6
[35]. In practice, the choice of intervention requires cases per million in European populations [37]. It most
careful consideration of lesion anatomy and risk of commonly presents in middle age, with a peak incidence
complications in individual patients. in the sixth decade. There is a slight male preponder-
Few studies have investigated urinary abnormalities ance. Pan has a well-recognised association with hepati-
or renal histopathology in Takayasu arteritis. In a large tis B, with disease onset typically occurring 4 months
Chinese cohort, the prevalence of proteinuria was esti- after infection [38], and the incidence of PAN is increased
mated to be approximately 9%, which has been attrib- in regions of endemic HBV infection. Loss of function
uted to hypertensive or ischaemic glomerulopathy. In mutations in ADA2, the gene encoding the enzyme ade-
498 S. P. McAdoo
nosine deaminase 2, has been associated with the devel- dilatation (. Fig. 26.3b). In more advanced lesions,
opment of a PAN-like illness, with onset in childhood or vascular remodelling results in intimal hyperplasia and
adolescence [39]. fibrotic changes within the vessel wall.
26 Frequently biopsied sites in clinical practise include
the skin (including subcutaneous fat containing
26.5.2 Clinical and Laboratory Features medium-sized arteries), nerves and muscles, though the
latter may lack diagnostic sensitivity. Renal biopsy may
Patients often present with constitutional inflammatory be considered, though there slightly increased risk of
symptoms, in association with multisystem vascular bleeding due to vessel rupture.
involvement. Cutaneous manifestations such as pur-
pura, erythematous nodules and livedo reticularis are
common (>50%; . Fig. 26.2), along with neuropathy 26.5.4 Imaging
(mononeuritis multiplex or asymmetrical motor and
sensory polyneuropathy; 75%) and gastro-intestinal dis- Selective arteriography is the imaging modality of choice
ease (abdominal pain, rectal bleeding; 40%) [40]. Less for evaluating PAN (. Fig. 26.4). Arterial saccular or
commonly, the central nervous system (20%), heart fusiform microaneurysms (1–5 mm in diameter) are typ-
(10%) or testes (20%) are involved. ically seen, often in association with vascular ectasia,
Laboratory tests may reveal an acute phase response, luminal irregularity, stenosis or occlusion. Non-invasive
and testing for hepatitis infection and serologies associ- angiographic techniques (CTA, MRA) may also be
ated with other forms of vasculitis (ANCA, ANA) used, particularly with continued improvements in
should be undertaken. imaging resolution, and they may have a role in moni-
toring disease progression or response to treatment
while avoiding repeated invasive angiography.
26.5.3 Pathology
a c
. Fig. 26.3 Renal pathology in polyarteritis nodosa. (a) Multiple (c) Circumferential necrotising arteritis and perivascular inflamma-
wedge-shaped cortical infarcts in a post-mortem kidney specimen. tion in an arcuate artery. (Images provided by Professor Terry Cook,
(b) Necrotising arteritis in a large muscular interlobar artery, with Imperial College London)
disruption of external elastic lamina and early aneurysm formation.
One small randomised trial found that relapse rates were may be considered as an adjunct in acute disease to
higher in patients who received 6 versus 12 monthly reduce immunosuppressive burden in patients with
doses of intravenous cyclophosphamide; however this active viraemia [38].
study included a high proportion of patients with micro-
scopic polyangiitis [45]. Remission-maintenance treat-
ment is usually offered for 18–24 months, though the 26.5.6 Renal Involvement in PAN
risk of relapse in PAN appears to be lower than in other
forms of vasculitis; a large retrospective study, for exam- The kidney is the most commonly affected visceral
ple, found that 21.8% of patients relapsed during aver- organ in PAN. Historical and autopsy series report renal
age follow-up of 5.7 years [40]. There are limited data on involvement in up to 75% of cases, though contempora-
the use of biologic therapies such a rituximab or tocili- neous studies report lower frequencies of approximately
zumab in the treatment of PAN. 50% [40], perhaps due to recent changes in classification
The treatment of HBV-associated PAN requires criteria for systemic vasculitides.
both antiviral therapy and immunosuppression directed The renal, interlobar and arcuate arteries may be
to the severity of disease manifestations. Plasmapheresis affected, resulting in cortical ischaemia and infarction
500 S. P. McAdoo
26
. Fig. 26.4 Renal and mesenteric angiography in polyarteritis nodosa, demonstrating multiple arterial microaneurysms, with a predilection
for vessel branching points. (Images provided by Professor Alan Salama, University College London)
Case Study
recurrence of constitutional symptoms, without headache. diagnosis of early-onset hypertension, and multiple atten-
She was found to have an acute phase response and a dances to hospital with abdominal pain in the preceding
nephritic urine sediment. Renal biopsy revealed a focal year, for which no clear cause had been found. Testing for
and segmental pauci-immune necrotising glomerulone- hepatitis viruses was negative. He received treatment with
phritis. Concurrent testing for ANCA demonstrated high- pulsed intravenous cyclophosphamide and oral corticoste-
titre anti-PR3 antibodies. She was treated with rituximab roids for a diagnosis of PAN. This case illustrates the ini-
and corticosteroids, resulting sustained clinical remission tial non-specific features of PAN and the rare occurrence
after 1 year. In retrospect, her initial presentation could be of life-threatening bleeding following aneurysm rupture.
compatible with a diagnosis of granulomatosis with
poylangiitis (GPA) without initial renal involvement (not- Case 3
ing that ANCA were not determined at first presentation); A woman in her early 20s initially presented with head-
alternatively, this patient may have sequential diagnoses of ache, visual disturbance and a raised acute phase response
GCA and GPA. This case illustrates the diagnostic chal- without constitutional symptoms. After initial recovery
lenge in vasculitis, and the utility of kidney biopsy in the her condition flared and was complicated by myocarditis
presence of urinary abnormalities. with significant hypertension. Following supportive treat-
ment, she recovered, only to represent a year later with
Case 2 carotidynia and symptoms suggestive of cerebral ischemia
A 24-year-old male presented to the emergency depart- including transient loss of consciousness and intermittent
ment with acute severe flank pain, followed by an episode visual disturbance. Blood tests revealed a moderate rise in
of syncope. Blood tests revealed a haemoglobin of 59 g/L, ESR and CRP. She was referred to rheumatology where
CRP 157 mg/L, creatinine 92 umol/L. Urgent cross-sec- subsequent imaging revealed Takayasu arteritis with tho-
tional imaging demonstrated a large perinephric haemor- racic aortitis, proximal stenoses affecting the great vessels
rhage (. Fig. 26.5). Subsequent CT angiography and stenosis affecting the proximal coeliac trunk and the
demonstrated multiple small aneurysms in both kidneys, left renal artery resulting in a small ischaemic left kidney
the spleen and the pancreas. Further history revealed a (. Fig. 26.1).
observation of 41 patients. Medicine (Baltimore). tors: a prospective trial comparing glucocorticoids and six or
1995;74(5):238–53. twelve cyclophosphamide pulses in sixty-five patients. Arthritis
39. Navon Elkan P, Pierce SB, Segel R, et al. Mutant adenosine Rheum. 2003;49(1):93–100.
deaminase 2 in a polyarteritis nodosa vasculopathy. N Engl J 46. Briggs JD, Jones E. Renal transplantation for uncommon dis-
26 Med. 2014;370(10):921–31. eases. Scientific Advisory Board of the ERA-EDTA Registry.
40. Pagnoux C, Seror R, Henegar C, et al. Clinical features and European Renal Association-European Dialysis and Transplant
outcomes in 348 patients with polyarteritis nodosa: a system- Association. Nephrol Dial Transplant. 1999;14(3):570–5.
atic retrospective study of patients diagnosed between 1963 and 47. Little MA, Hassan B, Jacques S, et al. Renal transplantation in
2005 and entered into the French Vasculitis Study Group systemic vasculitis: when is it safe? Nephrol Dial Transplant.
Database. Arthritis Rheum. 2010;62(2):616–26. 2009;24(10):3219–25.
41. Ribi C, Cohen P, Pagnoux C, et al. Treatment of polyarteri- 48. Hunder GG, Bloch DA, Michel BA, et al. The American
tis nodosa and microscopic polyangiitis without poor-prog- College of Rheumatology 1990 criteria for the classification of
nosis factors: a prospective randomized study of one giant cell arteritis. Arthritis Rheum. 1990;33(8):1122–8.
hundred twenty-four patients. Arthritis Rheum. 49. Arend WP, Michel BA, Bloch DA, et al. The American College
2010;62(4):1186–97. of Rheumatology 1990 criteria for the classification of
42. Mukhtyar C, Guillevin L, Cid MC, et al. EULAR recommen- Takayasu arteritis. Arthritis Rheum. 1990;33(8):1129–34.
dations for the management of primary small and medium ves- 50. Lightfoot RW Jr, Michel BA, Bloch DA, et al. The American
sel vasculitis. Ann Rheum Dis. 2009;68(3):310–7. College of Rheumatology 1990 criteria for the classification of
43. de Groot K, Harper L, Jayne DR, et al. Pulse versus daily oral polyarteritis nodosa. Arthritis Rheum. 1990;33(8):1088–93.
cyclophosphamide for induction of remission in antineutrophil
cytoplasmic antibody-associated vasculitis: a randomized trial. Resources and Patient Information
Ann Intern Med. 2009;150(10):670–80.
Vasculitis UK: http://www.vasculitis.org.uk/.
44. Jayne D, Rasmussen N, Andrassy K, et al. A randomized trial
United Kingdom and Ireland Vasculitis Registry: https://research.
of maintenance therapy for vasculitis associated with antineu-
ndorms.ox.ac.uk/ukivas/.
trophil cytoplasmic autoantibodies. N Engl J Med.
Vasculitis Foundation: https://www.vasculitisfoundation.org/.
2003;349(1):36–44.
Vasculitis Clinical Research Consortium: https://www.
45. Guillevin L, Cohen P, Mahr A, et al. Treatment of polyarteritis
rarediseasesnetwork.org/cms/vcrc.
nodosa and microscopic polyangiitis with poor prognosis fac-
505 27
Goodpasture’s or
Anti-glomerular Basement
Membrane (GBM) Disease
Alan D. Salama
Contents
References – 513
Glomerular tuft
Crescent
these data based on the outcomes reported from institu- with creatinine >500 μmol/l
tions with significant experience in the management of
such patients. Clearly, novel treatments may be of equal
benefit, but there have been no formal trials comparing
intravenous pulsed cyclophosphamide, rituximab ciclo- short (1-year)- and long (20-year)-term renal outcome
sporin A or mycophenolate mofetil. However, there are following immunosuppressive therapy [2] and should be
anecdotal reports of all of these agents being used with treated with standard therapy or modified regimens if
variable outcomes [18–22], but these have tended to be contraindications to standard therapy are found. Recent
used in patients in whom cyclophosphamide has failed outcomes from a national analysis in Ireland demon-
or has led to complications, and so they cannot be rec- strate overall higher rates of ANCA co-positivity and
ommended as first-line therapies. Ongoing trials with poorer recovery of renal function with over 70% of
IgG-cleaving enzymes (IdeS) that attenuate IgG effector patients reaching ESRD [23]. Similar poor outcomes
functions are ongoing and could provide alternative or were reported in retrospective cohort analysis in the UK
adjunctive therapeutic approaches in the future. [24, 25], with up to 84% dialysis dependency at 1 year
and less than 5% of those dialysis-dependent at presen-
tation achieving independent renal function at long-
27.7 Outcomes term follow up, while the best clinical predictor of poor
outcome was found to be oligoanuria (<500mls/day) on
Retrospective cohort studies have confirmed that renal the day of diagnosis [24], again emphasising the need for
outcome is dependent on the severity of the renal dam- early diagnosis.
age at presentation, with those patients with greater
severity of glomerular disease (based on the crescent
score) and worse renal function having the highest 27.8 When Not to Treat?
degree of end-stage renal failure at 1 year despite immu-
nosuppressive therapy [2] (see . Table 27.3). All series Since data demonstrate that patients presenting with
demonstrate that patients with serum creatinine levels dialysis dependency and 100% crescents, i.e. crescents
greater than 600 mcmol/l had the worst outcome with in all glomeruli on the section, do not tend to recover
regard to renal survival at 1 year. In the largest series independent renal function, if diagnosis is delayed and
reported by Levy [2], those with presenting creatinine patients are already dialysis-dependent with extensive
>500 mcmol/l and requiring dialysis at presentation crescentic change on biopsy, many practitioners would
fared the worst with few regaining independent renal not treat with immunosuppression unless there was
function (see . Table 27.3), despite treatment. Those coexistent pulmonary haemorrhage. However, there
with creatinine >500 mcmol/l but not requiring immedi- are patients who do not present requiring dialysis but
ate (within 72 hours of presentation) dialysis had bet- develop dialysis dependency in the early hospitalisa-
ter renal outcomes than those who required immediate tion period. These may well benefit from immunosup-
dialysis upon presentation. Finally, those patients with pression, and the decision should be made based on a
less severe glomerular damage and better preserved balanced assessment of the individual risk of immuno-
renal function(creatinine <500 mcmol/l) have excellent suppression.
Goodpasture’s or Anti-glomerular Basement Membrane (GBM) Disease
511 27
In some circumstances, such as those patients with a 29]. If recurrence does occur, augmented immunosup-
living kidney donor, even with dialysis dependency and pressive treatment may be used but is successful in only
100% crescents, treatment may be warranted to allow a minority of cases [29].
more rapid elimination of anti-GBM antibodies and
early transplantation. In the absence of immunosup-
pressive therapy, anti-GBM antibodies may persist for 27.10 Anti-GBM Disease in Alport’s Disease
up to 3 years [26]. Following Transplantation
Alport’s disease arises from mutations in the type IV
27.9 Transplantation collagen chains found in the glomerular basement mem-
brane, which is the α5 (IV) chain in the X-linked form of
Early experience of transplantation in the face of posi- disease. Following transplantation of a kidney contain-
tive anti-GBM antibodies resulted in rapid disease ing a normal α5(IV) chain, an alloimmune response to
recurrence [27]. It is therefore essential that transplan- the collagen IV chain can arise and lead to development
tation is deferred until there has been a prolonged of anti-GBM antibodies. While this can be found in up
period of anti-GBM antibody negativity, and using this to 20% of patients, only 5–6% go on to develop a cres-
approach recurrence is rare [8]. Although there are no centic glomerulonephritis which tends to be extremely
trial data to guide this period of time, we and others difficult to treat, even with augmented immunosuppres-
wait 6 months from the time of first antibody negativ- sion [30]. Once this anti-collagen response has devel-
ity, before proceeding. Persistent low-level anti-GBM oped, subsequent transplantation is increasingly likely
antibody has been removed prior to transplantation by to result in disease recurrence.
immunoadsorption, with those patients who could not While monitoring Alport’s patients who have under-
have antibody successfully removed not undergoing gone renal transplantation, it is important to realise
transplantation [26]. Cases of late anti-GBM disease that many anti-GBM assays are now using recombinant
recurrence following cessation of transplant mainte- α3 (IV) and not whole GBM as a substrate. They will
nance immunosuppressive therapy or following viral therefore not detect anti-α5 (IV) antibodies, to which the
infection have been reported, but are uncommon [28, transplanted X-linked Alport’s patient will react to [31].
Case Studies
800
Prednisolone
700
Cyclophosphamide
600
27 PEx
500
400
Anti-GBM titre (AU)
400
300
200
100
Normal Range 0
0 50 100 150
Time/days
. Fig. 27.3 Changes in anti-GBM titre with treatment of patient 1, demonstrating rapid decline in autoantibody titre with plasma
exchange and ongoing immunosuppression
collagen alloantibodies in X-linked Alport syndrome. Nephrol retrospective study of 14 cases]. Ann Med Interne (Paris) 1990;
Dial Transplant. 1996;11(10):1983–8. 141(5): 409–15.
32. Daly C, Conlon PJ, Medwar W, Walshe JJ. Characteristics and
outcome of anti-glomerular basement membrane disease: a Patient Information and Guidelines
single-center experience. Ren Fail. 1996;18(1):105–12.
Rare Renal UK; see http://rarerenal.org/clinician-information/
33. Bouget J, Le Pogamp P, Perrier G, et al. [Anti-basement-
vasculitis-clinician-information/
membrane antibody mediated, rapidly progressive, glomeru-
27 lonephritis. Diagnostic and therapeutic strategy based on a
UKIVAS: http://www.vasculitis.org.uk/about-vasculitis/anti-gbm-
goodpastures-disease
515 28
Contents
References – 529
28.1 Systemic Lupus Erythematosus baseline (see 7 Cases 28.1 and 28.2). About 50% of
patients will present with a reduction in glomerular fil-
n Learning Aims tration rate (GFR) and occasionally with acute kidney
1. SLE is a chronic multi-system disease that fre- injury (AKI).
quently affects the kidney.
2. Immunosuppressive treatment is required to pre-
vent the progression of end-stage renal disease 28.1.3 Epidemiology
(ESRD).
28 3. SLE is a major cardiovascular risk factor. The majority of individuals affected by SLE are women
4. Fertility, pregnancy and contraception require spe- of child-bearing age, although diagnosis is often after
cific management in women with SLE. the age of 40 in Europeans [1]. The prevalence ranges
from 20 to 150 cases per 100,000 population, with the
highest prevalence reported in Brazil. In the United
28.1.1 Introduction Kingdom, the prevalence is almost 1 in 1000, with a
female predominance of 9:1 [1]. Numbers appear to be
Systemic lupus erythematosus (SLE) is a chronic multi- increasing, as the disease is recognised more readily and
system autoimmune disorder. Kidney involvement is as survival increases. SLE is more common in people of
common and is a major contributor to disease morbid- African, Hispanic or Asian ancestry, who also experi-
ity and mortality. At presentation, up to 50% of patients ence greater organ involvement. The 10-year survival is
with SLE will have clinical evidence of renal involve- ~70%, with the major causes of death being infection,
ment with haematuria, with or without proteinuria. cardiovascular disease and cancer. In the United
Renal excretory function is often normal. During fol- Kingdom, approximately one-third of patients develop
low-up, renal involvement will be evident in >60%, with lupus nephritis, which tends to occur early (within the
an even greater representation amongst children and first 3 years following diagnosis) [2, 3]. Current treat-
young adults. ments have improved the 5-year renal survival to
50–95%.
Definition
Lupus nephritis is an inflammation of the kidneys
caused by SLE. It most commonly affects the glomer- 28.1.4 Aetiopathology
uli, but can also affect the tubulointerstitium and vas-
culature. SLE is characterised by polyclonal B-cell activation and
the presence of autoantibodies, particularly directed
against nuclear components, leading to inflammation in
multiple body systems. The aetiology of SLE is unclear,
but it is likely multifactorial, incorporating several envi-
28.1.2 Clinical Features ronmental, genetic, hormonal and immunoregulatory
factors. Generation of autoantibodies and subsequent
In general, the identification of lupus nephritis follows tissue deposition of immune complexes – some passively
on from the diagnosis of SLE. Symptoms of SLE trapped in the glomeruli and others attached to glomer-
include alopecia, arthralgia, epilepsy, haematological ular structures – lead to glomerulonephritis. Subsequent
abnormalities (anaemia, lymphopenia, thrombocytope- complement fixation initiates an inflammatory and
nia), mouth ulcers, skin rash (discoid, malar or photo- cytotoxic reaction. The autoantibodies may themselves
sensitive rashes), serositis and Raynaud’s phenomenon. be cytotoxic.
Hypertension is also often present. However, lupus Renal lupus can manifest in several different ways,
nephritis should be considered in any multi-system dis- which may exist concurrently. These include glomerulo-
ease (particularly in young females) with unexplained nephritis, vasculopathy and tubulointerstitial disease (see
haematuria and proteinuria. . Table 28.1).
All patients with known SLE should undergo regular
urinalysis for haematuria and proteinuria to allow early 28.1.4.1 Glomerular Disease
detection of lupus nephritis, which is usually clinically The pattern of injury in lupus glomerulonephritis
silent. Proteinuria can be quantified using a spot protein- reflects the glomerular compartments in which immune
to-creatinine ratio or an albumin-to-creatinine ratio. deposits accumulate. Immunofluorescence labelling of
Serum creatinine is frequently within the normal range renal biopsies reveals that the deposited immunoglobu-
at presentation, even in the presence of significant lins are of multiple classes and that they activate the
inflammatory disease, but may be elevated compared to classical pathway of complement activation, with C1q
Systemic Lupus Erythematosus, Antiphospholipid Syndrome and the Kidney
517 28
5 Vascular immune complex deposits in the intima and
. Table 28.1 ISN/RPS histological classification of lupus
nephritis
media of small arteries and arterioles: common and
without prognostic significance [6].
Class I Normal glomeruli by light microscopy but 5 Non-inflammatory necrotising vasculopathy (lupus
mesangial immune deposits on immunofluores- vasculopathy): intimal and luminal mixed immune
cence deposits, fibrin and other plasma proteins; uncom-
Class II Purely mesangial hypercellularity of any degree mon but associated with class IV nephritis and a
or mesangial expansion by light microscopy, poor prognosis [7].
with mesangial immune deposits 5 Thrombotic microangiopathy: may be seen indepen-
Class III Focal proliferative lupus glomerulonephritis dently of lupus glomerular disease, especially in
<50% glomeruli affected those with the antiphospholipid syndrome; variable
Class IV Diffuse proliferative lupus glomerulonephritis
prognosis [8].
>50% glomeruli affected 5 Renal vasculitis: inflammatory destructive vasculitis
Disease may be segmental (IV-S or global IV-G) often with fibrin deposits; this is rare and not well
Class V Membranous lupus glomerulonephritis
characterised [9].
5 Renal vein thrombosis: more common in the presence
Class VI Advanced sclerotic lupus glomerulonephritis of the nephrotic and antiphospholipid syndromes.
>90% glomeruli globally sclerosed with no
disease activity
rituximab arm than in the placebo, there were no differ- MAINTAIN trial, which looked at 105 patients with
ences in the primary clinical endpoint at 1 year [31]. class III (31%), class IV (58%) and class V (10%) lupus
Although the data currently available do not support the nephritis and followed them up for 3 years [38]. Here,
routine use of rituximab in lupus nephritis, this may be induction was with intravenous CYC with patients ran-
down to trial design – with rituximab added to standard domised to azathioprine (mean maximum daily dose
therapy in reasonably small numbers of patients with a 124 mg) or MMF (mean maximum daily dose 2 g). The
short follow-up period. Anecdotally, the early use of rates of all primary and secondary endpoints, including
rituximab has also allowed a reduction in corticosteroid remission, steroid withdrawal and disease flares, were
28 use [32]. However, a randomised clinical trial equal amongst the two groups. In contrast to this, the
(RITUXILUP) comparing induction with rituximab ALMS study published in 2011 showed MMF to be
2 × 1 g, a single dose of 500 mg methylprednisolone and superior to azathioprine in terms of renal benefits [39].
MMF 2 g/daily with a standard induction regimen of This may be due to differences in racial contribution
MMF 3 g/daily plus tapering oral corticosteroids 0.5 mg/ (MAINTAIN involved only Europeans, whereas ALMS
kg/day was terminated early due to difficulties recruiting a mixture of patients, some of whom were non-
patients not already on maintenance steroids. Thus, Caucasians, who may be more likely to respond to
rituximab may well have a role in treating resistant MMF) and the larger size of the ALMS study.
patients, in preventing flares or in reducing the number Nevertheless, azathioprine in doses of 1–2.5 mg/kg/day
of doses of other immunosuppressive medications, but is safe over a long period of time [40]. Macrocytosis, leu-
further studies are required. copenia and interactions with allopurinol are all poten-
Overall, there remains significant uncertainty about tial side effects, alongside the obvious risk of infection
the most effective treatments for lupus nephritis, partic- with all immunosuppressive agents. Furthermore, aza-
ularly due to heterogeneity in treatment regimens, and thioprine has only a small oncogenic potential, and
the small number of clinical trials. pregnancy during maintenance azathioprine is relatively
safe. Although MMF has a similar long-term toxicity
28.1.6.5 Maintenance Therapy profile, it should not be used during pregnancy, which is
for Proliferative Lupus Nephritis a major consideration given that many patients with
Once remission has been achieved, the longer-term goals lupus nephritis are women of child-bearing age. MMF
of maintenance therapy are: should also be avoided during breastfeeding. Our prac-
5 To prevent disease flares tice is to routinely use MMF as maintenance therapy
5 To avoid smouldering disease activity that may result unless pregnancy is planned in the short term. We would
in irreversible renal damage then electively switch to azathioprine as part of pre-
5 To prevent long-term side effects of treatment conception planning.
28.1.7 Cardiovascular Risk strated similar pregnancy outcomes to the general popu-
lation, albeit few of the women included had significant
SLE is one of the strongest known risk factors for car- renal involvement [57].
diovascular disease (CVD), which is one of the leading There are a number of factors to consider when a
causes of death in patients with lupus [52]. The risk of patient with SLE wants to have a baby. Pregnancy in
a woman under the age of 45 with SLE developing ath- women with lupus nephritis is associated with an
erosclerosis, even in the absence of renal involvement, increased risk of foetal loss and with worsening of the
is 50-fold greater than that of an age-matched control. renal and extra-renal manifestations of SLE. Pre-
28 A number of traditional and non-traditional risk fac- eclampsia is also a frequent complication of pregnancy
tors contribute. Hypertension, impaired glucose toler- in SLE, and differentiating between pre-eclampsia and
ance and altered lipid profiles are common and active disease can be extremely difficult. Maternal SLE
exacerbated by chronic corticosteroid use. CVD bur- is also associated with an increased risk of premature
den is also significantly increased in patients with delivery and intrauterine growth restriction. There may
chronic inflammatory conditions. The development be an increased risk of learning disabilities in the off-
and progression of CKD further increase CVD risk. spring, especially in males.
Thus, alongside immunosuppressive treatment of the The prognosis for both mother and child is best
nephritis, CVD risk should be assessed and treated when the disease, including renal disease, has been
aggressively in all patients with SLE, with or without quiescent for at least 6 months prior to the pregnancy.
nephritis. We would recommend a pre-pregnancy renal biopsy
We recommend all patients with SLE (both with and to confirm histological disease activity. If the patient
without nephritis) be treated with an angiotensin- is prescribed maintenance therapy, this should be con-
converting enzyme (ACE) inhibitor or an angiotensin verted to azathioprine with or without corticoste-
receptor blocker. These agents are first line for achiev- roids. Hydroxychloroquine should be continued
ing optimum blood pressure (BP) control in proteinuric during pregnancy to reduce the risk of flares, poten-
CKD. They reduce intra-glomerular pressure, lower tially improve placental function and reduce the risk
systemic BP, reduce proteinuria and delay CKD pro- of complete heart block in babies born to mothers
gression. Emerging data suggest that ACE inhibitors with anti-Ro antibodies [58]. Accordingly, all women
may also delay the development of renal involvement in with anti-Ro and anti-La antibodies should be offered
SLE [53]. In this study, the use of ACE inhibitors was foetal echocardiography from approximately
also associated with a decreased risk of disease activity. 16 weeks’ gestation [59]. Thrombotic risk should be
The use of hydroxychloroquine is also recommended as assessed, and thrombotic prophylaxis with low-
it improves lipid profiles and inhibits platelet aggrega- molecular-weight heparin offered to those with
tion [54]. antiphospholipid syndrome and/or significant pro-
teinuria [55]. All women should be offered low-dose
aspirin from 12 weeks to reduce the risk of pre-
28.1.8 Pregnancy and Reproductive Health eclampsia and may benefit from this being started
pre-conception [59]. Breastfeeding is feasible for most
Fertility may be affected by SLE. The major cause of women with SLE, and steroids, azathioprine, enala-
infertility is CYC-associated premature ovarian failure, pril, amlodipine and aspirin may all be used safely
and so pre-treatment fertility preservation should be during lactation [55].
considered in all pre-menopausal women prior to CYC Effective contraception and appropriate contracep-
use. Ovarian stimulation to preserve oocytes is contro- tive counselling should be offered to all pre-menopausal
versial due to the risk of thrombosis and/or disease flare women with SLE. Oestrogen-containing hormonal con-
[55]. Some evidence exists, mainly in cancer patients traceptives are usually avoided, due to the risk of hyper-
receiving CYC, for the use of LH-releasing hormone tension, thrombosis and disease flares. However, a
analogues that work by inhibiting ovarian function dur- number of progesterone-based methods are suitable,
ing CYC treatment [56]. In vitro fertilisation can be used including the progesterone-only pill, Mirena IUD and
in patients with SLE, and a recent study has demon- subdermal implant.
Systemic Lupus Erythematosus, Antiphospholipid Syndrome and the Kidney
523 28
28.1.9 Case Studies Arterial thrombosis occurs most frequently in the cen-
tral nervous system, usually in the form of a stroke or
Tips and Tricks transient ischaemic attack. Less common presentations
include venous sinus thrombosis, myelopathy, chorea,
1. Consider lupus nephritis in any patient, particu- migraine and epilepsy.
larly young women, with multi-system disease and Anticardiolipin antibodies are also associated with
haematuria and/or proteinuria. cognitive impairment in SLE. Considerable interest, and
2. Ensure all patients with SLE have regular urinaly- controversy, has focused on the relationship between
sis and checks of renal function and blood pres- APLS and cognitive impairment. Cognitive deficits
sure. range from subtle findings to transient global amnesia
3. Lupus nephritis is unlikely in the absence of hypo- to permanent and profound cognitive impairment. The
complementaemia. cognitive deficits reported in APLS are sometimes but
4. Immune complex deposition in multiple compart- not always associated with white matter lesions.
ments within the kidney is characteristic of lupus Other clinical manifestations of the APLS include
nephritis. cardiac valvular disease – the mitral valve is more com-
5. Pregnancy outcomes in lupus are best with careful monly affected than the aortic; regurgitation more com-
pre-conception planning. mon than stenosis. Renal involvement in the APLS has
6. Ensure all women of reproductive age are using only been described relatively recently [60]. Thrombotic
appropriate contraception. microangiopathy is the commonest feature of APLS
nephropathy, but other histological findings include
fibrous intimal hyperplasia and focal cortical atrophy. A
28.2 Antiphospholipid Syndrome (APLS) typical presentation of APLS nephropathy is hyperten-
sion with (often sub-nephrotic range) proteinuria and
28.2.1 Introduction renal insufficiency. Other clinical features of the APLS
include haemolytic anaemia, thrombocytopenia, skin
Antiphospholipid syndrome is a unique form of involvement with livedo reticularis – present in ~25% of
autoantibody-induced thrombophilia, characterised patients with APLS and a marker of patients at risk of
by recurrent (arterial and venous) thrombosis and arterial thrombosis – avascular bone necrosis and adre-
pregnancy complications. The syndrome arises due to nal insufficiency. Obstetric complications of the APLS
endothelial cell, monocyte and platelet activation by include recurrent miscarriage, foetal death, severe pre-
antiphospholipid antibodies with anti-β2-glycoprotein eclampsia and placental insufficiency.
1 activity. Endothelial cells then express a number of Clinically, the most severe, but fortunately the most
adhesion molecules and together with monocytes infrequent, form of the syndrome is catastrophic APLS
upregulate the production of tissue factor. Activation characterised by widespread small vessel thrombosis
of platelets results in an increase in their expression with multi-organ failure. Catastrophic APLS is associ-
of glycoprotein 2b-3a and synthesis of thromboxane ated with a >50% mortality.
A2. Endothelial cell, monocyte and platelet activa-
tion results in a prothrombotic state and, alongside
complement activation, provokes thrombosis. This 28.2.3 Epidemiology
usually occurs in the presence of a second hit such as
infection or surgery. Traditional cardiovascular risk About 40% of patients with SLE have antiphospholipid
factors such as smoking, inflammation or oestrogen antibodies, but <40% of those will eventually have
therapy may play an important role at this point – thrombosis. However, thrombotic APLS is regarded as a
such factors are present in >50% of patients with the major adverse prognostic factor in SLE. In women with
APLS. recurrent miscarriage (~1% of the general population),
APLS is eventually diagnosed in 10–15%.
5 Vascular thrombosis – arterial, venous or small ves- 1. Check all patients with SLE for the presence of
sel antiphospholipid antibodies (lupus anticoagu-
5 Pregnancy morbidity – one or more of: lant, anticardiolipin antibody and/or anti-β2-
5 One or more deaths of a healthy foetus at 10 or more glycoprotein 1 antibody).
weeks’ gestation 2. Catastrophic APLS can be precipitated by a ‘trig-
5 One or more premature births of a healthy baby ger’ such as disruption to usual anticoagulation,
28 before 34 weeks’ gestation because of eclampsia or surgery, infection or, importantly, renal biopsy
pre-eclampsia (and the sub-therapeutic anticoagulation this
5 Three or more unexplained consecutive spontaneous entails).
abortions before 10 weeks’ gestation
? Questions
28.2.5 Treatment 1. Does ANA positivity confirm a diagnosis of SLE?
2. How would you treat a young woman with creati-
The goal of therapy is to prevent thrombosis either in nine 63 μmol/L, urine protein/creatinine ratio 63
those individuals with antiphospholipid antibodies who mg/mmol and evidence of endocapillary prolifer-
have already had a thrombotic event (secondary preven- ation in less than half her glomeruli on renal
tion) or in those who without previous thrombosis (pri- biopsy?
mary prevention). 3. What specific treatments should be avoided in
Current treatment for secondary prevention in those women with SLE planning a pregnancy?
individuals presenting with a first venous thrombosis is 4. What specific treatments are recommended for
with lifelong anticoagulation, usually with warfarin, women with SLE planning a pregnancy?
with a target INR of 2.0–3.0. For those who have had
v Answers
recurrent venous thrombosis or arterial thrombosis, a
1. No – although the vast majority of patients with
higher INR may be desirable.
SLE are positive for the anti-nuclear antibody
Current recommendations for primary prevention of
(ANA), it can also be found in Sjögren’s syndrome,
APLS are not clear. However, the annual thrombotic
scleroderma and rheumatoid arthritis.
risk of patients with SLE and antiphospholipid anti-
Importantly, a low titre of ANA (1:40) can be
bodies is about 3–4%, and so we would recommend the
found in up to 30% of healthy volunteers.
use of low-dose daily aspirin in these patients.
2. Despite the seemingly preserved renal function
Importantly, other vascular risk factors should be
(and it would be important to calculate the esti-
treated aggressively in all patients with antiphospholipid
mated GFR in this case, as young women should
antibodies.
have very low creatinine levels) and moderate pro-
Systemic Lupus Erythematosus, Antiphospholipid Syndrome and the Kidney
525 28
teinuria, this patient has class III lupus nephritis. appropriate to keep ACE inhibition going until
We would recommend induction immunosuppres- the woman has a positive pregnancy test.
sion with corticosteroids (prednisolone 40 mg daily) Cyclophosphamide and rituximab cannot be used
and MMF 1 g twice daily to achieve remission. in pregnancy.
3. MMF is teratogenic and so contraindicated in 4. Hydroxychloroquine should be continued during
pregnancy. Ideally, patients should be swapped to pregnancy, as it reduces the risk of disease flares
azathioprine 3–6 months prior to conception, to and the risk of neonatal lupus syndrome and/or
ensure their disease remains in remission, despite congenital heart block. All women with lupus
the change in therapy. ACE inhibitors are contra- should take 75 mg aspirin from 12 weeks, and in
indicated in the second and third trimesters of some women, this should be started pre-
pregnancy and, however, appear not to cause conception. Folic acid (400 mcg daily) and vita-
birth defects in early pregnancy. Therefore, for min D supplementation should also be prescribed
women with significant proteinuria, it may be prior to and during pregnancy.
Case 28.1
A 19-year-old Caucasian woman presented with swelling of patient was treated with a tapering course of oral cortico-
her ankles and a purpuric rash over both legs. She had steroids and MMF 2 g/day. She was also started on pro-
recently returned from a holiday in Spain and noticed feeling phylactic low-dose aspirin. Clinical improvement was rapid
lethargic with aching joints. She had recently started taking alongside an improvement in renal function, liver enzymes
oral tetracycline for acne. Initial investigations showed: and proteinuria (. Fig. 28.1c). MMF was tapered to 1 g/
Hb 109 g/L Urea 6.2 mmol/l Blood +++ ANA 1/640 (speckled pattern)
WCC 5.6 × 109/l Creatinine 102 μmol/l (no Protein +++ dsDNA 22 U/ml
previous measure)
Platelets 109 × 109/l ALT 225 U/l Protein/creatinine ratio ENA negative
924 mg/mmol
Albumin 22 g/l MSU negative Positive lupus anticoagulant
CRP 87 mg/L C3 0.61 g/L
C4 0.14 g/L
A renal biopsy was performed (. Fig. 28.1a, b) which day after 2 years and all immunosuppression stopped after
showed a diffuse, segmental and global, necrotising and a total of 3 years’ treatment. The patient had a disease
proliferative glomerulonephritis, with one crescent. There relapse 3 months following this and was re-commenced on
was no evidence of chronic renal damage. These changes oral corticosteroids – which were gradually tapered to
were consistent with WHO class IV lupus nephritis. The zero – and MMF on which she remains at last clinic review.
526 E. Miller-Hodges et al.
a b
28
c 120
MMF 2g/day & oral corticosteroids
100
MMF 1g/day
Creatinine (mmol/L)
80
60
40
20
0
0 5 10 15 20 25 30
Time (months)
. Fig. 28.1 a Glomerulus with global proliferation (>50% of its. c Change in serum creatinine following diagnosis. There is a
the tuft area) (H&E stain). b Glomerular tuft (H&E stain) show- rapid fall, even with what seems only a minor elevation in serum
ing “wire loop” capillary walls thickened due to immune depos- creatinine at presentation
Systemic Lupus Erythematosus, Antiphospholipid Syndrome and the Kidney
527 28
Case 28.2
A 37-year-old female presented with arthralgia, lethargy lethargy, night sweats, fevers, cough and mouth ulcers,
and alopecia. She was of Chinese origin and had one child. with a high titre of dsDNA antibodies. She was given a
She had been diagnosed 10 years earlier with idiopathic diagnosis of SLE and treated with oral corticosteroids and
thrombocytopenic purpura and treated with oral cortico- hydroxychloroquine. She had been well for the last 2 years.
steroids alone. Five years later, she had presented with Initial investigations showed:
Hb 102 g/L Urea 7.2 mmol/l Blood +++ dsDNA >200 U/ml
WCC 3.1 × 109/l Creatinine 90 μmol/l (previously Protein +++ C3 0.21 g/L
54) C4 0.02 g/L
A renal biopsy was performed (. Fig. 28.2a, b) which 2 g/day as maintenance therapy. There was a rapid and sus-
showed a diffuse, segmental and global, necrotising and tained improvement in the patient’s symptoms and bio-
proliferative glomerulonephritis, with crescents. There was chemical parameters (. Fig. 28.2c, d). After 12 months of
no evidence of chronic damage. These changes were in MMF, the dose was reduced from 2 g to 1 g/day and the
keeping with WHO class IV lupus nephritis. Given the patient was continued on this long term. Note that serum
prominent crescents, the patient was treated with a taper- creatinine and proteinuria continued to improve even after
ing dose of oral corticosteroids alongside six doses of 12 months of treatment.
intravenous CYC. The patient was then switched to MMF
100
80
60
40
20
0
0 5 10 15 20 25 30
Time (months)
b d
400
Urine protein:creatinine ratio
250
200
150
100
50
0
0 5 10 15 20 25 30
Time (months)
. Fig. 28.2 a Kidney cortex (H&E stain) at low magnification, ment in serum creatinine following treatment with intravenous
showing segmental abnormalities in 4 of 5 glomeruli but mini- cyclophosphamide at induction, followed by MMF for mainte-
mal chronic tubulointerstitial damage. b Glomerulus at high nance treatment. Renal function continues to improve for almost
magnification (H&E stain), showing marked proliferation 2 years after starting treatment. d Reduction in proteinuria fol-
affecting just over 50% of the tuft area (i.e. global). c Improve- lowing treatment
528 E. Miller-Hodges et al.
Case 28.3
A 31-year-old woman with a long history of SLE pre- sion and eventually became profoundly nephrotic
sented to the renal clinic prior to planning a pregnancy. (. Fig. 28.3a, b). She delivered a small but healthy baby
She had received multiple treatments for relapsing lupus by emergency Caesarian section at 36 weeks. She contin-
nephritis over the preceding 10 years but was not currently ued to have nephrotic range proteinuria following delivery
taking any immunosuppression. She had blood and pro- and was treated with corticosteroids, azathioprine and
tein on urine dipstick. Whilst undergoing investigations, enalapril. Proteinuria improved but remained elevated,
28 including renal biopsy, to ascertain the level of disease with a protein/creatinine ratio of 100–150 mg/mmol.
activity, she became pregnant. The renal biopsy was con- Following cessation of breastfeeding, she was switched
sistent with class IV lupus nephritis, so she was treated from azathioprine to MMF and proteinuria completely
with azathioprine, prednisolone and hydroxychloroquine. resolved. Steroids were successfully weaned, and she has
Early pregnancy was uneventful, but by 30 weeks, she had been maintained on MMF until a recent switch to azathio-
become increasingly proteinuric with worsening hyperten- prine prior to planning her next pregnancy.
a 1000
800
700
600
500
400
300
200
100
0
0 5 10 15 20 25 30 35 40 45 50
Time (months)
b 50
45
40
35
Serum Albumin (g/L)
30
25
20
15
10
Pregnancy Switch to MMF following cessation of breastfeeding
5
0
0 5 10 15 20 25 30 35 40 45 50
Time (months)
. Fig. 28.3 a Proteinuria increasing during pregnancy, and persisting, at a lower level, until the switch to MMF at 8 months
post-partum. b Serum albumin falls significantly during late pregnancy with the development of frank nephrotic syndrome
Systemic Lupus Erythematosus, Antiphospholipid Syndrome and the Kidney
529 28
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531 29
Practical Immunosuppression
Guidelines for Patients
with Glomerulonephritis
Ruth J. Pepper and Alan D. Salama
Contents
References – 541
. Table 29.1 Intravenous cyclophosphamide regimen used . Table 29.2 Steroid reducing protocol
in systemic vasculitis demonstrating dose adjustment for
both age and renal function Prednisolone (non-enteric coated) Starting dose: 1 mg/kg
protocol daily orally
Age (years) Creatinine µmol/L
<300 >300 Week 1 50 mg (<50 kg), 60 mg
<60 15 mg/kg/pulse 12.5 mg/kg/pulse (50–75 kg), 75 mg (>75 kg)
29.2.4 Infection, Bone and Gastric abnormal complement factor may be contributing to
Prophylaxis disease. In those oligo-anuric or anuric patients, the salt
load from the 4.5% albumin solution can be considerable,
Prevention of steroid side effects warrants prophylactic and increased fluid removal with subsequent dialysis
treatment with regard to gastric, bone and fungal com- may be necessary to prevent fluid overload.
plications. All patients on high-dose steroids should The dose of plasmapheresis should be calculated
receive gastric protection with proton pump inhibitors based on plasma volume or body weight, and typically
or H2 antagonists. Bone protection with calcium D3 1–1.5 plasma volumes are exchanged per session
combination (1 g of calcium/day) and consideration for (generally 50–60 ml/kg). It is important to review the
bisphosphonate use if renal function allows and if there delivered dose that is achieved, as failure to respond may
be due to inadequate plasma exchange.
29 is any pre-existing bone mineral density loss. Fungal
Plasmapheresis has been shown to be of benefit in
prophylaxis may be in the form of nystatin suspension
or low-dose fluconazole (but confirm no possible drug anti-GBM disease, when it is delivered for 14 exchanges
interaction with other immunosuppressants such as or until the anti-GBM antibody is negative. Early trial
calcineurin inhibitors). Pneumocystis prophylaxis, with data also suggested a benefit in patients with ANCA-
co-trimoxazole, dapsone or nebulised pentamidine, is associated vasculitis (AAV) and severe renal involve-
warranted in patients treated with cyclophosphamide ment (creatinine >500 µmol/L) [12, 13], although there
or rituximab. Recent appreciation of an increased risk was no long-term benefit with regard to renal failure or
of reactivation of certain viruses, especially hepatitis B, death [7]. However, a recently concluded trial (PEXIVAS)
has prompted recommendations for prophylaxis compared plasma exchange in patients with severe AAV
depending on the type and dose of immunosuppres- and concluded the plasma exchange, in addition to
sives and appears to be most important in those patients pulsed methylprednisolone, did not reduce the composite
at risk (e.g. HBV core antibody positive) treated with endpoint of mortality or ESRD. Subgroup analysis may
rituximab [11]. yet suggest benefit in patients with pulmonary haemor-
rhage [6].
There is no evidence for a benefit of plasmapheresis
29.2.5 Plasmapheresis in SLE [14] or in other forms of rapidly progressive glo-
merulonephritis, but it is often used in such patients
Plasmapheresis removes a number of plasma proteins with renal deterioration in the hope that there may be
that may contribute to disease pathogenesis, including some benefit (see RPGN below).
autoantibodies, immune complexes, complement
components, clotting factors and microparticles derived
from inflammatory or endothelial cells. There are two 29.2.6 Fertility Sparing Measures
main ways of performing plasmapheresis, using a plas- and Pregnancies
mafilter or a centrifugal bowl. The advantage of the for-
mer is that it is easily performed by most dialysis nurses, Fertility impairment is related to the use of cyclophos-
but the filter may limit removal of larger molecules such phamide and is in part related to the age of the patient
as IgM; by contrast, bowl centrifugation has the advan- and the pre-treatment sperm viability or ovarian func-
tage of removing all plasma components, but may be tion. It is therefore always best to sperm bank men of
limited in availability in certain units. Further modifica- child-bearing age, prior to cyclophosphamide treat-
tions of these techniques exist including the double fil- ment, and discuss ovarian protection or egg harvesting
tration plasmapheresis (DFPP) method, which returns in women. Practically, the induction therapy for egg
some of the smaller plasma molecules (such as albumin) harvesting is not suited to acutely ill patients who may
to the patient, necessitating less replacement fluid; cryo- need to start cyclophosphamide therapy urgently, and
filtration which is when the plasmapheresis is performed so a more favoured approach is the use of gonadotro-
at lower temperatures in an attempt to increase removal pin-releasing hormone (GnRH) analogues prior to the
of immune complexes; and plasma absorption when use of cyclophosphamide treatment, which may be
specific affinity columns are used to allow greater appropriate in female patients up to the age of 40 years
removal of certain molecules such as immunoglobulin [15]. The use of goserelin monthly (3.6 mg) or three
(using protein A columns). monthly is generally adequate for induction of chemi-
Replacement fluid should be in the form of 4.5% cal menopause. There are no data, however, confirming
albumin, unless there is a bleeding tendency, a recent that this approach results in a better proportion of
invasive procedure or the procedure is aimed at replacing patients with preserved fertility, but many practitioners
a missing factor, such as in atypical HUS where an use such an approach nonetheless. The EUROLUPUS
Practical Immunosuppression Guidelines for Patients with Glomerulonephritis
535 29
also been demonstrated to be effective as maintenance
. Table 29.3 Drug modifications in those planning treatment in AAV with higher rates of remission com-
pregnancy pared to azathioprine [17]. The fully humanised anti-
CD20 monoclonal antibody ofatumumab and
Can be continued in Needs to be Uncertain
pregnancy discontinued
obinutuzmab have been used successfully in patients
with lupus nephritis and AAV in patients unresponsive
Azathioprine Mycophenolate Rituximab or intolerant due to infusion reactions to rituximab.
Steroids mofetil/MPA Belimumab, a monoclonal antibody directed against
Tacrolimus or Cyclophosphamide
ciclosporin A ACE inhibitors/ARB
the B cell-activating factor (BAFF or BLyS), has recently
Hydroxychloroquine Statins obtained both FDA and NICE approval as an add-on
IVIG treatment in patients with SLE; however, it is not
indicated in patients with severe lupus nephritis. Current
trials are either ongoing to investigate the use of a
combination of belimumab with rituximab in both
lupus nephritis and AAV, as BAFF levels increase
low-dose intravenous cyclophosphamide regimen has following rituximab therapy and may predispose to
been demonstrated not to impact the ovarian reserve in disease relapse when B cell repopulation occurs.
patients as assessed by serum levels of anti-Mullerian
hormone [16].
In those planning a pregnancy, this should be ideally
delayed for a period such as 6 months following the last
29.2.8 MMF and Azathioprine
dose of cyclophosphamide. The patient should also have
MMF is extensively used as induction therapy in SLE
had a period of disease remission for several months
and has been shown to be of equal efficacy in inducing
before planning a pregnancy. Certain maintenance
remission in lupus nephritis as cyclophosphamide – with
immunosuppressives can be continued, while others
better tolerability in certain ethnic groups (such as
need to be stopped or switched to more appropriate
African-Americans and Hispanics). Some centres
equivalents. Examples of drugs that can be or cannot be
advocate therapeutic drug monitoring, although many
continued in pregnancy are shown in . Table 29.3.
trials treated to a particular dose. Starting at a lower
dose and increasing rapidly may allow for fewer
gastrointestinal side effects.
29.2.7 Rituximab and Other B Cell-Targeted
Azathioprine requires no such dose adjustments, but
Therapies thiopurine methyltransferase (TPMT) levels may be
checked prior to commencing therapy as this can allow
This anti-CD20 monoclonal antibody, first introduced dose adjustment in patients likely to suffer bone marrow
for the treatment of lymphoma, is now extensively toxicity, with low TPMT activity. Care should be taken
used in autoimmunity and in many forms of glomeru- if patients are on allopurinol as this increases azathio-
lar disease. It is administered as a slow intravenous prine toxicity. Monitoring of liver function tests and a
infusion with steroid and antihistamine premedication full blood count regularly will help prevent hepatitis and
(methylprednisolone 125 mg and chlorpheniramine). leucopenia. Azathioprine is infrequently used for induc-
Infusion reactions are the most common adverse tion therapy, but rather as a common maintenance
event. B cell depletion is generally achieved after one agent. It is more effective than MMF in vasculitis main-
dose but may be less efficacious if significant mono- tenance, with significantly longer time of relapse-free
clonal is lost in the urine, in nephrotic states. B cell remission in patients treated with azathioprine com-
numbers can be checked following administration. It pared to MMF.
may be administered as two infusions 2 weeks apart
(each of 1 g) or as a four-dose weekly regimen of
375 mg/m2. Both appear to be equally efficacious in 29.2.9 Complement Antagonism
glomerular disease.
Secondary hypogammaglobulinaemia may result, Animal models and clinical data have implicated com-
and the more severe this is, the more likely the patient plement in various glomerular diseases, including pauci-
will develop an infectious complication. IgG levels immune small vessel vasculitis. Avacopan is an oral
should be monitored in case levels are low and replace- selective C5a receptor inhibitor and has recently been
ment immunoglobulin may be required. Rituximab has trialled in the treatment of AAV demonstrating non-
536 R. J. Pepper and A. D. Salama
inferiority to corticosteroids when used with a cyclo- copenia. New trials in AAV have demonstrated that
phosphamide- or rituximab-based induction regimen induction therapy with rituximab is as effective as cyclo-
[18, 19]. phosphamide [20, 21], while studies in SLE have failed
to demonstrate benefit of additional RTX therapy above
standard treatment [22, 23]. Since there have been few
29.3 Protocols for Particular Glomerular randomised studies of the treatment of other causes of
Diseases RPGN, we are left to extrapolate protocols from these
studies.
29.3.1 Rapidly Progressive 29.3.1.1 Anti-GBM Disease
Glomerulonephritis Treatment should be initiated immediately in those in
29 whom it is appropriate. Recommendations are to initi-
Rapidly progressive glomerulonephritis (RPGN) is ate daily plasma exchange for a total of 14 sessions or
defined as sudden loss of renal function, with halving of until the anti-GBM antibody has disappeared. Plasma
GFR within 3 months. Prompt diagnosis and treatment exchange should be against human albumin solution,
is crucial to prevent irreversible loss of renal function. unless there has been a recent renal biopsy or active
Histologically, RPGN is caused by a crescentic bleeding, and then it should be replaced in part (300–
glomerulonephritis, which is due to severe glomerular 600 ml) with fresh frozen plasma (FFP) [24]. Long-
injury, as a result of rupture of the glomerular capillary term immunosuppression is not required due to the
loop basement membrane. Crescentic glomerulone- monophasic nature of the disease, with cyclophos-
phritis is generally defined as having more than 50% of phamide treatment recommended for 2–3 months and
glomeruli involved with crescents, which are identified steroid for no more than 6–9 months (see
by the presence of at least two layers of cells in Bowman’s . Table 29.4).
space.
RPGN can be commonly categorised into being
caused by: 29.3.1.2 Immune Complex
Glomerulonephritis
5 Anti-glomerular basement membrane (GBM) dis- This describes the formation of immune deposits, which
ease contain immunoglobulins, complement and other
5 Immune complex glomerulonephritis proteins within the glomerulus resulting in glomerular
5 Pauci-immune glomerulonephritis, associated with injury. There are several underlying causes of a RPGN
ANCA in most cases with immune complex deposition histologically.
The standard of care has long been steroids and cyclo- IgA Nephropathy (IgAN) and IgA Vasculitis (IgAV
phosphamide, with trials in pauci-immune GN demon- or Henoch-Schönlein Purpura)
strating that newer regimens using lower doses of While there are data demonstrating the efficacy of
cyclophosphamide delivered as intravenous pulses pro- immunosuppression with steroids in patients with IgAN
vide equal efficacy and fewer adverse events such as leu- with moderate proteinuria (1–3.5 g/day) and mild renal
29 may be beneficial
Corticosteroids 60 mg/day: taper Gastric protection
decreasing to ≤10 mg by Bone protection
24 weeks
Azathioprine 2 mg/kg TPMT activity: low levels will require Can replace MMF as maintenance
decreasing the dose therapy if pregnancy being
FBC, LFTs: monitor after initiation of considered
therapy
Consider:
Rituximab 1 g days 1 and 15 Peripheral B count (CD19) to assess Prevention of infusion reaction give
depletion methylprednisolone 125 mg
Belimumab Days 0, 14, 28, then every
28 days
has been part of the gold standard induction agent for rituximab, plasmapheresis provided no benefit using the
many years, although its use at high doses for prolonged same endpoint. However, subgroup- and meta-analysis
periods resulted in significant adverse effects. Treatment have suggested a possible benefit in those patients with
regimens have been refined over the years to reduce the pulmonary haemorrhage or advanced renal failure [39].
total cumulative dose of cyclophosphamide. Numerous There is now an increasing use of intravenous cyclo-
EUVAS (European Vasculitis Study Group) trials have phosphamide in this group of patients with severe renal
investigated optimal regimens for different disease failure to reduce the incidence of leucopenia, with
states. The CYCLOPS trial included patients with a patients receiving 6–10 pulses of cyclophosphamide.
serum creatinine <500 µmol/L and demonstrated that The dose of steroids is usually started at 1 mg/kg, with
the combination of pulsed intravenous cyclophospha- tapering to a dose of 10–15 mg/day by 3 months and
mide and oral steroids was as effective at inducing dis- 5 mg by 1 year. Maintenance therapy consists of long-
ease remission as an oral cyclophosphamide regimen term immunosuppression following the period of induc-
but induced fewer episodes of leucopenia [2], although tion therapy. The CYCAZAREM trial demonstrated
long-term follow-up has shown that this intravenous that cyclophosphamide at 3–6 months could be safely
regimen is associated with increased relapses [3]. substituted for azathioprine (2 mg/kg/day) [40], while a
. Table 29.1 demonstrates the intravenous dosing regi- study demonstrated that MMF is not as effective as aza-
men used in this study. thioprine in maintenance therapy [41], and so should be
The MEPEX study investigated patients with more reserved for patients who cannot tolerate azathioprine.
advanced renal failure (serum creatinine >500 µmol/L) There is an increasing use of rituximab in patients with
and demonstrated the benefits of plasma exchange, AAV, with two randomised trials providing evidence that
alongside oral cyclophosphamide and corticosteroids in its use as induction therapy is equivalent to that of cyclo-
renal recovery at 3 months and 1 year [12]. However, phosphamide [20, 21]. The RAVE trial compared oral
long-term follow-up of this study cohort suggested no cyclophosphamide with rituximab, excluding those with
benefit at 5 years with regard to a combined endpoint of severe renal failure (creatinine >4 mg/dl), although patients
ESRD or death. This was confirmed in the randomised with less severe renal disease were included [20] and dem-
PEXIVAS trial, demonstrating that in patients treated onstrated equivalence of RTX and CYP but superiority of
with pulsed corticosteroids and cyclophosphamide or RTX for those with relapsing disease. RITUXVAS
Practical Immunosuppression Guidelines for Patients with Glomerulonephritis
539 29
. Table 29.6 Induction and maintenance doses of immunosuppressive agents in ANCA-associated vasculitis
included those with severe (dialysis-dependent) renal pared rituximab (500 mg days 0 and 14, followed by
involvement and demonstrated the rituximab regimen not months 6, 12 and 18) with azathioprine for maintenance.
to be inferior [21]. Both the 375 mg/m2 × 1/week for This trial demonstrated higher rates of sustained remis-
4 weeks (regimen in RAVE and RITUXIVAS) and 1 g sion with rituximab [17]. The RITAZAREM trial com-
repeated after 2 weeks appeared equally effective. With pared repeated doses of rituximab to azathioprine in
regard to maintenance therapy, the MAINRITSAN trial relapsing disease in patients who have undergone induc-
included patients with AAV who entered remission follow- tion therapy with rituximab, and showed reduced relapse
ing induction therapy with cyclophosphamide and com- rates in rituximab treated patients [42].
Case Study
. Table 29.6 shows the treatment options in AAV. 2. Kidney biopsies can be performed safely in preg-
nant women early in the pregnancy if clinically
indicated and are associated with change in man-
Tips and Tricks
agement in up to 45% of patients. In the case of a
newly diagnosed lupus patient with possible nephri-
1. Consider rituximab induction therapy as an alterna-
tis, the severity of the kidney disease would be help-
tive to cyclophosphamide therapy, especially in
ful to counsel her with regard to renal outcomes,
those patients with relapsing PR3-ANCA vasculitis.
need for medication and pregnancy progress and
2. In AAV patients treated with rituximab induction,
outcomes. She could be treated with azathioprine,
those who remain B cell depleted and ANCA neg-
tacrolimus (especially if significantly proteinuric),
ative are at low risk of relapse.
corticosteroids and hydroxychloroquine.
29 3. Check hepatitis serology prior to starting immu-
3. Yes, she can have rituximab. Approximately 20%
nosuppression and consider lamivudine prophy-
of patients with AAV have some degree of hypo-
laxis in those patients who are hepatitis B core
gammaglobulinaemia at presentation. This does
antibody positive with regular monitoring of hep-
increase with regular rituximab therapy, but if she
atitis B surface antigen. Additionally, a patient’s
has not suffered infections, she can be induced
Varicella Zoster virus (VZV) status is important,
with rituximab and only considered for prophy-
as if naïve and exposed, to VZV the immunocom-
lactic antibiotics or IVIG replacement if she
promised state may result in life-threatening infec-
develops recurrent infectious illnesses with wors-
tion. VZV immunoglobulin can be administered
ening hypogammaglobulinaemia. Some clinical
in VZV-naïve patients on immunosuppression.
immunology services will test response to vaccines
4. PJP prophylaxis should be used for 3–6 months
to decide if IVIG replacement is necessary.
following rituximab and for the duration of cyclo-
phosphamide therapy.
5. In patients requiring cyclophosphamide, the low-
dose EUROLUPUS regimen is effective and Appendix: Information for Renal Patients
exposes patients to low overall doses of the drug, Receiving Cyclophosphamide Therapy
and therefore, this can be extended or repeated if
needed. Generally, we try and minimise total This information sheet describes cyclophosphamide,
cyclophosphamide dosage, and it is good to keep how it is administered and some of the side effects it
a running total of overall dose exposure so as to may cause. Please ask a member of staff if you want
prevent excessive doses. Doses of 10–20 g may be information about other alternatives to treatment with
necessary for severe relapsing patients. cyclophosphamide or if you have any other questions.
How Is It Given?
? Chapter Review Questions
1. Can tacrolimus be added to steroids and MMF in Cyclophosphamide can be given by injection into a vein
the treatment of lupus nephritis? (intravenously) or as a tablet. Your doctor will agree
2. A patient with newly diagnosed SLE, blood and with you as to which the best route is for you to receive
protein in the urine is pregnant. Should you per- the drug.
form a kidney biopsy, and what treatments could Tablets may have to be taken for a number of months;
she have? the intravenous infusion is generally given every
3. A newly diagnosed young female AAV patient has 2–4 weeks. The length of the treatment will depend on
an IgG level of 6.5 g/l (NR 7–16). Can you treat your condition and response to treatment, but it gener-
her with rituximab induction, or should she have ally lasts 3–4 months.
cyclophosphamide? If you are receiving the intravenous infusion, you
will attend the renal day ward. You will need to stay for
v Answers
up to 2 hours, although generally it takes less time.
1. Yes, in cases of class V or III/IV + V lupus nephri-
tis, tacrolimus can be added to patients with a sig-
nificant nephrotic syndrome. Generally, tacrolimus
therapy is then subsequently weaned and stopped
How Does Cyclophosphamide Work?
after 12–24 months of treatment to avoid long-
Cyclophosphamide works by depressing (‘damping
term exposure to calcineurin inhibition therapy.
down’) your immune system. The aim of the treatment
Practical Immunosuppression Guidelines for Patients with Glomerulonephritis
541 29
is to reduce the inflammation that is causing the prob- the renal day ward during working hours, or the on-call
lem with your affected organs such as kidneys, lungs or renal registrar out of hours, who can be reached through
nose. switchboard.
If you require any further information or advice,
please ask either your doctor or nurse.
What Are the Possible Side Effects?
Nausea and vomiting may occur if you take cyclophos- Contact Details
phamide. This can be controlled by giving you anti-sick-
ness (anti-emetic) tablets as needed. Call main switchboard……………………
Increased risk of infection is a result of the suppres- Renal pharmacy…………………………..
sion of white blood cell production in your bone mar- Vasculitis/lupus clinic …………………….
row. White blood cells help to fight infection. Your levels If you would like a large print or audio version of this
of white blood cells will be monitored. If you develop a information, please ask a member of staff.
temperature, fever or any signs of infection, please con-
tact either the ward or your GP. You should also report
any bruising/bleeding or excessive tiredness. You will be References
given an antibiotic tablet (or nebuliser if you cannot tol-
erate the tablets) to stop certain infections, but this will 1. Faurschou M, Sorensen IJ, Mellemkjaer L, et al. Malignancies
not prevent all infections. in Wegener’s granulomatosis: incidence and relation to cyclo-
phosphamide therapy in a cohort of 293 patients. J Rheumatol.
Bladder irritation is a possible side effect if you are
2008;35(1):100–5.
receiving intravenous cyclophosphamide. Symptoms 2. de Groot K, Harper L, Jayne DR, et al. Pulse versus daily oral
include blood in the urine and symptoms of cystitis. You cyclophosphamide for induction of remission in antineutrophil
may be given a drug called mesna during the intravenous cytoplasmic antibody-associated vasculitis: a randomized trial.
infusion that will help to prevent this occurring. If you Ann Intern Med. 2009;150(10):670–80.
3. Harper L, Morgan MD, Walsh M, et al. Pulse versus daily oral
notice any blood in your urine after discharge home,
cyclophosphamide for induction of remission in ANCA-
please contact the ward. associated vasculitis: long-term follow-up. Ann Rheum Dis.
Hair thinning may occur. This is not permanent and 2012;71(6):955–60.
will grow back after treatment. 4. Pepper R, Chanouzas D, Tarzi R, et al. Intravenous cyclophos-
Mouth sores may develop if you are taking the tablets phamide and plasmapheresis in dialysis dependent ANCA
associated vasculitis. J Am Soc Nephrol. 2011;22:560A.
and you will be given a supply of mouth lozenges to help
5. Monach PA, Arnold LM, Merkel PA. Incidence and prevention
prevent this. Good oral and dental hygiene is important. of bladder toxicity from cyclophosphamide in the treatment of
Contraception and fertility should be discussed with rheumatic diseases: a data-driven review. Arthritis Rheum.
your doctor or nurse as cyclophosphamide may affect 2010;62(1):9–21.
your ability to conceive or father a child. With a standard 6. Walsh M, Merkel PA, Peh CA, et al. Plasma exchange and glu-
cocorticoids in severe ANCA-associated vasculitis. N Engl J
treatment course, the risk of this happening is relatively
Med. 2020;382(7):622–31.
small. Women may find their periods altered and men 7. Walsh M, Casian A, Flossmann O, et al. Long-term follow-up
may wish to discuss sperm banking. of patients with severe ANCA-associated vasculitis comparing
plasma exchange to intravenous methylprednisolone treatment
is unclear. Kidney Int. 2013;84(2):397–402.
8. Chanouzas D, McGregor JAG, Nightingale P, et al. Intravenous
Cyclophosphamide and Pregnancy pulse methylprednisolone for induction of remission in severe
ANCA associated Vasculitis: a multi-center retrospective
Cyclophosphamide may cause several different birth cohort study. BMC Nephrol. 2019;20(1):58.
9. Pepper RJ, McAdoo SP, Moran SM, et al. A novel glucocorti-
defects if it is taken either at the time of conception or coid-free maintenance regimen for anti-neutrophil cytoplasm
during pregnancy. Be sure that you practice effective antibody-associated vasculitis. Rheumatology (Oxford).
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543 30
Contents
References – 563
n Learning Objectives
. Table 30.1 Mechanisms of renal impairment secondary
1. Infectious causes of renal disease are common, and to infection
the growing global population with CKD is more
at risk of AKI in the setting of sepsis; prevention 1. AKI Usually bacterial but can occur as a
and rapid diagnosis of sepsis in renal patients are secondary to consequence of severe viral infection, e.g.
vital. indirect SARS-CoV-2 (Covid-19) infection, viral
consequence of haemorrhagic fevers, fungaemia or
2. A good travel history including activities, occupa-
acute sepsis protozoal infection, e.g. falciparum
tion and what area (urban or rural) is very impor- malaria. Associated with exotoxins and
tant for differential diagnosis in undiagnosed renal endotoxins (such as myoglobin or
disease. haemoglobinuria)
3. Infections can cause renal disease via a variety of 2a. Direct Usually acute or chronic bacterial
mechanisms including pre-renal, post-renal, direct infection of the pyelonephritis but particularly in the
renal involvement, as a consequence of persis- kidney immunocompromised can be viral, fungal
30 tent infection or a post-infectious phenomenon. or mycobacterial, typically causing intersti-
tial nephritis
Periodically, kidney dysfunction will be the diag-
nostic clue leading to the diagnosis of persistent 2b. Direct Obstruction secondary to schistosomiasis
infection elsewhere in the body. infection of the or tuberculosis
urinary tract
4. Some persistent infections may mimic autoimmune
disease and neoplastic disease and are an impor- 3a. Indirect Usually immune complex mediated
tant consideration in the differential diagnosis. effects of following successful immune response,
infection – classically post-streptococcal glomerulone-
post-infectious phritis but may also cause interstitial
nephritis and haemolytic uraemic
30.1 Introduction syndrome (HUS) (E. coli O157:H7).
Typically with spontaneous resolution but
Infections are an important cause of renal dysfunction may provoke autoimmune disease (e.g.
vasculitis) secondary to molecular mimicry
and can cause this through a variety of mechanisms (see
. Table 30.1). Most commonly, this is in the form of 3b. Indirect Usually immune complex mediated from
acute kidney injury (AKI) as collateral damage in (1) effects of persistent chronic antigen exposure and
infection – per- resulting in glomerulonephritis classically
acute severe sepsis but also may occur due to (2a) direct sistent infection secondary to sub-acute bacterial (or fungal)
infection of the renal parenchyma (see also 7 Chap. 54) infection such as endocarditis, shunt
or (2b) obstruction secondary to involvement of the uri- nephritis, osteomyelitis but also secondary
nary tract. Renal impairment may result as a secondary to chronic viral infections such as hepatitis
phenomenon which can either be (3a) post-infectious B, hepatitis C and HIV. Spontaneous
resolution does not occur until underlying
(classically post-streptococcal glomerulonephritis (GN)) pathogen is eradicated. Long-term infection
or as a result of (3b) persistent infection such as endo- may also result in AA amyloid, immunotac-
carditis or chronic viral infections (hepatitis B, hepatitis toid, cryoglobulinaemia and fibrillary
C and HIV are discussed separately in the following involvement
chapter). There is often a significant degree of overlap in
these processes; for instance, while the vast majority of
AKI secondary to Covid-19 infection is secondary to more prone to some infections (particularly nosocomial)
indirect injury resulting in acute tubular injury, the virus and more vulnerable to complications of non-specific
does demonstrate renal tropism, and renal invasion sepsis, such as AKI.
seems to be associated with proximal tubular injury, and A detailed assessment is important in cases of AKI
possibly other glomerular lesions can co-exist. related to infection (see 7 Box 30.1). Key points in the
By identifying the infective agent and its persistence assessment include travel history, recent unwell contacts,
is important for treatment and prognosis. The second- specific activities (e.g. water sports, hiking/camping, cav-
ary effects of infection – resulting in glomerulonephritis, ing, visits to farms), sexual history and drug history
interstitial nephritis or obstruction – are responsible for including, if any, prophylactic medication taken, e.g.
a large burden of renal disease worldwide. antimalarials or antibiotics. Significant examination
With increasing globalisation and travel, the epide- findings include bite marks, rashes, hepatosplenomegaly
miology of infection-related renal disease is changing; in and lymphadenopathy. As discussed below, it is impor-
this chapter, we focus on those significant diseases found tant to have a high index of suspicion and where possi-
globally that may present to renal physicians. However, ble distinguish between post-infectious and ongoing
it should not be forgotten that renal patients will be infection as the management is different.
Infections and the Kidney
545 30
a b
30
. Fig. 30.1 (a) Necrotic fingers in a patient with meningococcal line and/or complete loss of normal renal architecture. He required
sepsis and AKI. The severity of the ischaemic injury to the kidneys long-term dialysis dependence and illustrated the profound effect of
was sufficient to cause cortical necrosis. (b) Renal biopsy of the same a short episode of severe sepsis on the renal microcirculation
patient on failure to recover from his AKI. Showing the ghostly out-
Europeans with a parasitaemia of >5%, the level of 24 hours) and if missed urine microscopy might reveal
parasitaemia being an important risk factor [3]. The haemoglobin casts (. Fig. 30.2b) or as acute tubular
rates of AKI secondary to falciparum malaria in injury and haemosiderin deposition on biopsy
endemic areas are less well defined but appear to be (. Fig. 30.2c).
much lower at around 3–5% in adults; however, because
of the prevalence of malaria, this still represents a sig-
nificant cause of AKI and if present still augurs a poor
prognosis. Hypotension, hyperbilirubinaemia, intra- 30.2.1 Covid-19 (SARS-CoV-2) and Other
vascular haemolysis and hypoxia (although unlike in Severe Respiratory Viruses
the cerebral vessels, schizonts do not adhere to and
block renal vasculature) all contribute to the acute Middle East respiratory syndrome (MERS) and SARS-
tubular injury which is the predominant finding; how- CoV were both associated with a higher mortality than
ever, mild mesangial proliferation with transitory glo- SARS-CoV-2 of approximately 10–37%. In this setting
merular proteinuria and tubulointerstitial nephritis do of severely ill patients, AKI rates of up to 27% were
occur. Finally, massive intravascular haemolysis (result- reported with the impression that this degree of AKI
ing in blackwater fever) secondary to the use of quinine was commensurate with collateral renal damage in very
(also reported with the use of artesunate) for the treat- sick patients. However, it was recognised that the ACE2
ment of falciparum malaria is an important cause of receptor and dipeptidyl peptidase-4, both highly
AKI. The pigment nephropathy associated with intra- expressed in the kidney, acted as ligands for MERS,
vascular haemolysis results in a greater incidence/risk SARS-CoV and, subsequently, SARS-CoV-2 viruses
of AKI than would otherwise be attributed to sepsis permitting direct entry to the kidney.
alone (. Fig. 30.2a) [4]. Early diagnosis and effective Following initially low rates of reported AKI associ-
antimalarial treatment with artesunate are critical, as is ated with Covid-19 in Wuhan, China, much higher rates
avoiding excessive fluid replacement; these patients are of AKI have been noted elsewhere in patients presenting
at high risk of cerebral and pulmonary oedema (both to hospital, with rates between 25% and 37% in second-
associated with a high mortality rate). Renal replace- ary care and up to 90% of those in ICU requiring venti-
ment therapy reduces mortality in malaria-associated lation. Proteinuria and microscopic haematuria are
AKI, and planning provision for this is important given common in patients but heavy proteinuria relatively rare
the good prospects for rapid renal recovery. In addi- or transient. Understandably very few patients had renal
tion, ready access to acute dialysis is likely to promote biopsies, and the majority that have been reported were
the restrained use of IV fluids. Patients treated with from autopsy samples. These have predominantly
intravenous artesunate should be followed up to detect revealed severe, non-specific acute tubular injury.
late haemolytic events. Black urine secondary to intra- Lymphocytic infiltration and oedema were also com-
vascular haemolysis is a pretty strong diagnostic clue as mon findings with thrombotic occlusion of capillary
to the cause of AKI but may clear very rapidly (within loops secondary to microthrombi also reported in these
Infections and the Kidney
547 30
a b
. Fig. 30.2 (a) Haemoglobinuria in acute falciparum malaria. AKI, 3 days after acute malaria and ‘dark urine’. (c) Renal biopsy of
Urine on right, spun urine from patient with blackwater fever com- a patient with blackwater fever and AKI. Renal biopsy performed
pared with normal urine (right). (b) Haemoglobin cast (large homo- 10 days after AKI shows acute tubular injury and haemosiderin
geneous and acellular) in a patient with high-level parasitaemia and (brown) deposited in the tubules secondary to exposure to large
‘blackwater fever’. The patient’s urine was clear at presentation with quantities of haemoglobinuria
cohorts. Viral RNA and presumed virus have also been ondary to the disproportional direct viral invasion of
identified from infected kidneys. In the few cases where the proximal tubular epithelial cells.
biopsies have been performed in less critically ill patients Approximately 5% of patients with Covid-19 infec-
(presumably selected because of a presentation less con- tion need hospitalisation, often in the setting of poor
sistent with secondary acute kidney injury), collapsing fluid intake, increased fluid losses, generalised sepsis,
focal segmental glomerulosclerosis (cFSGS) does seem hypoxia, right heart failure and ‘cytokine storm’.
to be a genuine association, albeit relatively rarely. This Anecdotally, an initial, and understandable, approach
would fit with the known associations between cFSGS of ‘running patients dry’ to avoid adult respiratory dis-
and some viral infections such as parvovirus and HIV tress syndrome in the UK almost certainly contributed
and may have more to do with a systemic cytokine to a huge incidence of AKI in Covid-19-infected
response. patients.
In addition, it is clear small numbers of patients have While direct involvement of Covid-19 remains con-
clearly presented with a Fanconi-like picture with leak troversial, it seems highly likely that the vast majority of
of low molecular weight proteins, amino acids, uric acid AKI in this setting relates to non-specific, ‘indirect’
and phosphate associated with acidosis, presumably sec- acute tubular injury.
548 E. Williams et al.
30.3 Direct Renal Involvement organs, although disproportionate renal blood flow is
likely to result in a great burden of infection. There are
The commonest direct infection of the kidneys is ascend- other infections, however, that are more renal specific or
ing infection by uropathogenic bacteria in the form of ‘nephrotropic’. The infective causes of interstitial
pyelonephritis (see 7 Chap. 54). Less commonly, the nephritis are listed in . Table 30.2 and include exam-
kidney can be directly infected by haematogenous ples where the pathological process is driven by direct
spread organisms resulting in an acute or sub-acute infiltration but also others where the interstitial nephri-
interstitial nephritis (TIN). In systemic sepsis with bac- tis may be a post-infectious phenomenon without direct
teria such as Staphylococcus aureus, the kidney may involvement. It is worth noting that while the role of
develop multiple micro-abscesses along with all other some infectious agents causing TIN is well established,
a b
30
. Fig. 30.3 (a, b) Renal biopsy of a patient with hantavirus infection: (a) low power showing marked acute tubular injury and some eryth-
rocytes in the interstitium and (b) high power of interstitial haemorrhage
cally interstitial haemorrhage in the outer medulla, common cause of AKI [14]. There is a significant male
which is highly suggestive of the diagnosis (see preponderance (4:1), and this likely relates to sex bias in
. Fig. 30.3) [11]. Serological tests for IgM and IgG at-risk employment such as farmers, fish workers, min-
against hantavirus are confirmatory, and in the early ers, slaughterhouse workers and the military [15]. The
phase, peripheral blood RT-PCR may detect virus. incidence in Western countries is falling but does still
Microscopic haematuria, raised AST level and raised occur. In the UK, there are approximately 50–60 cases in
leucocyte count at the time of admission are useful pre- England and Wales (50% acquired abroad) each year.
dictors of patients who are at risk of developing oliguric Worldwide, it is one of the leading zoonotic causes of
renal failure [12]. morbidity particularly in resource-poor countries with
Management consists of excluding other causes of approximately a million cases and approximately 60,000
viral haemorrhagic fevers, bacterial sepsis and MAHA, deaths per annum. In Western countries, the proportion
and treatment is supportive with renal replacement ther- of cases that are travel acquired is increasing signifi-
apy required in ~10%, and ribavirin may be helpful [13]. cantly [16], with a shift from work-related to leisure-
Most patients’ renal function and blood pressure return acquired infection particularly in those partaking in
to baseline, but some remain with a degree of renal adventure sports; for example, outbreaks have been
impairment and hypertension. Mortality from HFRS is reported after triathlons and isolated cases related to
between 1% and 15%, Dobrava virus having a worse pets [17].
prognosis than Puumala virus infection [6]. Incubation period can range from 2 to 26 days (aver-
age 10 days) with the length of illness averaging 14 days.
Symptoms are often non-specific in the first week with
30.3.2 Leptospirosis fevers, malaise, headache, meningism, anorexia, nausea,
vomiting, diarrhoea and abdominal, chest and back
Leptospirosis is a zoonosis caused by the spirochete pain. Physical signs such as hepatomegaly, splenomeg-
(gram-negative bacteria) Leptospira interrogans. aly, rash, jaundice and conjunctival suffusion typically
Leptospirosis should be suspected in a patient with non- occur in the second week [18]. Weil’s disease is the pres-
specific prodrome who then develops AKI and dispro- ence of jaundice and AKI in a patient with serologically
portionate hyperbilirubinaemia, particularly with an ‘at confirmed leptospirosis infection and occurs in around
risk’ history. Infections in humans are usually transmit- 5–10% of those infected, less commonly in children. The
ted from rats and domesticated livestock through con- second phase of the disease is immunologically medi-
tact with animal urine usually in contaminated water ated and may be associated with a myositis, AKI, myo-
through breaches in the skin or mucous membranes. carditis and gastrointestinal and pulmonary (a poor
Leptospira interrogans is almost ubiquitous, but lepto- prognostic sign) haemorrhage. Thrombocytopenia
spirosis is more common in the tropics due to farming occurs in 50% often associated with a neutrophilia, but
practices, flooding and infection and is more common leucocytopenia can also occur. Liver transaminases are
during rainy seasons or after hurricanes when it can be a often minimally to moderately raised (<200 U/l), but
Infections and the Kidney
551 30
hyperbilirubinaemia is disproportionate and a vital clue. relatively uncommon but may manifest as cystitis, inter-
Low-level proteinuria and haematuria are common, and stitial nephritis, glomerulonephritis and renal abscess
AKI is non-oliguric in about 50%, often with hypoka- [23, 24]. The diagnosis is often missed as the multitude
laemia. Creatine kinase is elevated in roughly 50%. of symptoms associated with brucellosis such as fevers,
Diagnosis is made on culture from the blood early in the malaise, sweating, headaches and bone and joint pain
disease or by serology. Urine cultures may become posi- may mimic autoimmune conditions or malignancy.
tive from the second week of illness and may remain so Renal parenchymal involvement is predominantly a
for up to 30 days after resolution of symptoms. Newer granulomatous tubulointerstitial nephritis but can also
PCR-based assays are increasingly being used to diag- be associated with indirect involvement secondary to
nose infection [19]. persistent infection in the form of a glomerulopathy
Secondary factors for the development of AKI in associated with Brucella endocarditis or membranopro-
leptospirosis include hypotension, hypovolaemia, jaun- liferative glomerulonephritis (MPGN) sometimes
dice and rhabdomyolysis. The main finding on biopsy is appearing many months after initial symptoms [25].
interstitial nephritis, oedema and acute tubular injury; Diagnosis can normally be confirmed by culture or
mild mesangial proliferation in common with many serology. Brucella can be cultured from blood, bone
infectious diseases may be present early on. The pre- marrow or other appropriate fluids with bone marrow
dominant site of direct injury by leptospira in the kid- aspirate having the highest yield for positive cultures.
ney is the proximal convoluted tubule with decreased There is a significant risk of aerosol transmission in
activity of the sodium-hydrogen co-transporter proxi- microbiology laboratories; therefore, staff must be
mally and NKCC co-transporter in the thick ascending informed of the possibility of brucellosis so that the cul-
limb. Therefore, sodium and water transport across the tures can be incubated in appropriate isolation facilities
tubule wall is impaired causing polyuria and hypokalae- and appropriately prolonged. A diagnosis can also be
mia secondary to more potassium (and magnesium) made on the basis of an appropriate clinical syndrome
being excreted distally [20]. together with rising antibody titres on serological tests.
Treatment is largely supportive as the condition is Brucella antibodies may persist long after recovery of
usually self-limiting. The role of antibiotics is controver- infection, so caution is needed in interpreting serological
sial, and a systematic review concluded that there was tests in the context of chronic infection and relapsing
insufficient evidence to indicate the benefit of antibiotics infection and in patients from endemic areas.
in established disease [21]. Antibiotics are only benefi- Treatment is generally with a combination of antibi-
cial in the early phase of the disease. If the patient is able otics that include doxycycline, rifampicin and aminogly-
to take oral medications, then doxycycline 100 mg twice coside.
a day is a good choice as it also covers rickettsial dis-
eases which are an important differential diagnosis.
Cefotaxime and ceftriaxone are good intravenous alter- 30.3.4 Syphilis
natives. Benzylpenicillin is no longer recommended as
first-line therapy since it will not cover rickettsiosis. The incidence of syphilis caused by Treponema pallidum
Antibiotic therapy is usually given for 5–7 days. is on the increase in Western Europe and the USA par-
Mortality figures for Weil’s disease vary significantly ticularly in men who have sex with men [26]. There are
depending on the series and case mix but amounts to well-documented cases of renal involvement associated
roughly 5–15%. Advanced age, alcohol abuse, oliguria, with secondary syphilis, although this does not result in
presence of arrhythmias and jaundice have been shown a high incidence of renal disease. Presentation may be
to be predictors of severe leptospirosis infection [22]. with the classical maculopapular rash involving palms
For those who survive, good renal recovery is the norm. and soles, and proteinuria which may be nephrotic
range. The commonest histological pattern is membra-
nous GN [27], but MPGN, PRGN and interstitial
30.3.3 Brucellosis nephritis have been described as having solid renal
lesions due to syphilitic gumma. Although rare, it is
Brucellosis is a zoonosis caused by Brucella spp., most important to exclude treponemal infection as part of the
commonly Brucella melitensis. Human infection is nor- screening for unexplained renal involvement as the treat-
mally acquired after contact with fluids from infected ment is simple and effective. Diagnosis is established by
domestic animals and livestock or derived food products the presence of IgM/IgG by ELISA tests. IgG antibod-
such as unpasteurised milk and cheese particularly in the ies persist for life. Positive ELISA IgM needs to be inter-
Mediterranean region. There is little literature on bru- preted with care; although a positive IgM reflects active
cellosis causing renal involvement, and it appears to be infection, IgM antibodies can persist for 12–18 months
552 E. Williams et al.
30
30.3.5 Visceral Leishmaniasis
Viral:
1. Hepatitis B Membranous GN, MPGN, polyarteritis nodosa
2. Hepatitis C MPGN, MPGN with cryoglobulinaemia, membranous GN, fibrillary GN
3. HIV HIVAN collapsing FSGS, immune complex GN (MPGN, lupus-like) FSGS, thrombotic
microangiopathy, IgA
4. Coxsackie B Mesangial proliferative (rare)
5. Influenza A/B/H1N1 Reported but more commonly causes AKI secondary to rhabdomyolysis and systemic
sepsis
6. Epstein-Barr virus Crescentic and leucocytoclastic reported but rare, TIN more common
30 7. Measles MPGN, mesangial proliferation more common in patients with sub-acute sclerosing
pan-encephalitis
8. Mumps Mesangial proliferative (rare)
9. Parvovirus Collapsing FSGS or post-infectious pattern, HSP, MPGN, thrombotic microangiopathy,
cryoglobulinaemia
10. Cytomegalovirus Rare: membranous, FSGS, MPGN, HUS, link with IgA now controversial; all less common
than TIN
11. Varicella zoster Mesangial proliferative, renal vasculitis, HUS reported clinically significant disease seems
very rare
12. Rubella Mesangial proliferative (rare)
13. ECHO Mesangial proliferative (rare)
14. SARS-CoV-2 Collapsing FSGS associated with infection, glomerular capillary microthrombi
Bacterial:
1. Staphylococcus species Especially S. aureus and usually in the setting of active, ongoing infection
2. Streptococcus species Especially group A, S. pyogenes, S. pneumoniae and viridans; both post-infectious GN and
secondary to active infection
3. Salmonella species Typhi, paratyphi and enteritides; predominantly induces a TIN but glomerulonephritis is
well described
4. Coxiella burnetii MPGN with or without cryoglobulinaemia especially in the setting of endocarditis
5. Leptospira species Case reports of GN but predominantly ATI and TIN
6. Yersinia enterocolitica Post-infectious pattern
7. Mycoplasma pneumoniae Post-infectious pattern, rapidly progressive GN
8. Legionella Case reports of proliferative GN but predominantly TIN and ATI
9. E. coli 0157:H7 HUS
10. Campylobacter jejuni HUS
11. Neisseria Case reports of GN associated with gonorrhoea and meningitides but vast majority
associated with AKI
12. Treponema pallidum Congenital and secondary syphilis associated with membranous GN
13. Brucella abortus MPGN (rare)
14. Mycobacterium leprae and TB Amyloid
Infections and the Kidney
555 30
Fungal:
1. Candida
2. Histoplasma capsulatum
3. Coccidioides immitis
Protozoal:
1. Plasmodium malariae Evidence of nephrotic syndrome secondary to P. malariae circumstantial and no longer
convincing
2. Toxoplasma gondii Rapidly progressive GN, congenital nephrotic syndrome (pyrimethamine inhibits tubular
secretion of creatinine)
3. Trypanosoma cruzi, brucei
4. Leishmania donovani MPGN, amyloid, ATI (urinary concentrating defect) and TIN
5. Strongyloides stercoralis MPGN
Heleminthic:
1. Schistosoma species MPGN, amyloid, FSGS
2. Wucheria bancrofti Amyloid, MPGN (rare)
3. Onchocera volvulus MPGN
4. Loa loa Membranous GN, MPGN, FSGS
30.5.1 Post-Infectious Renal Disease Relapses of vasculitis are more common in patients
with nasal carriage of S. aureus, although whether this is
Renal dysfunction as an indirect effect of the immune as a result of molecular mimicry or a non-specific supe-
response to infection is classically exemplified by acute rantigen effect is not clear.
post-streptococcal glomerulonephritis but also occurs
as the phenomenon of haematuria following upper
respiratory tract infections (as with IgA nephropathy) 30.5.2 Acute Post-Streptococcal
and more rarely following pneumonia or gastroenteritis Glomerulonephritis (APSGN)
secondary to other infectious agents such as
Streptococcus pneumoniae, Salmonella spp. and APSGN remains the most common cause of nephritis
Mycoplasma pneumoniae. It is worth reiterating that worldwide, but the epidemiology over the past 40 years
synpharyngitic haematuria (and proteinuria) occurs has changed significantly, and it is now relatively rare
rapidly (within 1–3 days) of upper respiratory tract as a childhood infection in resource-rich countries. It
infections with IgA, whereas post-infectious glomerulo- is estimated that there are nearly half a million cases
nephritis from other causes typically occurs 1–2 weeks of APSGN globally with an incidence of 10–30 per
after the primary infection and post-infectious glomeru- 100,000/year (0.3 per 100,000/year in Europe),
lonephritis is likely to be accompanied by hypocomple- although severe cases of rapidly progressive glomeru-
mentaemia and a raised anti-streptolysin O (ASO titre) lonephritis represent <1%. The vast majority occur in
if due to a streptococcal infection. children at a mean age of 7 and in the developing
There are other post-infectious associations in world making it still the commonest cause of acute
nephrology thought to be driven by molecular mimicry; nephritis in children although it is rare in children
the infectious antigen provoking a cross-reactivity auto- below the age of 2. There is a second peak in incidence
immune response to a similar autoantigen. For example, in those over 60 years with a predisposition to those
there is an association between antibodies to human with co-morbidity, alcohol or parenteral drug abuse
lysosomal membrane protein (LAMP-2) and the devel- and is strongly associated with social deprivation.
opment of ANCA-positive vasculitis following infection Rates are falling significantly in China and South
with E. coli expressing FimH adhesion molecules which America with persistently high rates in sub-Saharan
have a homologous epitope. Africa and the Indian sub-continent [34].
556 E. Williams et al.
APSGN occurs secondary to nephritogenic strains of resolve spontaneously within 2 weeks, although the
group A streptococcal infection such as pharyngitis/ton- microscopic haematuria and proteinuria often persist a
silitis/upper respiratory tract or skin infection, but there little longer.
have been reported outbreaks due to group C streptococ- Blood cultures and swabs may be positive for S. pyo-
cal infection (S. zooepidemicus) from unpasteurised milk genes, but ASOT, anti-hyaluronidase and anti-DNase
[35]. Typically, APSGN is a disease of the socioeconomi- antibodies are more sensitive. Glomerular haematuria is
cally disadvantaged and frequently occurs in clusters and universal and red blood cell casts are common. One of
epidemics especially following skin infection and com- the most useful diagnostic pointers is a depressed C3
monly associated with scabies and skin sores [36]. level (typically C4 is normal) which frequently falls
before the onset of any clinical features of APSGN and
is one of the last tests to return to normal and so may
30.5.3 Aetiopathogenesis suggest the diagnosis in a late presentation and help dif-
ferentiate from IgA or pauci-immune vasculitis.
30 Only some strains of S. pyogenes have nephritogenic A renal biopsy is rarely necessary, but if performed
potential, and this is attributable to two nephritogenic typically demonstrates a diffuse hypercellularity (prolif-
antigens: nephritis-associated plasmin receptor (NAPlr) erative) of the endothelium (resulting in reduced perfu-
and streptococcal pyrogenic exotoxin B (SPEB). Both sion) and mesangium with infiltration of the tuft with
of these are capable of activating complement via the neutrophils (see . Fig. 30.2). Immunohistochemistry
alternative pathway, inducing the production of IL-6 reveals deposits of IgG, C3 (but not C4 or C1q) in the
and MCP-1 by mesangial cells (promoting immune mesangium and glomerular capillary wall with pathog-
recruitment) and both capable of inducing an antibody nomonic sub-epithelial humps on electron microscopy,
response in the host. It has been assumed that the patho- although sub-endothelial deposits can also occur in the
genesis of APSGN is akin to serum sickness with circu- disease. A small proportion of patients can have a more
lating immune complexes to the nephritogenic antigens fulminant course with >50% crescents and a RPGN
depositing in the kidney; however, there is still debate (. Fig. 30.6).
about the precise mechanism of the damage to the kid- Management is largely supportive with sodium and
ney as C3 (alternative pathway activation) is deposited water restriction and diuretics. Haemodialysis is rarely
before IgG complexes [37]. Other possibilities include required but may be needed in severe acute renal failure.
IgG binding to the GBM secondary to molecular mim- Appropriate antibiotic therapy such as penicillin is
icry or in situ deposition of IgG to streptococcal anti- sometimes given to those with APSGN as often it is dif-
gens trapped in the kidney. ficult to know if the streptococcal infection is ongoing,
although there is currently no convincing evidence of
benefit. Prophylactic antibiotics, however, are indicated
30.5.4 Clinical Features in epidemic areas and in close contacts of those affected
as early antibiotic therapy in group A streptococcal
Typically, there is a latency of 1–2 weeks after pharyngi- infections appears to reduce the risk of developing
tis before features of APSGN develop, but it is usually APSGN.
later after skin infections at around 3–6 weeks. History
of an infection is an important diagnostic clue; however,
approximately 20% of serologically positive household
contacts in APSGN epidemics do not show signs of the
original streptococcal infection. Patients usually present
with oedema, haematuria which may be macroscopic
(classically cola coloured) and hypertension (80–90%).
Hypertensive crises including encephalopathy are rela-
tively common in childhood presentations. Autoimmune
haemolytic anaemia is also reported but a relatively rare
complication of APSGN. Proteinuria is usually sub-
nephrotic with nephrotic syndrome in <4%, although
said to be more common in adults. Less than 1% develop
rapidly progressive glomerulonephritis with crescent
formation; however, renal impairment is common espe-
cially in the elderly, and patients may present with con- . Fig. 30.6 Light microscopy of post-streptococcal glomerulone-
gestive cardiac failure. For most patients, symptoms phritis with proliferative, hypercellular glomerulus rich in neutrophils
Infections and the Kidney
557 30
Overall mortality is less than 1% globally represent- immunological defence and unlikely to resolve until the
ing about 5000 (potentially preventable) deaths per year, infection is treated. Common causes include hepatitis B,
97% of which are in resource-poor countries. The short- hepatitis C and HIV and are shown in . Table 30.4.
term prognosis for the majority is usually very good in Globally, some tropical diseases such as filariasis are
children but worse in the elderly with other co- also implicated.
morbidities. In these patients, mortality can be up to
25% and a significant proportion seem to progress to
CKD. Of the elderly patients that do survive but have 30.6.1 Malaria
persistent nephrotic range proteinuria, around 75% will
go on to develop chronic renal failure [38]. Progression In the 1970s, it was felt that a significant proportion of
to end-stage renal failure (ESRF) occurs in less than 2% childhood nephrotic syndrome in sub-Saharan Africa
of all patients with PSGN, with less than 1% of children was related to chronic malarial infection principally
progressing to ESRF after PSGN. Consequently, with Plasmodium malariae (quartan malarial
APSGN has been largely considered benign; however, it nephropathy (QMN)). The evidence for this was largely
has been speculated that childhood APSGN might per- circumstantial, and even if QMN was a significant clini-
manently reduce nephron mass and contribute to the cal entity, it seems a rare beast these days [41]. In practi-
huge burden of CKD in Aboriginal communities that cal terms, any patient with nephrotic syndrome in the
also have a high burden of diabetes and hypertensive tropics ought to have a malaria screen and positive
renal disease [39]. Recurrence of PSGN is uncommon results treated, but it should no longer be assumed that
but has been reported. malaria is the principal cause of nephrotic syndrome.
Endocarditis Yes Yes Low Low Yes Secondary ANCA (low titre), RhF and
cryoglobulins very common
SAAGN No Yes Normal Normal Yes Polyclonal Ig increase
GPA/MPA No +/− Normal Normal No Primary ANCA
Case Study
Case 1 with three casual male partners in the last 3 months. HIV,
A 27-year-old lawyer attended A + E with maculopapaular hepatitis B and hepatitis C serology negative. Treponemal
rash. antibody positive with an RPR of 1:512. He was diagnosed
On palms and soles (. Fig. 30.7), inguinal lymphade- with secondary syphilis and treated with a stat dose of
nopathy and pedal oedema. His urine dip showed 3+ pro- intramuscular benzathine penicillin 2.4 MU.
tein and no blood. Serum albumin was 24 g/L, creatinine His rash resolved, and renal function and urine dip-
124 μmol/L, and urea 9 mmol/L. He underwent renal stick returned to normal. Secondary syphilis is rare but
biopsy which showed membranous nephropathy. After increasing particularly in men who have sex with men and
direct questioning, he stated that he had unprotected sex is an important diagnosis to make as eminently treatable.
. Fig. 30.7 Classic maculopapaular rash on palms of hands and soles of feet found in secondary syphilis. Photographs courtesy of
Dr. Parameswaran Sashidharan
Infections and the Kidney
561 30
a b
30
c d
60
150
48
Doxycycline started
100 B
36 A
g/l
24
50
12 C
0 0
6 months
12 Months
e 3000
Doxycycline started
2400
1800
mg/mmol
1200
600
0
12 Months
. Fig. 30.8 (a) CT-PET scan demonstrating intense FDP Albumin pre- and post-antibiotics. (d) C-reactive protein and
uptake in the aortic graft. (b) Serum amyloid P scan demonstrat- serum amyloid protein following initiation of antibiotics. (e) Uri-
ing uptake in the liver, spleen, kidneys and aortic graft. (c) Serum nary protein following initiation of antibiotics
Infections and the Kidney
563 30
Tips and Tricks 3. 1–2 weeks after streptococcal infection compared
with 1–3 days for IgA
1. Direct questioning on sexual and travel history is 4. Hantavirus, AKI following a viral prodrome and
very useful as patients may not deem it relevant. marked thrombocytopenia with preserved clot-
2. Testing for and managing infections must always ting, interstitial haemorrhage on biopsy
be done in conjunction with the local infectious 5. Amphotericin and tubulointerstitial nephritis
diseases/microbiology and/or virology teams.
Public Health England’s Rare and Imported
Pathogens Laboratory (RIPL) are happy to dis- References
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565 31
Blood-Borne Viruses
and the Kidney
Rachel K. Y. Hung, Douglas Macdonald, Sanjay Bhagani,
Mark Harber, and John Booth
Contents
References – 581
n Learning Objectives
. Table 31.1 The spectrum of renal disease encountered in
1. Renal disease in HIV can be due to direct HIV- patients infected with HIV
mediated injury of renal tissue, consequences
of immunodeficiency or toxicity of medication HIV associated Examples
including combined antiretroviral therapy. As HIV
treatment improves, ageing HIV patients are at HIVAN See . Table 31.3
Immune complex kidney
an increased risk of kidney disease from common
disease
comorbid conditions, namely diabetes and hyper- Thrombotic microangiopa-
tension. thy
2. Renal disease in hepatitis C tends to occur in Diffuse infiltrative lympho-
chronic infection and is commonly associated with cytic syndrome
cryoglobulinaemia. Hepatitis B is strongly asso- HIV treatment associated
ciated with membranous glomerulonephritis or
ART nephropathy Proximal tubulopathy with
membranoproliferative glomerulonephritis and TDF
can present as polyarteritis nodosa. Crystallopathy with
31 indinavir
Granulomatous TIN with
atazanavir
31.1 Introduction
Immune reconstitution
inflammatory syndrome
The main blood-borne viruses HIV, hepatitis B (HBV)
(IRIS)
and hepatitis C (HCV) are responsible for a huge burden
of renal disease worldwide. These chronic infections Immunodeficiency associated See . Table 31.4
produce a complex and fascinating spectrum of kidney Anti-microbial toxicity Tubulointerstitial nephritis
diseases which have the potential to cause end-stage kid- or ATI with antibiotics
ney disease (ESKD). New advances in antiviral treat- Renal parenchymal infection Tuberculous granulomatous
ment are altering the epidemiology of these diseases and interstitial nephritis
in many cases permitting near-normal life expectancy. Viral nephropathies, e.g.
With this has come both new renal disorders secondary CMV
to antiviral toxicity and also an increasing population of Neoplasia Infiltration, e.g. by
‘well’ patients with ESKD and chronically suppressed lymphoma
virus raising new challenges for transplantation. Other commonly encountered
conditions
Immune complex kidney HBV-associated membra-
31.2 Human Immunodeficiency Virus disease nous nephropathy
and the Kidney HCV-associated mesangio-
capillary GN
The widespread use of combination antiretroviral ther- Non-collapsing FSGS (NOS
apy (cART) in HIV has dramatically enhanced patient or hilar variants)
survival and reduced the incidence of AIDS, but also Acute tubular injury Hypovolaemia, sepsis,
altered the spectrum of renal disease encountered in nephrotoxic drugs
Western populations (. Table 31.1) [1]. Rates of HIV-
Diabetic or hypertensive
associated acute kidney injury (AKI) have more than kidney disease
halved in the cART era, parallel to a decline in severe
AA amyloid Associated with injection
infection episodes [2, 3]. The incidence of HIV’s arche-
drug use
typal renal lesion, HIV-associated nephropathy
(HIVAN), has also diminished. In turn, rates of multi- TDF tenofovir disoproxil fumarate, TIN tubulointerstitial
factorial CKD have risen, driven by increasing average nephritis, CMV cytomegalovirus, ATI acute tubular injury,
patient age and prevalence of common comorbidities HBV hepatitis B virus, HCV hepatitis C virus, FSGS focal seg-
such as hypertension and diabetes. Specific nephrotox- mental glomerulosclerosis, NOS not otherwise specified
icities of cART have also emerged.
HIV-positive patients should be screened for renal
disease by means of eGFR measurement, urinalysis and
protein/creatinine ratio (uPCR) at diagnosis, prior to race, hypertension or cardiovascular disease, diabetes,
starting cART and at periodic intervals no greater than viral hepatitis, family history or potentially nephrotoxic
1 year [4]. Patients with risk factors for CKD (black mediations) need enhanced surveillance.
Blood-Borne Viruses and the Kidney
567 31
. Fig. 31.2 Prevalence of hepatitis C worldwide in 2015. Prevalence of viraemic people by country a and absolute number of viraemic
individuals b. (Reproduced with permission from Blach et al. [23])
nosuppression [24]. Where there is a high index of suspi- develop in up to 10% of patients with cryoglobulinaemia
cion for HCV infection and the HCV-Ab test is negative, and rarely may present as minimal change nephropathy.
an HCV RNA test should be carried out. It has been difficult to detect HCV antigens histo-
logically in renal lesions, and a direct role of HCV anti-
gens in renal disease is unproven. MPGN is usually
31.4.3 Pathology associated with deposition of IgM, IgG and C3 in the
mesangium and capillary walls. Electron microscopy is
The predominant renal lesion in HCV is membranopro- important in establishing the diagnosis by demonstrat-
liferative glomerulonephritis (MPGN) which can also ing sub-endothelial deposits and may also reveal cryo-
occur independently of detectable cryoglobulinaemia. globulin deposition. Fibrillary and immunotactoid
Other glomerular lesions such as interstitial nephritis glomerulonephritis, although rare, have both been docu-
and necrotising small vessel vasculitis (especially in asso- mented with HCV and again emphasise the importance
ciation with cryoglobulinaemia) have all been reported of electron microscopy in the assessment. Crescentic
[25, 26] (see 7 Box 31.1). The finding of membranous nephritis can occur in the setting of underlying MPGN
glomerulonephritis should prompt consideration of or in the context of a necrotising vasculitis (usually cryo-
hepatocellular carcinoma (sought by checking globulin associated) or fibrillary GN. Thrombotic
α-fetoprotein and liver imaging). Lymphoma may microangiopathy has been reported (predominantly
574 R. K. Y. Hung et al.
post-transplant), and hepatitis C is an infrequent cause and the European Association for the Study of the Liver
of isolated interstitial nephritis, possibly due to direct (EASL) should be consulted for the most up-to-date
viral cytotoxic effects. . information (see patient information).
Several reports have described reactivation of hepati-
tis B virus (HBV) infection in individuals previously
Box 31.1 Renal Involvement in Hepatitis C exposed to HBV infection after successful treatment for
Glomerular HCV with DAA-based therapy [28, 29]. Markers of HBV
Cryoglobulin positive exposure or active infection should be assessed before ini-
MPGN tiation of HCV DAA treatment, particularly in immuno-
Fibrillary suppressed patients post-renal transplantation. Patients
Immunotactoid without active infection of HBV but evidence of prior
Amyloid exposure (e.g. hepatitis B core antibody positive) should
Cryoglobulin negative be actively monitoring for HBV reactivation using HBV
MPGN DNA and liver function tests every 12 weeks during DAA
Membranous GN (exclude hepatocellular therapy and for 6 months thereafter. Patients with active
carcinoma)
31 FSGS
HBV infection not on treatment should also be moni-
tored for rising viral loads or abnormal liver function
Mesangial deposits tests which may indicate HBV treatment initiation.
Amyloid (if associated with IV or SC drug Severe cryoglobulinaemia or HCV-associated glomer-
abuse) ular disease (e.g. nephrotic syndrome or RPGN) typically
Vasculitic requires immunosuppressive therapy in addition to DAA
Thrombotic microangiopathy (post-transplant) treatment. The anti-CD20 monoclonal antibody ritux-
Tubulointerstitial nephritis imab is recommended as first-line therapy by KDIGO,
Interstitial nephritis secondary to virus and is commonly co-prescribed with corticosteroids. This
Interstitial nephritis secondary to interferon recommendation is supported by data from two ran-
domised controlled trials of rituximab combination ther-
apy with pegylated interferon-alpha. The role of rituximab
31.4.4 Treatment and Outcome in the DAA era is less clear, with rapid reductions in vas-
culitis scores observed in prospective observational stud-
It is recommended that all patients are screened for HCV ies of patients with cryoglobulinaemic vasculitis treated
infection at the time of initial evaluation of CKD, start with DAA therapy alone [30]. While paradoxical flares of
of dialysis or evaluation of kidney transplantation using cryoglobulinaemic GN were often reported in the inter-
a hepatitis C antibody immunoassay, followed by ribo- feron era, this appears rare with DAAs, and the current
nucleic acid testing (HCV RNA) if the immunoassay is consensus is that antiviral treatment should not be
positive. All patients with HCV-associated renal disease delayed. Antiproteinuric agents such as ACEi/ARBs
or any CKD patient found to be infected with HCV on should be used along with other antihypertensive drugs
screening should be evaluated for antiviral therapy. and diuretics where appropriate to achieve the recom-
Treatment of HCV previously consisted of pegylated mended blood pressure targets for patients with CKD.
interferon and ribavirin with poor efficacy and high Survival in HCV-infected patients with ESKD on
adverse event rates in CKD. This was contraindicated dialysis is reduced compared to kidney transplant recip-
after renal transplantation due to the increased risk of ients. DAAs allow for successful clearance of HCV in
rejection or direct nephrotoxicity. nearly all patients before and after transplantation;
The advent of direct-acting antivirals (DAAs) has therefore, all eligible HCV-infected ESKD patients
heralded a major breakthrough in HCV treatment, with should be considered for transplantation. The use of
close to 100% cure rates and mild and infrequent side DAAs in kidney transplant recipients requires careful
effects. The latest KDIGO guidelines [27] recommend consideration and monitoring due to potential drug
using an interferon-free regimen chosen in consultation interactions with immunosuppressive agents used in
with a hepatologist and tailored to HCV genotype, viral transplantation. As most of these agents are metabo-
load, previous treatment history, drug interactions, lised via the cytochrome P450 pathway in the liver, sub-
GFR, stage of hepatic fibrosis, kidney or liver trans- strate competition can occur with DAAs which undergo
plant candidacy and overall comorbidities. With the the same metabolic pathway. The ‘HEP Drug
emergence of third-generation pan-genotypic DAAs, Interactions’ website is a useful resource for the latest
guidelines are simplifying. Both the American guidance on potential drug interactions with DAAs
Association for the Study of Liver Diseases (AASLD) (7 https://www.hep-druginteractions.org).
Blood-Borne Viruses and the Kidney
575 31
. Fig. 31.3 Global endemicity of HBV from 1957 to 2013. (Reproduced with permission from Schweitzer et al. [31])
. Table 31.6 Stages of hepatitis B infection as measured by antigenaemia, antibodies, viral DNA and ALT
Stage of infection Surface ‘e’ antigen IgM IgG Hepatitis Anti- Anti- ALT
antigen (HBeAg) anti-core anti-core B virus HBe HBs
(HBsAg) antibody antibody DNA
aIn very early infection, the IgM anti-core can be negative and by definition so can the IgG
bN = normal
Management of HBV-
associated Renal
Disease
Normal GFR,
mild proteinuria Rapidly Progressive
Polyarteritis Nodosa
(≤ 3.5g/day) Glomerulonephritis
ETC or TAF
+ ETC or TAF
NA-based treatment
Corticosteroids +
with ETC or TAF if
± Corticosteroids
indicated by standard
Cyclophosphamide/ ±
guidelines
Rituximab Plasma Exchange
• Maintain BP
<130/80mm/Hg
• ACE inhibitor
• Active
monitoring
. Fig. 31.4 Treatment of HBV-associated renal disease. ETC entecavir, NA nucleoside analogue, TAF tenofovir alafenamide. (Adapted
from Pipili et al. [37])
transplant recipients. The nucleoside analogues lamivu- bioavailability for tenofovir in hepatocytes. TAF-based
dine, emtricitabine and telbivudine all have a low genetic treatment has been approved in HIV patients with renal
barrier to resistance and therefore should be avoided as impairment. Prospective randomised studies of TAF
monotherapy. Adefovir and tenofovir disoproxil fuma- versus TDF in hepatitis B monoinfection have reported
rate (TDF) have both been associated with Fanconi syn- lower rises in creatinine in the TAF group at 2 years [35].
drome and cumulative renal toxicity. Minimising The indication for treatment in HBsAg-positive
consequences of HBV infection is of paramount impor- patients is determined by viral load, the presence or
tance, and NAs with a high genetic barrier to HBV resis- absence of liver inflammation (as determined by amino-
tance are typically the best options for HBV-positive transferases and/or biopsy), the stage of liver disease
patients with CKD. Tenofovir alafenamide (TAF) is a (determined by liver biopsy or non-invasive fibrosis
novel prodrug of tenofovir with superior absorption to assessment) and risk factors for hepatocellular carci-
tenofovir disoproxil fumarate (TDF) and can be admin- noma (HCC). Thresholds for initiation of treatment
istered at approximately tenfold lower doses with similar according to these criteria change frequently, and the lat-
578 R. K. Y. Hung et al.
est American Association for the Study of Liver Diseases cyclophosphamide or rituximab (for suppression of vas-
(AASLD), the European Association for the Study of culitis) and plasma exchange (for removal of circulating
the Liver (EASL) or the Asian Pacific Association for the immune complexes) may be useful for improving kidney
Study of the Liver (APASL) should be consulted. function and disease manifestations. If immunosuppres-
The goal of treatment is to lower the risk of liver sive therapy is administered, all HBsAg-positive patients
fibrosis progression and/or HCC through sustained sup- should receive pre-emptive NA therapy, ideally 2 weeks
pression of viral replication. HBsAg seroconversion and before, during and for at least 6–12 months after com-
HBV DNA clearance is the ideal result but rarely pleting immunosuppressive therapy.
achieved, and suppression of virus replication (with or There is hugely encouraging data showing almost
without eAg seroconversion) is often sufficient to induce complete eradication of childhood MN secondary to
proteinuria remission with preservation of renal func- hepatitis B following universal vaccination programmes,
tion. Nucelos(t)ide therapy may need to be lifelong for and a similar approach to control other infective agents
many patients regardless of the presence of renal dis- may well have comparable benefits.
ease, although finite therapy may be possible for patients
who achieve HBsAg or HBeAg loss and anti-HBe sero-
31 conversion [36]. EASL guidelines (2017) recommend the 31.6 HTLV1 and 2
use of entecavir (if lamivudine naïve) or TAF in HBsAg-
positive dialysis patients or transplant recipients. There are a smattering of case reports of glomerular
Entecavir requires dose adjustment in patients with an lesions in patients with HTLV1 and 2 infection includ-
eGFR <50 mL/min. TAF does not require a dose adjust- ing lupus-like nephropathy, TINU and MPGN. It is dif-
ment if eGFR >15 mL/min. ficult to be clear if these are genuine associations, and
While antiviral monotherapy may be sufficient to although one might expect glomerular disorders in
treat HBV-associated nephropathy in patients who do patients with chronic viraemia, the rarity of these
not have severe or life-threatening disease, additional reports given the global prevalence of HTLV infection
treatment strategies are required for those with RPGN (3.8% of Japanese dialysis patients) suggests HTLV-
and PAN (. Fig. 31.4). Corticosteroids with or without associated renal disease is rare.
Case Study
Case 1 cally, and the two entities can only be separated on renal
A 49-year-old Zimbabwean black African male with no biopsy. Both HIVAN and ICKD are indications to start
past medical history is diagnosed with HIV-1 infection on cART, although if significant tubular atrophy and fibrosis
first contact with medical services in the UK. He is asymp- are present on biopsy at the time of diagnosis, many
tomatic aside from mild ankle swelling and oral candida patients will continue to progress towards ESKD regard-
noted on examination. His blood pressure is 147/82. Blood less of viral control.
tests disclose a creatinine of 170 μmol/L, an albumin of
29 g/L and a urine protein/creatinine ratio of 450 mg/ Case 2
mmol. His CD4 count is 136 cells/μl and HIV viral load A 72-year-old Ugandan man presents with a 3-month
54,000 copies/mL. Urinalysis showed protein 4+, blood 2+ history of lethargy and weight loss. A new diagnosis of
and nil else, while an ultrasound showed bilateral echo- HIV is made with a CD4 count of 25 cells/μl and a viral
genic and enlarged kidneys. A kidney biopsy was per- load of 1.1 million copies/mL. At this attendance, serum
formed and revealed collapsing glomerulopathy, creatinine was 113 μmol/L and urine protein/creatinine
accompanied by tubular dilatation with microcysts, char- ratio 54 mg/mmol. He was started on cART: tenofovir
acteristic of HIVAN (. Fig. 31.5). disoproxil fumarate (TDF), ritonavir-boosted daruna-
In this patient with untreated HIV and advanced vir and lamivudine, with co-trimoxazole for PCP pro-
immunodeficiency, likely causes for renal disease are direct phylaxis. Six weeks later, he represents with widespread
HIV-mediated renal injury or consequences of immunode- lymphadenopathy, hepatosplenomegaly, fevers and
ficiency (e.g. renal parenchymal infection). Heavy protein- night sweats. CRP was 150 mg/L, creatinine 230 μmol/L
uria, microscopic haematuria and hypoalbuminaemia all with 1+ protein and 1+ blood on urinalysis, corrected
point towards a glomerular locus of disease. While the calcium level 2.85 mmol/L and repeat CD4 count 150
diagnosis in this instance was HIVAN, HIV immune com- cells/μl. Bacterial cultures of urine and blood were
plex kidney disease (ICKD) may present almost identi- sterile, while renal ultrasound confirmed normal sized,
Blood-Borne Viruses and the Kidney
579 31
Case 3
A 41-year-old white male presents with rib pain. He was
diagnosed with HIV-1 8 years ago and is currently taking
TDF, emtricitabine and efavirenz with good viral control.
He is also hypertensive taking amlodipine. Blood tests dis-
close a creatinine 125 μmol/L, urea 6 mmol/L, albumin
45 g/L, phosphate 0.59, CD4 750 cells/μL and viral load
<40 copies/mL. His urine protein/creatinine ratio was
b 95 mg/mmol and an albumin/creatinine ratio was 12 mg/
mmol. A urine dip showed protein 1+, glucose + and nil
else. An X-ray revealed a pseudo-fracture (Looser’s zone)
in his scapula, suggestive of osteomalacia (. Fig. 31.7).
This patient has developed hypophosphataemia, gly-
cosuria and presumed low molecular weight proteinuria
(evidenced by the elevated uPCR and near-normal uACR)
consistent with Fanconi syndrome. The most likely cul-
prit in this scenario is TDF. Inhibition of mitochon-
drial DNA replication in proximal tubular cells may be
involved in the pathogenesis of TDF-induced nephropa-
thy. Hypophosphataemia results from renal phosphate
wasting and leads to osteomalacia with bone pain and
pseudo-fractures in the most severe cases. TDF-induced
. Fig. 31.5 a Silver stain of renal biopsy showing a global col-
tubulopathy has been reported in both patients with nor-
lapse of capillary loops accompanied by ‘pseudocrescent forma- mal and impaired baseline renal function. A decline in
tion’ and b dilated tubules with microcyst formation renal function frequently precedes overt toxicity (perhaps
due to the consequent increase in blood tenofovir levels),
unobstructed kidneys. Serum creatinine failed to fall and other risk factors include white ethnicity, older age
despite appropriate IV fluid therapy and discontinuation and co-administration with a ritonavir-boosted protease
of co-trimoxazole and TDF. A core lymph node biopsy inhibitor. Patients on TDF require regular checks both
was undertaken and tissue stained positive for acid-fast of renal function (to pre-empt toxicity in patients with a
bacilli with mycobacterium tuberculosis subsequently declining eGFR) and markers of tubular toxicity (particu-
grown on culture. A kidney biopsy was performed: larly uPCR, serum phosphate and urinalysis for glycos-
this showed non-caseating granulomata with acute uria). Patients on TDF should be switched to TAF-based
tubular injury and a CD4 cell-rich interstitial infiltrate cART if they develop evidence of renal impairment, hypo-
(. Fig. 31.6). phosphataemia or accelerated bone-density loss.
The patient has developed a renal immune reconstitu-
tion inflammatory syndrome (IRIS) in the context of dis- Case 4
seminated tuberculosis. IRIS is most commonly seen in A 65-year-old man was referred to the renal unit with an
individuals presenting with advanced immunodeficiency in acute onset of severe peripheral oedema. He has a past
whom commencement of cART triggers a rapid increase medical history of diabetes mellitus, hypertension and
in CD4 T cell numbers; organ injury corresponds to the HCV genotype 1 infection 10 years ago and had received
580 R. K. Y. Hung et al.
31
5. Ibrahim F, Naftalin C, Cheserem E, et al. Immunodeficiency and 23. Blach S, Zeuzem S, Manns M, et al. Global prevalence and geno-
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583 VI
Tubulointerstitial
Disease
Contents
Acute Tubulointerstitial
Nephritis
Vasantha Muthu Muthuppalaniappan and Simon Ball
Contents
References – 596
NSAIDs and proton pump inhibitor [9, 10]. An early AIN but is now rare. Importantly, this means that
presentation within days of drug initiation seems likely patients sometimes present with a raised creatinine but
to represent a secondary response. There are no hard ‘quiet urine’ the assumption being that there is not an
and fast rules, but since many cases arise in the setting of acute inflammatory process, identification of sterile
polypharmacy, deduction of plausible temporal rela- pyuria may be the only clue to an acute pathology.
tionships provides some evidence of likely causation. It There may be defects in tubular handling of water,
is, therefore, important to get a clear drug history, if nec- sodium and hydrogen ions resulting in nephrogenic dia-
essary, from the primary practitioner or other third betes insipidus, salt-losing nephropathy, renal tubular
party, ideally with previous exposure and preceding acidosis (RTA) and Fanconi syndrome, which can all
renal tests. lead to the initial presentation. In particular, type 1 RTA
is a relatively common (~10%) manifestation of Sjögren’s
syndrome (a lower than expected venous bicarbonate
32.2.4 Diagnosis and Investigation and relatively alkaline urine may hint at this), whilst
impaired renal function is less common [12].
32.2.4.1 Urinary Analysis
Eosinophiluria is defined by >1% of WBC in urine which 32.2.4.2 Blood Analysis
is detected by a Hansel or Wright stain. It is associated The finding of eosinophilia in patients with AIN, even
drug induced, has insufficient predictive value to con-
32 with AIN in the absence of other disease processes
tribute significantly to the initial diagnostic algorithm.
which include cystitis, prostatitis, pyelonephritis, athero-
embolic renal disease, acute tubular necrosis and rapidly However, if present, it can help define a likely aetiology
progressive glomerulonephritis. Eosinophiluria has a when there are multiple offending drugs, particularly in
poor predictive value in establishing a diagnosis of AIN patients who have spent significant time in secondary
due to its poor sensitivity at 31% with a low positive pre- care. Evidence of eosinophilia is only seen in 25–35% of
dictive value of 16% and specificity at 68% [11]. The use cases, but the absence of eosinophilia does not exclude a
of Wright’s stain is less sensitive than the Hansel stain diagnosis of AIN [3, 13]. Retrospective analysis of the
when looking for eosinophiluria. It is imperative to eosinophil count can be used to define a likely time
remember that eosinophiluria is also associated with frame for the immune response often more precisely
acute tubular necrosis, post-infectious glomerulonephri- than renal function in patients who have been critically
tis, atheroembolic disease, urinary tract infections, pre- ill. For example, in patients found to have AIN following
renal AKI and prostatitis. prolonged illness and AKI initially attributed to acute
Other urinary sediments that raise the possibility of tubular injury, a retrospective finding of progressive
AIN include renal tubular epithelial cell casts reflecting eosinophilia can help identify candidate drugs and per-
a tubular cell injury with/without necrosis and white cell haps more importantly help exclude others. This has real
casts in the absence of infection. value since these patients have often been exposed to
Proteinuria is usually mild and often less than 1 g/ multiple agents.
day with a significant fraction of the proteinuria con- Most patients would have a rise in serum creatinine
sisting of low molecular weight proteins (e.g. immuno- in AIN prompting further investigation of their AKI
globulin light chains, beta2 microglobulin, lysozyme, with approximately 23–58% requiring renal replacement
peptide hormones). Low molecular weight proteinuria therapy at presentation [14–16]. Screening for autoim-
is common, and the uPCR can be disproportionally mune and infectious aetiologies may aid diagnosis of
higher than the uACR. This is because in normal condi- AIN. This will generally include a screen for ANCA,
tions, proteins of low molecular weight are re-absorbed ANA, ENA (including SS-A and SS-B (anti-Ro and
by the proximal tubules and only a small amount is anti-La), Igs, protein electrophoresis (polyclonal gam-
excreted. However, in AIN (a disease involving tubular mopathy being an important clue to autoimmune or
structures), this function is impaired and leads to the infectious causes) and complement levels. Raised IgG or
characteristic tubular proteinuria. Analysis of low IgG4 levels or hypergammaglobulinaemia with low
molecular weight proteins (such as urinary retinol-bind- serum complement level may suggest an IgG4-related
ing protein (uRBP), beta2 microglobulin (β2M) or α1- disease or hypocomplementaemic interstitial nephritis.
microglobulin) may indicate a tubular origin and be Serum ACE may be helpful in the diagnosis of sarcoid.
strongly suggestive of AIN. Specific serological testing and screening for mycobacte-
Similarly, haematuria is usually non-visible and low rial infection (EMU and ELISPOT) and other causative
level on conventional stick urinalysis. Visible haematu- organisms outlined in . Table 32.2 may help ascertain a
ria was reported in early reports of methicillin-induced non-drug-induced AIN.
Acute Tubulointerstitial Nephritis
589 32
These distinct features are important when discriminat-
. Table 32.2 Infections causing tubulointerstitial nephritis
ing for SLE or vasculitis-induced AIN. Cells are pre-
Virus Bacteria Others
dominantly T cells and macrophages, but classically
eosinophils may be present (although are not specific); B
Hantaviridae Legionella Leishmania cells and neutrophils are also often present. Granulomas
Epstein-Barr virus Leptospira Toxo-
and giant cells may occur and suggest particular under-
plasma lying aetiologies (see . Tables 32.2 and 32.3)
(. Figs. 32.2 and 32.3). Predominant neutrophilia on
HIV Mycobacterium
tuberculosis
the biopsy may suggest an infectious cause of AIN. A
lymphocytic dominance is seen in NSAID-induced
Measles Streptococcus AIN.
Polyomavirus Brucella In most cases, renal histology does not identify an
Cytomegalovirus Mycoplasma
underlying aetiology. Even Mycobacterium tuberculosis-
associated AIN rarely demonstrates caseating granulo-
Adenovirus Chlamydia mata with positive Ziehl-Neelsen staining. Consideration
Herpes simplex Salmonella of the clinical context, the precise histology and cor-
virus roborating information including screening for autoim-
Hepatitis A Yersinia mune and infectious aetiologies is required. It is prudent
to assess the renal biopsy for interstitial fibrosis and
Hepatitis B Campylobacter
tubular atrophy as the extent of these findings on the
Hepatitis C Rickettsia biopsy sample is associated with renal recovery and vari-
Strep species able degree of CKD.
Immunofluorescence (IF) and electron microscopy
Staph species
may not aid or provide any additional information or
diagnostic value in drug-induced AIN. However, IF in
anti-TBM disease would reveal linear deposits of IgG
32.2.4.3 Imaging along the TBM.
A CXR or HRCT may be helpful in diagnosing AIN
Diagnostic Challenges
thought to be caused by TB or sarcoid. The renal ultra-
sound in cases of AIN may show increased cortical The most frequent diagnostic challenge is to consider
echogenicity or enlarged kidneys but is otherwise non- AIN in patients who have other causes of CKD or AKI
contributory. Enlarged kidneys noted on ultrasound and to thereby expedite investigation by renal biopsy.
may be an inviting clue to the presence of an acute In the case of CKD, the presence of proteinuria gives
inflammatory interstitial nephritis which can be assessed useful information. The presence of proteinuria with
further with a CT. 67Ga scanning has been reported to renal dysfunction would usually indicate renal biopsy;
distinguish between AIN and acute tubular injury conversely, in diabetes mellitus, it may be the absence of
(ATI), which may be of some use in special cases in proteinuria that suggests an alternative diagnosis such
which renal biopsy is contraindicated and the likely dif- as AIN. There may be little proteinuria in hypertensive
ferential diagnosis is ATI. ischaemic nephropathy, and the indications for renal
biopsy will be informed by the history, rate of change of
32.2.4.4 Renal Biopsy and Histology Findings renal function, renal size and the presence of a candi-
None of the clinical manifestations or investigations are date cause of AIN.
diagnostic of AIN. In patients presenting de novo with In the case of AKI with a putative diagnosis of acute
renal impairment, this is not a significant challenge tubular necrosis (ATN), alternative diagnoses should be
because in practice, presentation with unexplained renal considered if renal failure is out of keeping with degree
failure and normal-sized kidneys would indicate a renal of physiological disturbance or unexpectedly prolonged.
biopsy, providing the diagnosis which is also the current This would indicate further investigation by renal biopsy.
gold standard for establishing AIN. An unexpected rash or eosinophilia might also lower the
On biopsy, inflammatory cells can be seen invading threshold for early biopsy in patients otherwise thought
the interstitium, breaching the tubular basement mem- to have ATN.
brane and evoking a tubulitis (. Fig. 32.1). The patho- As mentioned previously, on rare occasions where
logical process of AIN is often patchy except in severe renal biopsy is precluded (generally by an absolute need
cases and does not involve the glomeruli or vessels. for anti-coagulation), then a gallium scan may give some
valuable information; however, this is rare.
590 V. M. Muthuppalaniappan and S. Ball
A wide range of medications have been implicated in AIN; therefore, any medication should be considered as a potential cause. Those
shown have consistently been reported in case series and/or case-control studies.
1Reported association with granulomatous AIN
. Fig. 32.2 Medium power renal biopsy showing intense acute . Fig. 32.3 High power image of a giant cell in a patient with acute
TIN with diffuse inflammatory cells and gross granulomata in a TIN
patient with AKI and a calcium of 3.9 mmol/L detected after start-
ing vitamin D supplements
Acute Tubulointerstitial Nephritis
591 32
32.2.4.5 Biomarkers Still in Research Phase widespread use of this class of agents, then this may be
Monitoring of sensitive urinary markers of tubulointer- increasingly recognised in patients with rheumatoid and
stitial damage, such as neutrophil gelatinase-associated inflammatory bowel disease, in both of which there are a
lipocalin, liver-type fatty acid-binding protein and kid- number of other potential causes of renal impairment.
ney injury molecule-1, has been suggested as a non- Sjögren’s syndrome is commonly associated with
invasive test to evaluate early damage and evolution of renal tubular acidosis, but approximately 4% of patients
interstitial nephritis [17]. with primary Sjögren’s syndrome develop overt renal
disease, half of whom have AIN and the others glomer-
ular disease [20]. Thus, it is important to enquire about
dry eyes or mouth which is an important clue being the
32.2.5 Causes of AIN
predominant presenting symptom in Sjogren’s.
IgG4-related disease (IgG4-RD) is a systemic fibroin-
Drugs by far are the commonest cause of AIN also
flammatory immune-mediated condition. IgG4-RD is
known as an allergic reaction account for 70–75% of all
characterised by elevated levels of serum IgG4 (seen in
AIN from biopsy series [13, 18]. Antibiotics (30–50%)
two-thirds of patients), lymphoplasmacytic and IgG4
are the main culprit, followed by NSAIDs and proton
plasma cell-positive infiltrates in a range of organs with
pump inhibitors. Any drug can cause AIN, and knowl-
variable degree of fibrosis that has a characteristic ‘stori-
edge of these drug reactions has come from case reports/
form’ pattern [21, 22]. There is a typical pattern of pro-
studies and retrospective series supported by biopsy
gressive expansile interstitial fibrosis in affected tissues
findings of AIN. Checkpoint inhibitors (anti-CTLA-4
and a plasma cell-rich TIN frequently with eosinophils.
antibody and anti-PD-1 inhibitors) which are used in
It is most often associated with ‘autoimmune’ pancreati-
various forms of cancer have recently been shown to
tis; however, there can be widespread organ involvement
cause AIN. However, these drugs are more commonly
with inflammatory masses, sialadenitis, sclerosing chol-
associated with other immune-related adverse events
angitis, aortitis and retroperitoneal fibrosis. The patho-
such as dermatitis, colitis, pneumonitis and hepatitis. In
genesis of this condition is poorly understood but
fact, nephrotoxicity tends to develop more frequently as
consistent with an autoimmune or an allergic disorder.
a consequence of the above side effects. Drug-related
One-third of cases are associated with an AIN that man-
AIN is idiosyncratic and not dose dependent, and recur-
ifests most often with AKI, however can present as a
rence of exacerbation can occur with a second exposure
renal mass. A retrospective study from Australia showed
of the same or related drug which occurs more rapidly
that IgG4-related TIN represented 1% of the total renal
when rechallenged (refer to Case History 1). Drugs that
biopsies performed over a 10-year period with 13% of all
can cause AIN are also often associated with other side
biopsies showing TIN [23]. The majority of data pertain-
effects which are worth noting as this may help with
ing to IgG4 TIN comes from two series of renal biopsies:
identifying the offending drug. AIN caused by drugs
a Japanese and an American cohort [24, 25]. Renal
can occur up to an average of 2 weeks or even longer
involvement of IgG4-RD causes hypocomplementae-
after starting the medication. See . Table 32.3 for an
mia, but the mechanism causing low C3/C4 levels is not
extensive list of drugs that can cause AIN.
entirely clear. Tubular basement membrane immune
Multisystem diseases associated with AIN account
complexes are also common. Treatment of IgG4-RD is
for 10–20% of cases [13, 18]. AIN is often part of a mul-
with corticosteroid therapy and B cell depletion in ste-
tisystem disease, and renal manifestations may be the
roid resistant or intolerant cases [26]. Maintenance ther-
quickest route to the diagnosis. Many of these condi-
apy with low-dose prednisolone and/or azathioprine,
tions are covered elsewhere in more detail, but it is worth
MMF, calcineurin inhibitors are necessary in multiorgan
noting that renal limited AIN can occur as an early
disease and relapse with elevated serum IgG4 levels [26].
manifestation of what might normally be classified a
Since IgG4-RD is a relatively newly identified and
multisystem disease.
defined disease, further improved understanding of the
Sarcoidosis is associated with renal granulomata very
pathogenesis is still needed to help guide diagnosis and
commonly; however, clinical manifestation of AIN is
treatment.
relatively uncommon [19]. A more common cause of
Systemic lupus erythematosus Tubulointerstitial
renal impairment is hypercalcaemia. There are reports
inflammation is a common and prognostically signifi-
that some forms of glomerular disease are more common
cant manifestation of the SLE which correlates highly
in those with sarcoidosis; however, this remains to be
with renal progression but not with other features of dis-
proved. In recent years, a sarcoid-like illness has been
ease activity [27]. In a small number of patients, intersti-
associated with the use of anti-TNF therapy, and this has
tial nephritis is a predominant feature, and this is
been documented to cause a granulomatous interstitial
commonly associated with a renal tubular acidosis.
nephritis. Although evidently rare, given increasingly
592 V. M. Muthuppalaniappan and S. Ball
Granulomatosis with polyangiitis (GPA) (formally tation is as a granulomatous interstitial nephritis. This
known as Wegener’s granulomatosis) may also be mani- may present with unexplained renal impairment usually
fest as an AIN usually in association with, but some- with a fever, but sometimes remarkably few other symp-
times without, glomerular inflammation [28]. toms. The microbiological diagnosis may not be imme-
TIN with uveitis (TINU) syndrome is rare and has a diately established, the granulomas are not necessarily
female bias (3:1) and a median age of onset of 15, caseating and the Ziehl-Neelsen stain is usually negative.
although cases presenting in middle age are well docu- The diagnosis may only become apparent at a later date
mented. The condition accounts for 5–10% of all AIN or be inferred from a beneficial response to anti-
[13, 18]. Presentation is initially with TIN in two-thirds tuberculous chemotherapy.
of patients, 20% TIN with uveitis and only 15% initially Leptospirosis can result in AIN. The incidence of
as uveitis. In some cases, onset seems to be drug induced. renal failure varies widely in different series but is com-
Other common features reported include fever, weight mon. Other features include presentation with a ‘flu-like
loss, rash, arthralgia, myalgia, anorexia and malaise. illness’, particularly with disproportionate jaundice,
Renal involvement may manifest as renal impairment, thrombocytopenia in some with a bleeding diathesis and
concentrating defects or features of the Fanconi syn- multisystem involvement including pulmonary and cen-
drome. The presumed aetiology is immune dysregula- tral nervous system involvement.
tion with T cell infiltration, but recently IgG antibodies Hantavirus in Europe typically causes nephropathia
have been demonstrated against tubular epithelial cells, epidemica, in which a ‘flu-like illness’ is accompanied by
32 and predictably HLA associations are emerging. The AKI and thrombocytopenia. Travel to endemic areas
TIN of TINU is usually treated with steroids but may may identify the risk [29], perhaps most likely from
resolve spontaneously and generally has a good progno- Central and Eastern Europe. AIN can be striking and is
sis, although in one group, 15% of patients developed often associated with interstitial haemorrhage.
CKD. The prognosis of the uveitis (which is usually In HIV infection, a post-mortem series of HAART
anterior) is less good in that it is much more likely to experienced patients found that 5/89 patients had intersti-
relapse chronically. tial nephritis. The most common cause of interstitial
nephritis in this group appears to be drug associated but
only rarely is this attributable to components of HAART
32.2.6 Infectious Diseases Associated and more commonly due to NSAIDs and co-trimaxazole.
with AIN Epstein-Barr virus is occasionally associated with an
AIN, usually as part of a systemic disease [30]. Reports
A myriad of infectious diseases have been reported caus- that AIN of undetermined cause may be significantly
ing renal disease and specifically with AIN (these condi- contributed to by EBV infection [31] seem not to have
tions are covered in more detail in the chapter ‘Infection been supported by subsequent studies [32].
and the Kidney’). Infectious diseases causing AIN are BK virus is a polyomavirus that causes interstitial
seen in 4–10% of all AIN cases [13, 18]. Whilst with nephritis sometimes granulomatous in renal transplant
some such as tuberculosis, hantavirus and leptospirosis patients and occasionally in other immunosuppressed
the aetiology is clear, causality with some other infec- patients (in whom it may also cause a haemorrhagic cys-
tious agents is not yet proven. titis). The diagnosis is made by renal biopsy; however,
Acute pyelonephritis is characterised by neutrophil quantification of viral DNA in the plasma by poly-
inflammation centred on tubules generally considered merase chain reaction (PCR) or examination of the
to be consequent upon an ascending bacterial infec- urine for decoy cells provides non-invasive means of pre-
tion, although this may not always be proven. Although dicting those at risk. It presents with deteriorating renal
this could reasonably be considered a form of intersti- function, and the diagnosis is made by renal biopsy. The
tial nephritis, it is by convention considered separately. backbone of treatment is reduction of immunosuppres-
Tubulointerstitial nephritis can complicate various sion. Various other treatments have been tried, although
systemic infections (see . Table 32.2). In a large ethni- none have yet been proven to be effective.
cally diverse, urban UK practice, over the course of the Pyelonephritis (covered in detail in Chap. 54) is com-
last 10 years, we have observed relatively few cases defi- monly due to an ascending bacterial infection from the
nitely attributable to infection; these have been due to lower urinary tract which is commonly seen in young
Mycobacterium tuberculosis and leptospirosis. The cau- women who are sexually active or in adults with diabetes,
sation of AIN will however inevitably be significantly renal stones or if immunocompromised. Patients often
affected by the location and population served by any present with fevers, flank pain and urinary symptoms.
centre. Urinalysis often would reveal a pyuria with white cell
Mycobacterium tuberculosis can affect the urinary casts and positive urine culture. The key features of the
tract in various ways; however, one important manifes- renal biopsy in pyelonephritis are the dominant presence
Acute Tubulointerstitial Nephritis
593 32
of neutrophils rather than lymphocytes which are classi- 32.2.7.2 Prognosis and Long-Term Outcome
cally observed in AIN due to hypersensitivity reaction. of Drug-Induced AIN
The long-term outcome of AIN, especially drug induced,
is good. A study from Japan noted that the recovery of
32.2.7 Treatment of AIN AIN occurs in two phases: an initial rapid phase of
recovery over 6–8 weeks, followed by a slower phase
The treatment of AIN depends upon a thorough clinical recovery which can last up to 1 year to ascertain baseline
investigation of potential underlying causes, some of renal function [39]. Longer duration of exposure to the
which have been discussed above. AIN associated with offending drug is associated with worse chance of renal
the aforementioned multisystem inflammatory diseases function recovery [14]. Increased age and persistence of
is invariably treated with corticosteroids, in some AKI for >3 weeks, but not severity of AKI, are associ-
instances with additional immunosuppression. ated with worse long-term outcomes [13, 10].
Adverse prognostic factors in AIN recovery include
32.2.7.1 Management of Allergic AIN or [14, 39]:
Drug-Induced AIN
Drug-induced AIN requires early identification and 5 Diffuse (versus patchy) inflammation on biopsy
immediate withdrawal of the likely offending agent. 5 Excess number of neutrophils (1–6%); extent
Corticosteroid treatment has been used to expedite the 5 Severity of interstitial fibrosis and/or tubular atrophy
rate and extent of renal recovery in drug-induced 5 Smaller kidneys on ultrasound had poorer response
AIN. However, the role of corticosteroids remains con- to steroids
troversial as evidence from retrospective studies that
were generally small in size was conflicting. A study of These factors were found to correlate most closely with
61 patients with drug-induced AIN undertaken in Spain the final glomerular filtration rate. A considerable pro-
has suggested that better outcome was associated with portion of affected patients with AIN; up to 36% of
earlier corticosteroid treatment [33]; however, the retro- patients with AIN develop CKD [13]. Therefore,
spective nature of this analysis means that no recom- patients with AIN should have long-term follow-up
mendation can be conclusive. A similar-sized study from with a clinician for blood pressure and renal function
Ireland suggests no benefit [3]; however, the delay in cor- monitoring.
ticosteroid administration was up to 3 weeks in this If a drug is suspected of causing AIN, then it is
study. Further studies since have demonstrated long- imperative that the patient is aware they are allergic to
term favourable outcomes in those treated with cortico- this drug, and if there is doubt about an important agent,
steroids [16, 33, 34]. Early treatment with corticosteroids such as penicillin, then it is critical that the practitioner is
(within the first 5–7 days) after discontinuation of the aware and monitors renal function within a few days of
offending drug can reduce the amount of tubulointersti- any rechallenge. Nephrologists have the responsibility of
tial fibrosis that develops and association with better ensuring that this information is clearly imparted.
recovery of renal function [33, 35, 36].
There are no prospective studies or established guide- Tips and Tricks when Approaching a Case of Suspected AIN
lines till date suggesting the use of corticosteroids rou-
tinely, but it seems reasonable to recommend that if E Consider AIN if there is a temporal relationship
used, corticosteroids should be introduced early. Several of drug, infection or systemic process with a
authors have recommended an early pulse of corticoste- progressive rise in serum creatinine. Remember
roids for 3 days, followed by a reducing course of oral that manifestation of drug-induced AIN differs
prednisone (0.5–1 mg/kg/day) over ~6 weeks [18], whilst for different drugs but generally an average
others (conventional dosing strategy) have recommended latency period of 10–14 days has been sug-
prednisolone at 1 mg/kg (maximum dose of 60 mg gested.
orally) with a view to taper over the next 2–3 months E Always look for extra-renal manifestations or
[16]. Regardless of the initial dose of steroids, Gonzalez other haematological or biochemical abnormal-
and colleagues suggested continuing prednisolone at ities which can help point out towards the
1 mg/kg for the first 4–6 weeks as most recovery in renal offending drug.
function occurs within this time frame. E Think AIN is abnormal urinary sediment with
There has also been emerging evidence and anec- evidence of pyuria, non-nephrotic range pro-
dotal reports suggesting benefit from mycophenolate teinuria and eosinophiluria.
mofetil [37], cyclophosphamide and cyclosporine [38], E Always try to identify the offending agent and
though the evidence on these treatments remains sparse. withdraw and assess serum creatinine.
594 V. M. Muthuppalaniappan and S. Ball
Case Study
E Consider renal biopsy if suitable and no contra-
indications. Case 1
E Consider corticosteroid therapy if no contrain- A 75-year-old man presented non-specifically unwell
dications at a suggested dose of 1 mg/kg/day with AKI 3 (creatinine 830 μmol/L) and hyponatrae-
tapered over 2–3 months if nil improvement in mia (sodium 124 mmol/L). He was otherwise haemo-
serum creatinine with conservative measures. dynamically stable and had only 1+ of protein in his
E Think of the presence and/or extent of intersti- urine with no evidence of pre- or post-renal (renal
tial fibrosis with scarring if poor response with sizes normal) causes or sepsis. He was on no over-the-
corticosteroid therapy. counter medication but was prescribed a calcium
channel blocker, beta blocker, thiazide diuretic and
proton pump inhibitor (PPI). He had also finished a
course of penicillin for a community-acquired chest
Summary and Key Points
infection. A renal biopsy confirmed an acute tubu-
5 AIN is a hypersensitivity reaction leading to
lointerstitial nephritis (TIN) which was presumed to
inflammation of the renal interstitium.
be drug induced. His renal function improved rapidly
5 Commonly caused by drugs, infections and auto-
with conservative measures. A review of previous
immune and systemic conditions.
32 5 Presents with acute kidney injury +/− classic pre-
blood tests demonstrated a previous milder episode
of AKI, 3 years before (see . Fig. 32.4). Reviewing
sentation of hypersensitivity (maculopapular rash,
the medications with his practitioner, it was clear that
eosinophilia/eosinophiluria, fever) +/− proteinuria
this correlated with a course of PPI for indigestion
(less than 1 g/day) +/− haematuria.
and not related to penicillin or thiazide, although the
5 Resolution of symptoms is with withdrawal of the
connection has not been made at the time. It is not
offending drug or treatment of the underlying
always possible to determine which medication is
cause if not due to medications.
responsible for an AIN, and avoiding key drugs for
5 Definitive diagnosis is made via renal biopsy as
life on speculation may result in disadvantage to the
other investigations (laboratory and imaging) lack
patient. A thorough review of the drug history and
specificity and sensitivity.
biochemistry may identify a candidate drug or, as in
Management consists of supportive care, careful this case, allow a stratification of the risk from mul-
fluid balance, withdrawal of offending drugs and corti- tiple candidate drugs.
costeroid therapy.
Creatinine
1000
? Chapter Review Questions 2. Which clinical feature below is not commonly asso-
1. What is the commonest offending drug that can ciated with AIN?
cause an allergic AIN? (a) Fever
(a) NSAIDs (b) Visible haematuria
(b) Antibiotics (c) Arthralgia
(c) Proton pump inhibitor (PPI) (d) Proteinuria
(d) Checkpoint inhibitors (CPI)
596 V. M. Muthuppalaniappan and S. Ball
3. What is the best diagnostic test available to estab- tial screening but have a poor diagnostic utility as
lish a diagnosis of AIN? often IgG4 levels can be affected by other disease
(a) 67Ga scanning conditions as well. Corticosteroids are the first-
(b) Renal biopsy line agent for inducing remission in active IgG4-
(c) Eosinophiluria related disease. Rituximab is the commonest
(d) Analysis of low molecular weight protein in biological agent used in IgG4-related disease.
urine
Acquired Chronic
Tubulointerstitial Nephritis
Heidy Hendra, Mark Harber, and Ben Caplin
Contents
References – 608
aEvidence for the factors in parentheses as a cause of aCIN are supported by limited data (e.g. the evidence may suggest these factors
may be the cause of acute rather than chronic interstitial nephritis or derive from animal models)
602 H. Hendra et al.
33
. Fig. 33.2 Global distribution of acquired chronic interstitial of CKDu; Yellow: High population prevalence of aristolochic acid
nephritis. Red: Recent population-based evidence of high rates of nephropathy or Balkan endemic nephropathy; Blue: Historic high
CKDu (Mesoamerican nephropathy or chronic interstitial nephritis rates of analgesic nephropathy; Green: Historic clusters of CKD due
in agricultural communities); Orange: Reports of possible high rates to environmental metal contamination
ulations or clusters of disease due to known causes (see min/1.7 m2) is close to 20% in some communities [3].
below . Fig. 33.2). For example, the UK Renal Registry This clinical syndrome is described as CKD of undeter-
suggests only 18% of incident ESKD patients have a pri- mined cause (CKDu). . Figure 33.2 illustrates regions
mary renal disease diagnosis of ‘other’ (the category that where clusters aCIN due to known causes as well as
would include aCIN but also a number of other unre- CKDu have been reported.
lated diagnostic entities; . Fig. 33.3), although in some
regions, patients with aCIN, who have not been biopsied,
may fall into an ‘unknown’ category, making robust esti- 33.4 Aetiopathology, Features
mates of the prevalence difficult to establish. and Management
There are regions where known causes of aCIN con-
tribute, or have contributed, to a substantial burden of
ESKD, for example, aCIN secondary to Aristolochia in 33.4.1 Drugs
the Balkans [1] or phenacetin in Australia [2]. However,
more recently, there is an increasing recognition of 33.4.1.1 Lithium
aCIN of unknown cause that has reached epidemic lev- Lithium therapy is associated with a number of renal
els in areas of South Asia and Central America (and disorders including (most commonly) diabetes insipi-
perhaps elsewhere) where the prevalence of impaired dus, a more generalised tubular dysfunction, CKD and
kidney function (a single value of eGFR <60 mL/ acute kidney injury in overdose. Additional complica-
Acquired Chronic Tubulointerstitial Nephritis
603 33
Renal vascular tis (CIN), but avoiding other nephrotoxic agents and
disease early treatment of hypercalcaemia would seem prudent.
Pyelonephritis Although there is good pre-clinical evidence that
amiloride blocks lithium uptake into the tubular cell,
Uncertain this agent has not been robustly evaluated in the man-
Polycystic kidney
disease agement of lithium-induced CIN.
O
OH
33.4.2 Metals
33.4.8 Chronic Kidney Disease . Fig. 33.5 Renal biopsy from a patient with Mesoamerican
nephropathy. PAS stain ×20. The biopsy demonstrates areas of tubu-
of Undetermined Cause lar atrophy and interstitial fibrosis along with periglomerular fibrosis
but without evidence of glomerular cell proliferation. Some intersti-
Notwithstanding the diagnostic uncertainty as to the tial inflammation is seen in scarred areas. (Image courtesy of Annika
33 precise cause of disease even where aCIN is identified Wernesson and Julia Wijkstrom, Karolinska Institute, Sweden)
on biopsy, this group of conditions is a relatively rare
cause of CKD in many populations, particularly in ents as a typical aCIN with little in the way of positive
high-income regions. Clusters of high prevalence of clinical findings until uraemia develops, although symp-
aCIN due to known causes occur globally and are dis- toms of hyperuricaemia are often particularly promi-
cussed above, but it is also increasingly clear that forms nent in advanced MeN. The natural history of CKDu is
of aCIN of unknown cause are responsible for a huge poorly described, but evidence from Central America
burden of (often untreated) ESKD in a number of pop- suggests MeN is a highly aggressive disease [36] and
ulations in low- and middle-income countries anecdotally young men will progress from a serum cre-
(. Fig. 33.2). The umbrella term CKD of undeter- atinine in the normal range to ESKD in as little as
mined cause (CKDu) is useful to describe the epidemic 5 years.
levels of aCIN of unknown aetiology, specifically in Although renal biopsy is not routinely available in
Central America, where it is termed Mesoamerican most communities impacted by CKDu, these have been
nephropathy (MeN) [32], and Sri Lanka, where it is performed in the research context [37, 38].
labelled as chronic interstitial nephritis in agricultural Histopathology (. Fig. 33.5) is remarkably similar
communities (CINAC) [33]. It should be emphasised between endemic areas (Central America versus Sri
that CKDu, a highly prevalent aCIN occurring in low- Lanka) and demonstrates tubulointerstitial damage,
and middle-income settings, is not synonymous with the fibrosis, signs of glomerular ischaemia (but no prolifera-
ESKD of unknown causes reported in the renal regis- tion or immune complex deposition) and typically low
tries of high-income countries which likely represents a levels of inflammatory infiltrate.
heterogeneous group of conditions including chronic Proposed causes of these diseases are wide ranging
undiagnosed glomerulonephritis, congenital abnormali- and include recurrent pre-renal injury and heat stress
ties and vascular disease. However, the relationship (due to extremely poor work conditions), agrichemical
between CKDu in low- and middle-income countries toxicity, metal exposure, as yet unidentified infection,
and the clusters of aCIN of unknown aetiology occur- myco- or phytotoxins, nephrotoxic drugs or contami-
ring in specific populations living in other higher-income nated alcohol, and underlying genetic predisposition, all
parts of the world is unclear, for example, the excess of either individually or in combination. However, despite
CKD seen in those of Guajarati origin in the UK [34]. over a decade of research efforts, conclusive evidence as
As discussed in the ‘Epidemiology’ section above, to the cause of disease (or diseases, as despite the simi-
CKDu is currently the leading cause of death among larities CKDu may represent a number of different con-
working-age men in Nicaragua [35]. The disease pres- ditions) remains absent.
Acquired Chronic Tubulointerstitial Nephritis
607 33
Tips, Tricks and Pitfalls v Answers
1. Patients with aCIN typically present without clear
Patients with aCIN may well be asymptomatic with- symptom. Proteinuria, haematuria and hyperten-
out hypertension or urinary abnormalities on routine sion are often absent; however, urinary concen-
screening. trating defects or electrolyte abnormalities can be
Presentation may be with incidental low eGFR an early sign of aCIN.
(even within the normal range but low for age). 2. Nephrogenic diabetes insipidus (NDI) is the com-
Renal biopsy may not provide a clear diagnosis, and monest renal adverse effect of lithium therapy as it
a thorough social, medical, travel and occupational his- occurs in up to 40% of patients. A study from Sweden
tory is key to establishing the cause of disease. estimated ~0.5% of the lithium-treated population
reach ESKD and those with lithium-induced ESKD
make up less than 1% of the RRT population.
? Chapter Review Questions 3. Characteristics of analgesic nephropathy in CT
1. What can be an early sign of aCIN? are papillary necrosis/calcification and indented
2. What is the commonest renal adverse effect of or irregular kidney contours; however, one should
lithium therapy, and how common is it for patient beware in mind that similar appearances can be
who is receiving long-term lithium treatment to found in patients with sickle-cell-associated kid-
progress to ESKD? ney disease.
3. What would one see on CT in patients with anal- 4. While many metals have been implicated in aCIN,
gesic nephropathy? mercury is also associated with membranous
4. Which heavy metal exposure has been reported to nephropathy.
cause membranous nephropathy? 5. Formation of covalent DNA adducts which lead
5. Aristolochic acid can lead to urothelial malig- to mutations in the TP53 tumour-suppressor gene
nancy in some patients with renal disease. Which underlies the development of urinary tract malig-
mutation underlies this development? nancy in patients taking aristolochic acid.
Case Studies
1. A 29-year-old was referred by his GP when found to be abnormal renal function (130micromol/L). He had a
anaemic (haemoglobin of 81) when presenting to history of investigations for abdominal pain, malaise
donate blood. He was a bit tired and would pass urine and weight loss for which no cause was found and gen-
once a night, but was otherwise asymptomatic and no eral malaise. He had been taking some traditional
history of renal injury, no past medical history and no medicines. On examination, he had a non-specific mac-
family history of note. He had no prescribed, over-the- ular rash predominantly on the palms and soles of his
counter, recreational or homeopathic medication. feet but also on both forearms and neck. Investiagtions
Examination revealed a well-looking individual with a demonstrated a urine protein 1+ on urinalysis (urine
blood pressure of 125/73. Urinalysis reveled 1+ pro- protein: creatinine ratio 84) with no blood, urea
tein, with no white blood cells on urine microscopy, 12.5mmol/L, bicarbonate 17mmol/L, haemoglobin
blood tests demostrated creatinine 430micromol/L, 79g/L. Further screening demonstrated a proximal
urea 21 mmol/L, normal calcium, ESR 6mm/hr, CRP tubular acidosis as part of Fanconi’s syndrome. The
3mg/L. Virology, immunology and myeloma screen kidney lesion was attributed to chronic heavy metal
were all clear. An ultrasound revealed smallish (9 cm) toxicity, which was confirmed on both blood and hair
kidneys with a normal bladder. samples and thought to be due to exposure to ground
A biopsy subsequently showed relatively preserved water or the herbal remedy. Heavy metal poisoning
glomeruli with disproportionate chronic tubulointersti- typically presents with non-specific symptoms such as
tial damage. The original cause was not identified, but malaise, disproportionate anaemia (as in this case),
minimal findings on the dipstick, nocturia and a good/ tubular disorders and rashes. In chronic arsenic poi-
low blood pressure (in the absence of a pre- or post- soning, a macular rash on the palms and soles is char-
renal cause) are strongly suggestive of an aCIN. Active acteristic.
autoimmune, allergic and infectious causes would seem 3. A 62-year-old tennis coach and retired professional
unlikely given the lack of inflammatory response and a tennis player was referred with a low eGFR (27 mls/
presumptive diagnosis of aCIN might have been made min and creatinine of 220micromol/L). With the
without a biopsy. exception of two hip and one knee replacement, he
2. A 41-year-old self-employer IT technician from had no significant medical history and remained very
Bangladesh was referred to clinic for investigation of fit. The urine was inactive with minimal proteinuria.
608 H. Hendra et al.
Kidneys were 8.5 cm bilaterally on ultrasound. On acteristic lobulated appearance consistent with
direct questioning, he had a heavy consumption of AN. As with many aCIN progression of AN appears
analgesics for much of his professional career (exceed- to be relatively slow once the causative agent is with-
ing the 3000 doses typically associated with analgesic drawn, particularly in the absence of high-level pro-
nephropathy). A non-contrast CT demonstrated char- teinuria.
33.5 Conclusion 15. Emmerson BT. “Ouch-ouch” disease: the osteomalacia of cad-
mium nephropathy. Ann Intern Med. 1970;73(5):854–5.
16. Nogawa K, Kido T. Biological monitoring of cadmium exposure
Acquired chronic tubulointerstitial disease represents a in itai-itai disease epidemiology. Int Arch Occup Environ Health.
heterogeneous group of disorders which although a gen- 1993;65(1 Suppl):S43–6.
erally rare cause of CKD in high-income countries are 17. Hsu LI, et al. Arsenic exposure from drinking water and the inci-
responsible for clusters of ESKD due to known causes in dence of CKD in low to moderate exposed areas of Taiwan: a
14-year prospective study. Am J Kidney Dis. 2017;70(6):787–97.
a number of regions. Furthermore, forms of aCIN with- 18. Hellstrom L, et al. Cadmium exposure and end-stage renal dis-
out a known cause prevalent in low- and middle-income ease. Am J Kidney Dis. 2001;38(5):1001–8.
countries are increasingly recognised as a significant 19. Sommar JN, et al. End-stage renal disease and low level expo-
global health problem. Identification of the causative sure to lead, cadmium and mercury; a population-based, pro-
agent can be challenging but is critical as amelioration of spective nested case-referent study in Sweden. Environ Health.
Genetic Tubulointerstitial
Disease and Nephronophthisis
Alice Gage, Buddhika Illeperuma, and Mark Harber
Contents
34.1 Introduction
34 34.3 ADTKD-UMOD
In 2015, KDIGO produced a consensus report which pro-
posed the current classification of ADTKDs to replace Uromodulin (also known as Tamm-Horsfall glycoprotein)
previous nomenclature which included ‘medullary cystic is a genuinely fascinating molecule produced solely in the
kidney disease’ as well as providing guidance on diagnosis kidney and with pleiotropic roles [4]. These include preven-
and management which has enhanced awareness and tative roles in stone formation by reducing aggregation of
understanding of these conditions [1]. The main genes calcium in super-saturated filtrate and urinary tract infec-
associated with ADTKD are UMOD, MUC1, REN and tion by binding to uropathogenic E. coli inhibiting bacte-
HNF1B, although new mutations and genes allied to this rial adhesion to uroepithelial cells. It is also involved in salt
group continue to be discovered. They share an incon- and water regulation via the NKCC2 co-transporter and
spicuous renal presentation, with the not infrequent potassium ROMK channel as well as being implicated in
occurrence of cysts which can be cortical or medullary innate immunity and immune regulation within the kidney.
and do not usually result in renal enlargement. However, In this context, variants of uromodulin have been associ-
there are some clinical clues to indicate the pathological ated with a propensity to stone formation, CKD and
process and differentiate between the individual diseases hypertension in the general population.
(. Fig. 34.1). The current state of knowledge with ADTKD-UMOD is probably the commonest form
ADTKDs is very nicely reviewed by Devuyst et al. [2]. of ADTKD, with one UK study finding a prevalence of
These conditions range from rare to very rare, 2% in ESRD patients [5]. It results from mutations in the
although it is likely that they are underdiagnosed given uromodulin gene that are mostly missense mutations
the paucity of constitutional symptoms or urinary find- causing disruption of conserved cysteine residues and
ings that normally trigger investigation. A recent analy- resulting in misfolding of the mature protein.
sis of patients with end-stage renal failure in Ireland
found a prevalence of 0.54% with a mutation consistent
with ADTKD; this group comprised 42.6% MUC1, 34.3.1 Aetiology and Pathogenesis
32.5% UMOD and 13% NHF1-ß mutations [3]. An
increased awareness of these conditions is likely to result Misfolded uromodulin is abnormally trafficked with
in a greater prevalence and earlier diagnosis as well as reduced expression on the apical surface of the epithe-
the discovery of new mutations. lial cell and progressive accumulation in the endoplas-
Inherited renal ciliopathies include ADPKD, mic reticulum particularly in the thick ascending limb
X-linked disorders such as oral-facial-digital syndrome (TAL). This results in ER stress, apoptosis, progressive
and a heterogeneous but important group of autosomal interstitial fibrosis, tubular atrophy, microcyst formation
recessive conditions such as ARPKD (discussed else- and a secondary inflammatory infiltrate.
Genetic Tubulointerstitial Disease and Nephronophthisis
613 34
. Fig. 34.1 Genes associated with ADTKD and associated clinical notype may vary significantly in NHF1-ß so as to appear unrelated
features. All are associated with CKD, minimal proteinuria/bland kidney conditions. CAKUT congenital abnormalities of the kidney
urine and an autosomal dominant family history, although the phe- and urinary tract, MODY maturity-onset diabetes of the young
34.3.2 Clinical Features Although not a standard test, it may be possible to dem-
onstrate excess uromodulin by immunofluorescence or
In common with all ADTKDs, the presentation of to demonstrate low levels of urinary uromodulin. A
ADTKD-UMOD is usually unflamboyant, with pro- definitive diagnosis is likely to rely on genetic testing.
gressive CKD, a bland urinary sediment, an absence of
hypertension and a mild urinary concentration defect.
Hyperuricaemia (70%) and gout (50–75%) are common. 34.3.4 Treatment
Gout tends to be early onset (mean age 21), and men are
often worse affected [6]. The clinical course is very vari- There is no specific treatment for ADTKD-UMOD
able, but the median age of ESRD is in the mid-50s. apart from normal supportive measures for progressive
Cysts are seen in a proportion of patients, but their CKD. As with most tubulointerstitial disease, hyperten-
absence should not be considered strong evidence sion is not a major feature and diuretics may exacerbate
against the diagnosis. As mentioned previously, this is hyperuricaemia. Management of hyperuricaemia with
one reason why the old name of ‘medullary cystic kid- xanthine oxidase inhibitors makes sense in controlling
ney disease type 2’ has been retired. In addition, the gout, although there is no data to suggest that it slows
absence of early onset gout in many people with the dis- progression. Uricosurics such as benzbromarone or
order has rendered the alternative name of ‘familial losartan (but probably not salicylic acid) might also be
juvenile hyperuricaemic nephropathy’ similarly unhelp- helpful. Renal transplantation is curative (with disease
ful. recurrence in an allograft not described), but potential
familial live donors need genetic screening to exclude
the diagnosis.
34.3.3 Diagnosis
34.4.1 Aetiology and Pathogenesis ing [7]. However, genetic testing showing a heterozygous
mutation in the MUC1 sequence is currently the best
Mucin-1 is a membrane-bound mucoprotein found on way to confirm a diagnosis [8].
the apical surface of epithelial cells in many tissues
including reproductive organs, glandular tissue and the
renal tubules. The protein has an extracellular domain, 34.4.4 Treatment
which includes a variable number of Mucin repeats, a
transmembrane domain and a cytoplasmic tail that can The management of ADTKD-MUC1 is based around
undergo phosphorylation mediating several intracellu- preventing the sequelae of CKD. Maintaining adequate
lar processes. Its functions include promoting cell hydration and avoiding nephrotoxic medications are
growth and survival as well as preventing pathogen inva- also important. If an individual progresses to end-stage
sion of the cell [8]. renal failure, transplantation is a curative intervention
In ADTKD-MUC1, there is a single cytosine ade- and good outcomes have been reported in this patient
nine insertion in the variable number tandem repeat group. Given the mode of inheritance and variable age
which encodes the extracellular Mucin repeat part of of development of CKD, family members who come
the protein. The aberrant protein Mucin-1–frame- forward for live donor transplantation should undergo
shifted (MUC1-fs) is unable to serve its intended protec- genetic testing to determine their status.
tive function and accumulates in the cytoplasm leading
to premature cell death [9]. This causes progressive
nephron loss and therefore chronic kidney disease. 34.5 ADTKD-REN
Interestingly, in ADTKD-MUC1, this effect is isolated
to renal tubular cells and not seen in other tissues. ADTKD-REN is a rare but interesting group of dis-
34 eases resulting from mutations in the renin gene leading
to progressive CKD with a bland urinary sediment.
34.4.2 Clinical Features There are some clinical features that make it more dis-
tinguishable.
ADTKD-MUC1 is notable for its lack of distinctive
characteristics [10], and this almost certainly contributes
to a relatively late age of initial diagnosis (40 years). 34.5.1 Aetiology and Pathogenesis
Individuals present with an elevated serum creatinine
and bland urinary sediment in the context of a family These conditions result from mutations in either the
history of autosomal dominant kidney disease. renin promoter, prosegment or mature renin peptide.
Hyperuricaemia and gout do occur but to a lesser degree Renin is expressed throughout the renal tubule and jux-
than in ADTKD-UMOD, and again renal cysts are taglomerular apparatus. In normal circumstances, pre-
sometimes observed in affected individuals (hence the prorenin is translocated to the endoplasmic reticulum
older name of medullary cystic kidney disease type 1 where it is cleaved to form prorenin and some is translo-
that has now fallen out of use). However, they do not cated to the lysozyme and cleaved to form active renin.
have any other biochemical or imaging abnormalities to Mutations of the promoter and prosegment lead to fail-
point towards a specific diagnosis. The kidneys are nor- ure of normal translocation and processing, resulting in
mal or small in size depending on the degree of chronic reduced functional renin and an accumulation of
kidney disease. Biopsy findings are also non-specific mutated peptide in the ER. This stresses the ER causing
with features of interstitial fibrosis, tubular atrophy and apoptosis, premature cell death and ultimately CKD.
vasculopathy with minimal inflammation. While the Patients with mutations solely affecting the mature
mutations demonstrate complete penetrance, the age of renin peptide probably avoid or incur less cell death
progression to end-stage renal failure varies widely from from deposition of abnormal peptide but will share the
20 to 60 years (average 51) [7]. characteristics of a low renin state.
There needs to be a high suspicion of a diagnosis of Reduced renin levels result in clinical features that may
ADTKD-MUC1 in an individual with progressive CKD give useful diagnostic clues. An early feature is mild to
and a family history of autosomal dominant kidney dis- moderate anaemia which is hypoproliferative and asso-
ease in the absence of significant cystic disease on imag- ciated with low erythropoietin levels. This may present
Genetic Tubulointerstitial Disease and Nephronophthisis
615 34
in the second year of life and if apparent in the context as slowly progressive CKD. HNF1B mutations are also
of CKD tends to be out of proportion with eGFR. The associated with extra-renal manifestations including
anaemia may improve or disappear in adolescence sec- maturity-onset diabetes of the young (MODY), abnor-
ondary to the increase in sex hormones. The hyporeni- mal liver function tests and genital tract abnormalities.
naemic state results in a lowish blood pressure and a
propensity for pre-renal AKI with relatively mild insults
or a disproportionate drop in eGFR with NSAIDs. 34.6.1 Aetiology and Pathophysiology
Patients tend to have mildly elevated serum potassium
levels. They may also have hyperuricaemia and therefore How HNF1B mutations result in adult renal disease has
can present with gout. Patients with mutations involving not been fully elucidated but includes abnormal
the renin promoter or prorenin segment tend to have epithelial-mesenchymal transformation, aberrant
slowly progressive CKD, reaching end-stage renal fail- TGF-β expression and mitochondrial disease [11].
ure at an average age of 52, w hereas those with abnor-
malities of the mature renin peptide are more likely to
present earlier with gout in their 20s with a greater range 34.6.2 Clinical Features
of age at the time of development of end-stage renal dis-
ease (median age of 64). Despite the autosomal dominant inheritance of NHF1-ß
mutations, the diagnosis is often difficult as there can be
a large variation in clinical presentation. Even within
34.5.3 Diagnosis one family, individuals can present with seemingly iso-
lated developmental abnormalities of the kidney and
Unexplained childhood anaemia, episodes of unex- urinary tract. Renal manifestations in adulthood include
pected AKI, mild hypotension, mild hyperkalaemia and CKD minimal proteinuria, hypomagnesaemia and renal
gout early in life are all suggestive and should be cystic change that can result in renal enlargement (in
enquired about particularly in the context of reduced which situation patients may be misdiagnosed with the
eGFR and a family history. These features, although far more common autosomal dominant polycystic kid-
subtle, should give a pretty high index of suspicion, but ney disease).
the definitive diagnosis is through genetic testing as Extra-renal manifestations that are helpful in raising
biopsy findings are non-specific but may show IFTA in the diagnosis are MODY (initially non-insulin-
the context of normal glomeruli. dependent diabetes before 25 years) with CT findings of
pancreatic atrophy. Unexplained raised liver function
tests are relatively common, and some patients may have
34.5.4 Treatment early hyperparathyroidism and autism or develop chro-
mophobe renal cell carcinoma. Ultrasound scans of
Protecting the patient’s intravascular volume by avoid- older children with NHF1-ß suggest that abnormal cor-
ing a low-salt diet makes sense, and fludrocortisone is ticomedullary differentiation is common (78%) is are
helpful in maintaining intravascular volume. hyper-echoic kidneys (50%), with subcortical cysts
Theoretically, fludrocortisone will have a negative feed- detectable in 70% and around a third of kidneys small at
back on renin production and therefore slow injury to presentation (REF). However, this represents patients
tubules from denatured proteins, although to date clini- scanned at an early age presumably because of some
cal benefit has not been proven. Patients should also aspect of presentation or family history. Findings may
avoid NSAIDs and volume depletion and may benefit be less clear in those patients destined to develop ESRD
from uric acid reduction with xanthine oxidase inhibi- in late adulthood.
tors. Transplantation is curative.
34.6.3 Diagnosis
34.6 ADTKD-HNF1B
The diagnosis may be suggested by the family history, a
Mutations of the HNF1B gene, which encodes low magnesium or high uric acid level, although none of
Hepatocyte Nuclear Factor-1-β, are associated with this is pathognomonic. MODY is an important clue,
renal disease in two main ways: (a) via a variety of con- and a review of an abdominal CT specifically for pan-
genital abnormalities of the kidney and urinary tract creatic atrophy might be indicative as might be persis-
(CAKUT) and tubular development and (b) later in life tently abnormal liver function tests with normal
with ADTKD, fibrosis and tubular atrophy presenting synthetic function and no alternative explanation or
616 A. Gage et al.
genital abnormalities. Renal biopsy is likely to show dis- est cause of ESRD in the first three decades of life
proportionate IFTA but relatively preserved glomeruli (. Fig. 34.2). They are, not infrequently, associated
which should raise ADTKD as a diagnosis but is not with extra-renal manifestations that result in significant
diagnostic. The definitive diagnosis is based on genetic disability. The proteins encoded by NPHP 1-13 are all
testing. expressed either in the primary cilia, the centrosome or
basal bodies at the base of cilia in renal epithelial cells.
This may result predominantly in renal disease or in a
34.6.4 Treatment proportion of patients serious extra-renal consequences
and responsible for a growing variety of clinical mani-
There is no specific treatment for ADTKD-NHF1-ß festations such as Joubert, Jeune, Meckel-Gruber and
mutations, but it makes sense to educate and support the Bardet-Biedl syndromes with tapetoretinal degeneration
patient in avoiding obesity and avoiding drugs that are (retinitis pigmentosa) and progressive blindness a com-
diabetogenic. Transplantation is curative for renal mani- mon feature (20%). The understanding of the mutations
festations but with a presumably high risk of NODAT in causing these diseases is improving rapidly and is com-
patients with pancreatic atrophy treated with CNIs and prehensively reviewed by Devlin and Sayer [13].
steroids. The commonest (comprising 20%) of the nephro-
nophthisis is NPHP-1 and ranges from 1:10,000 live
births in Finland to 1:50,000 in Canada but seemingly
34.7 Rarer Forms of ADTKD less common elsewhere. As a group, they are responsible
for between 2% and 15% of ESRD in children and usu-
There are a small number of rare pedigrees described ally diagnosed early in life.
with other mutations resulting in tubulointerstitial kid-
34 ney disease. Mutations of the alpha-subunit of SEC61
have been shown to be associated with abnormal trans- 34.7.3 Aetiology and Pathophysiology
location through the ER and accumulation of abnormal
SEC61 in the tubular epithelial cells. These mutations As with ADTKD, a variety of genetic mutations result
are associated with a rare phenotype of small kidneys, in a common pathway of renal epithelial cell disease. In
simple cysts and neutropenia. nephronophthisis, the common pathway is via ciliary
dysfunction. NPHP mutations impair intracellular sig-
nalling resulting in dysregulated tissue growth and
34.7.1 Mitochondrial Cytopathy-Related development of cysts. Histology demonstrates intersti-
Interstitial Renal Disease tial fibrosis and atrophy, tubular cysts, thickened/multi-
layered basement membranes, relatively well-preserved
Until now, the most common presentation of mitochon- glomeruli (although secondary atrophy occurs with pro-
drial DNA diseases involving the kidney has been gression) and with limited inflammation [14].
Fanconi syndrome with case reports of FSGS and ste-
roid-resistant nephrotic syndrome. However, a study of
a large pedigree of maternal inherited tubulointerstitial 34.7.4 Clinical Features
disease recently identified a mutation causing functional
impairment of mitochondrial tRNA. The phenotype The clinical features are somewhat heterogeneous
was not associated with Fanconi syndrome or any sys- depending on the mutations involved and severity of
temic neurological deficit. Given the huge metabolic renal dysfunction. Urinary concentration disorder may
workload of the kidney and the relatively subtle presen- be an early symptom with polyuria and polydipsia.
tation of this form of mitochondrial disorder, it would Renal dysfunction is usually associated with normoten-
not be surprising if further mitochondrial mutations are sion (perhaps not with NPHP-2) and a bland urine and
found to result in tubulointerstitial disease. The biggest normal or small kidneys on ultrasound. Cysts may be
diagnostic clue here was maternal transmission [12]. apparent but they are usually small. Retinitis pigmen-
tosa typically presents with loss of night vision and
then progressive visual loss. Those with other extra-
34.7.2 Nephronophthisis renal manifestations may present very early with learn-
ing difficulties and cerebellar, hepatic, ocular or
Nephronophthisis is a heterogeneous (and expanding) psychomotor signs. The key features of some epony-
group of ciliopathies with autosomal recessive inheri- mous syndromes linked with NPHP are shown in
tance that are important because they are the common- . Table 34.1.
Genetic Tubulointerstitial Disease and Nephronophthisis
617 34
Nephrocystin - 1 Inversin Nephrocystin-3 Nephrocystin-4 Nephrocystin-5 Nephrocystin-6 Gli-similar protein-2 RPGRIP1L NEK-8
mutations mutations mutations \nephroretinin \Retinitis mutations mutatios mutations Mutations
mutations pigmentosa
ESRD aged 13 ESRD before 2 ESRD aged 19 GTPase regulator Variable CKD Juvenile CKD Joubert Renal cysts
years of age. (10-adulthood) Variable age of (RPGR) syndrome Cardiac and
ESRD from 11-34 mutations Cerebellar vermis Meckel- liver disease
Retinitis Retinitis Cerebellar ataxia aplasia (MTS), Gruber
pigmentosa pigmentosa Retinitis pigmentosa Retinitis Childhood ESRD Joubert’s syndrome syndrome
Oculomotor Situs inversus Hepatic fibrosis, pigmentosa Bardet-Biedl
apraxia Heart valve, Oculomotor apraxia Oculomotor severe syndrome
Occasionally Septal defects Cone-shaped epiphyses apraxia Retinitis Meckel-Gruber
Joubert syndrome Hepatomegaly Heart valve or septal pigmentosa syndrome
and Cholestatic defects, Retinitis pigmentosa
liver disease Situs inversus amaurosis
Hypertension polydactyly
Relatively large CAKUT
kidneys
. Fig. 34.2 Characteristics of the first nine NPHPs demonstrating nitis pigmentosa (20%)). MTS molar tooth sign, CAKUT congenital
common themes in terms of CKD and extra-renal manifestations abnormalities of the kidney and urinary tract, ESRD end-stage
including Senior-Loken syndrome (combination of NPHP and reti- renal disease
Case Study
Nephrology Interface
Contents
Rheumatological Conditions
and the Kidney
Conall Mac Gearailt, Áine Burns, and Bernadette Lynch
Contents
References – 638
Rheumatological Conditions and the Kidney
625 35
n Learning Objectives vascular damage, immune activation and inflammation,
1. To educate about renal complications of rheuma- culminating in fibrosis which is responsible for the clini-
tological conditions cal manifestations of the disease [2]. . Table 35.1 sum-
2. To inform about potential renal adverse events marizes the prevalence of extra-renal clinical
subsequent to treatment of rheumatological condi- manifestations seen in SSc.
tions
3. To focus on the epidemiology, pathophysiology
and clinical presentation of conditions such as 35.3 Definition of SRC
scleroderma and rheumatoid arthritis and their
renal manifestations Scleroderma renal crisis (SRC) is characterized by the
4. To provide a useful reference for nephrologists development of accelerated hypertension and acute
dealing with patients with rheumatological disease kidney injury (AKI). The definition of SRC is sum-
in day-to-day clinical practice marized in 7 Box 35.1. SRC usually occurs relatively
5. To aim to encourage a closer working relationship early (within the first 4 years) in the course of aggres-
between rheumatology and nephrology in order to sive skin disease but has also, rarely, been reported to
improve patient outcomes occur in those without obvious or occasionally pre-
ceding skin change and is the presenting feature of
this disease in 22% of SSc patients. Although modula-
35.1 Introduction tors of the renin-angiotensin system have improved
the outcome in SRC, this complication still carries
In this chapter, we aim to educate about renal complica- very significant morbidity with many patients ren-
tions of rheumatological conditions. We also discuss dered permanently dependent on dialysis, and mortal-
complications of therapies which may occur from treat- ity still approaches 25% even in specialist centres [3].
ment. We focus on the renal manifestations of sclero-
derma, rheumatoid arthritis as well as other
rheumatological disorders, demonstrating the epidemi- Box 35.1 Renal Crisis Classification
ology, pathophysiology and clinical manifestations of Definition of SRC
these conditions. The presentation of renal complica- New onset of blood pressure >150/85 mmHg
tions may present acutely, such as in scleroderma renal obtained at least twice over a 24 hour period
crisis, or decades later, as in secondary amyloidosis in Documented decrease in the renal function as
rheumatoid arthritis. We aim to illuminate the most per- defined by a decrement of >30% in the calculated
tinent information relating to the kidney in the field of glomerular filtration rate (eGFR)
rheumatology. This will be a useful aid to any nephrolo- Corroborative features
gist given the proximity of the study of nephrology and Microangiopathic haemolytic anaemia
rheumatology. Hypertensive retinopathy
New onset of urinary RBCs (other causes having
been excluded)
35.2 Scleroderma and the Kidney Flash pulmonary oedema
Oliguria or anuria
Systemic sclerosis (SSc) is a debilitating, chronic, sys- Typical renal biopsy features (. Fig. 35.4)
temic, autoimmune disease of unknown cause. It is clas-
sified as limited or diffuse dependent on skin involvement.
The incidence and prevalence of SSc vary in different
populations where it seems to be more prevalent in the 35.4 Epidemiology of Scleroderma Renal
United States (286 cases per million adults) than in Crisis
Europe (31 cases per million adults) with an annual inci-
dence of 1–20 cases per million. SSc is three times more The reported incidence of scleroderma renal crisis
common in females than males and typically presents (SRC) in SSc patients varies depending on whether lim-
between the ages of 30 and 60 years [1]. Typical skin fea- ited disease is included, but is likely to occur in approxi-
tures of SSc are well described and include skin thicken- mately 10% of patients with diffuse systemic disease.
ing, sclerodactyly, finger pulp pitting, fingertip The presence of RNA polymerase antibodies and recent
ulceration, digital gangrene and telangiectasia, some of initiation or intensification of steroid therapy (>15 mg
which are illustrated in . Figs. 35.1 and 35.2. SSc causes per day) together with rapidly progressing skin scores
626 C. M. Gearailt et al.
a b
c d
35
. Fig. 35.1 Clinical features of scleroderma showing typical shiny, atrophic skin and Raynaud’s of hands a with dry ulcers at the tip of
middle finger b and calcinosis c which is illustrated on plain radiograph of the hand at the thumb d
a b
. Fig. 35.2 Gangrenous thumb a and index and ring finger with telangiectasia of the palm and thumb b
Rheumatological Conditions and the Kidney
627 35
found vasculopathy with digital gangrene developing in
. Table 35.1 Prevalence of extra-renal manifestations of
SSc
tandem with the SRC.
The cardinal feature of SRC is sustained (usually severe) The aetiology of SSc is unknown, but much evidence
hypertension, and evidence of AKI may be present. supports an autoimmune basis for its development.
Intravascular haemolysis has been found in 50% of SRC Vascular dysfunction is thought to be one of the initiat-
patients and is confirmed by the presence of reduced ing steps in SSc and is mediated by cytokines produced
platelet counts, anaemia, reduced haptoglobin levels, by activated lymphocytes and by antibodies against
red cell fragments and schistocytes on blood film endothelial cells. It is believed that this immunological
together with very elevated lactate dehydrogenase activity leads to an exaggerated production of fibro-
(LDH) levels (often >2000) and normal clotting. blasts and abnormal collagen build-up. Genetic and
CXR may reveal evidence of pulmonary oedema or environmental factors are likely to be relevant, but their
pulmonary fibrosis. An enlarged cardiac silhouette exact role has yet to be determined.
might result from a peri-cardial effusion. The autoantibodies identified in scleroderma patients
Echocardiography is useful to exclude clinically signifi- correlate with distinct subsets of the disease. These
cant effusions, to assess pulmonary pressures and to autoantibodies often have a relatively high specificity,
measure ejection fractions and identify any co-existing but their sensitivity is moderate. . Table 35.2 summa-
valvular abnormalities. Most patients presenting with rizes these autoantibodies and their correlation with dis-
SRC have non-significant peri-cardial effusions. ease subsets.
Troponin and BNP may be useful indicators of myocar-
dial ischaemia and failure, respectively.
Nailfold capillaroscopy and cold pressor testing 35.10 Management
(. Fig. 35.3) can be very helpful in those patients who
do not have a known or obvious diagnosis of SSc at pre- The outcome of SRC has greatly improved in the last
sentation or in whom the skin changes are minimal or half century. Increased awareness of this complication
absent.
35 with regular BP measurements (especially in susceptible
groups) allows earlier diagnosis with improved out-
comes [12–14]. Renal biopsies are considered to be help-
35.8 Pathology ful (to exclude other pathologies and assess prognosis)
but should be delayed until the patient’s BP is well con-
The renal pathological findings in SRC are indistin- trolled and platelet counts have recovered.
guishable from any other cause of accelerated hyperten- In the era before treatment with inhibitors of the
sion [2]. Vessels show profound intimal proliferation renin-angiotensin-aldosterone system, 1-year mortality
that may occlude the vessel lumen completely and fibri- approached 100% although. More recent series report
noid necrosis may be present in vessel walls. Glomeruli survival rates of 70–80%, although significant numbers
collapse with wrinkling of the basement membrane still become dialysis dependent following SRC. Renal
(. Fig. 35.4). The prognostic value of measurements of recovery typically occurs very slowly with median time
renal scarring does not seem to follow the patterns seen to dialysis independence of 9 months (1–34 months).
in other renal diseases [5–8]. Following discontinuation of dialysis, Penn et al. have
a b
. Fig. 35.3 Cold pressor testing, performed by asking a patient to and abnormal b response suggestive of Raynaud’s. (Courtesy of
immerse their hands in cold water for 1 minute, and a thermography Kevin Howell, Department of Rheumatology, Royal Free Hamp-
study is performed after 10 minutes to assess rewarming. Normal a stead)
Rheumatological Conditions and the Kidney
629 35
a b
. Fig. 35.4 Histological appearances of a typical renal biopsy ing (onion skinning). Panel c (Haemotoxylin & Eosin stain) is a lon-
taken following an SRC. Severe acute small vessel vasculopathy: gitudinal section through a very abnormal, almost completely
Panels a and b (silver stain) show shrunken collapsed glomeruli with occluded vessel. (Images courtesy of Professor AJ Howie, Depart-
wrinkling of basement membranes particularly panel b. Interlobular ment of Histopathology, Royal Free Hampstead)
arteries show virtual occlusion by loose concentric intimal thicken-
. Table 35.2 Frequency and clinical associations of hallmark systemic sclerosis (SSc)-associated autoantibodies [9–11]
dcSSc diffuse cutaneous systemic sclerosis, lcSS limited cutaneous systemic sclerosis, PH pulmonary hypertension, PF pulmonary
fibrosis, PM/DM polymyositis/dermatomyositis, SDV severe digital vasculopathy, SRC scleroderma renal crisis, RA rheumatoid
arthritis, GI gastrointestinal
630 C. M. Gearailt et al.
During a scleroderma Be very careful when administering Nutrition Gut involvement in scleroderma is
crisis, the patient’s fluids as pulmonary oedema can very common as is bacterial
vasculature is very stiff be precipitated very easily. Give overgrowth. During a SRC, pay
and cannot tolerate very slowly preferably while paying attention to nutrition from an early
large shifts in intravas- attention to physiology: CVP, stage. A PEG may be beneficial.
cular fluid. A patient’s pulse rate, stroke volume, cardiac Consider early and sometimes
systemic vascular output repeated eradication of bacterial
resistance may increase overgrowth
very rapidly, dramati-
In the months after a You may need to reduce the
cally reducing cardiac
SRC BP seems to be amount of anti-hypertensive
output
settling medication a patient is taking (as
New patients with SRC Aim to reduce BP relatively slowly renal blood vessels remodel). Get
(10% per day) unless the patient is the patient to monitor their own
fitting or in pulmonary oedema BP and aim to titrate the BP meds
when BP needs to be reduced to achieve target BP. Stop Ca
rapidly (lower MAP by 20% or to channel blockers and alpha
a diastolic pressure of 100– blockers retaining the ACEI or
110 mmHg during the first hour). ARB if possible as the latter drugs
This will improve the chances of encourage vascular remodelling
inducing recovery of renal and the evidence suggests that
function renal recovery is more likely to
occur if these agents are continued
A new SRC patient. Systemic vascular resistance is very
What agents should I high. This is usually renin and A patient who remains Recovery of renal function occurs
use to bring down BP angiotensin mediated; hence, dialysis dependent in approx. 40% of dialysis-
during the immediate ACEI and ARBs are the most following a renal crisis dependent post-SRC patients, but
crisis appropriate treatment, although recovery is very slow and can occur
iloprost works well to reduce BP up to 18–24 months after starting
and inhibit platelet aggregation as dialysis. You may want to delay list-
well as smooth vascular endothe- ing on renal transplant waiting list
lium. The dose of iloprost can
Which modality of Continuous therapies (CVVHD/
easily be titrated to target
dialysis to use in the CVVHF) are very useful during an
BP. Short-acting ACEs, e.g.
event of AKI acute crisis. Peritoneal dialysis
captopril, can also be useful as
provides a gentle therapy which has
doses can be titrated more rigidly,
the advantage of avoiding
but do not worry any ACEI better
intravascular volume fluid shifts,
than none. GTN and labetalol can
but individual patient’s hands
be used, but avoid cardio-selective
(contractures) or occasionally the
beta blockers for reasons outlined
severely thickened abdominal skin
below
may preclude this choice
Tachycardia during a Many patients undergoing SRC
SCC develop marked sinus tachycardia.
This is a physiological response to
the very reduced stroke volumes as
the ventricle aims to pump against 35.12 Renal Disease in Mixed Connective
massive SVR. Aim to reduce the Tissue Disease
SVR and the tachycardia will
settle. Do not use beta blockers as
CO will be reduced and your Criteria for the diagnosis of mixed connective tissue dis-
patient may collapse ease (MCTD) include the presence of a positive anti-
Low platelet counts Do not be tempted to transfuse
U1-RNP autoantibody, the presence of either swollen
with evidence of with platelets. This will resolve fingers or Raynaud syndrome and features of at least
microangiopathic when BP settles and transfused two of the following connective tissue diseases: systemic
haemolytic anaemia platelets can aggravate the MAHA lupus erythematous (SLE), systemic sclerosis (SSc) and
(MAHA) polymyositis (PM) [17].
632 C. M. Gearailt et al.
Renal manifestations of MCTD have been reported million people with a female preponderance (3:1) and a
in 11–40% of patients (most commonly membranous peak incidence at 50–60 years.
glomerulonephritis), but severe renal disease is Renal involvement is rare in patients with PM/DM
rare [17–20]. Anti-U1-RNP antibodies, which are pres- and predominantly secondary to rhabdomyolysis causing
ent in all patients with MCTD by definition, may be acute tubular injury secondary to the effect of myoglobin-
protective against the development of diffuse prolifera- uria [21]. The glomerular lesion most commonly associ-
tive glomerulonephritis. Patients who have renal disease ated with PM is mesangial proliferative
in MCTD have more systemic manifestations than those glomerulonephritis. However, there are reports of patients
without. 7 Box 35.5 outlines the types of renal disease with PM who developed rapidly progressive
seen in patients with MCTD. Overlap in scleroderma GN. Membranous GN is more commonly associated
patients and a few cases of renal crisis, with abrupt onset with DM and highly unlikely in PM. Proteinuria and
of severe hypertension and renal dysfunction, have been microscopic haematuria are observed in renal disease
reported. The histological findings on renal biopsy of associated with PM. . Table 35.4 summarizes the com-
these patients are identical to that seen in scleroderma mon findings observed in renal disease in myositis.
renal crisis; similarly, patients with scleroderma and Treatment is aggressive fluid resuscitation and alkaliza-
MCTD may develop membranous nephropathy. There tion in order to avoid acidosis, hyperkalaemia and the
are a few case reports of patients who developed acute need for dialysis. The use of renin-aldosterone antago-
renal failure contemporaneously with an exacerbation nists have also been shown to prevent proteinuria and
of MCTD. progression of chronic kidney disease.
Box 35.5 Types of Renal Disease in MCTD 35.14 Renal Disease in Sjögren’s Syndrome
Membranous glomerulonephritis (commonest)
Mesangial proliferative glomerulonephritis (com- Sjögren’s syndrome (SS) is characterized by lymphocytic
mon) infiltrates of salivary and tear glands leading to ocular
35 Membranoproliferative glomerulonephritis and mouth dryness. It is reported to affect 0.1–0.6% of
Focal and segmental glomerulosclerosis the general adult population with a female preponder-
Scleroderma renal crisis ance (female-to-male ratio at least 9:1). The peak inci-
Renal infarcts (associated with anti-cardiolipin anti- dence of the disease occurs after the menopause in the
body syndrome) (rare) mid-50s.
Renal amyloidosis (rare) Renal involvement in SS is frequent, and 16–67% of
Minimal change disease (rare) patients have manifestations such as interstitial nephri-
Collapsing glomerulopathy (very rare) tis or glomerulonephritis [22–25]. Interstitial nephritis is
the commonest renal lesion in primary SS and occurs
early in the disease process with lymphocytic infiltration
into and subsequent tubular atrophy and fibrosis.
Glomerulonephritis (GN) is rare in primary SS and usu-
35.13 Renal Disease in Polymyositis ally occurs late in the disease. It is thought to be due to
and Dermatomyositis immune complex deposition in the glomeruli. Three his-
tological types of GN have been reported in SS: mem-
The inflammatory myopathies, polymyositis (PM), der- branoproliferative (MP) GN, mesangioproliferative GN
matomyositis (DM) and inclusion body myositis (IBM), and membranous GN. The histology of each of these is
are rare diseases with an annual incidence of 2–7 per one summarized in . Table 35.5.
Polymyositis Dermatomyositis
Interstitial Interstitial infiltrate which can develop 35.15 Renal Disease in Sarcoidosis
nephritis into interstitial atrophy and fibrosis
Type I MPGN Predominance of subendothelial deposits Sarcoidosis is a multisystemic inflammatory disorder of
Type II MPGN Predominance of intramembranous
unknown aetiology characterized by the presence of epi-
deposits thelioid non-caseating granulomas in involved organs. It
has a worldwide distribution, with the highest geo-
Type III MPGN Subepithelial and subendothelial deposits
Burkholder type and mesangial dense deposits
graphic prevalence in Northern Europe. Sarcoidosis is
slightly more prevalent in women with a peak incidence
Type III MPGN Intramembranous and subendothelial between 20 and 40 years of age, with a second peak in
Strife type deposits with marked basement
membrane irregularities
women over the age of 50.
Kidney involvement in sarcoid is rare (0.7–1%) and
Mesangioprolif- is usually diagnosed after lung disease is already evident.
erative GN
It occurs in chronic sarcoidosis and is very rare in acute
Membranous GN sarcoidosis. Renal sarcoidosis can result in nephrotic
syndrome, tubulointerstitial disease or glomerulone-
phritis but AKI secondary to hypercalcaemia is more
common than direct renal involvement (. Table 35.7)
[26–28].
. Table 35.6 Types of renal disease in SS, associations and
outcome
. Table 35.6 summarizes the types of renal disease . Table 35.7 Types of renal dysfunction in sarcoidosis
in SS, their clinical presentation and outcome. Interstitial
disease typically manifests as hyposthenuria (excretion Renal involvement Prevalence (%)
of urine of low specific gravity due to an inability of the
Hypercalcaemia Common
tubules of the kidneys to produce concentrated urine)
and type I or type II renal tubular acidosis. Type I renal Hypercalciuria (+/− Very common
tubular acidosis is commoner. There is no consensus on stones)
the treatment of tubulointerstitial nephritis (TIN) in SS, Renal tubular dysfunc- Common
but our local practice is to use medium-dose steroids tion
and a steroid-sparing agent such as azathioprine, using Granulomatous Very small percentage of
the acute phase response, IgG level and pyuria as mark- interstitial nephritis clinically relevant cases
ers of disease activity. Glomerular disease Rare
GN is rare in SS. The outcomes in these patients are
Renovascular disease Rare
diverse, but patients tend to have a less favourable out-
come. Renal failure is common, and it is often associ- Obstructive uropathy Rare
ated with cryoglobulinaemia and vasculitis. There are no
634 C. M. Gearailt et al.
Renal disease in AS is relatively common with a reported Finally, some of the medication used in rheumatological
prevalence of 10–35%. . Table 35.9 outlines the differ- disease can cause renal disease or need modification of
ent types of glomerular involvement seen in AS. Renal dose to avoid generalised toxicity (. Table 35.10). It is
disease can also be caused by treatments such as important to assess the medication history in patients
NSAIDs, sulphasalazine and azathioprine, which can with chronic musculoskeletal disorders and unexplained
cause tubulointerstitial nephritis. renal impairment as well as ensuring that doses are
Amyloidosis is more prevalent in aggressive and adjusted and renal function monitored in patients with
active AS and in older patients with long-standing dis- impaired renal function.
636 C. M. Gearailt et al.
NSAIDs OA, RA, ankylosing Acute tubular Use for shortest possible duration;
spondylitis necrosis complications common; avoid in renal
impairment
Methotrexate RA, PsA, JIA Renal insufficiency Uncommon; reduce dose in renal
impairment; avoid in severe renal
disease
Sulphasalazine RA, inflammatory arthritis Proteinuria Ensure adequate fluid intake
with associated bowel
disease
Mycophenolate mofetil Lupus nephritis, vasculitis Haematuria; raised No dose adjustment needed
serum creatinine
Leflunomide RA, PsA Hypertension Avoid in renal failure due to lack of
data
Penicillamine RA, JIA, Wilson’s disease Proteinuria, Used infrequently; dose reduction in
haematuria renal impairment; avoid use with
NSAIDs
Janus kinase inhibitors (tofacitinib, RA, PsA No known renal Reduce dose if eGFR <30
baricitinib) complication
Anti-TNF inhibitors (adalimumab, RA, PsA, AxSpA Glomerulonephritis No renal adjustment
etanercept, infliximab, certolizumab, in case reports
35 golimumab)
IL-6 inhibitors (tocilizumab) RA, JIA, GCA Nephrolithiasis: No renal adjustment
uncommon
CD20 depletion therapy (rituximab) RA, SLE, vasculitis No renal adjustment
Allopurinol Gout prophylaxis Reduced excretion Dose adjustment in renal disease
Febuxostat Gout prophylaxis No adjustment; avoid in IHD
Colchicine Acute gout Reduced excretion Dose adjustment in renal disease;
avoid in severe renal impairment
Bisphosphonates (alendronate, Osteoporosis Reduced excretion Avoid if eGFR <30 mL/min
zoledronic acid, ibandronic acid)
Denosumab Osteoporosis Increased Use with caution if eGFR <30 mL/
hypocalcaemia risk min
Teriparatide Osteoporosis Nephrolithiasis Avoid in severe renal impairment
NSAIDs non-steroidal anti-inflammatory drugs, OA osteoarthritis, RA rheumatoid arthritis, PsA psoriatic arthritis, JIA juvenile idio-
pathic arthritis, AxSpA axial spondyloarthropathy; GCA giant cell arteritis, IHD ischaemic heart disease
Long-standing rheumatoid arthritis, new peripheral Check eGFR and PCR and think secondary amyloidosis
oedema, urine dip positive for protein
Gout and renal disease Consider switching to febuxostat if eGFR<30 mL/min and difficulty reduc-
ing uric acid below 360 μmol/L. Caution is needed as associated increased
risk of ischaemic heart disease with febuxostat
Myositis and renal disease Rare. Consider rhabdomyolysis and check urinary myoglobins
Rheumatological Conditions and the Kidney
637 35
Case Study
Case 1 tip of her third digit of her left hand. She has obvious
A 51-year-old lady, originally from India, presented to the Raynaud’s phenomenon with multiple calcinosis on both
rheumatology review clinic with a 30-year history of rheu- hands. Telangiectasia is present on her hands and face. She
matoid arthritis. Her past medical history is significant for also has a noticeable chest wall rash. Her respiratory exam
hyperlipidaemia. Her medications consist of aspirin 75 mg, reveals fine bibasal creps. Neurological examination is nor-
atorvastatin 20 mg, prednisolone 5 mg once a day and mal. Her blood pressure is 198/100 and heart rate is 134.
paracetamol 1 g TDS/PRN. She has no known ischaemic Sinus tachycardia on ECG. Creatinine 250 μmol/L
heart disease. She describes significantly worsening SOB (90 μmol/L 6 months previously), eGFR 26 mL/min (72 mL/
with associated swelling of her lower limbs. On examina- min on most recent bloods). Chest X-ray shows changes
tion, she has long-standing RA changes with no active consistent with pulmonary oedema. Scleroderma renal cri-
synovitis. Pitting oedema is present to mid thighs. ECG sis is diagnosed, and the patient is treated with aggressive
shows normal sinus rhythm with no ischaemic changes. blood pressure management with ACE inhibitors.
Urine dip shows 3+ protein. Bloods reveal eGFR 31 mL/
min/1.73 m2 and proBNP 132 pg/mL. Urine PCR was Case 3
230 mg/mmol. She was seen in clinic by both a nephrolo- A 63-year-old man presents to rheumatology clinic for
gist and rheumatologist and was subsequently diagnosed review. He reports ongoing pain in his left MTP 1 joint
with secondary amyloidosis secondary to long-standing which is tender to touch. His past medical history is sig-
RA. nificant for gout, OSA, HTN, type 2 diabetes mellitus and
chronic kidney disease. His medications include allopuri-
Case 2 nol 200 mg, linagliptin 5 mg and lercanidipine 10 mg. He
A 72-year-old lady presented to the emergency department reports good medication compliance. On exam, he has a
with a 3-day history of headache, a 1-week history of tender left MTP 1 joint in foot with associated erythema.
increasing SOB and a 1-month history of a new third digit He also has gouty tophi of his right second and third MCP
necrotic ulcer on her right hand. She reports a history of joints of his right hand. Bloods include a uric acid of
hypothyroidism, asthma and Raynaud’s. Her medications 450 μmol/L and an eGFR of 28 mL/min. Upon discussion
include levothyroxine 75 mcg and salbutamol PRN. She with his rheumatologist, the decision is taken to switch
recently received a course of tapering steroids for an exacer- from allopurinol to febuxostat 80 mg. He is also given a
bation of asthma. On exam, she has a necrotic ulcer on the short course of tapering steroids for his acute flare.
4. Which of the following statements is incorrect? 10. Moinzadeh P, Nihtyanova SI, Howell K, Ong VH, Denton
A. Anti-U1-RNP antibodies may be protective CP. Impact of hallmark autoantibody reactivity on early diag-
nosis in scleroderma. Clin Rev Allergy Immunol.
against the development of diffuse prolifera-
2012;43(3):249–55.
tive glomerulonephritis 11. Nihtyanova SI, Parker JC, Black CM, Bunn CC, Denton CP. A
B. Renal involvement in polymyositis tends to be longitudinal study of anti-RNA polymerase III antibody levels
caused by rhabdomyolysis in systemic sclerosis. Rheumatology (Oxford).
C. Glomerulonephritis is rare in Sjögren’s disease 2009;48(10):1218–21.
12. D’Angelo WA, Fries JF, Masi AT, Shulman LE. Pathologic
D. Renal sarcoidosis may result in nephrotic syn-
observations in systemic sclerosis (scleroderma). A study of
drome fifty-eight autopsy cases and fifty-eight matched controls. Am J
E. Behcet’s disease is more common in males Med. 1969;46:428–40.
13. Denton CP, Lapadula G, Mouthon L, Müller-Ladner U. Renal
5. Which of the following drugs used in rheumatol- complications and scleroderma renal crisis. Rheumatology
ogy requires a renal dose adjustment? (Oxford). 2009;48(Suppl 3):iii32–5.
14. Hudson M, Baron M, Lo E, Weinfeld J, Furst DE, Khanna
A. Golimumab D. An international, web-based, prospective cohort study to
B. Febuxostat determine whether the use of ACE inhibitors prior to the onset
C. Tofacitinib of scleroderma renal crisis is associated with worse outcomes –
D. Rituximab methodology and preliminary results. Int J Rheumatol.
2010;2010:347402.
E. Tocilizumab
15. Penn H, Howie AJ, Kingdon EJ, Bunn CC, Stratton RJ, Black
CM, et al. Scleroderma renal crisis: patient characteristics and
long-term outcomes. QJM. 2007;100:485–94.
v Answers
16. Pham PTT, Pham PCT, Danovitch GM, Gritsch HA, Singer J,
1. C Wallace WD, et al. Predictors and risk factors for recurrent
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3. D review of the literature. Am J Transplant. 2005;5:2565–9.
4. E 17. Radstake TR, Gorlova O, Rueda B, Martin JE, Alizadeh BZ,
Palomino-Pakozdi A, Nihtyanova S, Moinzadeh P, Ong VH,
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S, et al. Programmed initiation of hemodialysis for systemic
641 36
Contents
The incidence of renal impairment depends on the aeti- Hepatorenal syndrome is a functional renal impairment
ology. For example, post paracetamol overdose, the inci- characterised by a number of haemodynamic abnormal-
dence of AKI is as high as 75%. Using the definitions ities. The pathogenic mechanisms outlined below prob-
outlined above, the incidence of AKI in hospitalised ably integrate, and these are broadly illustrated in
patients with cirrhosis is 19–54%. There is a broad dif- . Fig. 36.1.
ferential, but HRS is the principal aetiology in 12–18%
of cases. In 1993, a study showed that HRS occurred in
18% of patients with cirrhosis and ascites at 1 year and 36.5.1 Peripheral Arterial Vasodilation
39% at 5 years [14–17]. Chronic kidney disease occurs in
about 1% of those with cirrhosis, and HRS-CKD occurs The peripheral arterial vasodilation seen with portal
in between 16% and 61% of those with HRS [2, 12]. hypertension plays a key role in the pathogenesis of
HRS. As the liver progressively fibroses, intrahepatic
portal pressure increases, leading to splanchnic pool-
36.4 Differential Diagnosis for Renal ing. Nitric oxide release from the splanchnic vascula-
Dysfunction in Those with Liver ture endothelium also increases, due to portal
Disease hypertension-induced shear stress or bacterial translo-
cation and cytokine-induced increased nitric oxide
This is broad and is summarised in . Table 36.3. synthase activity, resulting in local vasodilation. These
Getting the diagnosis correct has critical implications circulatory changes have been confirmed in studies
for patient management and prognosis. There is often a where increased blood flow in the superior mesenteric
shared underlying aetiology causing both the renal and artery was demonstrated compared with the femoral,
liver disease. Essentially, pre-renal and intrinsic renal correlating with the degree of liver dysfunction. The
causes predominate, and pre-existing renal conditions consequence of this splanchnic pooling is a reduction
should always be considered, with HRS often a diagno- in effective arterial blood volume and vascular resis-
sis of exclusion [1, 4, 15, 17–19]. tance [1, 4, 19].
644 A. O’Riordan and T. Ware
. Table 36.3 Differential diagnosis for renal impairment in a patient with liver disease
Pre- Volume depletion or inadequate fluid resuscitation from, for example, excessive diuresis and large volume paracentesis
renal Gastrointestinal haemorrhage
Diarrhoea from excessive laxative use
Septic shock
Drugs, e.g. non-steroidal anti-inflammatory agents
Hepatorenal syndrome
Renal Acute tubular injury from persistent hypoperfusion, nephrotoxins (e.g. contrast, aminoglycosides, calcineurin inhibitors,
paracetamol or salicylate overdose), very high levels of bilirubin or microorganisms
Drug- or toxin-induced interstitial nephritis from, for example, antibiotics, proton pump inhibitors and poisonous mush-
rooms
Glomerular disease related to the cause of the underlying liver disease (e.g. alcohol, viral hepatitis)
De novo glomerulonephritis: IgA, membranous or membranoproliferative glomerulonephritis
Other causes with proteinuria/haematuria including diabetes, myeloma, amyloid, vasculitis
Conditions that can affect the liver and kidney:
Drug or poison toxicity (e.g. paracetamol overdose)
Hypersensitivity reaction to, for example, antibiotics
Infectious diseases (e.g. hantavirus, leptospirosis, hepatitis B or C virus)
Sickle cell disease
Metabolic syndrome linked with non-alcoholic steatohepatitis, hypertension and diabetes-induced renal disease
HELLP syndrome
Polycystic kidney and liver disease
Post- Obstruction (rare)
renal
36
36.5.2 Haemostatic Compensatory dilators. In addition to the factors already mentioned,
Mechanisms an inadequate adrenal response to stress such as sepsis is
also thought to play a role in the pathophysiology of
HRS [1, 3, 19, 20].
To maintain homeostasis in response to the above, there
is baroreceptor-mediated activation of the renin-
angiotensin-aldosterone and sympathetic nervous sys- 36.5.3 Cirrhotic Cardiomyopathy
tems with subsequent release of anti-diuretic hormone
resulting in sodium and water retention. Baroreceptors The increased sympathetic nervous system leads to a
are principally located in the aortic arch and carotid hyperdynamic circulation with tachycardia and
sinus; however, they are also present in other organs increased cardiac output to overcome the decreased
including the liver. Here, there is evidence for a hepa- systemic vascular resistance and blood pressure.
torenal baroreflex whereby afferent hepatic pressure sen- However, as liver disease progresses and when addi-
sors can influence renal blood flow, GFR and salt and tional demands are placed on cardiac function, e.g.
water excretion via neurohormonal mechanisms that with infection, cardiac response may be inadequate
increase renal sympathetic activity. Renal blood flow despite the absence of known cardiac disease. This has
may be preserved in the early stages of cirrhosis when been described as cirrhotic cardiomyopathy where there
local vasodilators such as prostaglandins and nitric is reduced cardiac contractility, diastolic dysfunction
oxide can overcome the vasoconstrictor effects, but as and electrophysiological abnormalities. The pathophys-
liver disease progresses, this equilibrium cannot be iology of this blunted cardiac response may be due to
maintained, and renal hypoperfusion and HRS can some underlying cardiac hypertrophy and fibrosis,
ensue. Vasoconstriction is not isolated to the kidney but increased production of negatively inotropic mediators
has been shown in other vascular beds too. However, the or functional changes in the cardiomyocyte plasma
splanchnic vascular bed escapes the effects of the potent membrane properties. These changes are potentially
vasoconstrictors due to the local concentration of vaso- reversible post-LT [19, 21].
Hepatology and the Kidney
645 36
Portal hypertension
TIPS
Vasoconstrictors
Hepatorenal Dilutional
syndrome Oedema Ascites hyponatraemia
. Fig. 36.1 Pathophysiology of hepatorenal syndrome and treatment options. Abbreviations: TIPS transjugular intrahepatic portosystemic
shunt, RAAS renin-angiotensin-aldosterone system, ADH anti-diuretic hormone
36.6 Clinical Evaluation of Liver Patients sion. Precipitating events such as a change in medica-
with Renal Dysfunction tions, haemorrhage, infection, recent diarrhoea or
vomiting, or large volume paracentesis, should be ascer-
tained.
The key things to determine when assessing a patient Hepatorenal syndrome is an important cause to
include a history of any known renal and liver disease, exclude and is characterised by a constellation of clini-
the aetiology and chronicity of these illnesses including cal features, outlined in . Table 36.2. Most patients will
the presence of cirrhosis or signs of portal hyperten- give a long history of chronic liver disease, with ascites
646 A. O’Riordan and T. Ware
being a prominent feature. Depending on the speed of notoriously poor indicator of renal function in patients
onset and severity of the renal dysfunction, HRS can be with cirrhotic liver failure due to poor nutrition, reduced
classified into HRS-AKI and HRS-CKD, as outlined hepatic creatinine production and muscle mass, leading
above. The latter can suddenly progress to HRS-AKI to a delay in diagnosing and treatment based on the tra-
after a precipitating event [2, 7]. ditional creatinine threshold [1]. Commonly used eGFR
On examination, volume assessment is key to the equations overvalue true GFR, when compared to
evaluation of patients with renal dysfunction. radio-isotopic methods potentially. This makes the
Hypotension and tachycardia are features of volume application of the usual CKD stages based on eGFR
depletion and sepsis. A low mean arterial blood pressure alone problematic. However, despite these reservations,
<80 mmHg is also seen in HRS-AKI due to splanchnic creatinine and eGFR are currently the easiest and most
pooling. This can also be precipitated by factors such as widely available tools for the assessment of renal func-
diuretics, paracentesis, sepsis or blood loss. The hypo- tion. Cystatin C is also problematic and influenced by
tension is typically accompanied by tachycardia, a man- clinical factors [13, 23, 24].
ifestation of the hyperdynamic circulation. The One of the most notable biochemical features of
haemodynamic changes are not always confined to the HRS is hyponatraemia. Water retention can exceed that
kidney, and other vascular beds may also be involved of sodium, and so a dilutional hyponatraemia develops
with a reduced cardiac output and encephalopathy in in about two-thirds of patients. This parameter can be
more severe cases. Stigmata of chronic liver disease will useful in differentiating HRS from other aetiologies of
usually be evident in those with HRS. Clinical signs of renal impairment such as acute tubular necrosis.
an underlying infection such as peritonitis should be Natriuresis is impaired so one of the other classical find-
elucidated to enable prompt treatment. Impaired natri- ings in HRS is a urinary sodium <10 mmol/L in the con-
uresis is a feature of HRS, and an inability to excrete text of a serum sodium <135 mmol/L and a urine
free water results in peripheral oedema and ascites, and osmolality that is greater than that of serum [8, 20, 22].
this is typically diuretic resistant. Patients may develop To help distinguish HRS from other parenchymal
oligo-anuria with a urine output <500 ml/day. causes of renal impairment in cirrhotics, a number of
Pulmonary oedema can occur in this setting but is not a tests can be useful (. Table 36.4a). A urinary protein-
typical feature of HRS. A bland urinary sediment is creatinine ratio should be performed if the dipstick is
36 characteristic given the functional nature of the renal positive along with examination of urinary sediment for
impairment in HRS, although patients with liver disease casts. If the proteinuria is found to be >500 mg/dL and
may have a number of possible causes for underlying there is microscopic haematuria (>50 urinary red cells
CKD including glomerulonephritis, so haematuria, pro- per high-powered field) or any other clinical features to
teinuria and urinary casts should be excluded. Finally, suggest parenchymal renal disease, then consider an
the skin should be evaluated for signs of a vasculitis rash alternative diagnosis. However, HRS can develop in the
that can be seen in those with viral hepatitis-related context of a pre-existing renal condition, so this must be
cryoglobulinaemia [3, 4, 22]. taken into account. If no contraindications exist, a renal
biopsy may be useful in this scenario to help determine
the underling aetiology. This is particularly so if a com-
36.7 Investigations bined liver and kidney transplant is being considered, as
the degree of renal fibrosis will help predict renal prog-
Renal function needs to be monitored carefully in those nosis post-LT and avoid unnecessary renal transplanta-
with liver disease, particularly when there is diuretic- tion in those with HRS. The latter is characterised by a
resistant ascites, hyponatraemia, peritonitis or gastroin- lack of significant parenchymal histological changes
testinal haemorrhage. However, creatinine is a and typically recovers with LT alone.
Creatinine at least × 2 above Proteinuria <500 mg/day Normal renal Normal renal histopathol-
baseline Sodium <10 mEq/L ultrasound ogy
Sodium <130 mmol/L Red blood cells <50 per high-powered
field
Hepatology and the Kidney
647 36
and effective treatment is imperative to prevent progres-
. Table 36.4b Caption
sion [7].
Conditions that cause both Some useful investigations As previously alluded to, NSAIDs inhibit renal per-
renal and liver disease fusion and so should not be used in those with cirrhosis.
Other drugs such as aminoglycosides and angiotensin-
Hepatorenal syndrome See . Table 36.4a converting enzyme inhibitors should also be avoided,
Toxin or drug toxicity or Toxicology screen where possible. Radiological contrast should be admin-
hypersensitivity Eosinophilia istered with caution in those at risk of developing
Urine microscopy may show AKI. Typically, ascites is initially treated with fluid and
muddy brown casts
sodium restriction, but diuretics especially aldosterone
Kidney biopsy
antagonists are frequently required. However, overzeal-
Hepatitis B or C virus- Hepatitis B surface antigen ous diuresis can have a negative impact on renal perfu-
related glomerulonephritis Hepatitis C antibody, PCR or
sion and hence precipitate AKI. Aldosterone antagonists
antigen
Urine protein-creatinine ratio can precipitate dangerous hyperkalaemia and so should
Urine microscopy for red cell be used with caution in those with poor renal function.
casts Preventative strategies include regular monitoring of
Cryoglobulins, rheumatoid renal function for all those on diuretics [1, 19].
factor and complement levels
If renal function does deteriorate, then the first step
Kidney biopsy
is to correct intravascular volume depletion, preferably
Leptospirosis Culture with 1 g/kg albumin per day. This acts as a circulatory
Microscopic agglutinin test
expander and may also have antioxidant properties, so is
Polymerase chain reaction
the fluid of choice for resuscitation in all patients with
Hantavirus Anti-hantaviral IgM AKI-HRS. Diuretic doses should be reduced or even
Sickle cell disease Haemoglobin electrophoresis stopped. In this scenario, the optimum treatment for
HELLP syndrome Full blood count
ascites is paracentesis, with appropriate albumin sup-
(haemolysis, elevated liver Blood film looking for red cell port for those who require removal of large volumes of
enzymes, low platelets) fragments or schistocytes over 5 L (8 g/L of ascites drained). Without albumin,
Haptoglobins approximately 20% will develop HRS. Paracentesis may
Reticulocytes also relieve raised intra-abdominal pressure impeding
Lactate dehydrogenase
Liver function tests
renal venous return. There needs to be a low threshold
for hospital admission in patients with deteriorating
Polycystic kidney and liver Abdominal ultrasound renal function aiming to restore renal perfusion. Some
disease
may require high dependency or intensive care unit sup-
port to facilitate close monitoring of vital signs and
urine output. Adrenal insufficiency may be an exacer-
As with all other causes of renal impairment, per- bating factor in some, and hydrocortisone administra-
forming a renal ultrasound scan should be a priority to tion may also have a role [1, 8, 9, 15].
evaluate for evidence of parenchymal disease and to In a third of cases, HRS is triggered by bacterial
exclude obstruction. peritonitis and is associated with increased cytokine
A summary of some useful investigations for condi- release. Therefore, rapid diagnosis and treatment of any
tions that cause both renal and liver dysfunction is out- sepsis, including peritonitis, is imperative. Along with
lined in . Table 36.4b [1–4, 13, 25]. antibiotic therapy, albumin administration has also been
shown to decrease the risk of HRS from 30.6% to 8.3%
compared with controls. This is felt to be due to an
36.8 Precipitating Factors, Prevention improvement in haemodynamics and renal perfusion
and Initial Therapy along with antioxidant effects. For high-risk patients,
the use of antibiotic prophylaxis with norfloxacin or cef-
Acute kidney injury is frequently triggered by complica- triaxone helps to reduce the risk of spontaneous bacte-
tions such as peritonitis, acute alcoholic hepatitis and rial peritonitis and HRS and improves survival [1, 8, 9,
gastrointestinal haemorrhage. Hence, prompt diagnosis 19, 26, 27].
648 A. O’Riordan and T. Ware
For those with CKD and liver disease, the key fac- onstrated that terlipressin resulted in reversal of HRS in
tors in patient management and prevention of progres- 42% versus 15.4% in the placebo group. The relative risk
sion include those mentioned above, but also attention of death was 0.63. It is important to evaluate cardiac
needs to be given to the management of the underlying risk prior to the initiation of these agents. Relapse after
cause of the CKD (e.g. diabetes, hepatitis-related glo- cessation of terlipressin is rare and usually responds to
merulonephritis). Blood pressure should be controlled, re-treatment. Alpha-1 adrenergic receptor agonists such
and proteinuria minimised, where possible. as midodrine and noradrenaline can also be effective in
reversing HRS. Noradrenaline has been compared to
terlipressin, and both are equally effective in terms of
36.9 Treatment of AKI and AKI-HRS renal recovery and patient mortality, although the for-
mer is less expensive and has fewer side effects. Octreotide
If the preventative and initial management strategies is a glucagon inhibitor with vasoconstrictive effects on
outlined above fail and AKI develops secondary to the splanchnic circulation. When given with midodrine,
HRS, then several therapies are available. The elimina- it has had a positive effect on renal haemodynamics,
tion of creatinine thresholds from the diagnostic criteria although benefits were inferior to terlipressin in a ran-
should allow for earlier intervention. The key treatment domised controlled trial [1, 8, 13, 28, 29].
options in the management of HRS depend on the stage
of AKI present (7 Box 36.2) [7, 15].
36.9.2 Transjugular Intrahepatic
Portosystemic Shunt (TIPS)
Box 36.2 Treatment of HRS-CKD
5 Diuretics for ascites initially but withdraw if Here, a metal stent is inserted to bridge the portal and
diuretic resistant central venous systems aimed at reducing portal hyper-
5 Water and sodium restrict (80–120 mmol/day) for tension. It is principally used in the treatment for refrac-
ascites tory variceal bleeding and diuretic-resistant ascites. One
5 Evaluate for sepsis or other precipitants and treat study demonstrated an improvement in renal function in
appropriately 75% of patients and a mean patient survival of 92 versus
36 5 Large volume paracentesis (>5 L) with albumin 12 weeks in those who underwent TIPS compared with
(8 g/L) support if diuretic-resistant ascites a control group. Patients need to be carefully selected, as
5 Antibiotic prophylaxis if at high risk of bacterial a TIPS can result in deterioration in those with severe
peritonitis with, for example, norfloxacin 400 mg/ liver failure, development of congestive cardiac failure
day or hepatic encephalopathy. In certain scenarios, TIPS
5 Consider transjugular intrahepatic portosystemic does have a role, as in those with HRS and refractory
shunt in appropriate patients ascites or as an adjunct to vasoconstrictors and albumin
5 Little data to support the use of vasoconstrictors while awaiting LT. It may also be an option to prolong
and albumin unless renal function is deteriorating survival in those for whom transplantation is contrain-
and HRS-AKI develops dicated [8, 13, 19, 30].
5 Evaluate for liver transplantation
The prognosis for patients with HRS is dreadful, and a In patients with glomerular disease, AKI or CKD due to
LT is the best treatment for a meaningful recovery. There underlying viral hepatitis, it is important to treat the
is a clear benefit with LT compared with other therapies underlying cause. Huge advances have been made in this
as it alleviates the underlying liver disease with a pro- area in recent times, particularly in relation to hepatitis
gressive improvement in the circulatory derangements C virus treatment. Previously, treatment of patients on
post-transplantation, thereby usually restoring renal dialysis or post-transplant with this infection was prob-
function. The negative impact of HRS on patient sur- lematic or impossible because of intolerable side effects
vival is highlighted by the fact that serum creatinine is a or increased risk of rejection. The timing of treatment
key variable in the Model for End-Stage Liver Disease and drug selection is complex and beyond the scope of
(MELD) score, used to prioritise patients awaiting this chapter, but guidelines have been published by the
LT. The number of patients receiving combined liver European Association for the Study of the Liver (EASL)
and kidney transplants rose by 300% in the United diseases with details on how to treat those with CKD,
States following the introduction of this score in 2002. on dialysis and pre- and post-renal transplantation [36,
However, a renal transplant is an inappropriate treat- 37]. It is important to emphasise that some commonly
ment for HRS unless they also meet the following sug- used drugs need to be avoided or the dose reduced when
gested criteria. Although there are no standard criteria, treating patients with CKD or on dialysis.
650 A. O’Riordan and T. Ware
36.10 Patient and Renal Outcomes careful and rapid assessment of patients for reversible
components and other causes for renal disease. New
Without a LT, patient survival with HRS is very poor. diagnostic criteria will help to facilitate this. It is critical
Median patient survival for those with HRS-AKI (for- to establish whether each patient with both renal and
merly type 1) is usually as short as 2–4 weeks, while it is liver failure is suitable for a LT or whether a combined
6.7 months in those with HRS-CKD (formerly type 2). liver kidney transplant may be more appropriate in a
HRS-AKI remains an independent predictor of mortal- small number of patients. Getting this right is likely to
ity irrespective of the MELD score, further highlighting have a huge impact on the patient’s outcome.
the negative impact that HRS has on patient outcome
[31, 38]. As previously mentioned, vasoconstrictor ther- Key Points of the Chapter
apy and liver transplantation do have a positive influ- 1. There is a new approach to the diagnosis of hepa-
ence on survival [1, 28]. However, even post-LT, patient torenal syndrome (HRS).
survival at 1, 3 and 5 years is inferior in those with HRS 2. A new treatment algorithm has been introduced for
compared with those without and survival is particu- the management of HRS type of acute kidney
larly poor in patients who remain on dialysis post-LT injury.
[39, 40]. 3. HRS is a functional type of renal failure that is
The aetiology of renal failure is also important, as usually reversible post-liver transplant.
HRS is linked to increased mortality compared to other 4. Albumin and vasoconstrictors are key pharmaco-
causes of renal failure. Three-month patient survival logical treatment options, and without liver trans-
was 15% with HRS, significantly less than that seen with plantation, prognosis remains very poor.
other causes of renal dysfunction [41]. However, if
patients are RRT dependant, survival in those with HRS
was not shown to be significantly different to those with
a diagnosis of acute tubular necrosis [31]. Tips and Tricks
Recovery of renal function following a LT alone is
usual after 3–6 weeks, but it may take longer and is not 1. Be aware of the patients who are at risk of devel-
guaranteed in all patients. Between 6% and 10% of oping hepatorenal syndrome (HRS) and take
36 patients remain dialysis dependant, and this figure has steps to prevent it where possible.
been reported to be as high as 25% compared with <1% 2. The creatinine threshold of 122 μmol/L for the
in patients without HRS. Up to 42% of HRS patients diagnosis of HRS-AKI has been abandoned so
continue to have some degree of CKD, but renal func- treatment can commence earlier.
tion declines in the non-HRS population too with 18% 3. Use albumin for fluid resuscitation.
having an eGFR <15 ml/min at 5 years post-LT. This 4. Consider other causes of AKI and CKD in
depends on a number of underlying risk factors includ- patients with cirrhosis before diagnosing HRS,
ing age, co-morbidities or pre-existing CKD. The use of which is a diagnosis of exclusion.
calcineurin inhibitors may have further deleterious Abbreviations: AKI acute kidney injury, CKD chronic
effects [39, 42, 43]. kidney disease.
Case 1 Case 2
A 53-year-old female was admitted with decompensated A 27-year-old female presented to an accident and emergency
cirrhosis due to alcoholic liver disease. She was on the department with a reduced level of consciousness, malaise and
waiting list for liver transplantation but had deteriorat- nausea. She had no significant past medical or surgical history
ing renal function and oliguria. She was disorientated of relevance and was not on any regular medications. The his-
and very oedematous with significant ascites despite tory revealed that she had taken a staggered, inadvertent
high-dose loop diuretics and so was undergoing inter- paracetamol overdose over the preceding week for flu-like
mittent large volume paracentesis supported by albumin symptoms and musculoskeletal pain. Socially she drank 5 units
infusions. Her blood pressure was 100/70 mmHg, pulse of alcohol per week for the preceding 6 months but previously
rate 98 beats per minute and temperature 37.5°C. A dip- drank more heavily, up to 40 units a week. Her initial blood
stick urinalysis revealed trace proteinuria and blood and results are illustrated in the table below, and she also had a
no casts were seen on microscopy. Significant lab results paracetamol level of 125 mg/L. She was commenced on acetyl-
were as follows: cysteine and intravenous fluids, transferred to the intensive care
unit and intubated for a falling Glasgow Coma Scale. She was
Selected laboratory At the time of On discharge commenced on inotropes for haemodynamic instability and
parameters initial renal from hospital continuous renal replacement therapy for oliguric renal failure
review
and metabolic acidosis. Her condition progressively deterio-
Sodium (mmol/L) 130 139
rated, and after discussion with the hepatology service, she was
listed for a super urgent liver transplant. The liver transplant
Potassium (mmol/L) 4.8 4.5 went ahead 2 days later, and the surgery was uncomplicated.
Urea (mmol/L) 35 8.1 She remained in the intensive care unit and on continuous RRT
Creatinine (μmol/L) 204 79
for another week before being commenced on intermittent hae-
modialysis. She was eventually discharged to the ward and con-
Bilirubin (μmol/L) 201 21 tinued to require dialysis for another week before this could be
International nor- 1.7 1.1 stopped. Her discharge bloods are indicated below. Renal
malised ratio recovery often lags behind hepatic recovery in paracetamol
Platelet count (×109/L) 84 178 overdose not needing a liver transplant, but either way, in a
young patient, the renal prognosis is likely to be good.
Urine protein-creatinine 47 Not available
ratio (mg/mmol)
Selected laboratory Prior to liver On hospital
Urinary sodium 19 Not available parameters transplant discharge
(mmol/L)
Sodium (mmol/L) 131 135
She had a negative immunology and myeloma screen. A Potassium (mmol/L) 5.3 4.1
renal ultrasound was unremarkable. A diagnosis of Urea (mmol/L) 14.1 2.7
HRS-AKI was made. The diuretics were stopped, and
Creatinine (μmol/L) 347 85
she was started on albumin and terlipressin intrave-
nously. Despite this, there was little improvement clini- Albumin (g/l) 25 28
cally or biochemically, and she decompensated Bilirubin (μmol/L) 68 22
following an episode of sepsis, becoming more con-
Aspartate aminotransferase 11,487 35
fused with haemodynamic instability. She was trans- (IU/L)
ferred to the intensive care unit where she was started
Alanine transaminase (IU/L) 8044 110
on intravenous antibiotics for suspected bacterial peri-
tonitis and continuous RRT. She improved signifi- Lactate 14
cantly, and the antibiotics were stopped a week later. pH 7.01 7.35
The encephalopathy also resolved, but she remained
International normalised 4.7 0.99
oliguric and so remained on continuous RRT. She
ratio
underwent a liver transplant a week later which was
without complications and made a full renal recovery. Haemoglobin 9.1 9.7
This case demonstrates the fulminant deterioration that Platelet count (×109/L) 57 187
can befall a patient with chronic liver disease and the
Urine protein-creatinine ratio 58 Urine dip
urgency of treatment as well as the potential for good (mg/mmol) negative
renal recovery when HRS is cured.
652 A. O’Riordan and T. Ware
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655 37
Contents
References – 669
Both reduced kidney function and albuminuria are 37.3 Atherosclerotic and Non-
associated with increased cardiovascular mortality. In a atherosclerotic Disease in the CKD
comprehensive population-based study, the risk of a Population
cardiovascular event was 1.4 and 3.4 times greater in
patients with CKD stage 3a and stage 5, respectively [1]. 37.3.1 Atherosclerosis
Furthermore, outcomes for CKD patients suffering car-
diovascular events are worse than for those with normal
The high co-prevalence of shared risk factors such as
kidney function [2]. Thus, cardiovascular events repre-
diabetes mellitus means that atherosclerosis is an impor-
sent the most important avoidable cause of morbidity
tant cause of cardiovascular disease in patients with kid-
and mortality in patients with impaired kidney function.
ney disease [6]. The process of plaque formation, rupture
and vessel occlusion is likely to be similar in those with
and without CKD. Furthermore, atherosclerosis is a
37.2 The Association Between CKD and CVD systemic disease, meaning that plaque formation in the
37 arterial supply to one organ (e.g. in the coronary arter-
The interrelationship between CVD and CKD is com- ies) (. Fig. 37.2d) is likely to reflect coexistent disease
plex and involves both atherosclerotic and non- in the arterial supply to other organs (e.g. in the renal,
atherosclerotic changes (. Fig. 37.1). Risk factors carotid or femoral arteries).
including hypertension, smoking and diabetes have been
linked to the progression of both CKD and cardiovas-
cular disease, suggesting that there may be common 37.3.2 Left Ventricular Disease
pathogenic mechanisms [3]. However, CKD itself, or its
complications such as hyperphosphataemia, may also Echocardiographic studies suggest that a large propor-
play an important causal role in the development of car- tion of patients with CKD have structural heart disease,
diovascular diseases. Impaired kidney function and rising from 30% of patients with CKD stage 2 to 75% in
albuminuria/proteinuria have been implicated in the those with stage 4 [7]. This usually manifests as left ven-
pathogenesis of a wide range of cardiovascular syn- tricular hypertrophy (. Fig. 37.2c). Although coronary
dromes including heart failure, sudden cardiac death artery occlusion will cause segmental infarction as in
and stroke [4]. Furthermore, a causal role for the kidney those with normal kidney function, there may also be
in cardiovascular disease is supported by the stepwise ultrastructural abnormalities of the heart, such as myo-
increase in the risk of adverse cardiac events at lower cardial fibrosis in those with abnormal kidney function.
levels of kidney function and the reduction in risk fol- Whether these changes reflect the consequences of isch-
lowing successful kidney transplantation. aemia secondary to coronary microvascular disease or a
The term ‘cardiorenal syndrome’ has been used to specific effect of metabolites that accumulate in CKD
describe the broad spectrum of diseases in which heart remains unclear. In addition, there is now evidence that
and kidney dysfunction overlap. In a classification pro- hypotension during haemodialysis may contribute to
posed in the Consensus Conference by the Acute recurrent cardiac ischaemia providing another mecha-
Dialysis Quality Group 2008 [5], cardiorenal syndrome nism to drive structural damage to the heart [8].
Chronic Kidney Disease: Cardiovascular Complications
657 37
nall Fibrosis
Renal
Left venticular hypertrophy
rotte
einuria
Proteinuria
Activation of renin-angiotensin, cardiac fibrosis
endothelin myocardial infarction
and sympathetic nervous systems heart failure
P
Phosphate retention Endothelial dysfunction
h
hyperparathyroidism arterial stiffening
Diabetes mellitus
hypercholesterolaemia
smoking
a b
d e
37
. Fig. 37.2 Cardiovascular changes in CKD patients. a An elec- ening (Courtesy Dr. Paul Bass, Consultant Pathologist, Royal Free
tron beam CT scan of the heart in a patient with CKD demonstrat- London). d Histological section of a diseased atherosclerotic artery
ing calcium in the left anterior descending coronary artery. b Plain showing obstructive lipid-filled subintimal plaque (arrow; ×300
x-ray of the hand in a patient on haemodialysis showing calcification H&E). e Histological section of arteriosclerotic artery demonstrat-
of the deep branches of the radial artery as well as osteopaenia of ing arterial wall thickening and medial calcification (arrows; ×300
the small bones of the hand. c Post-mortem specimen of the heart H&E). (d, e: Courtesy Professor Mary Sheppard, Department of
from a patient with CKD demonstrating left ventricular wall thick- Cardiovascular Pathology, St George’s University of London)
Patients with CKD who sustain a myocardial infarc- Raised levels of troponin T (cTnT) and troponin I
tion may present with ST elevation on ECG, however (cTnI) are thought to reflect myocardial injury and are
atypical ECG changes are common. Patients with mul- now routinely used to select patients for invasive inves-
tiple previous episodes of cardiac ischaemia may have tigations such as coronary angiography. However,
signs of previous infarction on ECG and the manifesta- patients with impaired kidney function may have
tions of any new ischaemia on the tracing may not be raised blood levels of cardiac troponins, even in the
obvious. absence of an acute coronary syndrome (. Fig. 37.3).
Chronic Kidney Disease: Cardiovascular Complications
659 37
a
35
Controls
30
CKD
Frequency (%) 25
20
15
10
0
9
5
+
1.
0.
0.
3.
4.
9.
9.
9.
30
1–
5–
2–
5–
5–
–1
–2
<
0.
3.
10
20
hs cTnl (ng/L)
b
45
Controls
40
CKD
35
30
Frequency (%)
25
20
15
10
0
<5
3
50
00
<1
<1
<2
<3
<5
<7
<
<1
to
<1
to
to
to
to
to
to
3
to
to
5
10
15
20
30
50
0
70
10
hs cTnl (ng/L)
. Fig. 37.3 Troponin levels in patients with CKD but without acute coronary syndrome. Distribution of highly sensitive troponin I (a) and
highly sensitive troponin T (b) in 148 subjects with CKD and 288 healthy controls. (Reprinted with permission from DeFilippi et al. [8])
As kidney function declines, circulating cardiac tropo- interpreting raised troponin levels in patients with
nin levels increase, with the majority of patients having chronic kidney disease, but the following generalisa-
raised cTnT and a minority having a cTnI above the tions can be made:
normal range [9]. These high levels of cardiac tropo- 5 Elevated troponin T and troponin I concentrations
nins have been attributed to (a) failure of clearance of should be interpreted with caution in CKD patients.
troponin breakdown products via the kidney, (b) sub- 5 A single measurement cannot be used to stratify a
clinical myocardial injury and (c) noncardiac produc- patient’s risk in the same way as in those with normal
tion of the proteins. This presents difficulties when kidney function.
660 K. Pates et al.
5 Troponin concentrations predict poor outcomes receiving dialysis are generally at higher risk of bleeding
including cardiovascular death in patients with than those with normal kidney function.
CKD. The higher the troponin, the greater the risk As discussed above, the haemodialysis procedure
of death. itself can lead to reductions in myocardial perfusion.
5 An acute rise in cardiac troponin (>20% above base- Haemodialysis should be avoided during and immedi-
line) is likely to reflect an acute myocardial injury. ately following acute coronary ischaemia unless there
are absolute indications such as hyperkalaemia or fluid
In patients receiving haemodialysis, the dialysis process overload. Some nephrologists also suggest that the hae-
itself may influence troponin levels, but the magnitude modialysis prescription should be modified in the period
of this effect may be dependent on the type of dialysis immediately following an acute coronary event in order
membrane used [10]. to maximise cardiovascular stability with short daily
treatment times, low blood flow, minimal ultrafiltration
37.4.1.2 Diagnostic Imaging and a high sodium concentration in the dialysis fluid
Angiography remains the investigation of choice for (see 7 Chap. 59).
detecting athero-occlusive disease of the coronary and
peripheral vessels. Other imaging modalities such as CT Delayed/Elective Intervention
angiography may soon become the standard approach Although PTCA appears relatively safe in patients with
for visualisation of arterial plaque. Coronary CT also moderate CKD, as in patients with normal kidney func-
allows assessment of the vessel wall, so the overall tion, there have been no studies showing a positive
degree of coronary calcification can also be quantified. impact on clinical outcomes when compared to maxi-
CT angiography requires contrast administration with mising medical therapy in this group [13].
the associated risks. Iodinated radiocontrast used in In subgroup analyses of CKD patients entered into
digital subtraction and CT angiography can lead to trials comparing PTCA to coronary artery bypass graft-
acute kidney injury. This is generally mild and revers- ing, there are no differences in the rate of death, stroke
ible if adequate precautions are taken before the proce- and myocardial infarction between these two approaches,
dure (hydration, temporary omission of ARBs, ACEi although revascularisation rates are substantially lower
and diuretics), although the potential to damage resid- following surgery [14]. However, the risks of major sur-
ual kidney function in patients approaching dialysis gery are high in patients with additional comorbidities,
must be taken into account when planning these inves- and postoperative death is more frequent in dialysis
37 tigations.
Given that myocardial disease may occur in the
patients. Therefore, the choice as to whether to proceed
to PTCA or to refer for CABG should be determined by
absence of occlusive plaque, cardiac functional studies clinical judgement in the absence of good quality evi-
can be useful in patients with advanced CKD. Possible dence.
approaches include myocardial perfusion scanning or
stress echocardiography, and there is evidence that the Medical Therapy
latter of these two approaches can provide useful prog- Anticoagulant treatment is routinely administered to
nostic information [11]. patients presenting with acute coronary syndromes.
There is no reason to assume that these agents will be
Treatment
37.4.1.3 less effective in patients with CKD. There is an increased
Emergency Reperfusion risk of bleeding among patients with CKD stages 4–5
In patients without impaired kidney function, primary and in addition, the low-molecular-weight heparins
percutaneous transluminal coronary angioplasty accumulate in advanced kidney disease. Newer direct-
(PTCA) improves outcomes following ST-segment ele- acting anticoagulants may have a more favourable risk-
vation myocardial infarction (or acute coronary syn- to-benefit ratio than warfarin according to the limited
dromes with evidence of myocardial injury) compared data available, but there are no data from prospective
to conservative treatment. Although the magnitude of randomised trials.
this benefit may be reduced as kidney function declines Antiplatelet agents such as clopidogrel and glycopro-
[12], reperfusion is considered first-line treatment in tein IIa/IIIb inhibitors have not been shown to benefit
most dialysis centres and the benefits of reperfusion are patients with CKD when added to aspirin in the context
likely to outweigh any risk to the kidney from radiocon- of acute coronary syndromes. Data from post hoc anal-
trast in almost all clinical scenarios. yses of large trials suggest that the addition of these
Where PTCA is not available, thrombolysis using agents does not reduce the incidence of further cardio-
t-PA or streptokinase is an alternative approach to vascular events or death, but increases the risk of serious
reperfusion. There is no reason to assume that patients bleeding [15]. Therefore, optimal medical therapy in the
with renal impairment should not benefit from throm- secondary prevention of ischaemic heart disease con-
bolysis. However, it should be remembered that patients sists of aspirin in addition to renin-angiotensin system
Chronic Kidney Disease: Cardiovascular Complications
661 37
inhibition, beta-blockade and statin therapy. There is no Echocardiography is a useful non-invasive investiga-
evidence indicating that beta-blockade or drugs target- tion in CKD patients with pulmonary oedema. Evidence
ing of the renin-angiotensin system are any less effective of reduced left ventricular ejection fraction suggests
in patients with CKD, therefore given the increased underlying cardiac dysfunction. However, abnormal left
prevalence of IHD, the number of patients needed to ventricular geometry is common in CKD patients as a
treat to gain benefit is likely to be smaller. However, result of chronic pressure and volume overload, cardiac
observational studies suggest that despite this likely ben- ischaemia and fibrosis, but many patients will be found
efit, patients with CKD are less likely to receive evi- to have diastolic dysfunction on echocardiography.
dence-based medical management following acute Assessment of left ventricular function is further com-
coronary syndromes as compared to patients with nor- plicated in patients receiving haemodialysis by the effects
mal kidney function [16]. of changes in volume status and the potential for myo-
cardial stunning. Thus, the timing of the investigation
with reference to the dialysis session may be an impor-
tant factor in interpreting the result. Based on these con-
37.4.2 Cardiovascular Causes of Shortness
siderations, assessment of cardiac function by
of Breath echocardiography in a dialysis-dependent patient can
only be reliable once intravascular volume status has
37.4.2.1 Aetiology and Clinical Presentation been optimised.
Symptoms and signs of pulmonary oedema may present
diagnostic difficulty in CKD patients who can develop 37.4.2.2 Acute Treatment
sodium and water overload due to a failure of natriure- As in the patient with normal kidney function, the treat-
sis, independently of left ventricular dysfunction. ment of acute pulmonary oedema in CKD includes
Additionally, CKD patients with left ventricular failure maintaining gas exchange and venodilation, followed by
secondary to structural abnormalities, such as LV hyper- salt and water removal. Nitrates remain the mainstay of
trophy, or ischaemic damage (due to coronary artery venodilatory therapy and intravenous therapy allows
occlusion or microvascular disease) will also develop minute-by-minute titration according to arterial blood
secondary salt and water retention. More rarely, a dis- pressure.
ruption of cardiac rhythm can precipitate pulmonary Loop diuretics, which have both natriuretic and
oedema. Many patients with CKD, particularly in the vasodilatory effects when given intravenously, are also
advanced stages (stages 4–5), present with a combina- useful in CKD patients, except in those who are anuric.
tion of left ventricular dysfunction and fluid overload Higher doses of loop diuretics are often required when
and may need hospitalisation to optimise management. GFR is reduced as compared to when kidney function is
Chest x-ray may show evidence of engorged pulmo- normal. These large doses (e.g. 500 mg of frusemide/
nary vessels (and the ECG may reveal a left ventricular furosemide) are best given by continuous infusion over a
strain pattern). The polypeptide N-terminal pro-brain 24 h period as rapid injection of large doses of these
natriuretic peptide (nt-proBNP) is a highly sensitive drugs can cause deafness. Additional blockade of
marker of cardiac stretch and left ventricular failure in sodium reabsorption in the distal nephron with thiazide
patients with a normal GFR. nt-proBNP is cleared by or potassium-sparing diuretics will lead to enhanced
the kidney, and levels are higher in CKD, with a step- natriuresis. Careful monitoring is required when using
wise increase as GFR falls, but whether additional this combined approach, which can lead to rapid intra-
mechanisms (reflecting the burden of cardiac pathol- vascular volume depletion with associated organ dys-
ogy) are also responsible for the higher levels observed function. In addition, acidosis and hyperkalaemia often
in patients with CKD is controversial. Therefore, complicate the use of potassium-sparing diuretics in
although nt-proBNP levels correlate with LV dysfunc- those with CKD.
tion in patients with mild and moderate CKD, the upper In patients who are dialysis dependent or acutely
limit of normal for the assay should be increased in this oliguric, ultrafiltration may be required and should be
group of patients. Levels of nt-proBNP are highest in initiated in a timely fashion. In the acute setting and in
dialysis patients and do not necessarily show an inde- situations where the metabolic disturbance is limited,
pendent association with LV dysfunction in this group isolated ultrafiltration without dialysis will improve
[16], although serial measurements may provide useful cardiovascular stability and may be the treatment of
additional information as to changes in total body salt choice. Furthermore, where diagnostic doubt exists as
and water overload. As in the case of troponin, the dial- to the aetiology of the shortness of breath in a dialysis
ysis procedure may influence circulating concentrations patient, a therapeutic trial of ultrafiltration may be use-
of this marker, and whatever the mechanisms of eleva- ful. Removal of as little as 500 mL of ultrafiltrate can
tion in patients with CKD, higher levels of nt-proBNP acutely improve symptoms if due to pulmonary
predict adverse outcomes. oedema.
662 K. Pates et al.
Prevention of recurrent pulmonary oedema usually exposed and provide targets for intervention, for exam-
requires attention to both cardiac and renal factors. ple, hypertension due to hypervolaemia and sympathetic
Management of fluid overload in non-dialysis- overactivity, or electrolyte disturbances with rapid ion
dependent CKD patients includes salt restriction and shifts associated with dialysis.
diuretic therapy, sometimes requiring combinations of The role of biomarkers such as troponins and brain
loop and thiazide or potassium-sparing agents. Care natriuretic peptides in risk stratification requires further
must be taken to avoid over-diuresis, progressive prere- study, as does the role of prolonged cardiac monitoring
nal dysfunction and biochemical deterioration. Regular such as the Holter system or implantable recording
review of volume status and blood biochemistry along devices.
with patient education and daily home monitoring of
weight are important strategies. Ultimately, failure of 37.4.3.2 Treatment
volume control in a CKD patient may be the primary Indications for rate vs. rhythm control in AF are the
indication for initiating long-term RRT. same in CKD patients as for those in the general popu-
Both ACE inhibitors and beta-blockers are likely to lation. However, the burden of comorbidities in CKD
have a valuable role in the management of left ventricu- patients and a higher prevalence of potential contraindi-
lar failure in CKD, with beneficial effects on cardiac cations for anti-arrhythmic drugs (such as structural
remodelling and clinical outcomes. The roles of spirono- heart disease or electrolyte imbalances) increases the
lactone and newer aldosterone antagonists have not importance of individualised decision making [18].
been adequately defined in patients with impaired kid- There are no randomised controlled trials specifically
ney function. Sodium-glucose cotransporter inhibitors comparing rate vs. rhythm control in patients with CKD
may also improve heart failure outcomes in patients or ESKD.
with type 2 diabetes and CKD and are currently under- A large trial assessing safety and clinical outcomes
going assessment in clinical trials. of catheter ablation of AF in patients with CKD showed
that catheter ablation is more effective than anti-
arrhythmic drugs alone for maintenance of sinus
37.4.3 Arrhythmia and Sudden Death rhythm, with similar short- and long-term complication
rates [19]. Anticoagulation in the primary prevention of
37.4.3.1 Aetiology and Clinical Presentation AF-associated stroke is discussed in detail below.
Atrial fibrillation (AF) is the commonest cardiac rhythm As with other arrhythmias, electrolyte disturbance
37 disturbance in CKD patients, complicating an estimated should be corrected where possible and exacerbating
drugs withdrawn. Investigations to exclude occult coro-
16–21% of patients with CKD not on dialysis and 15–40%
of those on dialysis (reference from Turakhaj et al.). AF nary ischaemia should be considered. Primary and sec-
increases mortality risk in CKD and may also increase the ondary prevention using implantable defibrillators in
risk of progression to end-stage kidney disease. The effect CKD indicates some benefit, although the long-term
on stroke and other outcomes related to AF are more dif- risk vs. benefit balance requires further study.
ficult to determine due to the numerous shared risk fac-
tors between CKD and AF. For example, both CKD and
AF are risk factors for stroke; however, whether the rela- 37.4.4 Noncardiac Athero-occlusive
tionship is independent or interdependent is currently Disorders
unknown. Other cardiac rhythm disturbances are less
common and less extensively studied, but may also pres- 37.4.4.1 Aetiology and Clinical Presentation
ent with syncope or other consequences of hypotension. Both stroke and peripheral arterial disease are more
The risk of sudden cardiac death in patients with common in CKD patients than in age- and gender-
CKD is high, accounting for 25–29% of all-cause mor- matched controls, and as discussed above, the arteries of
tality in haemodialysis patients, with the annual rate these patients may be structurally and functionally
higher than that seen in heart failure and post-infarction abnormal. As well as an increased prevalence of athero-
patients [17]. The risk in non-haemodialysis CKD sclerotic disease, increased vascular stiffness leads to
patients is also much higher than the general population reduced peripheral perfusion, and calcification of arter-
and is comparable to that of post-infarction patients. ies may impact on the success of revascularisation strat-
The underlying mechanism, however, as to whether the egies (both angioplasty and bypass).
fatal rhythm disturbances are bradyarrhythmias or The standard investigation for occlusive carotid ste-
tachyarrhythmias is poorly understood. Risk factors for nosis and peripheral vascular disease is digital subtrac-
sudden cardiac death include the long-standing patho- tion angiography. In obtaining consent for these
physiological abnormalities to which CKD patients are procedures, the patient must be aware of the risk of
Chronic Kidney Disease: Cardiovascular Complications
663 37
radiocontrast-induced nephropathy, and pre-procedure sis patients going on to experience lower-limb amputa-
precautions should be taken. tion in one American cohort study [21]. As with other
forms of vascular disease, risk factors should be man-
37.4.4.2 Treatment aged, but there are currently no evidence-based medical
Secondary prevention strategies for noncardiac athero- therapies for critical limb ischaemia. Furthermore, there
sclerotic events include risk factor optimisation, for are no randomised controlled trials investigating differ-
example, blood pressure and cholesterol lowering. This ent interventional management strategies and decisions
is discussed in detail below, but certain invasive inter- regarding angioplasty, bypass and amputation must be
ventions require specific attention. made on an individual patient basis. Involvement of the
multidisciplinary team is critical in such decision mak-
Thrombolysis for Stroke ing, which should involve close liaison between vascular,
Thrombolysis for acute stroke in patients with normal infectious diseases and nephrology teams.
kidney function presenting within 4.5 h is currently a
routine part of clinical practice. No evidence for an
increased risk of bleeding has been observed in patients 37.5 Prevention of Cardiovascular
with moderate CKD, although the benefits of thrombo-
lytic therapy in this group have not been specifically
Complications in Patients with Kidney
addressed. As discussed in the section on coronary Disease
reperfusion above, the increased risk of bleeding com-
plications must be considered when offering thrombo- 37.5.1 Traditional Vascular Risk Factors
lytic therapy to patients receiving dialysis. No and Treatment
randomised controlled trials of thrombolysis for acute
stroke in patients receiving haemodialysis have been 37.5.1.1 Blood Pressure
published, and opinion on the appropriateness of this Control of blood pressure has been shown to both reduce
treatment remains divided. the risk of cardiovascular events and retard progression
of kidney dysfunction in patients with CKD. Current
Carotid Endarterectomy for Prevention of Stroke guidelines recommend a systolic pressure of ≤140 mmHg
The benefits of endarterectomy in those with symptom- and a diastolic pressure of ≤90 mmHg, except in patients
atic high-grade carotid stenosis may extend to patients with urinary albumin-to-creatinine ratio greater than
with impaired kidney function, but the ratio of risk to 30 mg/mmol (i.e. microalbuminuria and macroalbumin-
benefit has not been properly defined in patients with uria) when this target should be reduced to
ESRD. ≤130/80 mmHg, regardless of the presence or absence of
diabetes. In a large randomised controlled trial (Systolic
37.4.4.3 Dialysis Around Acute Stroke Blood Pressure Intervention Trial (SPRINT)), intensive
Haemodialysis leads to brain swelling, with documented blood pressure lowering in patients with mild-to-moder-
changes in brain volume of around 3% attributable to ate CKD and hypertension (but without diabetes) to sys-
the procedure [20]. Therefore, most physicians would tolic <120 mmHg compared to <140 mmHg reduced the
attempt to avoid haemodialysis immediately after acute rates of cardiovascular events and all-cause mortality
brain injury unless there was an absolute life-threatening without evidence of a deleterious effect on CKD pro-
indication such as hyperkalaemia or pulmonary oedema. gression [22]. This again suggests the need for individual-
Dialysis prescriptions can be designed to maximise sta- ised decision making, particularly in elderly patients in
bility as described in 7 Chaps. 80 and 81, and systemic whom overtreatment of blood pressure may exacerbate
anticoagulation should be avoided, particularly in those postural hypotension and lead to falls.
with intracerebral haemorrhage or when the nature of
the stroke has not been determined. 37.5.1.2 Salt Restriction
Blood pressure control can be more difficult in patients
37.4.4.4 Outcomes of Interventions with moderate-to-severe CKD and is complicated by a
for Critical Limb Ischaemia degree of salt and water overload. Salt restriction, which
As with all other atherosclerotic diseases, outcomes for can improve blood pressure in those with normal kidney
patients with limb ischaemia caused by peripheral vas- function, may have an even more important role in those
cular disease worsen with declining kidney function. with renal dysfunction. Reducing salt intake in patients
Patients on dialysis have some of the highest rates of with CKD is therefore critical for control of blood
amputation and other complications from peripheral pressure, proteinuria and oedema. There is evidence that
vascular disease with over 13% of incident haemodialy- patients with CKD have a reduced taste sensation for
664 K. Pates et al.
140
ACE inhibition
of treatment. A serum creatinine rise reflecting a drop in
Systolic blood pressure (mmHg)
Aspirin Likely benefit in the prevention of both primary and No dose adjustment necessary
secondary CV events in CKD
Other Clopidogrel appears to be of limited in benefit/efficacy in Several glycoprotein IIa/IIIb inhibitors require dose
antiplatelet those with reduced GFR and may be associated with an adjustment in patients with reduced GFR
agents increased risk of bleeding. Evidence base is poor for other
ADP receptor blockers and glycoprotein IIa/IIIb inhibitors
Warfarin Possibly useful for primary prevention of stroke in patients No specific dose alteration required but care with
with atrial fibrillation and moderate CKD. Significant drug interactions required
increased risk of bleeding observed and doubt as to overall
benefit when used as primary prevention of stroke in patients
receiving haemodialysis
Heparins Reduce early ischaemic events in acute coronary syndromes. Dose reduction of LMWH in CKD. Factor Xa
LMWH accumulates in renal impairment. Increased bleeding monitoring or unfractionated heparin may be
seen with use of enoxaparin in CKD preferred in severe renal impairment
Oral factor May be a useful alternative to heparins and warfarin. Efficacy May require dose reduction in CKD
Xa in stroke and systemic embolism prevention non-inferior to
inhibitors warfarin with GFR 30–50 mL/min; however, significant
reduction in major bleeding events seen with apixaban and
edoxaban. Unknown effects with GFR <30 mL/min
Renin- Possible cardiovascular benefits, both in primary and Monitoring of biochemistry required following
angiotensin secondary prevention and probable benefit in slowing of commencement or dose increases. Hyperkalaemia can
blockade decline in kidney function. No clear evidence for combined occur and may require dose adjustment or with-
(ACEi/A2 use of ACE, ARB or renin inhibitors drawal. Stable increases in serum creatinine of
blockers/ 20–30% are generally thought to be acceptable
renin inhibi-
tors)
Beta- Possible benefit in patients with heart failure and CKD and in Most agents dosed as in normal renal function but
blockers secondary prevention post-MI. Can be used for rate control in may need to commence at low doses
atrial fibrillation
Diuretics Thiazide diuretics are useful antihypertensive agents in mild Thiazides may become less effective as GFR falls.
and moderate CKD. Addition of loop diuretics to other Combination therapy with loop and thiazide diuretics
antihypertensive therapy is a useful therapeutic strategy in recommended in CKD stages 4 and 5. Hyperkalae-
moderate-to-severe CKD. High doses of loop diuretics for the mia and acidosis may complicate the use of
treatment of oedema may be required in advanced CKD potassium-sparing diuretics in CKD
Calcium Similar benefit in terms of primary prevention of cardiovascu- No specific dose adjustments
channel lar events as compared to ACE inhibitors and diuretics in
blockers hypertensive patients with CKD. Dihydropyridines may
exacerbate proteinuria
Digoxin Can be used for rate control in atrial fibrillation Standard loading dose, but low maintenance doses
required in CKD. Risk of accumulation and toxicity
so monitoring levels is essential. Not removed in
haemodialysis patients
Cholesterol- Proven benefits of statin plus ezetimibe combination in No evidence for increased statin toxicity in CKD
lowering primary prevention of atherosclerotic CV disease in stage 3–5 when used in low doses, even when used in combina-
agents CKD. Probable benefit in patients receiving haemodialysis and tion with ezetimibe. Fibrates should be avoided in
following kidney transplantation patients with stage 4–5 CKD. High doses of statins
best avoided because of the potential for muscle
injury
(continued)
666 K. Pates et al.
20 Factors
Rate reduction 17% (95% CI 6-26 %)
15 Log-rank p=0.0021 37.7.1 Albuminuria
10
Albuminuria is an important independent risk factor for
5 cardiovascular events, even in patients with preserved
0
kidney function. Approaches aimed to reduce blood
0 1 2 3 4 5 pressure, such as salt restriction and renin-angiotensin
Years of follow-up blockade, will also reduce albuminuria.
appropriate for secondary prevention of cardiovascular As well as being prone to venous thromboembolism
events in CKD. Evidence for the use of alternative anti- (discussed in 7 Chap. 1), patients with nephrotic syn-
platelet agents such as clopidogrel for primary prevention drome are also at greater risk of cardiovascular events
of cardiovascular events in patients with CKD is lacking. such as stroke or coronary heart disease, with an esti-
mated fivefold increased risk of myocardial infarction
compared to the general population [36]. Reduction
37.6 Prevention of Stroke in Chronic Atrial in cardiovascular risk in the context of albuminuria
Fibrillation relies on achieving remission or even partial remission
where possible. Although no good evidence is avail-
In patients with normal kidney function, when antico- able, control of other risk factors such as hypercho-
agulation is indicated for the prevention of stroke or lesterolaemia and hypertension may also help reduce
embolism in atrial fibrillation, warfarin has previously the risk of vascular events. The routine use of aspirin
been the therapy of choice. However, a number of ran- would seem appropriate, although there is no evi-
domised trials that have compared the direct oral anti- dence base for this. Formal anticoagulation is also
coagulants (DOACs) to warfarin have shown that they used in severely hypoalbuminaemic patients as pro-
are non-inferior to warfarin in the prevention of stroke phylaxis against venous thromboembolism, and
and embolism in atrial fibrillation, with a reduction in whether this has a role in preventing arterial disease is
fatal bleeding events and probable reduction in haemor- unclear.
rhagic stroke. As such, DOACs are increasingly being
used as the anticoagulant of choice. In patients with
CKD, the benefits of warfarin on stroke risk reduction 37.7.3 Bone Mineral Disorder/
have also been observed [34], with warfarin prescription Hyperphosphataemia
associated with a 24% relative risk reduction. However,
in patients receiving haemodialysis, warfarin treatment Derangements in mineral metabolism occur even in
has been associated with a doubling in risk of intracere- patients with stage 3–5 CKD as part of the bone mineral
bral haemorrhage [35], so the risks of treatment may disorder (see 7 Chap. 3). Although increases in calcium
well outweigh the benefits in this group. Although aspi- and phosphate are associated with an increased risk of
rin therapy may be indicated for the prevention of car- cardiovascular events, whether this relationship is
diac events in this group, it does not appear to be directly causal and the degree to which different treat-
associated with a reduced risk of stroke. With a GFR of ment strategies alter this risk is not known. A large ran-
30–50 mL/min, as for those with normal kidney func- domised trial that measured the effect of the calcimimetic
tion, the efficacy of the DOACs apixaban and edoxaban agent cinacalcet in patients with moderate-to-severe sec-
in stroke and systemic embolism prevention is non- ondary hyperparathyroidism who were undergoing hae-
inferior to warfarin, with a significant reduction in modialysis showed no significant reduction in either the
major bleeding events. The effects in patients with a risk of death or the risk of non-fatal cardiovascular
GFR <30 mL/min have not been systematically studied. events [37].
668 K. Pates et al.
37.7.4 Medications early CKD and includes blood pressure reduction, statin
therapy and optimisation of diabetes. Management of
Several medications used in the treatment of kidney dis- clinical cardiovascular events in CKD patients should
ease have adverse cardiovascular profiles. Most com- be based on strategies of proven benefit in the general
monly used in kidney transplant recipients, calcineurin population, taking into account additional risks that
inhibitors are known to impact on cardiovascular risk result from a reduced eGFR. Ongoing trials in patients
factors. Ciclosporin use is associated with an increase in with CKD and analysis of CKD subsets recruited into
blood pressure and tacrolimus with an increased risk of cardiovascular trials are likely to inform future practice
diabetes. Similarly, corticosteroids can lead to insulin in this area.
resistance, weight gain and hypertension. Other drugs
that modify cardiovascular risk factors include sirolimus
(lipid abnormalities) and antiretrovirals used in HIV
treatment (lipid abnormalities).
Case Study
37.7.5 Evidence for Other Proposed Case 1
Kidney-Associated Risk Factors A man in his mid-60s with a long-standing stable renal
transplant and past history of ischaemic heart disease
A number of circulating markers that potentially con- became unwell following a community-acquired chest
tribute to vascular disease in the context of CKD have infection. He was treated for the chest infection but
been identified. These include homocysteine, uric acid, developed symptoms and signs of heart failure. He had
reactive oxygen species and endogenous inhibitors of several admissions and increases in diuretics but
nitric oxide synthesis. Although increased levels of all of remained dyspnoeic and had a relentless rise in creati-
these substances are associated with both reduced kid- nine from a baseline of 200 μmol/l with a trajectory
ney function and cardiovascular events, evidence for a strongly predicting the need for dialysis within
causal role remains inconclusive to date. 6–12 months (see red line figure). His renal dysfunction
There have been a number of small, unblinded stud- was felt to be secondary to cardiorenal syndrome, and
ies showing benefits associated with targeting these non- he underwent cardiac resynchronisation with dual pac-
traditional risk factors however, the results from larger ing, a further increase in diuretics and endovascular
37 high-quality controlled trials have been negative. For mitral valve repair for marked MR. His symptoms
example, in the case of homocysteine, there are a num- improved markedly, and his renal function stabilised
ber of studies reporting that increases are independently (albeit with the typical pre-renal saw-toothed pattern)
associated with future cardiovascular events in CKD with a creatinine averaging 300 μmol/l for 6 years.
[38], and there is also a simple therapeutic intervention, While one would always strive to optimise the treat-
folic acid, which has been shown to reduce levels. ment of cardiac failure, this illustrates the profound
However, evidence from several good quality ran- impact on renal function of achieving the best possible
domised trials demonstrate that treatment with folic control of heart failure in patients with cardiorenal
acid does not reduce the risk of cardiovascular events in syndrome.
CKD patients [39]. Therefore, although there are several
proposed novel mediators of cardiovascular risk in
CKD, the gap between exploratory studies and evi-
dence-based intervention remains.
37.8 Conclusions
7. Park M, Hsu CY, Li Y, et al. Associations between kidney func- 23. Kusaba T, Mori Y, Masami O, et al. Sodium restriction improves
tion and subclinical cardiac abnormalities in CKD. J Am Soc the gustatory threshold for salty taste in patients with chronic
Nephrol. 2012;23:1725–34. kidney disease. Kidney Int. 2009;76:638–43.
8. McIntyre CW, Burton JO, Selby NM, et al. Hemodialysis- 24. Slagman MC, Waanders F, Hemmelder MH, et al. Moderate
induced cardiac dysfunction is associated with an acute reduc- dietary sodium restriction added to angiotensin converting
tion in global and segmental myocardial blood flow. Clin J Am enzyme inhibition compared with dual blockade in lowering
Soc Nephrol. 2008;3:19–26. proteinuria and blood pressure: randomised controlled trial.
9. Defilippi C, Seliger SL, Kelley W, et al. Interpreting cardiac tropo- BMJ. 2011;343:d4366.
nin results from high-sensitivity assays in chronic kidney disease 25. Vogt L, Waanders F, Boomsma F, et al. Effects of dietary sodium
without acute coronary syndrome. Clin Chem. 2012;58:1342–51. and hydrochlorothiazide on the antiproteinuric efficacy of losar-
10. Lippi G, Tessitore N, Montagnana M, et al. Influence of sam- tan. J Am Soc Nephrol. 2008;19:999–1007.
pling time and ultrafiltration coefficient of the dialysis mem- 26. Baigent C, Landray MJ, Reith C, et al. The effects of lowering
brane on cardiac troponin I and T. Arch Pathol Lab Med. LDL cholesterol with simvastatin plus ezetimibe in patients
2008;132:72–6. with chronic kidney disease (Study of Heart and Renal Protec-
11. Bergeron S, Hillis GS, Haugen EN, et al. Prognostic value of tion): a randomised placebo-controlled trial. Lancet.
dobutamine stress echocardiography in patients with chronic 2011;377:2181–92.
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12. Szummer K, Lundman P, Jacobson SH, et al. Influence of renal and cardiovascular events in patients undergoing hemodialysis.
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vation myocardial infarction: data from the Swedish Web-Sys- 28. Wanner C, Krane V, Marz W, et al. Atorvastatin in patients with
tem for Enhancement and Development of Evidence-Based type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med.
Care in Heart Disease Evaluated According to Recommended 2005;353:238–48.
Therapies (SWEDEHEART). Circulation. 2009;120:851–8. 29. Holdaas H, Fellstrom B, Cole E, et al. Long-term cardiac out-
13. Sedlis SP, Jurkovitz CT, Hartigan PM, et al. Optimal medical comes in renal transplant recipients receiving fluvastatin: the
therapy with or without percutaneous coronary intervention for ALERT extension study. Am J Transplant. 2005;5:2929–36.
patients with stable coronary artery disease and chronic kidney 30. Charytan DM, Sabatine MS, Pedersen TR, et al. Efficacy and
disease. Am J Cardiol. 2009;104:1647–53. safety of evolocumab in chronic kidney disease in the FOU-
14. Ix JH, Mercado N, Shlipak MG, et al. Association of chronic RIER trial. J Am Coll Cardiol. 2019;73(23):2961–70.
kidney disease with clinical outcomes after coronary revascular- 31. ADVANCE Collaborative Group. Intensive blood glucose con-
ization: the Arterial Revascularization Therapies Study (ARTS). trol and vascular outcomes in patients with type 2 diabetes. N
Am Heart J. 2005;149:512–9. Engl J Med. 2008;358(24):2560–72.
15. Palmer SC, Di Micco L, Razavian M, et al. Effects of antiplate- 32. Mahaffey KW, Jardine MJ, Bompoint S, et al. Canagliflozin and
let therapy on mortality and cardiovascular and bleeding out- cardiovascular and renal outcomes in type 2 diabetes and chronic
comes in persons with chronic kidney disease: a systematic kidney disease in primary and secondary cardiovascular preven-
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37 445–59.
16. Fox CS, Muntner P, Chen AY, et al. Use of evidence-based ther-
Circulation. 2019; https://doi.org/10.1161/CIRCULA-
TIONAHA.119.042007. [Epub ahead of print].
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dial infarction and non-ST-segment elevation myocardial hypertensive patients with chronic kidney disease: a post-hoc
infarction in patients with chronic kidney disease: a report from subgroup analysis of a randomized controlled trial. J Am Coll
the National Cardiovascular Data Acute Coronary Treatment Cardiol. 2010;56:956–65.
and Intervention Outcomes Network registry. Circulation. 34. Olesen JB, Lip GY, Kamper AL, et al. Stroke and bleeding in
2010;121:357–65. atrial fibrillation with chronic kidney disease. N Engl J Med.
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disease and arrhythmias: conclusions from a kidney disease: 35. Winkelmayer WC, Liu J, Setoguchi S, et al. Effectiveness and
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671 38
Management of Diabetic
Nephropathy
Bryan Conway, Jane Goddard, Alan Jaap, and Alan Patrick
Contents
References – 687
Management of Diabetic Nephropathy
673 38
n Learning Objectives 38.2 Epidemiology
1. DN is the most common cause of end-stage renal
disease (ESRD), but more patients will die of car- Towards the end of the last millennium, there was a dra-
diovascular disease than reach dialysis; therefore, matic rise in the incidence of ESRD due to DN in devel-
management of cardiovascular risk factors is oped countries, chiefly as a consequence of the increased
essential. prevalence of type 2 diabetes [2, 3]. However, since 2000,
2. Modestly elevated albuminuria (microalbuminuria) the incidence of ESRD due to DN has broadly stabi-
is the earliest clinical indicator of nephropathy and lised, in large part due to improvements in the treatment
is associated with increased cardiovascular risk. of diabetes. Indeed, over the last few decades, the preva-
3. Less stringent glycaemic control is recommended lence of overt nephropathy in patients who have had
for those with more advanced kidney disease as the type 1 diabetes for 30 years has fallen from 30% histori-
increased risk of hypoglycaemia usually outweighs cally to 15% in recent cohort studies and to as little as
potential benefits. 9% in clinical trials [4].
4. Glucagon-like peptide-1 (GLP-1) receptor agonists There is a marked international variation in the inci-
and sodium-glucose co-transporter 2 (SGLT-2) dence of ESRD due to diabetic nephropathy. For exam-
inhibitors convincingly reduce renal and cardio- ple, in the USA, the incidence of ESRD due to diabetic
vascular events including delaying progression of kidney disease is almost 162 per million population
CKD and development of ESRD. (45% of total ESRD) [2], while in the UK, the incidence
5. Inhibition of the renin-angiotensin-aldosterone is much lower, at 29 per million population (28% of total
axis is first-line therapy for patients with evidence ESRD) [3]. This may be partly attributed to a lower pro-
of albuminuria, but blockade with two or more portion of the UK population being of high-risk eth-
agents is not recommended due to the risk of nicities; however, additional factors may also be
hyperkalaemia and acute kidney injury. important as Caucasian patients with diabetes and stage
3 or 4 chronic kidney disease (CKD) in the USA have a
threefold greater risk of progressing to ESRD compared
38.1 Introduction to Caucasians in Norway [5]. Measures of quality of
pre-dialysis care, including timely referral to nephrolo-
Diabetic nephropathy (DN) remains the single most gists, were superior in Norway, illustrating the impor-
common cause of end-stage renal disease (ESRD) in tance of developing systems that integrate primary care,
developed nations and is of increasing importance in diabetologists and renal physicians in the management
developing countries. The deleterious effect of diabetes of persons with diabetes and kidney disease.
on kidney function is reflected in the 12-fold increase in Of particular concern is the increasing prevalence of
the incidence of ESRD in men with diabetes compared obesity, diabetes and DN in developing countries [6].
with their non-diabetic counterparts [1]. Nephrologists Accurate assessment of the true prevalence of DN in
will see increasingly large numbers of patients with dia- developing countries is difficult. For example, CKD due
betes who have CKD, are on dialysis or have had a renal to DN is more prevalent in the Indian subcontinent than
transplant; therefore, the development of integrated sys- in developed countries; however, a much smaller pro-
tems to best manage their care to a high standard is a portion of patients with DN receive renal replacement
key priority. New developments in the treatment of dia- therapy, as relatively few patients are accepted onto
betes with significant cardiovascular and renal benefits government-funded ESRD programmes. As few people
are transforming the management of diabetic patients in developing countries can afford health insurance or
and have emphasised the need for early, focused and dialysis, it is likely that the majority of patients with
coordinated care. ESRD due to DN will unfortunately die of renal failure
[7]. Hence, the challenge is to develop education, screen-
ing and management programmes for diabetes and
Diabetic nephropathy can be defined as a triad of hypertension and to ensure access to subsidised medica-
albuminuria, evolving hypertension and progressive tions. Guidelines tailored to a resource-poor setting
decline in renal function in patients with diabetes, should be developed, and these may need to include less
often in association with other microvascular compli- stringent glycaemic targets and initially focus on those
cations and in the absence of evidence of alternative with moderate-to-severe hypertension. In countries with
renal diagnoses. limited resources, focus is typically directed towards
acute, symptomatic conditions; however, successful
674 B. Conway et al.
chronic disease management programmes have been to the diabetic glomerulus is a prerequisite for the devel-
reported, notably in Cuba, where the well-developed opment of advanced nephropathy [15].
primary care system has produced some of the highest
levels of attainment of target blood pressure control in
the world [8]. 38.3.4 Renin-Angiotensin System
Activation
38.3 Aetiology and Pathogenesis The intra-renal renin-angiotensin-aldosterone system
(RAAS) is activated in patients with diabetes, resulting
38.3.1 Genetic Factors in an increase in systemic and intraglomerular pressure,
which in turn may exacerbate proteinuria [16]. In addi-
While poor glycaemic and blood pressure control are tion, angiotensin II may directly promote inflammation
risk factors for nephropathy, it is well recognised that and increase matrix deposition by activating cytokines
some patients with diabetes develop nephropathy despite such as transforming growth factor-β [17]. Hence, there
good glycaemic and blood pressure control, while con- are theoretical advantages for inhibiting RAAS activ-
versely others who have poorly controlled risk factors ity, above and beyond lowering of blood pressure. This
remain free of renal disease. This suggests that subsets theory has been supported by the results of clinical tri-
of people with diabetes may be genetically predisposed als in which the reduction in the rate of decline in renal
to, or protected from, developing nephropathy. A role function observed with RAAS inhibition remains sig-
for genetic susceptibility is supported by differences in nificant even after correcting for changes in blood pres-
prevalence in various ethnic groups, with the proportion sure [18].
of patients with diabetes who develop nephropathy
being much higher in Blacks, Hispanics and indigenous
populations such as the Pima Indians [9]. In addition, 38.4 Natural History and Pathogenesis
diabetic nephropathy tends to cluster within families,
with the risk of DN being greater if there is a parental Diabetic nephropathy is a slowly progressive disease,
history of hypertension or cardiovascular disease [10]. typically taking at least 15–20 years from the diagnosis
Unfortunately, the specific genes that confer susceptibil- of diabetes to reach end-stage kidney disease. The natu-
ity to, or protection from, diabetic nephropathy have yet ral history of DN may be divided into five phases as
to be conclusively established. described by Mogensen (. Table 38.1) [19]. The cardi-
nal features are a triad of:
1. Progressive albuminuria: ranging from upper limit
38 38.3.2 Glycaemic Control of normal, through microalbuminuria to nephrotic-
range proteinuria.
The Diabetes Control and Complications Trial (DCCT) 2. Evolving hypertension: subtle abnormalities such as
confirmed a causal link between poor glycaemic control loss of nocturnal dipping precede and predict the
and overt nephropathy [11] and the development of onset of albuminuria [20]; blood pressure progres-
CKD [12] in patients with type 1 diabetes. Similar data sively increases, and by the time stage 4 CKD is
for patients with type 2 diabetes were generated from the reached, three or more agents are often required to
UK Prospective Diabetes Study (UKPDS) [13]. achieve the target blood pressure [14].
3. Declining renal function: in type 1 diabetes, an initial
hyperfiltration phase is often observed, which may
38.3.3 Hypertension predict the onset of microalbuminuria; this is fol-
lowed by an insidious decline in renal function
In the UKPDS, tight blood pressure control was at least towards end-stage kidney disease.
as effective as glycaemic control in preventing nephropa-
thy [14]. Indeed, the pre-eminent role of hypertension in
promoting progression to advanced diabetic kidney dis- 38.4.1 Pathological Features
ease is perhaps best illustrated by an experiment of
nature. In patients with diabetes and co-existing unilat- The glomerular pathology in DN has been classified by
eral renal artery stenosis, there was no pathological evi- the Renal Pathology Society into four stages: (1) increase
dence of DN in the kidney downstream of the stenosis, in basement membrane thickness, (2) increased mesan-
despite severe nephropathy in the contralateral kidney, gial matrix deposition, (3) nodular glomerulosclerosis
suggesting that transmission of systemic hypertension and (4) global glomerulosclerosis. An example of the
Management of Diabetic Nephropathy
675 38
classical Kimmelstiel-Wilson nodule is shown in rationale for performing renal biopsy is atypically fast
. Fig. 38.1a. The close relationship between diabetic progression of disease, such as a sudden increase in pro-
nephropathy and cardiovascular disease is evident from teinuria or a rapid decline in renal function, as such fea-
the observation that features of small vessel injury are tures suggest the presence of another renal pathology
common, including intimal arteriolar hyalinosis (see 7 Case 1). Retinopathy is present in up to 80% of
(. Fig. 38.1b) and glomerular fibrin caps, which are patients at the time of diagnosis of nephropathy; there-
due to the insinuation of plasma proteins into the vessel fore, the absence of retinopathy highlights the need to
wall. These findings are highly suggestive, but not consider an alternative diagnosis, but on its own, it is
pathognomonic, of DN as they may also be observed in rarely an indication for biopsy. Similarly, non-visible
non-diabetic patients with severe obesity. Tubular atro- haematuria may be observed in up to 20% of patients
phy, tubulointerstitial fibrosis and inflammation are also with diabetic kidney disease, with a minority of these
observed, and the severity of tubulointerstitial disease is patients demonstrating an alternative pathology on
the best predictor of clinical outcome [21]. renal biopsy [22, 23]. Importantly, people over 50 years
old who have unexplained non-visible haematuria
should be referred for further urological investigation.
38.5 Diagnosis While microalbuminuria is classically recognised as
the earliest clinical marker of diabetic nephropathy, a
The first clinical evidence of diabetic nephropathy is the reduction in renal function may occasionally be observed
onset of modestly elevated albuminuria (also known as in normoalbuminuric patients with type 1 diabetes,
microalbuminuria) defined as an albumin/creatinine often in association with typical structural changes of
ratio in the range of 2.5–30 mg/mmol for males and 3.5– DN and no evidence of alternative pathology [24]. In
30 mg/mmol for females in at least two out of three suc- type 2 diabetes, almost 75% of patients who have an
cessive measurements. Annual screening for eGFR <60 ml/min/1.73 m2 remain normoalbuminuric
microalbuminuria should be performed within 5 years [25]. Here, the absence of microalbuminuria may reflect
of the diagnosis of type 1 diabetes and from the time of the more heterogeneous nature of renal injury in type 2
diagnosis in patients with type 2 diabetes, as latent dia- diabetes, with a higher prevalence of non-diabetic renal
betes may have been present for some time prior to diag- disease such as hypertensive and ischaemic nephroscler-
nosis in the latter. DN is usually diagnosed on clinical osis. These findings highlight that, in addition to screen-
grounds, with relatively few patients undergoing renal ing for albuminuria, an assessment of renal function
biopsy, which is reserved for those patients with features should be performed on an annual basis in patients with
of atypical disease (. Table 38.2). The predominant both type 1 and type 2 diabetes.
676 B. Conway et al.
a 38.6 Management
predominantly because, in a subgroup of 342 overweight undergoing a radiological study involving the adminis-
and obese patients randomised to intensive therapy with tration of contrast agents. What is currently less clear is
metformin, there was less weight gain and a reduction in whether it can be safe in some circumstances, specifically
all-cause mortality and in a number of major cardiovas- when the rate of decline in renal function is very slow, to
cular outcomes, including stroke, in comparison to con- continue with metformin therapy even when the eGFR
ventional therapy [36]. Although similar trends were drops below 30 ml/min/1.73 m2, with appropriate moni-
seen in patients who were randomised to intensive ther- toring.
apy with sulphonylureas or insulin, the results in these
arms of the study did not attain statistical significance.
Given the fact that cardiovascular disease is the major 38.9.2 Sulphonylureas and Meglitinides
cause of excess morbidity and mortality in people with
type 2 diabetes, these findings led to a dramatic increase These drugs bind to specific, but different, receptors on
in the prescription of metformin, and for some time it the pancreatic beta cell and directly stimulate insulin
has been the oral hypoglycaemic of choice in overweight secretion. As such, they are inevitably associated with a
and obese patients. risk of hypoglycaemia, and this risk increases in the con-
A concern has been that metformin and its metabo- text of CKD. This is partly due to the accumulation of
lites are predominantly renally excreted and thus will these drugs and their metabolites, as the sulphonylureas
accumulate in renal impairment. Furthermore, there is a are predominantly renally excreted with the exception
well-established link between metformin and lactic aci- of gliquidone. Longer-acting sulphonylureas, such as
dosis, although to what extent metformin is directly glibenclamide, are probably best avoided completely,
causative remains a matter of some speculation. What is and the dose of other shorter-acting agents may need to
clear, however, is that the risk of lactic acidosis increases be reduced. All patients with CKD on sulphonylurea
in the context of acute kidney injury which, in turn, is therapy should be provided with the equipment to per-
much more common in those with pre-existing CKD. form regular home capillary blood glucose monitoring,
Previously, metformin was widely used by diabetolo- given the increased risk of hypoglycaemia.
gists in patients whose serum creatinine was 150– Meglitinides, with their shorter duration of action
200 μmol/l, with few problems. Routine reporting of than sulphonylureas, have been promoted largely in rela-
eGFR, however, initially led to recommendations that tion to targeting post-prandial hyperglycaemia, but have
metformin be discontinued in stage 3 CKD. In many not been widely embraced, at least in the UK, due to the
cases, this demonstrated just what an effective glucose- need for multiple daily dosing. These drugs may, how-
lowering agent metformin is in obese patients with type ever, be considered as a useful alternative to sulphonyl-
2 diabetes. Frequently, patients who had had excellent ureas in the context of CKD, especially repaglinide,
38 glycaemic control on metformin alone became hypergly- which is predominantly hepatically metabolised.
caemic when this drug was stopped. Other oral agents
proved less effective and often led to significant weight
gain. Insulin was frequently required, but despite the use 38.9.3 Pioglitazone
of large doses due to insulin resistance, resultant glycae-
mic control remained inferior to that achieved on met- Pioglitazone is now the only thiazolidinedione available
formin. in the UK. It is a peroxisome proliferator-activated
Such issues have led to a reassessment of the use of receptor-gamma (PPARγ) agonist, with multiple meta-
metformin in the context of CKD. There is currently bolic effects, including increasing insulin sensitivity. It is
general agreement that metformin should usually be metabolised by the liver and is hence potentially a useful
avoided when the eGFR drops below 30 ml/min/1.73 m2 drug in patients with CKD. However, pioglitazone is
but it is safe in most patients with an eGFR >45 ml/ associated with fluid retention and contraindicated in
min/1.73 m2. Between 30 and 45 ml/min/1.73 m2, regular the presence of congestive cardiac failure. More recently
monitoring of renal biochemistry is recommended, and identified concerns with pioglitazone relate to an
if renal function is steadily declining, it is appropriate to increased fracture risk, especially in post-menopausal
stop metformin before the eGFR falls to <30 ml/ women [38] and a possible increase in bladder cancer.
min/1.73 m2 [37]. Furthermore, as is recommended with
ACE inhibitors and angiotensin receptor blockers,
patients taking metformin should temporarily discon- 38.9.4 Insulin
tinue the drug when a situation arises which might lead
to a short-lived deterioration in renal function, e.g. if the In addition to patients with type 1 diabetes, many
patient is suffering from vomiting or diarrhoea or is patients with type 2 diabetes who develop CKD will
Management of Diabetic Nephropathy
679 38
have had diabetes for a long period of time and will 38.10.2 Dipeptidyl Peptidase-4 (DPP-4)
already be on insulin therapy due to declining beta-cell Inhibitors
function, with or without additional oral hypoglycae-
mic drugs. As the liver and kidneys are the major sites DPP-4 is the enzyme which inactivates GLP-1; there-
of insulin clearance/degradation, the half-life of insu- fore, DPP-4 inhibitors enhance GLP-1 levels by slow-
lin is prolonged in patients with CKD, and therefore ing down its degradation, but unlike the currently
there is a greater risk of hypoglycaemia with insulin available GLP-1 agonists, these drugs are active orally.
therapy. The healthy kidney is responsible for approxi- They are generally well tolerated and weight neutral;
mately one-quarter of the body’s gluconeogenesis; however, clinical experience is that they are often rather
therefore, a reduction in gluconeogenesis in patients less potent glucose-lowering agents than other avail-
with CKD adds to the hypoglycaemia risk. Additionally, able drugs, and our own experience has been that gas-
in patients with both type 1 and type 2 diabetes of long trointestinal side effects, such as nausea and vomiting,
duration, there is an increased prevalence of reduced may be more common with these agents in patients
or absent awareness of hypoglycaemic symptoms, with with CKD. Several drugs in this class are potentially
a corresponding increase in the frequency of severe useful even in patients with advanced CKD. Linagliptin
hypoglycaemic episodes. Hence, many patients on insu- is safe in all degrees of renal impairment, including
lin will need to have their doses dramatically reduced ESRD, and no dose reduction is required. Other drugs
as their renal function declines and some, even those in the class, including alogliptin, saxagliptin, sitagliptin
with type 1 diabetes, will have very low insulin require- and vildagliptin, can be used in moderate-to-severe
ments. renal impairment, although reductions in dose are
required.
or death (from renal or cardiovascular cause), with the blood pressure – e.g. 29% of patients in the tight BP con-
benefit likely to be greatest in those with greater protein- trol arm of the UKPDS trial required three or more
uria. In the DAPA-CKD trial, patients with and without antihypertensive agents [14].
diabetes were initiated on dapagliflozin down to a mini-
mum eGFR of 25ml/min/1.73m2. In those assigned to
dapagliflozin, there was a 44% reduction in the compos- 38.11.1 Proteinuria as a Specific Target
ite renal outcome which included a 50% decline in kid-
ney function, end-stage renal disease or death from renal In clinical trials, the risk of adverse renal outcomes
causes. Interestingly, the effect of dapagliflozin was sim- increases linearly with the level of baseline proteinuria,
ilar in patients with and without diabetes, confirming and a reduction in proteinuria is associated with a
that most of the renoprotective properties of SGLT2i reduced risk of renal events such as ESRD [50, 51].
are independent of blood glucose control. Indeed the Proteinuria is primarily modified by blood pressure
glucose-lowering effect of these drugs is likely to be reduction, though RAAS-active drugs may have addi-
diminished in patients with more advanced CKD. By tional anti-proteinuric effects by selectively reducing
promoting an osmotic diuresis, these drugs reduce intra- intraglomerular pressure. For example, in patients with
vascular fluid volume, although no increase in AKI was type 2 diabetes, irbesartan has been shown to have anti-
observed in the clinical trials above. SGLT-2 inhibitors proteinuric and renoprotective effects that are greater
modestly increase the risk of urogenital candidal infec- than other antihypertensive agents [52] and independent
tion, and there is also a minimally increased risk of bac- of blood pressure reduction [18]. Specific targeting of
terial ascending urinary tract infection, which would proteinuria reduction in a ‘regression’ clinic, with
clearly be undesirable in the context of CKD. In addi- sequential add-on of antihypertensive agents, reduced
tion, the CANVAS trial found an unexpected increase in the rate of decline in renal function in patients with
distal lower limb amputations in the canagliflozin treat- nephrotic-range proteinuria at baseline [53]. The rate of
ment group [43], which is important, given the high risk decline in renal function was lowest in those who
of peripheral vascular disease in patients with CKD due achieved <1 g/day of proteinuria; however, this was
to DN. much harder to achieve in patients who had a primary
renal diagnosis of diabetic nephropathy. The
CREDENCE study demonstrated that SGLT-2 inhibi-
38.11 Blood Pressure Control tors are effective in reducing renal decline (and cardio-
vascular mortality) in patients with marked proteinuria
Tight blood pressure control is at least as important as (urine protein/creatinine ratio of 300–5000) [45]. Hence,
proteinuria may act as a marker of treatment efficacy,
38 glycaemic control in slowing progression of diabetic kid-
ney disease. In the UKPDS, an improvement in blood and we advocate monitoring of proteinuria routinely in
pressure from 154/87 to 144/82 resulted in a 37% reduc- the clinic, aiming to reduce proteinuria by at least 50%
tion in the incidence of microvascular events [14]. although, in reality, the lower the better.
However, in contrast to the management of hypergly-
caemia, where tight glycaemic control results in a
reduced incidence of nephropathy that persists long 38.11.2 Choice of Antihypertensive Agent
after the end of the DCCT [46] and UKPDS trials
[4, 47], the benefit of tight blood pressure control tends 38.11.2.1 Renin-Angiotensin System Blockade
to recede with time [48], emphasising the need for strict As noted in the previous section, ACE inhibitors and
ongoing blood pressure control in preventing progres- angiotensin II receptor blockers (ARBs) have the ability
sive DN. to reduce intraglomerular pressure by preferentially
The target blood pressure for patients with diabetes dilating the efferent arteriole, and they may also counter
is controversial and may depend on the type of diabetes angiotensin II-mediated pro-inflammatory changes in
and the presence of proteinuria. In general, a reasonable the kidney.
target would be to reduce blood pressure to below
140/80 mmHg in those without albuminuria and kNormoalbuminuria
130/80 mmHg in those with albuminuria. However, A meta-analysis of 16 trials that included over 7000 nor-
extrapolating from the evidence obtained in non-diabetic moalbuminuric patients with both type 1 and type 2 dia-
patients from the Modification of Diet in Renal Disease betes suggested that ACE inhibitors prevented
Study [49], those with a protein excretion of >1 g/day microalbuminuria even in patients without hypertension
may benefit from a lower BP target of 125/75 mmHg. [54]. However, a recent study in normoalbuminuric
Polypharmacy is often required to achieve the target patients with type 1 diabetes found that while RAAS
Management of Diabetic Nephropathy
681 38
blockade reduced the incidence of retinopathy, it did not not tolerate ACE inhibitors, usually on account of
reduce the onset of microalbuminuria and importantly cough.
it did not alter the degree of mesangial matrix accumu-
lation observed on serial renal biopsies [55]. Furthermore, kAdvanced nephropathy
a meta-analysis of patients with type 2 diabetes found As the risks of hyperkalaemia and AKI due to RAAS
that there was no benefit of RAAS blockade compared blockade increase at low levels of renal function, a key
with other antihypertensive agents in the absence of question is at what level of renal function, if at all,
albuminuria [56]. On the basis of current evidence, RAAS blockade should be discontinued? One study
RAAS blockade cannot be recommended for primary demonstrated that in patients with a mean GFR of
prevention of nephropathy, although it may be indicated 26 ml/min/1.73 m2, a moderate dose of benazepril
for other reasons such as to prevent retinopathy and car- reduced progression to dialysis with no increase in the
diovascular disease. In particular, in the absence of incidence of hyperkalaemia [60]. However, this study
another indication, we generally do not use ACE/ARB was conducted in a Chinese population, where potas-
as first-line therapy in elderly patients with normoalbu- sium intake may be much lower than in Western societies.
minuria, as they are more likely to have renovascular Conversely, a recent study has indicated that, in patients
disease than diabetic nephropathy as a cause for their with very advanced CKD, stopping RAAS blockade
renal failure and hence are less likely to benefit, but are may facilitate an increase in glomerular filtration and
at an increased risk of AKI. delay the onset of dialysis [61]. The role of RAAS block-
ade in patients with advanced renal failure may become
kMicroalbuminuria clearer when the results of the STOP-ACEi trial emerge
Renin-angiotensin system blockade is indicated in in the next couple of years.
patients with microalbuminuria even when clinic blood
pressure is in the normal range. RAAS inhibition kHyperkalaemia
reduces the rate of progression from microalbuminuria Patients with DN and CKD frequently develop hyper-
to overt nephropathy and increases the rate of regres- kalaemia due to concomitant type 4 distal renal tubular
sion to normoalbuminuria in patients with type 1 diabe- acidosis, and this may limit the use of RAAS blockade.
tes [7]. These findings were only partially attenuated While it is reasonable to consider reducing the dose or
following correction for blood pressure, indicating an stopping RAAS blockade when the serum potassium
additional, blood pressure-independent effect of renin- concentration exceeds 6 mmol/L, this may be associated
angiotensin blockade [57]. Similarly, irbesartan pre- with poor renal outcome, particularly in patients with
vents progression from microalbuminuria to heavy proteinuria (see 7 Case 2). Therefore, our prac-
macroalbuminuria in patients with hypertension and tice is to keep patients on RAAS blockade as long as
type 2 diabetes [58]. possible if they have overt proteinuria, using a combina-
tion of low-potassium diet, kaliuretic diuretics and
kOvert nephropathy treatment of acidosis where applicable. The develop-
RAAS inhibition should also be the antihypertensive ment of new potassium binders, such as patiromer or
therapy of choice in patients with overt proteinuria, as sodium zirconium, which can reduce serum potassium
randomised controlled trials indicate that they reduce by approximately 1 mmol/L in patients with hyperkalae-
the risk of a doubling in creatinine [52]. Again the effect mia [62], may enable RAAS blockade to be continued
of ACE inhibitors and ARBs in this context is likely to safely; however, the benefit of this strategy on hard end-
be at least in part independent of their blood pressure- points has yet to be established.
lowering effect. Indeed, in the Irbesartan DN Trial
(IDNT), irbesartan therapy resulted in a 23% reduction kInitiation of RAAS blockade
in doubling of creatinine or the development of ESRD In all patients, the risk of an acute deterioration in renal
compared with amlodipine, despite blood pressure function or hyperkalaemia is greatest soon after starting
being comparable between the groups [52]. There is no or increasing the dose of RAAS blockade; therefore,
good evidence as to whether the use of an ACE inhibi- renal function should be checked within 7–10 days of
tor or an ARB is preferable. The bulk of evidence for dose adjustments. Some decline in renal function is to be
type 1 nephropathy is for ACE inhibitors, while in type expected, and indeed a meta-analysis of clinical trials
2 nephropathy, most trials have employed ARBs. A suggested that the greater the initial decline in renal
direct comparison of ACE inhibitors and ARBs in type function, the better the long-term renal outcome [63].
2 diabetes suggested similar efficacy [59]; therefore, The risk of a rapid decline in renal function is greatest in
given the substantial experience of the use of ACE those with intravascular volume depletion or where the
inhibitors, we generally advocate ACE inhibitors as renal auto-regulation system is inhibited, such as in
first-line agents, with ARBs reserved for those who do patients on concomitant diuretic therapy or following
682 B. Conway et al.
prescription of a non-steroidal anti-inflammatory agent. release of aldosterone to induce a kaliuresis. This risk
Patients should be warned to stop RAAS blockade prior was highlighted by the fact that, following publication
to major surgery or if they develop fever, vomiting or of the Randomised Aldactone Evaluation Study
diarrhoea (sick day rule). Specific issues in the use of (RALES), a fourfold increase in the number of prescrip-
RAAS blockade in patients with diabetic nephropathy tions of spironolactone was associated with an increase
are considered in ‘Tips and Tricks’. in the number of hospital admissions due to severe
hyperkalaemia [71]. At present, we tend to reserve spi-
kDual RAAS blockade ronolactone only for patients who have resistant hyper-
Dual RAAS blockade, using an ACE inhibitor and tension, concomitant cardiac failure or heavy proteinuria
ARB together, may have added benefit in lowering pro- and preserved renal function.
teinuria compared with monotherapy [64], but cannot
be recommended in patients with DN due to the 38.11.2.2 Other Antihypertensive Agents
increased risk of hyperkalaemia and AKI. In the kDiuretics
ONTARGET trial, the combination of an ACE inhibi- Loop and thiazide diuretics are a very useful adjunct to
tor and ARB resulted in an increased incidence of dou- RAAS blockade in patients with diabetes. Combination
bling of creatinine, dialysis or death [65]. The therapy further reduces blood pressure, mitigates against
VA NEPHRON-D trial randomised patients with type 2 hyperkalaemia and potentiates the anti-proteinuric
diabetes and proteinuria, who were already taking an effect of ACE inhibitors.
ARB, to the addition of an ACE inhibitor or placebo.
Dual therapy did not reduce adverse renal or cardiovas- kNon-dihydropyridine calcium channel blockers
cular outcomes, but there was an increased risk of As with RAAS blockade, these agents may have specific
hyperkalaemia and AKI [66]. anti-proteinuric properties [72] and indeed may syner-
gise with ACE inhibitors to reduce proteinuria [73]. We
kDirect renin inhibitors would reserve this class of agents for patients who con-
Although the direct renin inhibitor aliskiren has been tinue to have proteinuria despite RAAS blockade and
shown to act synergistically with ACE inhibitors/ARBs who have no cardiovascular indications for β-blockade.
to reduce proteinuria [67], the ALTITUDE trial, which
examined the efficacy of adding aliskiren to standard
ACE inhibitor/ARB therapy in patients with type 2 dia- 38.12 Cardiovascular Risk
betes and CKD, was stopped prematurely due to an
increase in stroke, renal failure, hyperkalaemia and In patients with diabetes, the presence of renal disease
hypotension in the aliskiren arm [68]. Therefore, the confers an increased risk of cardiovascular disease. For
38 addition of direct renin inhibitors to patients with DN example, in the UKPDS, there was a progressive increase
who are taking ACE/ARB is not recommended. in the risk of cardiovascular death with advancing
nephropathy, with annual mortality rates ranging from
kAldosterone antagonists 0.7% in normoalbuminuric patients to 2.0%, 3.5% and
The addition of spironolactone, eplerenone [69] or the 12.1% in those with modestly elevated albuminuria, pro-
non-steroidal mineralocorticoid antagonist finerenone teinuria or elevated creatinine/on renal replacement
[70] to ACE inhibition further reduces proteinuria. The therapy (RRT), respectively [74]. In general, the use of
FIDELIO-DKD trial randomised patients with overt statins in patients with diabetes results in a reduction in
proteinuria and eGFR 25–75 who were already on max- cardiovascular events, irrespective of whether they have
imum RAAS blockade tolerated to finerenone or pla- a prior history of cardiovascular disease or elevated
cebo. Those in the finerenone arm had an 18% reduction baseline LDL cholesterol levels [75]. Similar results were
compared with the placebo arm in the composite end- observed in the subset of patients with diabetes and
point of 40% reduction in eGFR or death due to renal CKD. Combination treatment with simvastatin and
disease. Unlike the studies with combination of ACE ezetimibe reduced cardiovascular events by 22% in
and ARB, there was no increase in the risk of AKI, patients with diabetes and CKD in the SHARP study,
however the study medication was stopped due to hyper- with an excess risk of myopathy of only 2 per 10,000 per
kalaemia in 2.3% of patients in the finerenone arm, patient years of treatment, although there was no reduc-
compared with only 0.9% of patients in the placebo tion in the risk of doubling of creatinine or need for
arm. Furthermore, the risk of hyperkalaemia may be RRT [76]. Hence, to prevent cardiovascular events,
greater with aldosterone antagonists than with other statins should be routinely prescribed in patients with
RAAS inhibitors, for which there is a mitigating safety diabetes and kidney disease, unless they are at very low
mechanism in that hyperkalaemia per se promotes risk of cardiovascular events (e.g. those <40 years old).
Management of Diabetic Nephropathy
683 38
38.13 Multifactorial Interventions clinic models such as nurse-specialist or pharmacist-led
cardiovascular risk reduction clinics may facilitate more
Holistic management of multiple renal and cardiac risk frequent review in order to achieve risk factor targets
factors represents the ideal model of care. An excellent more rapidly. Once target values for risk factors are
study from the Steno Diabetes Centre demonstrated achieved, and if renal function stabilises, patients may
that, in patients with type 2 diabetes treated over approx- be discharged to general diabetes clinics with clear
imately 8 years, targeting multiple risk factors, e.g. life- parameters for re-referral. Conversely, those with
style modifications (low-fat diet, moderate exercise, advanced kidney disease may migrate to a specialist low
smoking cessation), tight control of blood glucose, clearance clinic.
blood pressure and serum lipids and use of aspirin, Decisions on the optimal mode of care at a local
resulted in a reduction in mortality and a >50% reduc- level should be made in conjunction with nephrologists,
tion in the risk of developing overt nephropathy. These diabetologists and primary care physicians, and an
beneficial effects were sustained more than 13 years after example of a possible system of management is given in
the initial study visit [77]. A practical example of a suc- . Fig. 38.2.
cessful multifactorial interventional strategy is illus-
trated in 7 Case 3.
38.15 Management of Patients with
Diabetes on Renal Replacement
38.14 Models of Service Therapy (RRT)
Referral guidelines:
ACR>100 despite maximal dose ACE inhibitor or ARB
Deteriorating renal function (>4ml/min/1.73m2 per year)
Poorly controlled BP despite ≥ 3 antihypertensive agents
Tendency for hyperkalaemia (K>5.5)
Atypical features
NO
Approaching ESRD
. Fig. 38.2 Potential model of care pathways through a specialist diabetic kidney disease clinic
including eye and foot screening. Foot screening is par- of transplantation, compared with 356 days in non-
ticularly important given the high rate of lower limb diabetic patients [83]. Therefore, transplantation should
amputation in diabetes patients receiving RRT, and ini- be the mode of choice for RRT, in patients with DN
38 tiatives where regular foot checks are performed as part who are deemed medically fit; however, more rigorous
of routine care in dialysis units have been shown to cardiac investigations, potentially including angiogra-
reduce amputation rates. phy, may be necessary to attempt to minimise the
increase in peri-operative mortality. Furthermore, as
patients with diabetes and overt proteinuria are at high
38.15.2 Transplantation risk of progression to end-stage kidney disease, the
prospect of future transplantation should be consid-
While the survival rate on dialysis of patients with a ered early in the course of the disease, including steps
primary renal diagnosis of DN is poor, it can be dra- such as minimising blood transfusion.
matically improved by renal transplantation. Patients A key issue when considering transplantation is
with ESRD due to DN who receive a transplant will whether to perform a kidney transplant in isolation or
have a projected lifespan of 19 years, compared to simultaneous pancreas and kidney transplantation.
8 years for those who remain on dialysis on the trans- While the latter has much greater peri-operative risks,
plant waiting list [2]. Indeed, patients with DN are the improvement in metabolic control conferred by suc-
likely to gain the most benefit from transplantation, cessful pancreas transplantation is associated with
with projected survival increasing by 17 years and improved patient survival beyond the 10th year after
14 years for those aged 20–39 years and 40–59 years, transplantation, when compared to patients who have
respectively, compared to increases of 11 years and received a live donor renal transplant (HR 0.55,
7 years in non-diabetic patients [83]. While transplanta- p = 0.005), mainly due to a reduction in cardiovascular
tion confers an increased risk of early death in patients mortality [84]. The risk/benefit ratio may be particularly
with DN, largely due to peri-operative mortality, it attractive for younger patients and those with unstable
requires only 181 days for this early increase in risk to glycaemic control, who are prone to recurrent, severe
be outweighed by the subsequent survival advantages episodes of ketoacidosis and/or hypoglycaemia.
Management of Diabetic Nephropathy
685 38
38.16 Conclusion and are particularly important to consider in patients with
proteinuria, obesity or heart failure. More patients die of
DN remains the commonest cause of ESRD. Biopsy to cardiovascular disease than progress to ESRD; therefore,
confirm diagnosis is only required in atypical presenta- cardiovascular risk factors need to be addressed.
tions, most notably when proteinuria is rapidly increasing There is now a huge amount that we can offer
or renal function rapidly declining. Tight glycaemic and patients with diabetes, and there is a responsibility to
blood pressure control is paramount, with RAAS block- offer an efficient and comprehensive early review of
ade essential for those with proteinuria. New agents such as patients with proteinuria as these patients stand the
GLP-1 receptor agonists and SGLT-2 antagonists [85] also most to lose from neglect and the most to gain from
significantly improve renal and cardiovascular outcomes focused intervention and treatment.
Case Study
160
1200 12
140
1000 10
Blood pressure (mmHg)
120
Blood pressure
ACR (mg/mmol)
800 8
HbA1c (%)
100
HbA1c
600 80 6
ACR
60 eGFR
400 4
40
200 2
20
0 0 0
. Fig. 38.3 Evolution of blood pressure, proteinuria and renal function in a young woman with type 1 diabetes, demonstrating how with-
drawal of ACE inhibitor due to moderate hyperkalaemia resulted in a marked increase in proteinuria and a rapid decline in renal function
100 250
At last visit 600
90
(7 years of follow-up)
80 HbA1c 5.9% (diet) 200 500
Cholesterol 2.6mmol/L on statin
Blood Pressure (mmHg)
eGFR (ml/min/1.73m2)
eGFR 70
PCR (mg/mmol)
Non-smoker 400
PCR 60 150
50
Blood Pressure 300
40 100
Initial trajectory of
renal function 200
30
Typical level of
eGFR at which 20 50
100
dialysis required
10
0 0
Nov-03
May-04
Nov-04
May-05
Nov-05
May-06
Nov-06
May-07
Nov-07
May-08
Nov-08
May-09
Nov-09
May-10
Nov-10
May-11
Nov-11
May-12
. Fig. 38.4 Demonstration of how a multifactorial management Joint Renal Diabetes clinic with nephrotic-range proteinuria and
strategy reduced proteinuria and led to long-term stability of renal declining renal function
function in a man with type 2 diabetes who had been referred to the
Management of Diabetic Nephropathy
687 38
z Tips and Tricks level and falling quickly. When eGFR falls below
1. RAAS blockade is much more effective when com- 30 ml/min/1.73 m2, we carefully consider the
bined with a low-salt diet. options. However, if the rate of deterioration of
2. Advise a check of renal function within 7–10 days of renal function is very slow, we would consider
starting therapy or increasing the dose of an ACE reducing the dose and having a discussion with
inhibitor/ARB. the patient explaining the risks and benefits.
3. Warn the patient to stop the drug transiently should Importantly, if the patient is to remain on metfor-
they become unwell, e.g. fever, vomiting or diar- min, we routinely provide a ‘sick day rules’ card,
rhoea. advising them to stop metformin (and ACE inhib-
4. In patients with heavy proteinuria, but who have a itors/ARBs, NSAIDs and diuretics) transiently if
tendency for hyperkalaemia, try to maintain RAAS they become unwell.
blockade by controlling potassium with a thiazide 3. The target HbA1c should be relaxed in patients on
diuretic, or add sodium bicarbonate if the patient is dialysis as there is an increased risk of hypoglycae-
acidotic. Provide advice on a low-potassium diet and mia due to the accumulation of oral anti-
consider the use of potassium binders such as pati- hyperglycaemic agents and endogenous or
romer or sodium zirconium. exogenous insulin, and this risk exceeds any poten-
5. Warn females of reproductive age to plan to stop tial long-term benefit of tight glycaemic control.
ACE inhibitors/ARBs (in consultation with their The Association of British Clinical Diabetologists-
primary care physician) if they are planning to get Renal Association guidelines recommend an
pregnant or, in the event of an unplanned pregnancy, HbA1c target of 58–68 mmol/mol (7.5–8.5%).
to stop as soon as the pregnancy is confirmed.
6. Consider discontinuing therapy in patients with
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38
691 39
Contents
References – 710
n Learning Objectives
. Table 39.1 Mechanism of endocrine dysfunction in
1. The effects of renal diseases and medications on CKD
endocrine hormones require close monitoring
especially in patients with CKD. Mechanism Impact
2. Endocrine disorders and their treatments can
impact on the kidneys and vice versa. Increased Decreased GFR resulting in impaired
circulatory renal clearance
3. Strategies and protocols for combined and coor-
hormone • Glucagon
dinated care of patients with endocrine and renal • Fasting levels found to be 5× higher in
disease between both specialties are required for patients on HD than controls
optimisation of patient management and outcome. • Prolactin
• 5–6× higher prolactin levels seen when
eGFR<15
• Insulin
39.1 Introduction • 30–80% of endogenous insulin is
filtered in the kidney; reduced
The endocrine functions of the kidney are predictably clearance occurs when eGFR falls
impaired with progressive renal impairment. However, below 40
• Growth hormone
other non-renal-derived hormones are also influenced • 2.5× higher mean GH levels seen in
by changes, which occur in CKD (. Table 39.1). The advanced CKD, with a 2× longer
mechanisms of endocrine abnormalities include altered endogenous GH mean half-life
hormone binding and tissue responsiveness, decreased • Leptin
synthesis and reduced metabolic clearance of hormones Increased secretion of hormone
• Parathyroid hormone
due to the failing kidney and alterations of homeostatic • Growth hormone
signalling. Accumulation of metabolites
Conversely, disorders and treatment of endocrine • Parathyroid hormone
disease can impact on the kidney. The most devastating • Calcitonin
of these is diabetes, which has a profound global impact • Prolactin
and is currently the commonest cause of ESRD in many Decreased Decreased secretion by the kidney
countries. Approximately 40% of affected individuals circulatory • 1,25-dihydroxy vitamin D3
hormone • Erythropoietin
will develop diabetic nephropathy, which manifests com-
Decreased secretion by non-renal
monly as albuminuria, impaired GFR or both [1, 2]. endocrine glands
This is covered extensively in the chapter ‘Diabetes and • Testosterone
the Kidney’. • Oestrogen
• Progesterone
Decrease in target Altered target responses
39 39.2 Pharmacotherapy Interactions organ hormone • Growth hormone
sensitivity • Insulin
in Kidney and Endocrine Diseases • Parathyroid hormone
• Erythropoietin
Drugs used in treating endocrine disorders can impact • 1,25-dihydroxy vitamin D3
on the kidneys and vice versa. Examples of such interac-
tions are listed below in . Tables 39.2 and 39.3.
Propylthio- To treat hyperthyroidism Unclear; likely to trigger immune complex deposition ANCA-associated
uracil vasculitis
Acute interstitial
nephritis
Lupus nephritis
GnRH Prostate cancer Unclear but likely causes metabolic changes leading to AKI
agonistsa glomerular injury; loss of protective vasodilation effect of CKD
testosterone
Iodinated Used in various radiological Unclear, but likely due to haemodynamic effects of contrast AKI (contrast-
contrast examinations and interventional media, effects of reactive oxygen species and direct tubular induced nephropa-
procedures cellular toxicity thy)
aTo date only reported when used as androgen deprivation therapy in men with prostate cancer
. Table 39.3 Impact of drugs used in renal diseases on the endocrine system
Alemtuzumab Induction agent for kidney ↑ Risk of autoimmunity; emergence of Autoimmune thyroiditis
transplantation TSH receptor antibodies
Thiazides Diuretic ↓ Urinary calcium excretion Hypercalcaemia in those
with hyperparathyroidism
Glucocorticoids Immunosuppressant for kidney ↓ TSH secretion ↓ T4, T3 and TSH by
(high dose) transplantation and various renal ↓ TBG levels 18–50%
diseases
Co-trimoxazole Prophylaxis against PCP for kidney ↓ Thyroglobulin iodination ↓ T4 levels by 5–10%
transplant recipients ↑ Insulin release from pancreatic cells Hypoglycaemia (especially if
(sulphonamide mimics sulphonylureas) renal impairment present)
Heparin Anticoagulant during haemodialysis Activates lipoprotein lipase Spurious ↑ free T4 by
↑ Serum free fatty acids concentration 130–520%
↑ Displacement of T4 from TBG
Furosemide Loop diuretic ↓ T4 binding of TBG Spurious ↓ FT4 and T4 by
(high dose) 10–30%
Iodinated Used in various radiological Exposure to large iodide load; iodine used Thyroid storm
contrast examinations and interventional as substrate for thyroid hormone Acute destructive thyroiditis
procedures production
nephrotic syndrome has been associated with autoim- tions, with an increase in rT3 concentrations. Serum T4
mune thyroid diseases, such as Graves’ disease, where is the best marker for thyroid status in these patients
antithyroid antibodies have been demonstrated within and, if low, should be treated as clinically significant
glomerular immune deposits. Both Hashimoto’s thy- hypothyroidism.
roiditis and Graves’ disease have also been associated
with membranous nephropathy. 39.3.1.2 Vitamin D and Calcium
Annual thyroid function assessment is recommended Urinary losses of vitamin D-binding protein (VDBP) by
in nephrotic individuals when first diagnosed, especially the nephrotic glomeruli [6] lead to concurrent renal
since progressive reduction in renal clearance may exac- excretion of calcidiol (the precursor of calcitriol that is
erbate thyroid dysfunction. Steroids given to nephrotic primarily bound to VDBP). However, the effect of these
patients can also lower serum T3 and TSH concentra- changes of vitamin D on calcium homeostasis is uncer-
694 R. K. Y. Hung et al.
tain. Whilst this leads to reduced total serum calcium . Table 39.4 The effects of CKD on the hypothalamic-
pituitary-gonadal axis
levels, physiologically important free calcium concentra-
tion remains normal due to concurrent hypoalbuminae- Hor- Female Male Mechanism
mia resulting in a reduction in calcium binding capacity. mone
However, some patients may develop hypocalcaemia
secondary to low serum calcitriol concentrations. These FSH N ↑ Males: impaired spermatogen-
esis
patients exhibit a fall in ionised calcium concentrations
Females: normal in premeno-
and an elevation in serum parathyroid concentrations pausal females but with a
that can subsequently lead to bone disease characterised decreased FSH/LH ratio
by mixed osteomalacia and osteitis fibrosa [7, 8].
LH ↑ ↑ • Loss of normal pulsatile
release
39.3.1.3 Glucocorticoid Metabolism • Basal plasma concentrations
Urinary losses of cortisol-binding globulin (CBG) may raised due to decreased renal
lead to reduced serum cortisol in nephrotic patients [9]. clearance and catabolism
Males: low testosterone levels
The ACTH simulation test in these patients may hence
inhibit GnRH
be affected due to low cortisol levels associated with uri- Females: impaired oestradiol
nary losses of CBG. However, symptomatic hypocorti- feedback causes LH surge
solism does not occur as the percentage of unbound leading to anovulation and
cortisol is increased and serum free cortisol levels are infertility
normal. Prolac- ↑ ↑ Decreased renal clearance
tin Inadequate dopaminergic
inhibition
39.3.2 Chronic Kidney Disease Prolactin accumulation inhibits
pulsatile secretion of GnRH
• Males: reduced testosterone
39.3.2.1 Hypothalamic-Pituitary-Gonadal synthesis
Axis • Females: amenorrhoea,
lowers levels of oestradiol
CKD causes derangement of the hypothalamic-
pituitary-gonadal axis and affects males and females dif- Oestra- ↓ N • Levels normally preserved or
diol low but will be Lower with
ferently. These are summarised in . Table 39.4. The
hyperprolactinaemia
effects of CKD on the hypothalamic-pituitary-gonadal
axis in women are illustrated in . Fig. 39.1. Proges- ↓ – • Release during second half
terone of menstrual cycle reduced
due to defective follicle
luteinisation
39.3.3 The Somatotropic Axis
39 Testos- – ↓ • Reduced due to defective
terone release of GnRH and LH
39.3.3.1 Growth Hormone (GH)
and Insulin-Like Growth Factor
CKD induces a state of GH resistance and not GH defi-
ciency. Decreased numbers of GH receptors in target
organs and uraemia-related alterations in intracellular intake, persistent metabolic acidosis, calcitriol defi-
signal transduction at the post-receptor level lead to GH ciency, renal osteodystrophy, uraemic toxins and drug
resistance [10]. Concurrent increase of GH secretion in toxicity.
response to this and reduced clearance due to a falling
39.3.3.2 Thyroid Function
GFR cause elevated serum GH concentrations in chil-
dren and adults with CKD. Changes in nutritional Thyroid dysfunction and goitre development are more
intake and metabolic acidosis can also affect GH secre- prevalent in patients with CKD due to uraemia-
tion. Insulin-like growth factor-1 (IGF-1) is stimulated impaired peripheral metabolism of thyroid hormones
by GH and is mainly secreted by the liver. Its free con- [5]. Subclinical hypothyroidism is the most common
centration in serum decreases with progression of CKD thyroid disorder in CKD patients with low T3 levels
mainly due to the elevation of IGF-binding proteins -1, (. Table 39.5). This is secondary to impaired conver-
-2, -4 and -6 that binds free IGF-1. The overall contribu- sion of T4 to T3 due to metabolic acidosis and malnu-
tion of GH to growth retardation in children with CKD trition. Mineral deficiencies can also reduce T3 levels
is difficult to quantify as growth retardation in CKD is as GFR declines; selenium modulates the conversion
multifactorial including inadequate protein and calorie of T4 to T3 (via iodothyronine deiodinase activity)
The Endocrine System and the Kidney
695 39
Physiological Ovulation and Lactation In CKD
Hypothalamus Hypothalamus
GnRH GnRH
Breast development
Milk development
Anovulation
Ovulation
↓Oestrogen
↑Oestrogen
↓Renal clearance
Hyperthyroidism Hypothyroidism
Cardiovascular
Cardiovascular ↓heart rate
↑heart rate ↓cardiac output
↑cardiac output ↓cardiac contractility
↑cardiac contractility
↓Systemic vascular
↑Systemic vascular resistance
resistance
Glomerulus
Glomerulus ↓Filtration pressure
↑Filtration pressure ↓GFR
↑GFR
Tubules
Tubules ↓tubuloglomerular
↑tubuloglomerular feedback feedback
↑tubular mass ↓tubular mass
↑tubular resorptive capacity ↓tubular resorptive
↑urinary concentrating capacity
ability ↓urinary concentrating
ability
. Fig. 39.2 Haemodynamic and renal effects of thyroid underactivity and overactivity
fibrosis. Hyperthyroidism also contributes to anaemia which competes with T4 at the binding site of the
39 and can lead to EPO resistance. hormone-binding protein. Evaluation of thyroid func-
The prevalence of hypothyroidism increases from 5% tion should be done before heparin administration,
to 23.1% when GFRs of >90 mls/min/1.73 m3 fall to prior to commencing the dialysis session. In patients on
<30 mls/min/1.73 m3. This is likely due to a reduction in peritoneal dialysis (PD), TBG, T4 and T3 are lost in the
iodide excretion, resulting in an increase in serum inor- PD effluent. However, losses are relatively minor (10%
ganic iodide level and thyroid gland iodine content lead- of T4 and 1% of T3) and easily compensated for.
ing to gland enlargement, goitre development and
hypothyroidism in patients with ESRD. There is an 39.3.3.4 Insulin and Glucagon
increased frequency of thyroid nodules and thyroid car- The kidney removes about 30–80% of insulin per day.
cinoma, which may be associated with secondary hyper- Approximately 60% of insulin is cleared via glomerular
parathyroidism, a common condition in CKD patients filtration and 40% by extraction from the peritubular
[13]. Hypothyroidism is also associated with higher vessels. When GFR falls below 40 mls/min/1.73 m3,
mortality in dialysis patients due to hypothyroid-induced insulin clearance is reduced thus decreasing the insulin
cardiovascular disease. requirement in diabetic patients with CKD [14].
Chronic haemodialysis patients may have low thy- Peripheral insulin resistance also worsens with the fall
roid hormone levels with maintained euthyroid state due of GFR and is improved once renal replacement ther-
to a compensatory influence of cellular transport of thy- apy is started. The pathogenesis of insulin resistance is
roid hormones. A 24-hour transient increase in T4 postulated to be due to metabolic acidosis, chronic
occurs due to the use of heparin as an anticoagulant, inflammation, increased RAAS activity and also
The Endocrine System and the Kidney
697 39
increased concentration of glucagon and growth hor- much subtler particularly in the setting of CKD where
mone in patients with CKD [15]. the patient is somewhat protected against mineralocorti-
coid insufficiency and may simply manifest as loose
stools, general malaise and slow recovery after an illness.
39.3.4 Renin Angiotensin Axis Cortisol stress tests are complicated by ongoing steroid
ingestion, and in practical terms it is often simpler to
Renal artery stenosis is the archetypal endocrine renal give a short trial of boosted (2–3 times normal dose)
disease. Although other organs are essential for produc- steroids.
tion of angiotensinogen (liver) and activation (lung), the In a proportion of renal patients with nephrecto-
entire cascade is precipitated by renin production from mies, particularly in those with ADPKD, it is important
the juxtaglomerular apparatus in the kidney in response to document if the adrenal gland was inadvertently
to a reduction in blood flow, for example, as a result of removed at the time of surgery. The need for steroid
progressive arterial occlusion from atherosclerotic dis- replacement therapy or where it is contraindicated (e.g.
ease or fibromuscular dysplasia. The consequence is a von Hippel-Lindau patients with phaeochromocyto-
rise in angiotensin II and aldosterone, which drive salt mas) (. Fig. 39.4) has to be clearly documented in med-
and water retention and systemic vasoconstriction and ical records to avoid precipitation of crises.
hypertension. The time taken for recovery of the HPA axis after
stopping glucocorticoids following prolonged use is vari-
able and influenced by factors such as dose, time of day
39.3.5 Hypothalamic-Pituitary-Adrenal and duration of drug use. Drugs that affect the cyto-
chrome P450 enzyme pathway can also lead to changes in
Axis (HPA)
serum level of glucocorticoids. Enzyme inhibitors exert
incomplete inhibition of cortisol biosynthesis; conversely
Patients with CKD take glucocorticoids for various rea-
potent inducers will result in significantly less bioavail-
sons including treatment for their primary renal disease,
able cortisol in patients on long-term glucocorticoids.
post transplantation or other systemic diseases.
Exogenous glucocorticoids exert negative feedback to
the HPA axis by suppressing corticotropin-releasing
hormone (CRH) secretion that in turn suppresses corti- 39.4 The Effect of CKD on Common
cotropin (ACTH) secretion. Chronic usage leads to Endocrine Medications
adrenal atrophy and loss of cortisol secretory capability.
Abrupt cessation or too rapid withdrawal of glucocorti- 39.4.1 Antidiabetics
coids can cause symptoms of adrenal insufficiency,
which may manifest as an Addisonian crisis (see Diabetes mellitus is a growing epidemic and the leading
. Fig. 39.3 below). cause of chronic kidney disease worldwide. Clinicians
More commonly, patients can incur functional adre- are faced with treating diabetics with varying degrees of
nal insufficiency when steroids are not boosted at the renal insufficiency, and it is important to be aware of
time of an intercurrent illness or stressful events, e.g. how clearance of antidiabetic medications are affected
undergoing surgery. The symptoms and signs tend to be by the GFR (. Table 39.6).
. Fig. 39.3 Hyperpigmentation of the nipple and gums in a long- pressure. Blood tests revealed a rise in creatinine and a potassium of
standing renal transplant recipient who had abruptly stopped steroid 6.7 mmol/L. The combination of chronic adrenal suppression and a
maintenance 6–8 weeks before presenting to the clinic and 10 days very stressful event was sufficient to cause an Addisonian crisis,
following a car accident. He complained of malaise, tiredness and which responded rapidly to steroid replacement
loss of appetite. He was hypotensive with a postural drop in blood
698 R. K. Y. Hung et al.
a b
. Fig. 39.4 Adrenal mass consistent with a phaeochromocytoma. trolled with antihypertensive medications. On admission, she had
A 38-year-old female patient presents with headaches and occa- evidence of orthostatic hypotension and raised plasma norepineph-
sional palpitations. She has a history of von Hippel-Lindau disease rines, and a CT scan revealed a 82.5 mm mass above her left kidney
that manifested as retinal angiomas (bilateral amaurosis at the age of a that corresponded to an area of increased uptake in a MIBG scin-
16) and cerebellar hemangioblastomas (ataxia at the age of 26). She tiscan b
also suffers from hypertension diagnosed 6 years ago that is con-
Antidiabetics
Insulin Increased half-life with GFR decline Dosing altered to individual’s
response and need
Metformin Excreted unchanged in urine GFR < 30: contraindicated by manu-
facturer guidelines
GFR 30–44: maximum 1000 mg
Sulphonylureas Actively metabolised in the liver and renally Use in caution with GFRs <60 due
cleared to risk of hypoglycaemia
Thiazolidinediones Fully metabolised by the liver Can be used in CKD
Main side effects include water
retention, bone loss and increased
fracture rates
Alpha-glucosidase inhibitors Metabolised in GI tract; ~ 34% excreted by the Avoid in GFR <25
kidney
Dipeptidyl peptidase-4 (DPP4) inhibitors
Sitagliptin 80% cleared by the kidney GFR 30–50: reduce dose by ½
GFR <30: reduce dose by ¼
Saxagliptin Excreted via urine and can be removed via GFR <50: reduce dose by ½
dialysis
Linagliptin Minimal amounts cleared by the kidney Safe to use in CKD with no dose
adjustment
Sodium-glucose co-transporter 2 (SGLT2) inhibitors
Canagliflozin Actively metabolised in the liver and renally GFR < 30: avoid; if already taking,
cleared to continue medication even if new
drop in GFR to < 30
Dapagliflozin Avoid in GFR < 30
Empagliflozin Avoid in GFR < 30
Glucagon-like peptide (GLP-1) receptor agonists
Exenatide Renally cleared followed by proteolytic GFR < 50: use with caution
degradation GFR < 30: avoid
84% reduction in clearance in CKD [16]
Liraglutide No specific organ identified as major route of No dose adjustment required
elimination
Hormone agonists
Oestrogen Mainly metabolised in the liver No dose adjustment required
Leuprorelin (GnRH agonist) Degraded by peptidases and excreted in urine Increased risk of AKI when used in
men with prostate cancer as
androgen deprivation therapy
Increased risk of ovarian hyperstim-
ulation in women on dialysis
Hormone antagonists
Anti-oestrogens (e.g. tamoxifen) Metabolised in the liver with varying degrees No dose adjustment required
Anti-androgens (e.g. cyproterone) of elimination by the kidney
Enzyme inhibitors (e.g. anastrozole)
700 R. K. Y. Hung et al.
Condition Presentation
Cystic fibrosis Autosomal recessive disorder resulting in mutation of the cystic fibrosis transmembrane conductance receptor
(CFTR)
Endocrine manifestations
Progressive pancreatic exocrine failure leading to fat malabsorption due to deficiency in digestive enzymes
resulting in steatorrhoea, malnutrition and deficiency in fat-soluble vitamins A, D, E and K
Pancreatic endocrine failure leading to diabetes mellitus
Renal manifestations [17]
Nephrolithiasis and nephrocalcinosis (enteric hyperoxaluria)
Toxicity from recurrent aminoglycoside exposure due to frequent pseudomonal infections
AA amyloidosis secondary to chronic infection
Diabetic nephropathy
Recurrent infection-related episodes of acute tubular injury
Multiple Autosomal-dominant mutations in the tumour suppressor gene MEN1, which encodes a 610-amino acid protein,
endocrine menin [18], leading to a predisposition to tumour formation in:
neoplasia type 1 Parathyroid gland
Pituitary (anterior)
Pancreas
Endocrine manifestations
Primary hyperparathyroidism
Anterior pituitary tumours – most commonly prolactinomas (20%), although GH-, ACTH- and TSH-secreting
tumours are also seen
Neuroendocrine tumours of the gut and pancreas, most commonly gastrin (Zollinger-Ellison syndrome) and less
commonly, insulinomas
Carcinoid tumours – typically thymic and usually inactive as compared with sporadic forms
Renal manifestations
Hypercalcaemia-related volume depletion and nephrocalcinosis
Multiple Autosomal-dominant abnormality of the RET proto-oncogene on chromosome 10
endocrine MEN2A: parathyroid hyperplasia (in classic form or with Hirschsprung disease or cutaneous lichen amyloidosis
Neoplasia and familial forms)
type 2 MEN2B: phaeochromocytoma and medullary thyroid carcinoma but without parathyroid disease
39 Endocrine manifestations
Hyperparathyroidism – typically diffuse hyperplasia
Medullary thyroid carcinoma – often younger onset and more aggressive phenotype
Renal manifestations
Hypercalcaemia-related volume depletion and nephrocalcinosis
The Endocrine System and the Kidney
701 39
Condition Presentation
Sjogren’s Autoimmune rheumatological multisystem disorder characterised by sicca symptoms (dry mouth/eyes) with
syndrome keratoconjunctivitis or mikulicz syndrome (parotid and lacrimal gland hyperplasia)
Endocrine manifestations
Autoimmune thyroiditis; anti-thyroid antibodies commonly seen
Chronic atrophic gastritis associated with hypopepsinogenaemia and antiparietal cell antibodies
Pancreatic insufficiency – rarely clinically significant
Renal manifestations
Chronic tubulointerstitial nephritis
Renal tubular acidosis (RTA) – type 1 distal (Fanconi syndrome); mechanism uncertain but could be from an
absence of H+/ATPase in intercalated cells of the collecting ducts seen in one biopsy series [19] or due to
autoantibodies against carbonic anhydrase II leading to reduced H + production [20] and may be seen with
nephrocalcinosis and/or nephrolithiasis
Nephrogenic diabetes insipidus [21]
Hypokalaemia without RTA secondary to salt wasting-driven hyperaldosteronism [22]
Immune-mediated glomerulonephritis – most commonly membranoproliferative glomerulonephritis and
membranous nephropathy, although other glomerular lesions and nephrotic syndrome have also been seen on
renal biopsies [23]
Cryoglobulinaemia
Sarcoidosis Multisystem non-caseating granulomatous disorder
Endocrine manifestations [24]
Cranial diabetes insipidus and hyperprolactinaemia most commonly seen in hypothalamo-hypophyseal
infiltration (affecting 5%); may also result in hypothyroidism, hypoadrenalism, diabetes insipidus and SIADH
Thyroid infiltration uncommon but increased autoimmune thyroid disease seen
Fertility and menstrual abnormalities due to granulomatous infiltration of the testes, ovaries and uterus
Renal manifestations
Interstitial nephritis
Hypercalcaemia-related volume depletion and nephrocalcinosis and nephrolithiasis (calcium oxalate)
Tubular dysfunction including type 1 distal RTA
Glomerular disease (uncommon)
Obstruction secondary to retroperitoneal lymphadenopathy/fibrosis
Amyloidosis Extracellular deposition of insoluble amyloid fibrils
Two types: AA and AL amyloidosis
Endocrine manifestations [25]
Thyroid goitre
Gonadal dysfunction
Hypoadrenalism
Renal manifestations
Proteinuric CKD secondary to glomerular amyloid deposition (more common with AA amyloidosis)
Sickle cell Inherited point mutation of beta-globin gene resulting in abnormally structured haemoglobin (HbSS)
disease
Endocrine manifestations
Diabetes mellitus (only if iron overload)
Renal manifestations
Recurrent prerenal episodes of acute kidney injury during sickle crises
Medullary infarction and papillary necrosis
Nephrogenic diabetes insipidus
Glomerular lesions – most commonly FSGS
Renal medullary carcinoma
Drug toxicity (recurrent courses of antibiotics, analgesics and contrast agents)
(continued)
702 R. K. Y. Hung et al.
Condition Presentation
Condition Presentation
Fabry X-linked lysosomal storage disorder related to deficiency of alpha galactosidase A and resulting accumulation of
disease globotriaosylceramide in multiple organs
Endocrine manifestations [26]
Hypothyroidism
Infertility
Subclinical adrenal insufficiency
Renal manifestations
Progressive CKD with proteinuria and/or haematuria (usually progresses to end-stage renal failure in adulthood)
due to glycosphingolipid accumulation in podocytes, mesangial cells and vascular endothelium
Characteristic lysosomal lamellar cytoplasmic inclusions seen on electron microscopy of renal biopsies (Zebra
bodies)
Primary Autosomal recessive disorder resulting in defects in the enzymes responsible for conversion of glyoxalate to glycine
hyperoxal- (PH1) or glycolate (PH2) and resultant excess conversion to oxalate
uria (PH)
Endocrine manifestations [26]
39 Hypothyroidism
Renal manifestations
Excess urinary oxalate excretion leading to nephrolithiasis (calcium oxalate)
Nephrocalcinosis
Cystinosis Autosomal recessive disorder of lysosomal cystine transportation leading to intracellular accumulation
Endocrine manifestations [26]
Hypothyroidism
Diabetes mellitus
Renal manifestations
Type 1 distal RTA (Fanconi syndrome)
Progressive CKD from cystine deposition in renal parenchyma
The Endocrine System and the Kidney
703 39
Condition Presentation
Bardet-Biedl Autosomal recessive inherited condition resulting in short stature, weight gain, polydactyly, visual impairment and
syndrome hypertension
(and Laurence-Moon syndrome has a similar phenotype but occurs with spinocerebellar degeneration
Laurence-
Endocrine manifestations
Moon
syndrome) Hypogonadism
Diabetes mellitus
Renal manifestations
Vesicoureteric reflux
Congenital renal dysplasia and calyceal abnormalities
Alström Rare autosomal recessive condition leading to an inborn error of metabolism arising from a defect in the ALMS1 gene
syndrome
Endocrine manifestations [26]
Type 2 diabetes
Hypogonadism
Hypopituitarism and GH deficiency
Renal manifestations
Progressive CKD
Central A lack of antidiuretic hormone (ADH) due to damage to the pituitary gland or hypothalamus
diabetes Can occur due to head injury, surgery or tumours
insipidus
Endocrine manifestations
ADH low or absent
Renal manifestations
Polyuria exceeding 10 L/24 hours
Hypernatraemia
Nephrogenic Failure of kidney to respond to a normal release of ADH by the pituitary.
diabetes Can occur due to:
insipidus Acquired causes
Drugs: lithium, cidofovir, amphotericin
Other diseases: Sickle cell, amyloidosis, ADPKD, Bartter syndrome, Sjogren’s syndrome
Hereditary causes
X-linked recessive mutation of AVPR2 gene
Autosomal-dominant and recessive mutation of AQP2 gene
Endocrine manifestations
ADH normal or raised
Renal manifestations
Polyuria
Hypernatraemia
704 R. K. Y. Hung et al.
Condition Presentation
Sheehan’s syndrome Hypopituitarism caused by ischaemic necrosis postpartum due to hypovolaemia secondary to haemorrhage
or hypotension
Severe septic shock
Envenomation following snake bites
Endocrine manifestations
Varying degrees of hypopituitarism depending on area affected, but at least 75% of pituitary have to be
infarcted
Growth hormone and prolactin secretion most commonly affected (90–100%). Cortisol, ADH gonadotro-
phin and TSH deficiencies range from 50 to 100%
Renal manifestations
AKI in the setting of systemic shock
AKI secondary to chronic adrenal insufficiency
Cortical necrosis (any systemic shock severe enough to cause cortical necrosis may cause pituitary
infarction and vice versa)
Phaeochromocytoma Neuroendocrine tumour of the chromaffin cells from the medulla of the adrenals
(. Fig. 39.4)
Endocrine manifestations
Part of MEN 2 syndrome
Symptoms of sympathetic nervous system hyperactivity secondary to excess secretion of catecholamines
Renal manifestations
Part of von Hippel-Lindau syndrome
Hypertension
Low renin and aldosterone levels
AKI in setting of
Cardiogenic shock
Intravascular depletion
Rhabdomyolysis (due to muscle ischaemia from hypertensive crisis)
MAHA (rare)
39
. Table 39.10 Renal complications of endocrine diseases
a b
. Fig. 39.5 Oncogenic osteomalacia. Radiological findings in a radiological evidence of an intense uptake in soft tissue lesion in the
young female patient presenting with isolated hypophosphataemia left nasal cavity and ethmoid sinus detected using PET CT b with a
and pelvic stress fractures (a; MRI sacrum with stress fracture indi- radiolabelled octreotide analogue (68Ga-DOTATATE) confirmed
cated by the arrow), which was misdiagnosed as vitamin D defi- the diagnosis of a phosphaturic mesenchymal tumour leading to
ciency. Subsequent hyperphosphaturia was diagnosed on a calculated osteogenic osteomalacia. (Reproduced with permission from Mum-
fractional excretion of phosphate of 42%. A raised FGF23 level and ford et al. [29])
706 R. K. Y. Hung et al.
Case Study
160
96
ALT normalised
64
32
0
Month 2 4 6 8 10 12
. Fig. 39.6 Graph showing reduction of creatinine when thyroxine therapy was started. However, normalisation of creatinine, T4 and TSH
levels look over a year due to intermittent attendance
708 R. K. Y. Hung et al.
80 2.0 Free T4
(normal range
7-22 pmol/L)
60 1.5
pmol/L TSH
ml
(normal range
40 1.0 0.3-4.2 mu/L)
20 0.5
0.3
0 0
Month 1 2 3 4
Creatinine
100
80
60
umol/L
40
20
39 Month 1 2 3 4
. Fig. 39.7 and 39.8 These two graphs show the patient’s fall in creatinine levels (. Fig. 39.7) as free T4 levels rise (. Fig. 39.8). The cor-
rection of free T4 levels corresponds with an abrupt rise in the patient’s creatinine to baseline (blue arrows)
The Endocrine System and the Kidney
709 39
a b
. Fig. 39.9 Gadolinium-enhanced T1-weighted magnetic resonance image of the pituitary gland showing a normal gland a and a marked
diminution in the pituitary gland consistent with necrosis b. (Free access from Matsuzaki et al. [31])
and those who have received transplantation. 15. Siew ED, Ikizler TA. Insulin resistance and protein energy
However, all other potentially modifiable factors metabolism in patients with advanced chronic kidney disease.
Semin Dial. 2010;23:378–82.
will need to be corrected, e.g. nutritional intake,
16. Linnebjerg H, Kothare PA, Park S, et al. Effect of renal impair-
metabolic acidosis, renal bone osteodystrophy, ment on the pharmacokinetics of exenatide. Br J Clin Pharma-
anaemia, fluid and electrolyte abnormalities. The col. 2007;64:317–27.
goal in recombinant growth hormone therapy is 17. Yahiaoui Y, Jablonski M, Hubert D, et al. Renal involvement in
to achieve normal final height. cystic fibrosis: diseases spectrum and clinical relevance. Clin J
Am Soc Nephrol. 2009;4:921–8.
18. Thakker RV, Newey PJ, Walls GV, et al. Clinical practice guide-
lines for multiple endocrine neoplasia type 1 (MEN1). J Clin
Endocrinol Metab. 2012;97:2990–3011.
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SL. Absence of H(+)-ATPase in cortical collecting tubules of a
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sis. J Am Soc Nephrol. 1992;3:264–71.
farb J. Temporal trends in the prevalence of diabetic kidney dis-
20. Takemoto F, Hoshino J, Sawa N, et al. Autoantibodies against
ease in the United States. JAMA. 2011;305:2532–9.
carbonic anhydrase II are increased in renal tubular acidosis
2. Tong A, Sainsbury P, Chadban S, et al. Patients’ experiences and
associated with Sjogren syndrome. Am J Med. 2005;118:181–4.
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21. Nagayama Y, Shigeno M, Nakagawa Y, et al. Acquired nephro-
700.
genic diabetes insipidus secondary to distal renal tubular acido-
3. Harris RC, Ismail N. Extrarenal complications of the nephrotic
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4. Feinstein EI, Kaptein EM, Nicoloff JT, Massry SG. Thyroid
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function in patients with nephrotic syndrome and normal renal
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function. Am J Nephrol. 1982;2:70–6.
lar acidosis. Q J Med. 1993;86:513–34.
5. Iglesias P, Diez JJ. Thyroid dysfunction and kidney disease. Eur
23. Evans R, Zdebik A, Ciurtin C, Walsh SB. Renal involvement in
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2015;54:1541–8.
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24. Porter N, Beynon HL, Randeva HS. Endocrine and reproductive
7. Malluche HH, Goldstein DA, Massry SG. Osteomalacia and
manifestations of sarcoidosis. QJM. 2003;96:553–61.
hyperparathyroid bone disease in patients with nephrotic syn-
25. Ozdemir D, Dagdelen S, Erbas T. Endocrine involvement in sys-
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26. Vantyghem MC, Dobbelaere D, Mention K, Wemeau JL, Saudu-
SG. Vitamin D metabolites and calcium metabolism in patients
bray JM, Douillard C. Endocrine manifestations related to inher-
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711 40
Contents
References – 729
Dermatology in Kidney Disease
713 40
n Learning Objectives
. Table 40.1 Skin manifestations of diseases associated
1. Clinical presentation and management of the most with renal involvement
frequently encountered skin conditions associated
with renal disease. Systemic disorder Skin manifestations
2. Early recognition of skin cancers and their particu-
lar importance in the renal transplant population. Diabetes mellitus Necrobiosis lipoidica, perforating
dermatosis, eruptive xanthomas
3. Strategies for skin cancer prevention in renal trans-
plant recipients. Systemic lupus Photosensitivity, malar erythema,
erythematosus (SLE) cutaneous LE lesions, diffuse
alopecia, vasculitis
A wide variety of skin conditions arise in patients with Wegener granulomato- Palpable purpura, subcutaneous
chronic kidney disease (CKD). These are sometimes sis/polyarteritis nodosa nodules, livedo reticularis, ulcers
(PAN)
related to the underlying pathologic process causing the
renal disease but are also frequently associated with the Systemic sclerosis Acral or diffuse sclerosis, CREST
uraemic state itself. Cutaneous examination of patients syndrome, Raynaud’s phenomenon
with CKD has shown an almost 100% prevalence of Amyloidosis Purpura, xanthomatous papules,
skin disorders in dialysis populations [1], with a marked scleroderma-like changes
impact on quality of life [2]. In addition, there is over Anderson-Fabry disease Angiokeratomas
a 100-fold increase in the incidence of certain types of
HIV Eosinophilic folliculitis, Kaposi’s
skin cancer in renal transplant recipients, placing a sig-
sarcoma
nificant burden on healthcare resources as well as caus-
ing significant morbidity and in some cases mortality [3]. Cholesterol emboli Livedo reticularis, petechiae,
purpura
Early recognition of these skin problems can therefore
avert such complications, making a basic knowledge of Hepatitis C Purpura, porphyria cutanea tarda,
the dermatological conditions arising in the setting of lichen planus, cutaneous PAN
renal disease extremely valuable to practising nephrolo- Tuberous sclerosis Facial angiofibromas, ash-leaf
gists. macule, shagreen patch, periungual
The cutaneous manifestations of renal disease may fibromas
be broadly divided into three general categories: (1) skin
manifestations of diseases associated with chronic kid-
ney disease (7 Box 40.1), (2) skin manifestations of dis-
eases associated with renal involvement (. Table 40.1) 40.2 Skin Conditions Associated
and (3) skin conditions associated with renal transplan- with Chronic Kidney Disease
tation.
Examination of the skin and nails can reveal abnormali-
ties in patients with end-stage renal disease that precede
Box 40.1 Skin Conditions Associated with Chronic dialysis or kidney transplantation. Chronic renal failure,
Kidney Disease (Those Highlighted in Bold regardless of its cause, often produces xerosis, pruri-
Discussed Further in Text) tus, hyperpigmentation and nail changes. Although the
Uraemic pruritus majority of dermatological conditions in CKD are rela-
Calciphylaxis tively benign, a few skin diseases have the potential to
Nephrogenic systemic fibrosis cause serious morbidity and mortality. It is these condi-
Acquired perforating dermatosis tions which are discussed in more detail in this chapter
Porphyria cutanea tarda (7 Box 40.1).
Hyperpigmentation
Xerosis
Cutaneous infections (bacterial/fungal/viral) 40.3 Uraemic Pruritus
Purpura
Alopecia With improvements in dialysis and the development
Nail changes of biocompatible dialysis membranes, the prevalence
of uraemic pruritus (UP) has declined in the past
714 F. Ismail and R. Anand
40
. Fig. 40.1 Calciphylaxis at
a b
initial presentation (a) and 1
week later (b)
Dermatology in Kidney Disease
715 40
thiosulphate during dialysis at a dose of 5–25 g i.v. has
also shown to be effective and works by chelating cal-
cium from soft tissue [7]. This may need to be continued
for a period of weeks to months, in association with the
above measures.
form of PCT occurs in approximately 5% of patients on chronic discoid lesions tend to lead to scarring with
dialysis and can be precipitated by alcohol, oestrogens, more acute and subacute lesions resolving with pigmen-
hepatitis B or C infections or HIV. Pseudoporphyria tary change. Ordinary histology is poor at differentiating
is a condition clinically and histologically identical to between the subtypes of CLE with direct immunofluo-
PCT but characterised by normal serum and urine por- rescence positive in ~80% of involved skin. Potent topi-
phyrin levels. It is triggered by medications, e.g. amio- cal steroids are usually the mainstay of treatment of skin
darone, tetracyclines and naproxen. Photoprotection is lesions, along with photoprotection (SPF 50+ with UVA
the mainstay of managing such patients via the use of protection) and hydroxychloroquine. Patients with CLE
sunscreens and clothing. require accurate clinicopathological correlation, not least
to attempt to answer the question of the progression of
cutaneous disease to systemic disease.
40.8 Skin Manifestations of Diseases
Associated with Renal Involvement
40.8.2 Cutaneous Vasculitis and Renal
40.8.1 Lupus Erythematosus Disease
The various clinical types of cutaneous lupus erythe- Vasculitides can be classified based on the size of the
matosus (CLE) may be subdivided according to the risk vessel affected. Small-vessel vasculitides include Henoch-
of systemic involvement and clinical outcome. With the Schönlein purpura (HSP) and ANCA-associated vascu-
advent of immunological testing, groups such as sub- litis. Ninety percent of cases of HSP affect children and
acute cutaneous lupus have been described [10], and the renal involvement may not be apparent at the initial diag-
role of drugs in the development of lupus has also been nosis (. Fig. 40.5). Although occurring rarely in adults,
identified. Broadly speaking, CLE may be classified into the sequelae of disease tend to be more severe with more
three subsets: (1) chronic CLE (CCLE), of which the most significant renal impairment. ANCA-associated vasculi-
common manifestation is that of discoid lupus (DLE); tis includes Wegener’s granulomatosis with skin disease
(2) acute CLE (ACLE); and (3) subacute CLE (SCLE). occurring in 14–77% of patients and is associated with a
Significant systemic involvement occurs in up to 28% of higher frequency of renal involvement [13, 14]. Cutaneous
patients with CCLE with a higher proportion of patients lesions include palpable purpura most commonly on the
with SCLE (. Fig. 40.4) having the diagnostic criteria for lower legs, subcutaneous nodules and ulcers. Polyarteritis
systemic lupus but with mild systemic disease. Severe renal nodosa (PAN) is a medium- and small-vessel disease,
disease is uncommon [11, 12]. Mucocutaneous abnormal- which may be systemic or solely cutaneous. Skin lesions
ities occur in around 85% of patients with SLE. Clinically, occur in 25–50% of patients with systemic PAN and
include livedoid changes (. Fig. 40.6) and ulceration
attributed to a necrotising vasculitis, with subcutaneous
nodules formed by aneurysms of superficial blood ves-
sels. Renal involvement occurs in 25–60% of systemic
40 PAN and is a poor prognostic indicator.
. Fig. 40.4 Subacute cutaneous lupus erythematosus . Fig. 40.5 Henoch-Schönlein purpura
Dermatology in Kidney Disease
717 40
nantly occur on the scalp, face and upper trunk and are
observed in HIV-infected patients with a CD4 count of
less than 300 cells/mm3. Histologically, eosinophils are
present around the follicular epithelium. Treatment of
the underlying HIV infection with a rise in the CD4+
cell count may lead to resolution of the lesions. Other
treatment options include topical steroids, UVB photo-
therapy, oral tetracycline antibiotics and oral isotreti-
noin.
ESRD in the context of HIV is often multifacto-
rial. With advances in antiretroviral therapy (ART) and
improving prognosis of those living with HIV, renal
transplantation is no longer an absolute contraindica-
tion. Studies have demonstrated comparable patient
and graft outcomes comparing HIV-infected patients
on ART and uninfected patients [19]. However, there is
limited data on the long-term complications of trans-
plant immunosuppression in this population, and
whether more opportunistic skin infections, inflamma-
tory dermatoses and skin cancers are observed in this
patient population remains to be seen.
. Fig. 40.9 Fabry disease
. Fig. 40.10 Steroid-induced acne and striae Sebaceous gland hyperplasia can often be disfigur-
ing for patients and are characterised as small yellow
important to treat lesions promptly in order to mini- papules, often on the forehead and cheeks. They may
mise the subsequent risk of scarring. First-line agents be treated with gentle cautery, though lesions often
for patients with mild to moderate acne include topical recur. Low-dose oral retinoids may be considered if very
agents, such as benzoyl peroxide, and topical antibiotics extensive.
such as erythromycin or clindamycin. Use of oil-free or
water-based moisturisers and cosmetics should also be
recommended. More severe cases of acne may warrant 40.11 Skin Infections in Solid Organ
treatment with systemic agents, under the supervision of Transplantation
both dermatologists and nephrologists. These include
oral tetracyclines for a minimum of 2–3 months, in com- Infections of the skin in transplant recipients are com-
bination with suitable topical treatment, or if this fails, mon and can be caused by bacteria, mycobacteria, fungi
then the use of the oral retinoid isotretinoin. The latter and viruses (. Table 40.3). They can be challenging to
may only be prescribed by a dermatologist with close diagnose and treat as they may have an atypical appear-
monitoring of lipids and liver function, as well as enroll- ance secondary to the effects of immunosuppression.
ing women of childbearing age into a pregnancy preven- Human papillomavirus (HPV)-related cutaneous and
tion programme due to its teratogenicity. Most courses anogenital viral warts are very common. They are often
of isotretinoin last for 5–6 months but may often be lon- numerous and recalcitrant to treatment (. Fig. 40.11).
ger, depending on the dose used and how well it is toler- A number of therapeutic options are available, includ-
ated. Any scope for reducing the dose of the offending ing chemical or physical destruction, treatments that
agents (particularly steroids) should also be considered. enhance the local immune response and antiprolifera-
720 F. Ismail and R. Anand
Destructive Antiproliferative
Topical salicylic acida Podophyllin/podophyllotoxin
40 Cryotherapya Intralesional bleomycin
Thermocautery/curettage and cautery Retinoids: topical and systemic
Chemical cautery: silver nitrate Topical 5-fluorouracila
Laser: CO2/pulsed dye Occlusotherapy
Photodynamic therapy Vitamin D analogues, e.g. maxacalcitrol
Topical phenol Dithranol
Topical cantharidin Topical cidofovir
Trichloroacetic acid
Immune stimulation Virucidal
Topical imiquimoda Topical formaldehyde
Contact immunotherapy: diphencyprone Topical glutaraldehyde
Cimetidine
astatic melanoma over recent years, OTRs with advanced often on the lower legs and commonly associated with
malignancies have been largely excluded from clinical lymphoedema (. Fig. 40.18). Visceral involvement
trials testing the safety and efficacy of these therapies. occurs in 25–30% of OTRs. KS is especially preva-
Chae et al. reviewed the available data describing immune lent in Mediterranean and African populations and
checkpoint blockade in the OTR population assessing is related to HHV8. Serostatus at the time of trans-
the risk of allograft rejection associated with the various plant is the most important risk factor associated with
treatment regimens. They found that CTLA-4 inhibitors post-transplant KS, with a mean duration of onset
have been used safely and successfully in selected patients, 13 months post-transplantation. The main approach
whilst PD-1 inhibitors were associated with a higher risk to managing transplant-associated Kaposi’s sarcoma
of allograft rejection. Further clinical experience and is to reduce or even discontinue immunosuppressive
larger clinical trials involving immune checkpoint inhibi- therapy, which usually causes skin lesions to regress,
tors as monotherapies or combinatorial therapies are although it carries a risk of acute rejection of the graft.
needed to develop regimens that optimise the antitumour KS generally recurs when immunosuppressive therapy
immune response and minimise the risk of graft rejection is reintroduced or after a second transplantation. In
in organ transplant patients [30]. a study of 15 renal transplant recipients, it was found
that sirolimus inhibits the progression of dermal KS
when given at the usual immunosuppressive dose, with
40.17 Merkel Cell Carcinoma remission induced in all 15 subjects within 3 months
[32]. Thus, switching to an mTor inhibitor such as
Merkel cell carcinoma (MCC) is a rare yet aggressive sirolimus is recommended, with a >70% response
skin tumour occurring around 10 times more commonly rate within 3 months. Further treatment options for
in RTRs compared to the general population, in whom patients unresponsive to revision of immunosuppres-
it has a significantly worse prognosis. It often presents as sion include surgery, radiotherapy or chemotherapy
an asymptomatic solitary red nodule on sun-exposed sites, such as liposomal doxorubicin.
most commonly the head and neck, with ~70% rate of
metastasis and a 5-year survival of <50% (. Fig. 40.17).
They are of neuroendocrine origin and 80% are associ- 40.19 Specialist Transplant Skin Clinics
ated with the clonal integration of the Merkel cell poly-
omavirus (MCPyV) [31]. Management is predominantly The need for post-transplant skin cancer surveillance has
surgical, with the use of adjuvant radiotherapy for local been recognised in many international expert consensus
disease. Further research on the role of MCPyV may offer guidelines. In the UK, the National Institute for Health
hope for more targeted approaches to MCC treatment and and Clinical Excellence recommend surveillance in dedi-
prevention. The PD L1 antibody Avelumab, an immune cated dermatology clinics [33], and it has been shown
checkpoint inhibitor, has been approved by NICE in 2018 that such clinics significantly improve compliance with
as first-line treatment for advanced or metastatic MCC, sun protection and skin cancer awareness [34]. Other
though OTRs were excluded from initial studies. guidelines in Europe and the USA also advise special-
40 ist full skin examination of RTRs every 6–12 months;
however, these recommendations do not take account
40.18 Kaposi’s Sarcoma of individual risk nor the needs of practising clinicians
with limited resources. The effectiveness and cost-benefit
The incidence of Kaposi’s sarcoma (KS) among recipi- of skin surveillance in RTRs is unknown, and as such,
ents of solid organs is greater than 400 to 500 times a surveillance model for skin cancer in RTRs has been
the rate in the general population, with clinical pre- proposed by Harwood et al. [35], based on a 22-year pro-
sentation in transplant patients often confined to the spective study of more than 1000 patients. They define
skin. KS is a tumour of endothelial origin and presents surveillance intervals that enable close follow-up of
as purple papules, plaques and nodular lesions, most higher-risk individuals with routine follow-up of those at
much lower risk. This risk stratification is based upon a of skin cancers should be emphasised from the outset,
number of patient characteristics, including skin photo- i.e. to all patients on transplant waiting lists.
type, age at transplantation, sunburn history and history
of confirmed skin cancer. Garrett et al. evaluated the risk
factors for post-transplant skin cancer in a large multi- 40.20 Conclusions
centre study, with elevated risk imparted by increased
age, fair skin type and male sex. Understanding the risk Dermatological conditions in patients with renal dis-
factors and trends in post-transplant skin cancer is fun- ease are extremely common and varied. Having a basic
damental to targeted screening and prevention [36]. This understanding of these is essential, as early recognition
is of practical use to those setting up transplant skin clin- and management can have a huge impact both on the
ics, facilitating targeted surveillance and active manage- physical and psychological well-being of these patients.
ment to those who need it most. Within the transplant population, the clinical presenta-
Any such service should involve a multidisciplinary tion of skin conditions can often be difficult to recognise
approach with close interaction between dermatolo- and challenging to treat, and skin cancers in particular
gists, transplant clinicians, plastic surgeons/dermatol- are frequently multiple and more aggressive. Published
ogy surgeons, medical/clinical oncologists, pathologists, data regarding management of skin diseases in this
clinical nurse specialists and primary care physicians. patient cohort is limited or anecdotal and is predomi-
The relationship between dermatologists and transplant nantly extrapolated from guidelines in immunocom-
clinicians enables discussion of potential revision of petent individuals. It is therefore essential that further
immunosuppression in high-risk individuals as well as research within this population is undertaken and that
the potential need for systemic agents to be introduced. there exists a collaborative relationship between renal
The role of a specialist nurse should also be highlighted, and dermatology clinicians. Dedicated dermatology
in particular facilitating urgent access for patients as clinics are essential for managing this complex group of
well as undertaking nurse-led surveillance clinics and patients in order to improve both morbidity and mortal-
patient education in relation to photoprotection and ity from the rising incidence of skin diseases within this
skin cancer awareness. Preferably, primary prevention population.
726 F. Ismail and R. Anand
Case Study
40
revealed a ruptured epidermis with elimination of dermal mycophenolate mofetil. Examination revealed multiple
material, and special stains confirmed the diagnosis of per- palpable purple confluent papules and plaques around the
forating collagenosis. fistula site on her left arm, with oedema and tenderness
Management included the regular use of emollients (. Fig. 40.21). Full skin examination was otherwise unre-
and potent topical steroids for symptomatic relief. Given markable. A diagnostic skin biopsy revealed vascular
the extent of the lesions, he was commenced on TL01 (nar- channels lined with atypical endothelial cells amongst a
row band UVB) phototherapy following which he had fur- network of extravasated red cells and hemosiderin deposi-
ther limited improvement. tion, consistent with Kaposi’s sarcoma. This was further
supported by positive immunostaining for HHV8. She
Case 3 went on to have full body imaging which excluded visceral
A 52-year-old woman of Kenyan origin presented with a involvement.
1-year history of an evolving painful cutaneous eruption Her immunosuppression was modified with the grad-
around a functioning fistula on her left arm associated ual reduction of tacrolimus and the introduction of siroli-
with marked oedema, 18 months following a second kid- mus, with maintenance of her graft function. The
ney transplant. She was otherwise clinically well with no cutaneous lesions resolved within 3 months of switching
systemic symptoms and maintained on tacrolimus and her immunosuppression.
Case 4
A 68-year-old woman was admitted to hospital with a
3-month history of progressive bilateral breast pain and
necrotic ulceration. She noted this first began with darken-
ing of the skin with a ‘woody’ feeling within the breast.
This then began to break down centrally and ulcerate, leav-
ing a thick overlying black crust. She had end-stage renal
disease secondary to hypertension and type 2 diabetes and
had been on haemodialysis for 10 years.
Examination revealed dusky red mottling over the
breasts with a livedoid pattern at the periphery. Centrally
there were black eschars on both breasts and across the
abdomen. The surrounding skin was indurated and exqui-
sitely tender (. Fig. 40.22). A deep incisional skin biopsy
was performed on the left breast, which showed ulceration
and necrosis with calcification of small- to medium-sized
vessels and intravascular thrombi, as well as diffuse calcifi-
cation of small capillaries in the subcutaneous fat. These
changes were consistent with the diagnosis of calciphy-
laxis.
The frequency of dialysis was increased with immedi-
ate effect. Intravenous infusions of sodium thiosulfate
were administered during dialysis and meticulous wound
care administered, with a gradual improvement in the
cutaneous lesions over a 4-month period. . Fig. 40.22 Calciphylaxis
10. Sontheimer RD. Subacute cutaneous lupus erythematosus: RP, Sidhu-Malik N, Konnikov N, Werth VP, Keri JE,
25-year evolution of a prototypic subset (subphenotype) of Robinson-Bostom L, Ringer RJ, Lew RA, Ferguson R, JJ
lupus erythematosus defined by characteristic cutaneous, DG, Huang GD, Veterans Affairs Keratinocyte Carcinoma
pathological, immunological, and genetic findings. Autoimmun Chemoprevention Trial (VAKCC) Group. Chemoprevention
Rev. 2005;4(5):253–63. of basal and squamous cell carcinoma with a single course of
11. Gronhagen CM, Fored CM, Granath F, Nyberg F. Cutaneous fluorouracil, 5%, cream: a randomized clinical trial. JAMA
lupus erythematosus and the association with systemic lupus Dermatol. 2018;154(2):167–74.
erythematosus: a population-based cohort of 1088 patients in 26. Harwood CA, Leedham-Green M, Leigh IM, Proby CM. Low-
Sweden. Br J Dermatol. 2011;164:1335–41. dose retinoids in the prevention of cutaneous squamous cell
12. Chong BF, Song J, Olsen NJ. Determining risk factors for carcinomas in organ transplant recipients: a 16-year retrospec-
developing systemic lupus erythematosus in patients with dis- tive study. Arch Dermatol. 2005;141(4):456–64.
coid lupus erythematosus. Br J Dermatol. 2012;166:29–35. 27. Chen AC, Martin AJ, Choy B, Fernández- Peñas P, Dalziell
13. Walsh JS, Gross DJ. Wegener’s granulomatosis involving the RA, McKenzie CA, Scolyer RA, Dhillon HM, Vardy JL,
skin. Cutis. 1999;64(3):183–6. Kricker A, St George G, Chinniah N, Halliday GM, Damian
14. Frances C, Du LT, Piette JC, et al. Wegener’s granulomatosis. DL. A phase 3 randomized trial of nicotinamide for skin-
Dermatological manifestations in 75 cases with clinicopatho- cancer chemoprevention. N Engl J Med. 2015;373(17):1618–
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15. Moinzadeh P, Denton C, Krieg T, Black C. Fitzpatrick’s der- 28. Euvrard S, Morelon E, Rostaing L, Goffin E, Brocard A,
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cal and laboratory features in 474 cases. Semin Hematol. TUMORAPA Study Group. Sirolimus and secondary skin-
1995;32(1):45–59. cancer prevention in kidney transplantation. N Engl J Med.
17. Orteu CH, Jansen T, Lidove O, Jaussaud R, Hughes DA, 2012;367(4):329–39.
Pintos-Morell G, Ramaswami U, Parini R, Sundur-Plassman 29. Matin RN, Mesher D, Proby CM, McGregor JM, Bouwes
G, Beck M, Mehta AB, FOS Investigators. Fabry disease Bavinck JN, del Marmol V, Euvrard S, Ferrandiz C, Geusau
and the skin: data from FOS, the Fabry outcome survey. Br J A, Hackethal M, Ho WL, Hofbauer GF, Imko-Walczuk B,
Dermatol. 2007;157(2):331–7. Kanitakis J, Lally A, Lear JT, Lebbe C, Murphy GM, Piaserico
18. Hogarth V, Hughes D, Orteu CH. Pseudoacromegalic facial S, Seckin D, Stockfleth E, Ulrich C, Wojnarowska FT, Lin
features in Fabry disease. Clin Exp Dermatol. 2013;38(2): HY, Balch C, Harwood CA. Skin Care in Organ Transplant
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19. Stock PG, Barin B, Murphy B, Hanto D, Diego JM, Light plant recipients: clinicopathological features and outcome in
J, Davis C, Blumberg E, Simon D, Subramanian A, Millis 100 cases. Am J Transplant. 2008;8(9):1891–900.
JM, Lyon GM, Brayman K, Slakey D, Shapiro R, Melancon 30. Chae YK, Galvez C, Anker JF, Iams WT, Bhave M. Cancer
J, Jacobson JM, Stosor V, Olson JL, Stablein DM, Roland immunotherapy in a neglected population: the current use and
ME. Outcomes of kidney transplantation in HIV-infected future of T-cell-mediated checkpoint inhibitors in organ trans-
recipients. N Engl J Med. 2010;363(21):2004–14. plant patients. Cancer Treat Rev. 2018;63:116–21.
20. Lugo-Janer G, Sanchez JL, Santiago-Delphin E. Prevalence 31. Feng H, Shuda M, Chang Y, Moore PS. Clonal integration
and clinical spectrum of skin diseases in kidney transplant of a polyomavirus in human Merkel cell carcinoma. Science.
recipients. J Am Acad Dermatol. 1991;24:410–4. 2008;319(5866):1096–100.
21. Kwak EJ, Julian K, AST Infectious Diseases Community 32. Stallone G, Schena A, Infante B, Di Paolo S, Loverre A,
of Practice. Human papillomavirus infection in solid organ Maggio G, Ranieri E, Gesualdo L, Schena FP, Grandaliano
transplant recipients. Am J Transplant. 2009;9(Suppl G. Sirolimus for Kaposi’s sarcoma in renal-transplant recipi-
4):S151–60. ents. N Engl J Med. 2005;352:1317–23.
40 22. Wisgerhof HC, Edelbroek JR, de Fijter JW, Haasnoot GW, 33. National Institute for Health and Clinical Excellence.
Claas FH, Willemze R, Bavinck JN. Subsequent squamous- Improving outcomes for people with skin tumours includ-
and basal-cell carcinomas in kidney transplant recipients after ing melanoma: the manual (2006 guidance). http://www.nice.
the first skin cancer: cumulative incidence and risk factors. org.uk/nicemedia/live/10901/28906/28906.pdf.
Transplantation. 2010;89(10):1231–8. 34. Ismail F, Mitchell L, Casabonne D, Gulati A, Newton R,
23. Hofbauer GF, Bouwes Bavinck JN, Euvrard S. Organ trans- Proby CM, Harwood CA. Specialist dermatology clinics for
plantation and skin cancer: basic problems and new perspec- organ transplant recipients significantly improve compliance
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24. Green A, Williams G, Neale R, Hart V, Leslie D, Parsons P, Dermatol. 2006;155(5):916–25.
Marks GC, Gaffney P, Battistutta D, Frost C, Lang C, Russell 35. Harwood CA, Mesher D, McGregor JM, Mitchell L, L-Green
A. Daily sunscreen application and betacarotene supplemen- M, Raftery M, Cerio R, Leigh IM, Sasieni P, Proby CM. A sur-
tation in prevention of basal-cell and squamous-cell carci- veillance model for skin cancer in organ transplant recipients:
nomas of the skin: a randomised controlled trial. Lancet. a 22-year prospective study in an ethnically diverse population.
1999;354(9180):723–9. Am J Transplant. 2013;13(1):119–29.
25. Weinstock MA, Thwin SS, Siegel JA, Marcolivio K, Means 36. Garrett GL, Blanc PD, Boscardin J, Lloyd AA, Ahmed RL,
AD, Leader NF, Shaw FM, Hogan D, Eilers D, Swetter SM, Anthony T, Bibee K, Breithaupt A, Cannon J, Chen A, Cheng
Chen SC, Jacob SE, Warshaw EM, Stricklin GP, Dellavalle JY, Chiesa-Fuxench Z, Colegio OR, Curiel-Lewandrowski
Dermatology in Kidney Disease
731 40
C, Del Guzzo CA, Disse M, Dowd M, Eilers R Jr, Ortiz AE, Patient Information and Guidelines
Morris C, Golden SK, Graves MS, Griffin JR, Hopkins RS,
Further information for transplant patients, as well as patients await-
Huang CC, Bae GH, Jambusaria A, Jennings TA, Jiang SI,
ing an organ transplant, can be obtained via the British
Karia PS, Khetarpal S, Kim C, Klintmalm G, Konicke K,
Association of Dermatologists website: http://www.bad.org.uk
Koyfman SA, Lam C, Lee P, Leitenberger JJ, Loh T, Lowenstein
Other useful websites include the following:
S, Madankumar R, Moreau JF, Nijhawan RI, Ochoa S, Olasz
After Transplantation – Reduce Incidence of Skin Cancer (AT-
EB, Otchere E, Otley C, Oulton J, Patel PH, Patel VA, Prabhu
RISC Alliance): http://at-risc.org/Home.aspx
AV, Pugliano-Mauro M, Schmults CD, Schram S, Shih AF,
British Society for Skin Care in Immunocompromised Individuals
Shin T, Soon S, Soriano T, Srivastava D, Stein JA, Sternhell-
(BSSCII): http://www.bsscii.org.uk
Blackwell K, Taylor S, Vidimos A, Wu P, Zajdel N, Zelac D,
International Transplant Skin Cancer Collaborative (ITSCC):
Arron ST. Incidence of and risk factors for skin cancer in organ
http://www.itscc.org/
transplant recipients in the United States. JAMA Dermatol.
Skin Care in Organ Transplant Patients Europe (SCOPE): http://
2017;153(3):296–303.
www.scopenetwork.org/index.htm
733 41
Contents
References – 748
n Learning Objectives
1. To identify multisystem diseases which have both
renal and neurological manifestations
2. To develop an awareness of why renal function
maybe become impaired in the context of neuro-
logical disorders and their treatments.
3. To outline the neurological complications of com-
mon renal diseases and their treatments and to
develop a strategy for their prevention, investiga-
tion and treatment
41.1 Introduction
. Table 41.1 Genetic, immune-mediated and mitochondrial disorders with nephrological and neurological consequences
Genetic diseases
Polycystic kidney Intracranial aneurysm, particularly berry Multiple kidney cysts, progressive Targeted screening for
disease aneurysms in circle of Willis seen in CKD, ESRF requiring RRT patients with adult PKD and
5–15% PKD patients. Greater risk of family history of ICA or
rupture compared to sporadic aneu- SAH with time-of-flight
rysms. Increased risk of embolic stroke MRA [1]
due to mitral and aortic valve lesions
Alport syndrome Progressive bilateral sensorineural Haematuria progressing to
hearing loss, lenticonus, keratoconus, haematoproteinuria, CKD and
cataracts ESRF often by 40 years old.
Severity often consistent within a
family
Fabry’s disease Cerebral vasculopathy, acroparesthesia Renal failure due to accumulation Also characterised by skin
exacerbated by extremes of temperature of glycosphingolipids in small angiokeratomas. Death
and physical exertion, small fibre blood vessels usually in the fifth decade due
neuropathy, dysautonomia to uraemia or cerebrovascular
disease
Von Hippel- Retinal angiomatosis and CNS RCC, seen in 24–45% of VHL Require regular screening of
Lindau disease haemangioblastoma in 80% of patients patients. retina, kidneys and neuroaxis
(predominantly in cerebellum and spinal Renal cysts for early detection of
cord) tumours. Death usually from
metastatic RCC or cerebellar
haemangioblastomas
Wilsons Movement disorders (tremor, chorea, Haematuria, nephrolithiasis (rare). Kayser Fleischer rings seen in
dystonia, extrapyramidal features), Fanconi syndrome. Hepato-renal 85–100% of patients with
dysarthria, cognitive impairment, syndrome in CLD neurological involvement
neuropsychiatric
RCC Spinal cord and cerebral metastases [2] Bilateral nephrectomy may lead to
paraneoplastic neuropathy, limbic dialysis dependence
encephalopathy
Alstrom Cone-rod dystrophy, learning disabilities, Slowly progressive kidney failure
syndrome nystagmus, bilateral sensorineural
hearing loss
Ciliopathies
Nephronophthi- Tapetoretinal degeneration, oculomotor Polyuria and polydipsia, progress- Most common genetic cause
sis apraxia ing to ESRF requiring RRT of childhood kidney failure
Joubert Cerebellar and brainstem development Cystic kidney disease
syndrome abnormalities, hyperpnea, sleep apnoea,
hypotonia, seizures and developmental
delay
Senior Loken Retinal dystrophy Nephronophthisis
syndrome
Leber congenital Nystagmus, impaired pupillary Interstitial nephropathy, salt
amaurosis responses, early visual loss, keratoconus wasting and progressive CKD [3]
Cogan syndrome Corneal inflammation, vertigo, tinnitus, Systemic vasculitis in 15% causing
hearing loss renal failure
(continued)
736 A. Nagy et al.
Tuberous Epilepsy, learning disability, hydrocepha- Renal involvement in 40–80% of Characteristic skin lesions,
sclerosis lus, brain lesions (subependymal nodules, cases. Renal cysts and angiomyoli- pulmonary lymphangioleio-
cortical tubers (. Figs. 41.2 and 41.3) pomas causing pain, renal failure myomatosis, liver, lung and
and haemorrhage) pancreatic cysts, TSC-
associated neuropsychiatric
disease
Galloway Microcephaly, learning disability Nephrotic syndrome
syndrome
Ehlers-Danlos Cerebral aneurysms predisposing to Renal infarction. FMD affects renal
syndrome SAH. Bilateral carotid artery FMD in arteries in 85% of patients and leads
65% of patients with increased risk TIA, to hypertension
stroke and carotid dissection
Cystinosis Corneal cystinosis causing blindness, Renal Fanconi syndrome, ESRF
dysphagia, myopathy
Primary Peripheral neuropathy Recurrent kidney and bladder neph-
hyperoxaluria rolithiasis leading to CKD and
ESRF
Neurofibromato- NF1: multiple neurofibromas, lisch Renal artery stenosis, pheochromo-
sis nodules cytomas, hypertension
NF2: bilateral vestibular schwannoma
Hereditary Progressive cognitive impairment, distal Renal failure due to amyloidosis or
sensory and sensory neuropathy, hearing loss. reflux
autonomic
neuropathies
Riley-Day Progressive sensorimotor neuropathy Glomerulosclerosis and CKD Orthostatic hypotension and
syndrome with sympathetic autonomic dysfunction bladder dysfunction may
(familial cause recurrent AKI and
dysautonomia) progressive CKD
Immune-mediated diseases
Diabetes mellitus Commonest cause of neuropathy in Development of characteristic
developed countries. Distal symmetrical nodular glomerulosclerosis,
sensorimotor axonal neuropathy, vascular disease and progressive
autonomic neuropathy, carpal tunnel, CKD. Presence of diabetes and
mononeuritis multiplex, diabetic CKD significantly increases
amyotrophy, cardiovascular morbidity and
cranial neuropathies mortality
41 Granulomatosis 28% of patients develop neurological Rapidly progressive glomerulone- Necrotising granulomatous
with polyangiitis complications due to granuloma leading phritis leading to CKD and ESRF small vessel vasculitis
(previously to basilar meningitis, temporal lobe involving respiratory tract,
Wegener’s dysfunction, venous sinus occlusion and perforation of nasal septum,
granulomatosis) cranial neuropathies [4] saddle nose
Microscopic Peripheral neuropathy, mononeuropathy Rapidly progressive glomerulone-
polyangiitis multiplex phritis leading to CKD and ESRF
Eosinophilic Highest incidence of peripheral and Kidney involvement less common
granulomatosis central nervous systems of all ANCA- than other ANCA-associated
with polyangiitis associated vasculitides. Peripheral vasculitides
(Churg-Strauss) neuropathy is almost ubiquitous and
mononeuropathy multiplex affects
around 80% [5]
Sjogren’s Cranial neuropathies especially Acute/chronic tubulointerstitial Sicca symptoms. Increased
syndrome trigeminal neuropathy, dorsal root nephritis due to lymphocytic risk of B-cell non-Hodgkins
ganglionopathies, autonomic neuropathy infiltrate lymphoma
The Nervous System and the Kidney
737 41
41.3 Neurological Diseases and evaluation, including imaging, are vital for all patients
Medications Which Affect the Kidney with a neurogenic bladder. Renal failure in patients with
spinal cord disease can be avoided by maintaining low
41.3.1 Spinal Cord Disorders post-void residual volumes, avoidance of indwelling
catheters, care with nephrotoxic drugs and prompt treat-
ment of sepsis. Most patients are managed with clean
Congenital and acquired spinal cord damage may lead
technique intermittent catheterization and oral anticho-
to bladder dysfunction and indirectly to kidney disease.
linergic medications. The UK NICE guidance suggests
Risk of renal insufficiency increases with the following:
offering video-urodynamic investigations to people
indwelling urethral catheter, advanced age, time since
known to have high risk of renal complications (e.g.
spinal cord injury and vesicoureteric reflux from detru-
spina bifida and spinal cord injury) but not to those with
sor sphincter dyssynergia and raised bladder pressures.
low risk (e.g. most people with multiple sclerosis) [7].
Patients are at risk of developing reflux nephropathy,
Patients with spinal cord injury should be assessed and
hydronephrosis and pyelonephritis. Careful history and
followed up by a urologist.
738 A. Nagy et al.
41.3.3 Medications
41.4.1 Encephalopathy
Aciclovir Viral herpes encephalitis AKI due to distal intra-tubular crystal nephropa-
thy. Dose reduction needed in renal impairment.
Acetylcholinesterase inhibitors (donepezil, Dementia, neuromuscular junction May cause urinary retention and worsen bladder
galantamine, rivastigmine, pyridostigmine) disorders outflow obstruction.
Rivastigmine may require dose reduction
Pyridostigmine is renally excreted and requires
reduced dose in renal impairment
Anticholinergics (trihexyphenidyl, Movement disorders including Prostatism and urinary retention
procyclidine, oxybutynin, solifenacin, Parkinson’s disease and dystonia Excreted in urine and caution is advised in renal
tolterodine) Overactive bladder in MS impairment
COMT inhibitors (entacapone, tolcapone) Parkinson’s disease Rhabdomyolysis
Carbamazepine Epilepsy (generalised and focal) SIADH-like effect leading to fluid retention and
hyponatraemia
Gabapentin Focal epilepsy, neuropathic pain Acute renal failure (rare)
Ergot-based dopamine agonists (bro- Parkinson’s disease, rarely used in Retroperitoneal fibrosis
mocriptine, cabergoline) current practice
Non-steroidal anti-inflammatories Migraine, other headache disorders Interstitial nephritis, papillary necrosis, AKI on
CKD
Phenytoin Epilepsy Interstitial nephritis (rare)
SNRIs (venlafaxine, duloxetine), Neuropathic pain, mood disorders Rhabdomyolysis
TCAs (amitriptyline, nortriptyline) Psychiatric disorders, migraine Urinary retention and exacerbation of prostatic
prophylaxis hypertrophy
Typical antipsychotics (haloperidol, Tic disorders, behavioural Urinary retention
sulpiride) disturbance in neurodegenerative
disease
41.4.2 Myopathy
41.6.1 Confusion
aemic monomelic neuropathy involves urgent ligation of should be managed with due diligence and with a low
the fistula. threshold for excluding neurological infections due to
Dialysis dementia was described in the 1970s and their blunted inflammatory response to sepsis. In addi-
was strongly linked to prolonged exposure to aluminium tion, calcineurin inhibitors have a significant burden of
in municipal water supplies and aluminium-containing minor neurological symptoms. Tremor is said to occur
phosphate binders. Symptoms start with mixed dysar- in up to 40% patients on cyclosporine, sleep disturbance
thria and dysphasia and rapidly progress with more is common and less commonly patients may develop a
severe language dysfunction, myoclonic jerks, ataxia sensory neuropathy and myopathy. Calcineurin inhibi-
and seizures. Reduction of aluminium by means of tors may be associated with a reversible posterior leuko-
reverse osmosis has markedly reduced the incidence of encephalopathy syndrome. Early recognition, reduction
dialysis dementia. Given the availability of other non- or withdrawal of the immunosuppressive agent and
aluminium phosphate binders now available, clinical institution of antihypertensive medication is associated
guidelines advise against long-term use of aluminium- with an excellent clinical outcome.
containing phosphate binders [20, 21]. Desferrioxamine Rejection encephalopathy, usually seen within
is a chelating agent, which is used in the treatment of 3 months of transplantation, is characterised by head-
aluminium toxicity. ache, confusion and seizures in the context of systemic
features of graft rejection. Cytokine release during the
rejection process is thought to be implicated.
Post-transplant lymphoproliferative disorders may
41.7.2 Renal Transplantation be driven by EBV, and cases with neurological involve-
and the Immunosuppressed Patient ment may present with headaches, seizures, altered men-
tal state and focal neurological deficits. There is CNS
Almost one third of renal transplant recipients will involvement in 10–15% of cases. Prognosis depends on
develop neurological complications [38]. Surgical com- the extent of disease dissemination.
plications at the time of transplantation include neuro-
praxis of the femoral and lateral cutaneous nerve of the
thigh from intraoperative retraction. 41.7.3 Medications Commonly Used
Drug-induced suppression of cell-mediated immu-
in Nephrology and Dosing
nity renders patients at increased risk of opportunistic
infections, but it is worth reiterating that such patients Considerations
41.8 Mental Health in Kidney Disease factors may include the following: the feeling of total
dependency on a dialysis machine, restrictions on diet
Psychiatric illness is common among patients with end- and fluid, poor quality of life, reduced employment
stage renal failure, particularly those on haemodialysis and limited functional capacity. Untreated depression
compared with those treated conservatively or post may impact on treatment compliance, nutritional sta-
transplantation. The psychiatric disorders most fre- tus, impaired immune function and increased suicide
quently observed include affective disorders (particu- rates. Patients may require psychotropic drugs and
larly depression), anxiety, suicide, organic brain disease psychotherapy and benefit from a MDT approach.
such as dementia and delirium, drug-related disorders Some psychotropic drugs require dose changes in both
such as alcoholism, psychoses and personality disorders CKD and dialysis patient, e.g. paroxetine can lead to
[40]. Steroids and other immunomodulating drugs can seizures at higher doses, venlafaxine may cause hyper-
result in insomnia, mood swings, mania, behavioural tension at higher doses and mirtazapine can be sedat-
problems, severe depression and psychosis in 5–18% ing. Lithium is the treatment of choice for bipolar
patients [41]. disease but can be nephrotoxic, associated with neph-
Depression is under-recognised and undertreated rogenic diabetes and CKD due to chronic interstitial
in CKD. Patients with CKD are 1.5–3 times more nephritis and distal renal tubular acidosis. Progression
likely to require inpatient psychiatric treatment than of kidney disease can occur despite discontinuation of
patients with other chronic disorders. Contributing lithium.
746 A. Nagy et al.
Case Study
. Fig. 41.7 Electroencephalogram (EEG) showing normal alpha activity and a second EEG in a patient encephalopathic
with severe uraemia
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often have detrusor overactivity and high bladder peripheral nerves. Philadelphia: F.A. Davis; 1991.
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degeneration in uremic neuropathy. Mayo Clin Proc.
4. AKI develops due to obstructive nephropathy,
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The Nervous System and the Kidney
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40. Kimmel PL, et al. Psychiatric illness in patients with end-stage Patient Information and Guidelines
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NICE clinical guideline CG148: urinary incontinence in neurological
41. Cerullo M. Corticosteroid-induced mania: Prepare for the
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m e n t a l - h e a l t h / c o r t i c o s t e ro i d - i n d u c e d - m a n i a - p re p a re -
unpredictable.
751 42
Contents
42.4 Managing the Patient with CKD and Visual Impairment – 760
References – 764
a b
. Fig. 42.1 Fundus photograph showing copper wiring’ of vessels a with haemorrhage b in the left eye. c Grade IV hypertensive retinopathy
with retinal haemorrhages, cotton wool spots and papilloedema
cotton wool spots) were associated with a risk of newly long pre-diagnosis period of hyperglycaemia. Within
diagnosed clinical stroke that was 2–4 times as high as 20 years, 60% of non-insulin-dependent diabetics have
that for patients who did not have these signs after some degree of retinopathy.
adjusting for all other risk factors [6]. Retinal microvas-
cular abnormalities are associated with renal dysfunc- 42.2.2.2 Pathogenesis
tion, suggesting that common systemic microvascular Hyperglycaemia and hyperglycaemia-associated path-
processes may underlie the development of microvascu- ways such as oxidative stress, the formation of advanced
lar damage in the eye and kidneys. In the ARIC study, glycation end products, upregulation of protein kinase
individuals with retinopathy were twice more likely to C, increased polyol pathway flux and focal leucostasis
develop renal dysfunction than individuals without may be important [11].
these abnormalities. The initial response to hyperglycaemia is dilatation
Renal physicians could consider retinal morphology of the retinal blood vessels. These blood flow changes
when assessing cardiovascular disease risk in people are considered to be a metabolic autoregulation to
with CKD based on the work of the CRIC study, which increase retinal metabolism in diabetic subjects. Pericyte
found that worsening of hypertensive retinopathy was loss is another hallmark of the early events of DR. Since
associated with an increased risk of incidence of CVD pericytes are responsible for providing structural sup-
(OR 1.66) [7]. port for capillaries, loss of them leads to localised out-
pouching of capillary walls. This process is associated
42.2.1.3 Aetiology with microaneurysm formation, which is the earliest
Retinal vascular calibre changes reflect cumulative clinical sign of DR [12]. In addition to pericyte loss,
responses to aging, cardiovascular risk factors, inflam- apoptosis of endothelial cells and thickening of the
mation, nitric oxide-dependent endothelial dysfunction basement membrane are also detected during advancing
and other processes [8]. Data from recent population- disease, which collectively contribute to the impairment
based studies suggest that retinal arteriolar and venular of the blood retina barrier, capillary occlusion and isch-
calibre changes may reflect different vascular patho- aemia. Retinal ischaemia/hypoxia leads to upregulation
physiological processes that link to a range of demo- of VEGF through activation of hypoxia-inducible fac-
graphic factors (e.g. age, race/ethnicity); systemic tor 1 (HIF-1). Progressive disease is characterised by
medical conditions (e.g. blood pressure, diabetes); diabetic macular oedema or retinal and optic nerve neo-
inflammation, nitric oxide-dependent endothelial dys- vascularisation (proliferative diabetic retinopathy) as a
function and lifestyle factors (e.g., smoking); and genetic result of chronic ischaemia and the upregulation of vas-
factors. cular endothelial growth factor (VEGF) (. Fig. 42.2).
Diabetic macular oedema is the main cause of visual
loss in patients with diabetic retinopathy. This describes
42.2.2 Diabetic Retinopathy (DR) the sub- and intra-retinal accumulation of fluid in the
macula as a consequence of breakdown of the BRB.
42.2.2.1 Epidemiology Aberrant vessels may bleed into the vitreous causing
Diabetic retinopathy is the most common ophthalmic sudden vision loss. End-stage disease consists of fibrotic
complication of diabetes mellitus and was the most tractional bands and retinal detachment or neovascular
common cause of visual impairment in working age glaucoma.
adults in the UK until recently [9]. Current treatment strategies for DR aim at manag-
In a UK cohort of 7.7 million patients, the preva- ing the microvascular complications. Early-stage disease
42 lence of DR was 48.4% in the population type 1 diabetes is reversible or can be stabilised with improved systemic
mellitus (T1DM) and 28.3% in the population with type control of hyperglycaemia and blood pressure. Late-
2 diabetes mellitus (T2DM) [10]. Among patients with stage disease management will include combinations of
T2DM, the relative risk of DR varied significantly by intravitreal injections of pharmacologic agents, laser
region and was increased for older age groups, in men. photocoagulation and vitreous surgery. Intravitreal
The risk of severe DR increased in South Asian and administration of anti-VEGF agents is currently the
more socio-economically deprived groups. Fundoscopic mainstay of therapy for diabetic macular oedema and
changes may be found at diagnosis due to a potentially some neovascular complication.
Ophthalmology and the Kidney
755 42
. Fig. 42.2 Fundal photograph showing advanced proliferative diabetic retinopathy with visible microaneurysms, haemorrhages, hard
exudates and neovascularisation. Macular oedema is likely to be present on a 3D examination of the eyes
Systemic disease
Diabetes Common: retinopathy (95% and 60% prevalence in patients with type 1 and type Diabetic nephropathy (see
2 diabetics, respectively, with disease duration of over 20 years), cataract (2–5 text)
times more at risk than general population), glaucoma, keratopathy
Rare: optic nerve disease
Hypertension Retinal microvasculature: hypertensive retinopathy, choroidopathy, optic Hypertensive nephropathy (see
neuropathy text)
Vascular abnormalities: venous occlusive disease, retinal arteriolar macroaneu-
rysm formation and embolic events
PRES: reversible vasogenic oedema in the posterior brain, which primarily arises
from autoregulation failure and endothelial dysfunction. There are a number of
causes that may lead to the development of PRES such as malignant hyperten-
sion, pre-eclampsia/eclampsia and malignancy. Studies have indicated that
patients with CKD are more likely to develop PRES due to presumed endothelial
dysfunction
Multiple Cysts of the ciliary body (33–50%), retinal vascular lesions including retinal Light chain nephropathy and
myeloma arteriole and venous occlusion (up to 66%) [29] cast nephropathy, amyloid,
heavy chain nephropathy,
acute tubular injury secondary
to hypercalcaemia
Autoimmune
ANCA- Granulomatosis with polyangiitis (GPA): scleritis (16–38%), conjunctivitis Renal Vasculitis, crescentic
associated (4–16%), nasolacrimal obstruction, episcleritis, orbital myositis, retinal vasculitis, glomerulonephritis
vasculitis ulcerative keratitis
Microscopic polyangiitis: scleritis, conjunctivitis, episcleritis, retinal vasculitis,
ulcerative keratitis
Eosinophilic Granulomatosis with polyangiitis (EGPA): episcleritis, conjunctivi-
tis, neuroophthalmic manifestations, myositis, retinal vasculitis, ulcerative
keratitis
Systemic lupus Eye involvement in 20–40% of cases. Keratoconjunctivitis sicca is the most Lupus nephropathy (I–V)
erythematosus common presentation, while retinopathy and choroidopathy are most associated
(SLE) with visual loss. Also conjunctivitis, episcleritis, scleritis, uveitis, and keratitis
Tubulo- Uveitis that may proceed or follow TIN Acute tubulo-interstitial
interstitial nephritis with mononuclear
nephritis and cell
uveitis (TINU) Infiltration of the interstitium
Sarcoid Dry eyes, optic neuritis, cranial nerve palsies, lid inflammation and uveitis (up to Acute tubulo-interstitial
20% of patients) nephritis with mononuclear
cell
Infiltration of the interstitium,
acute tubular injury secondary
to hypercalcaemia
Polyarteritis Retinal artery thrombosis Renal micro infarction
nodosa
(continued)
758 M. Antonelou et al.
42 chamber. Photophobia, band keratopathy, poor colour vision and glaucoma may
develop
Hyperchloraemic metabolic
acidosis, hypophosphataemia
Hypocalcaemia, proteinuria,
renal Fanconi syndrome,
progressive chronic kidney
disease
Infection
Leptospirosis Conjunctival suffusion (and often jaundiced sclerae) Acute kidney injury
Metastatic Roth or Litten spots (white-centred (leucocytes and fibrin) retinal haemorrhages Proliferative glomerulonephri-
infection said to be present in 2% of bacterial endocarditis, conjunctival haemorrhage, tis, micro-infarction
choroidoretinitis and endo-ophthalmitis (the latter two more associated with
fungaemia))
Syphilis Syphilitic involvement of the eye (e.g. scleritis, posterior uveitis, or optic neuritis) Membranous glomerulonephri-
can range from subacute to chronic tis in secondary syphilis
Ophthalmology and the Kidney
759 42
Pierson syndrome is caused by mutations in LAMB2,
encoding laminin ß2, another important structural com-
ponent of the glomerular basement membrane.
Consequently, renal manifestations are characterised by
glomerular dysfunction, especially congenital nephrotic
syndrome. LAMB2 is also expressed in neuromuscular
junctions and the typical ocular manifestation is micro-
coria due to dysplastic ciliary muscles [24].
42.3.3 Metabolic
42.3.2 Disorders of Structure and Function Metastatic Band keratopathy – calcium deposition across
calcification the anterior surface of the cornea. Associated
with elevations of the serum concentration of
Ciliopathies commonly affect the kidney and eye due to calcium or calcium-phosphate product (see
the important role of cilia in both organ systems. The . Fig. 42.8)
photoreceptors in the eye possess a specialised cilium,
Uraemic Profound uraemia in association with
involved in photon capture and initiation of the signal- amaurosis/ preserved pupillary contraction on light
ling cascade initiating the visual process [19]. transient exposure and normal fundoscopic findings.
Consequently, ciliopathies are commonly associated cortical This abnormality clears within 24–48 hours of
with retinopathies, such as retinitis pigmentosa in blindness initiating dialytic therapy
Bardet-Biedl syndrome. In the kidney, epithelial cells in Raised Removal of urea and other solutes reducing
all nephron segments possess cilia, which are involved in intraocular serum osmolality more rapidly than ocular
a variety of processes. Common renal manifestations of pressure osmolality, steep gradient in the presence of
ciliopathies include cystic kidney disease, including ocular-blood barrier
nephronophthisis and cystic dysplasia [20]. Anterior Intradialytic hypotension and anaemia
Lowe syndrome, also known as oculocerebrorenal ischaemic
syndrome is caused by mutations in OCRL, encoding a optic
neuropathy
phosphoinositol-5-phosphatase, involved in endocytic
recycling [21]. Ocular manifestations include congenital Kidney transplantation
cataracts and glaucoma, whereas the renal phenotype is Opportunis- A variety of infections can involve the eye in
characterised by a proximal tubulopathy and progres- tic ocular patients who are immunosuppressed for renal
sive CKD [22]. infections conditions such as glomerular disorders or
Alport syndrome and related type 4 collagenopathies transplantation. Most commonly herpes
simplex virus and ophthalmic involvement of
are caused by mutations in genes encoding subunits of varicella zoster but potentially CMV, HHV8,
type 4 collagen, an important structural component in listeria, nocardia, mycobacteria, fungi such as
the basement membranes of the glomerulus, as well as Cryptococcus neoformans, candida and
of the lens, cornea and retina [23]. Consequently, clini- aspergillus infections, as well as parasites such
cal manifestations in the eye include lenticonus, but also as toxoplasmosis
corneal dystrophy and maculopathy, whereas in the kid- Medications used in CKD
ney glomerular dysfunction predominates, typically Hydroxy- Retinopathy with 7.5% prevalence in
haematuria and proteinuria. chloroquine individuals with more than 5-year exposure
760 M. Antonelou et al.
Case 1 Case 2
A 47-year-old male with insulin-dependent diabetes mel- A 46-year-old patient with SLE attends clinic complaining of
litus and stage 5 CKD attends the low clearance clinic blurring of her vision and difficulty reading. She has been on
complaining of (visual symptoms). He is hypertensive hydroxychloroquine 200 mg bd for 12 years. . Figure 42.10
and fluid overloaded. He has a right AV fistula in place shows her fundus photograph and autofluorescence.
and decision is made to start on haemodialysis. Following Hydroxychloroquine retinopathy is characterised by a
three consecutive days of haemodialysis, his visual symp- maculopathy with a ‘bullseye’ appearance and symptoms
toms improved. . Figure 42.9 shows his optical coher- include a paracentral or central visual-field scotomata.
ence tomography before and after his third haemodialysis Patients at increased risk of developing retinopathy include
session. those taking tamoxifen, with renal impairment or concom-
Diabetic macular oedema is the prevailing cause of visual itant retinal disease and a longer duration of treatment.
loss in patients with diabetic retinopathy. This describes the Cessation of treatment, though unsuccessful in reversing
sub- and intra-retinal accumulation of fluid in the macula as the damage caused, is the basis on which further visual loss
a consequence of breakdown of the blood retina barrier. is prevented.
High urine albumin-to-creatinine ratio (UACR) and low Any patients on hydroxychloroquine complaining of
eGFR diabetic retinopathy in these patients. blurred vision, decreased central vision or difficulty read-
. Fig. 42.9 Optical coherence tomography (OCT) scan of diabetic macular oedema in retina. a Pre-dialysis. b Post-dialysis
762 M. Antonelou et al.
42 ing should be referred to an ophthalmologist for assess- C3 and IgG). Drusen have been described in MPGN as
ment. The presence of risk factors warrants annual diffuse and often evenly spaced resembling drusen in age-
ophthalmic follow-up. related macular degeneration (AMD) but they are rarely
observed in subjects below the age of 50 years. The drusen
Case 3 in MPGN are similar to glomerular deposits in their sub-
This 29-year-old asymptomatic female had a kidney epithelial location and their composition from comple-
biopsy for deteriorating renal function and proteinuria ment components and immunoglobulins. Thickened
that was compatible with membranoproliferative glomeru- Bruch’s membrane in the young is also seen in MPGN
lonephritis (positive immunofluorescence for complement (. Fig. 42.11).
Ophthalmology and the Kidney
763 42
a b
. Fig. 42.11 a and b Autofluorescence showing drusen. Diffuse thickening pf Bruch’s membrane with nodular elevations at sites of
drusen on optical coherence tomography of the macula
dient between plasma and interstitial fluid moves 9. Liew G, Michaelides M, Bunce C. A comparison of the causes
water from the interstitial and aqueous humour to of blindness certifications in England and Wales in working
age adults (16–64 years), 1999–2000 with 2009–2010.
plasma fluid. These changes in oncotic pressure
BMJ Open. 2014;4(2):e004015. https://doi.org/10.1136/
and ultrafiltration lead to a decline in IOP at the bmjopen-2013-004015.
end of dialysis. IOP change is greater with a higher 10. Mathur R, Bhaskaran K, Edwards E, Lee H, Chaturvedi N,
plasma albumin level and degree of ultrafiltration. Smeeth L, et al. Population trends in the 10-year incidence
In the eyes with glaucoma, narrow angles or and prevalence of diabetic retinopathy in the UK: a cohort study
in the Clinical Practice Research Datalink 2004-2014.
impaired aqueous outflow, acute rises in IOP dur-
BMJ Open. 2017;7(2):e014444. https://doi.org/10.1136/
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pared to aqueous humour osmolarity, and a rela- treatments. Int J Mol Sci. 2018;19
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pericytes and mechanisms of pericyte loss during diabetes reti-
concentration may contribute to increases in
nopathy. Diabetes Obes Metab. 2008;10:53–63.
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may also result from differences in dialysis tech- Tack CJ, et al. Risk factors for development and progression of
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14. Jampol LM, Lahov M, Albert DM, Craft J. Ocular clinical find-
ings and basement membrane changes in Goodpasture’s syn-
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eases both inherited and acquired. 2255–65.
There is potential to improve the patient pathway 17. Dziarmaga A, Quinlan J, Goodyer P. Renal hypoplasia: lessons
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18. Harita Y, et al. Spectrum of LMX1B mutations: from nail-
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19. Chen HY, et al. Retinal disease in ciliopathies: recent advances
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2. Bhargava M, Ikram MK, Wong TY. How does hypertension
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765 43
Gastroenterology
and the Kidney
Sarah Blakey and Richard W. Corbett
Contents
References – 773
n Learning Objectives
. Table 43.1 Systemic diseases involving the kidney and
This chapter will cover: GI system
1. Systemic diseases where the GI tract and kidneys
may be affected Systemic Renal manifesta- GI manifestations
2. Renal conditions which arise directly from primar- disease tions
ily GI diseases and their treatment
Diabetes Diabetic Autonomic neuropa-
3. Safe prescription of laxatives including bowel
mellitus nephropathy: thy with gastroparesis,
preparation for patients with renal disease proteinuria, renal constipation
impairment
Coeliac disease IgA nephropathy; Malabsorption, small
43.1 Introduction haematuria, bowel lymphoma
proteinuria, renal
impairment
While as compared to, for instance, pulmonary-renal
syndromes, disease processes affecting both the gastro- Atherosclerosis Renal artery Abdominal pain,
intestinal (GI) system and the kidneys are less com- stenosis, ischaemic diarrhoea, gastroin-
nephropathy; testinal bleeding
monly recognised and may not be so clearly linked by a renal impairment
common pathophysiological mechanism. However,
despite this, there are a number of diseases where GI Systemic lupus Lupus nephritis; Pancreatitis, mouth
erythematosus haematuria, ulcers, abdominal
pathology predominates, yet an association with renal proteinuria, renal pain
disease is recognised; alternatively, there are a number impairment
of renal conditions where pathology arises secondary to
Amyloidosis Nephrotic Diarrhoea, malab-
the GI pathology or its treatment. This chapter also cov- syndrome; sorption, gastrointes-
ers the safe use of laxatives in renal disease and lists proteinuria, renal tinal bleeding and
some of the common side effects of medications used in impairment obstruction
the treatment of renal disease. Autosomal Loin pain, Polycystic liver
dominant macroscopic disease, diverticular
polycystic haematuria, renal disease, herniae
kidney disease impairment
43.2 Systemic Diseases Involving
the Kidney and GI System IgA vasculitis IgA-like Abdominal pain,
(Henoch- nephropathy: intestinal bleeding,
Schönlein haematuria, nausea and diarrhoea
A number of systemic conditions will affect both the purpura) proteinuria, renal
gastrointestinal system and the kidneys as well as poten- impairment
tially other organs. While the list in . Table 43.1 is by Small-vessel Pauci-immune Abdominal pain,
no means comprehensive, it includes commonly recog- vasculitis glomerulonephri- gastrointestinal
nised areas where pathology may result in multi-organ (ANCA- tis, renal bleeding, diarrhoea
involvement (. Fig. 43.1). A few conditions warrant associated impairment,
further discussion. vasculitis) microscopic
haematuria,
proteinuria
corrosive with strong chelating properties. It is ingested aticobiliary secretions and gastric acid. In patients who
in abundance in a broad range of foods that include cof- undergo the formation of a small bowel stoma, 15%
fee, tea, spinach and rhubarb, while a small quantity is may develop a high-output stoma defined by a stoma
produced endogenously. In healthy individuals, free oxa- output in excess of 2 L/day [7]. The most common rea-
late appears to bind to calcium in the small bowel before son for which is a short remaining length of the small
passing through the large bowel to be egested as calcium intestine (<200 cm), though infection, prokinetic drugs,
oxalate [3]. A small quantity is broken down by opiate withdrawal and recurrent inflammatory bowel
Oxalobacter formigenes, an enteric anaerobe, which may disease may all be implicated.
have some controlling oxalate homeostasis in individu- These patients are particularly susceptible to epi-
als consuming a high burden of oxalate [4]. Any sodes of recurrent hypovolaemic prerenal acute kidney
unbound oxalate is absorbed in the large bowel before injury due to the loss of both water and sodium. With a
being excreted in the urine along with any endogenously high-output stoma, the ability to concentrate sodium is
produced oxalate. lost within the jejunum, and sodium will leak precipi-
While hyperoxaluria may occur due to inborn errors tously into jejunal fluid, which has a sodium concentra-
of metabolism (primary hyperoxaluria), hyperoxaluria tion of around 100 mmol/L [8]. Hypomagnesaemia also
may also arise due to increased enteric absorption or ensues due to both secondary hyperaldosteronism and
excess oxalate intake (secondary hyperoxaluria). impaired gastrointestinal absorption of magnesium,
Gastrointestinal diseases, which predispose to steator- though hypokalaemia only occurs in those patients with
rhoea and malabsorption, are implicated. In this setting very short jejunal remnants.
excess free fatty acids competitively bind calcium While, given the high sodium and water losses, thirst
(saponification) in the small bowel lumen, inhibiting the may be a major symptom for patients with a high-output
formation of calcium oxalate. The excess free oxalate is stoma, consumption of hypotonic fluids will compound
then absorbed in the colon, a process enhanced further sodium losses, exacerbating the cycles of volume deple-
by the presence of free fatty acids and bile salts. tion. Seemingly paradoxically, the key to resolving the
Conditions in which malabsorption occurs, including fluid losses is to reduce the consumption of hypotonic
inflammatory bowel disease, small bowel resections for fluids (<500 ml/day) [9] . Equally, hypertonic fluids will
malignancy and Roux-en-Y gastric bypass surgery for result in greater stoma output. Since jejunal sodium
obesity [5], have all been associated with hyperoxaluria. absorption is coupled with glucose absorption, individu-
However, for this to occur, an intact colon is required; als benefit from the intake of >1 L/day of a glucose-
patients with malabsorption and a stoma proximal to saline solution, where the sodium concentration is
the colon will not develop enteric hyperoxaluria [6]. comparable to the jejunal concentration of sodium (90–
Hyperoxaluria results both in oxalate nephropathy 120 mmol/L), which for some may be at the limits of
and nephrolithiasis. The former leads to a progressive palatability.
renal impairment as the consequence of tubular crystal-
line deposits of calcium oxalate and tubular fibrosis.
Crystallisation of calcium oxalate in the collecting ducts 43.3.3 AA Amyloidosis
and urothelial system manifests as oxalate stones (neph-
rolithiasis). Furthermore, in patients with a high-output AA amyloid is an uncommon (<1% incidence) but sig-
stoma or other causes of diarrhoea, which predispose to nificant complication of inflammatory bowel disease,
volume depletion, the resultant glomerular filtrate may which predominantly manifests as proteinuric/nephrotic
be supersaturated with oxalate hastening the process. renal disease [10]. Crohn’s disease appears to be more
Management once identified can be difficult, and oxa- commonly associated than ulcerative colitis, possibly
late nephropathy may be irreversible. Key steps in limiting due to the inflammatory nature of Crohn’s. Control of
progression of disease are as follows: limiting the dietary inflammation may result in resolution of the nephrotic
43 intake of oxalate, use of calcium supplementation with state in some patients; however, a number of patients
meals to increase calcium binding and maintaining a dilute will progress to established renal failure.
urine through adequate volume intake. While supplemen-
tation with O. formigenes has been considered a potential
route for treatment, it has enjoyed limited success. 43.3.4 IgA Nephropathy
acute kidney injury, this is typically identified a month Given this, in patients with underlying renal disease,
following colonoscopy, though it may present within a guidelines advocate the use of solely polyethylene glycol-
few days of colonoscopy. Renal biopsy findings are of based bowel preparation. While this can be of a signifi-
widespread tubular calcium phosphate deposits. cant volume, use of smaller volumes (2 L rather than 4 L)
While many will recover, a number are left dialysis is associated with poorer bowel preparation and a greater
dependent. incidence of incomplete colonoscopic studies [16].
Bulk-producing Fibre, ispaghula husk With caution Requires a significant volume of fluid to avoid
agents intestinal obstruction. May affect absorption of other
medications
Stool softeners Docusate sodium Safe Requires adequate fluid intake
Case Study
Proton Pump Inhibitor-Induced Tubulointerstitial commenced. Within 3 months, her serum creatinine had
Nephritis dropped to 105 umol/L. Her weight loss subsequently resolved.
A 58-year-old Nepalese woman was commenced on
omeprazole by her GP after complaining of vomiting. The Oxalate Nephropathy
vomiting resolved; however, she subsequently lost around During post-surgical follow-up, a 77-year-old man was
25 kilograms in weight over a 4-month period. There were identified to have a progressive renal impairment with a
no other systemic symptoms. A blood test was performed rise in serum creatinine from 90 umol/L to a peak of 400
as part of investigations into her weight loss. This demon- umol/L. A year earlier, he had undergone a Whipple’s pro-
strated a severe acute kidney injury, with serum creatinine cedure (pancreatoduodenectomy) for a presumptive carci-
of 1121 umol/L (from a baseline of 41 umol/L on blood noma of the pancreas, which proved ultimately to be
tests taken 6 months earlier) (. Fig. 43.3). Urine dipstick histologically benign. He had experienced a number of
was newly positive for blood and 1+ protein (uPCR 46 mg/ diarrhoeal illnesses in the post-operative period.
mmol). Imaging showed 12.5 cm unobstructed kidneys. On assessment, his urine sediment was bland and kid-
Standard serological tests were unremarkable. neys were 10 cm and 11 cm in size. Renal biopsy was under-
43 A renal biopsy demonstrated moderate active tubu- taken and revealed widespread acute and chronic tubular
lointerstitial nephritis (TIN) without granuloma. The tem- injury, with oxalate crystals within several tubules
poral association would suggest this occurred as a result of (. Fig. 43.4), consistent with oxalate nephropathy. His
omeprazole, which is less likely to be associated with the renal function deteriorated rapidly, and he was established
classic triad of fever, rash and eosinophilia than other on dialysis before dying 18 months later.
causes of TIN. Alongside antibiotics and non-steroidal Fat malabsorption in patients with pancreatic insuffi-
anti-inflammatories, proton pump inhibitors are the most ciency leads to increased binding of calcium by free fatty
common cause of a drug-induced interstitial nephritis. acids and leads to higher levels of unbound oxalate avail-
She was switched to ranitidine for gastric protection, and able for absorption within the colon. This has also been
given the severity of her TIN, high-dose oral steroids were seen to occur with the use of orlistat, a gastrointestinal
Gastroenterology and the Kidney
771 43
500
250
Omeprazole 20mg
0
−10 −5 0 5
Time (months)
a b
. Fig. 43.4 Birefringent crystals of calcium oxalate in tubules on renal biopsy on low-power a and high-power b view (Images
courtesy of Dr. Candice Roufosse)
lipase inhibitor, which prevents the absorption of dietary end ileostomy formation for small bowel obstruction. She
fats. Renal tubular crystallisation of calcium oxalate may had a 44-year history of Crohn’s disease, managed with
be compounded by associated fluid losses and dehydration steroids and azathioprine. She had undergone associated
secondary to diarrhoea. interventions and complications, including previous total
Unfortunately, oxalate nephropathy often rapidly pro- colectomy, small bowel strictures requiring dilatation and
gresses in the advanced stages due to the rapid deposition enterocutaneous fistulae.
of calcium oxalate crystals within the kidney at a low Her kidneys were normal in size and urinary sediment was
GFR. Key steps to avoiding progression are adoption of a bland. Stoma output was intermittently very high and
low-oxalate diet, the use of calcium-based supplements unmanageable with St Mark’s solution and loperamide.
with meals to bind free oxalate and avoiding dehydration. Clinically, she was persistently hypovolaemic and occa-
sionally tetanic, owing to profound hypomagnesaemia and
resulting hypocalcaemia. Ad hoc management with intra-
Short Bowel Syndrome venous fluid did not achieve adequate correction of vol-
A 63-year-old woman had developed abnormal renal func- ume and electrolytes, with progressive rise in serum
tion and multiple episodes of AKI, following emergency creatinine despite loss of muscle mass, causing concern for
772 S. Blakey and R. W. Corbett
600
Serum Creatinine (µmol/L)
400
Ileostomy
200 formed
0
−5 0 5 10 15 20
Time (months)
. Fig. 43.5 Progressive renal impairment in a patient with a sodes of acute kidney injury resulted in a rapid, progressive and
high-output ileostomy, following emergency surgery for Crohn’s potentially irreversible decline in underlying renal function
disease. Chronic hypovolaemia compounded by two severe epi-
progressive and irreversible tubular fibrosis (. Fig. 43.5). concentration of at least 90 mmol/l (such as a St Mark’s
Ultimately, a multidisciplinary approach was taken, and solution) across the day (. Fig. 43.7).
the patient was trained to administer parenteral fluids
along with oral electrolyte replacement at home. Her nutri-
tional needs were met without the use of total parenteral Intravascular volume • Correct hypovolemia with intravenous saline
nutrition.
Given the absence of a colon to reabsorb oxalate, hyp-
eroxaluria was not implicated in this patient but may fre- • Do NOT encourage increased oral intake
• Reduce oral hypotonic fluids to 500ml/day
quently occur in those with a short gut. Managing patients Oral rehydration • Use a glucose/saline solution (with sodium
with progressive renal impairment and high-output stomas concentration >90 mmol/L) to sip
requires good communication between the patient’s
nephrologist and a gastroenterologist – ideally, the latter
• Use loperamide to reduce output: often
should have an interest in intestinal failure. While home Anti-motility drugs >16mg/day required
parenteral fluids via a tunnelled central venous catheter • ± codeine phosphate
may be a drastic step, in some patients it may be required
to avoid long-term dialysis.
• Reduce gastric secretions: high dose proton
An approach to the patient with a high-output ileos- Anti-secretory drugs pump inhibitor or H2-antagonist
tomy or jejunostomy is suggested in . Fig. 43.6. It is a • ± octreotide
to ESRD. J Am Soc Nephrol [Internet]. 2016;27(10):3153–63. phate bowel purgative: an underrecognized cause of chronic
Available from: http://www.jasn.org/cgi/doi/10.1681/ASN. renal failure. J Am Soc Nephrol. 2005;16(11):3389–96.
2015121377. 16. Hassan C, Bretthauer M, Kaminski MF, Polkowski M, Rem-
14. Oikonomou KA, Kapsoritakis AN, Stefanidis I, Potamianos backen B, Saunders B, et al. Bowel preparation for colonoscopy:
SP. Drug-induced nephrotoxicity in inflammatory bowel disease. European Society of Gastrointestinal Endoscopy (ESGE)
Nephron - Clin Pract. 2011;119(2):89–96. guideline. Endoscopy. 2013;45(02):142–55.
15. Markowitz GS, Stokes MB, Radhakrishnan J, D’Agati 17. Nightingale J, Woodward JM. Guidelines for management of
VD. Acute phosphate nephropathy following oral sodium phos- patients with a short bowel. Gut. 2006;55(SUPPL. 4):1–12.
43
775 44
Respiratory Medicine
and the Kidney
Marilina Antonelou, James Brown, and Sally Hamour
Contents
References – 784
n Learning Objectives
1. To highlight respiratory complications in patients
with renal insufficiency related to chronic kidney
disease itself or its treatment
2. To provide an overview of important associations
between renal and respiratory diseases
3. To emphasise the need for close collaboration of
the two subspecialties for the diagnosis and preven-
tion of disease
44.1 Introduction
. Table 44.1 Autoimmune and genetic disorders that affect both the lungs and kidneys
Autoimmune disorders
Goodpasture 40–60% of patients present with diffuse alveolar haemorrhage (DAH); they tend to be younger and smokers. In almost
syndrome three quarters of the cases, pulmonary haemorrhage precedes or coincides with glomerular disease
(anti-GBM
disease)
Granuloma- Single or multiple pulmonary nodules and masses in 70% of patients tend to be peripheral and contain air broncho-
tosis with grams. Ground-glass halos due to perilesional haemorrhage. Nodules will cavitate in 50% of patients (. Fig. 44.3),
polyangiitis and infection (tuberculosis, staphylococcal abscess) is an important differential here. DAH in 8–36%
Eosinophilic 90% of patients present with asthma in the second and third decade of life. Pulmonary lobules, peripheral ground
granulomato- glass and interlobular septal thickening
sis with
polyangiitis
Systemic Pulmonary involvement in 50 to 70% of SLE patients and presenting feature in 4 to 5% of patients. 12% will have
lupus accumulated an element of permanent lung damage at 10-year follow-up. Pulmonary complications are broad and
erythemato- include pleural disease (45%), interstitial lung disease (up to 15%), vasculitis with DAH in 1–5%, pulmonary embolism
sus (SLE) (9%), pulmonary hypertension (up to 17.5%), shrinking lung syndrome (1%) [23]
Systemic 75% of patients have interstitial lung disease, under 50% pulmonary hypertension. Patients with SSc with diffuse
sclerosis cutaneous involvement can develop fatal isolated pulmonary arterial hypertension. This complication occurs
(SSc) disproportionately more often in patients with serum anti-U3RNP antibody [24]
IgG4-related Pulmonary involvement in over 20% of patients including peribronchial inflammation, discrete nodules, reticulation or
disease septal thickening and consolidation [25]
Sarcoidosis Pulmonary involvement is seen in over 90% with renal involvement affecting less than 3% of patients with sarcoidosis.
Pulmonary manifestations include paratracheal and bilateral hilar lymphadenopathy, pulmonary infiltrates with
fissural nodularity that can progress to fibrosis, often with a mid to upper zone predisposition; however, changes can
be diverse [26]
Genetic disorders
Tuberous Lymphangioleiomyomatosis (LAM): found almost exclusively in women – proliferation of atypical smooth muscles,
sclerosis resulting in vascular and airway obstruction and cystic lung formation. The invading cells contain inactivating
(TSC) mutations in tuberous sclerosis proteins that result in mammalian target of rapamycin complex 1 (mTORC1)
pathway-driven cellular proliferation, hence the therapeutic role of sirolimus.
LAM is associated with mediastinal lymphangiomas, chylous pleural effusions and spontaneous pneumothorax
(. Fig. 44.4). LAM may replace nearly the entire lung parenchyma and necessitate lung transplantation; it may also
recur after transplantation.
Angiomyolipomas (AMLs): benign and soft-tissue-containing lesions found mainly in the kidney (85% of patients
with TSC) but are also seen in up to 50% of patients with sporadic LAM. Lesions greater than 4 cm are at risk of
spontaneous haemorrhage
Multifocal micronodular pneumocyte hyperplasia: solid or ground-glass pulmonary nodules between 2 and 14 mm in
size (tiny pulmonary hamartomas), in 40–60% of patients with TSC, affects men and women equally [27, 28]
(continued)
780 M. Antonelou et al.
Autosomal Lung involvement is not a frequent feature of ADPKD, patients do have a higher incidence of bronchiectasis, though
dominant typically mild [29]
polycystic
kidney
disease
(ADPKD)
Birt-Hogg- Autosomal dominant monogenic disorder caused by constitutional mutations in the FLCN gene that codes for the
Dubé protein folliculin. Lung cysts are the hallmark of the lung involvement, causing an increased risk of spontaneous
syndrome pneumothorax. The most severe manifestation of the syndrome is the predisposition to renal cell carcinoma [30]
(BHD)
Sickle cell Acute: acute chest syndrome, characterised by acute chest pain, fever and pulmonary consolidations; likely related to a
disease combination of pulmonary infarcts and pneumonia. Chronic: pulmonary hypertension in one-third of sickle cell
patients, with substantial mortality [31]
a b
. Fig. 44.3 Fluorodeoxyglucose (FDG)-positron emission tomography (PET) a in a patient with PR3-ANCA vasculitis with pulmonary
involvement showing a large cavitating pulmonary lesion b exhibiting intense mural FDG avidity
44.2.9 Pulmonary-Renal Syndrome ing autoimmune process. DAH is one of the strongest
predictors of mortality in patients with RPGN caused
The term pulmonary-renal syndrome (PRS), as first by antineutrophil cytoplasmic antibody (ANCA)-
described by Ernest Goodpasture in 1919, is used to associated vasculitis (AAV) and anti-GBM disease,
describe the occurrence of renal failure in association increasing the relative risk by up to 8.6-fold in patients
with respiratory failure, characterised by rapidly with AAV [32]. . Table 44.2 shows radiological and his-
progressive glomerulonephritis (RPGN) and diffuse tological features as well as causes of pulmonary-renal
alveolar haemorrhage (DAH) secondary to an underly- syndrome.
44
Respiratory Medicine and the Kidney
781 44
a b
. Fig. 44.5 Chest radiograph a and chest CT b of a patient with patient confirms bilateral perihilar consolidation and mediastinal
PR3-ANCA vasculitis who presented with acute kidney injury and adenopathy. The radiographic differential is wide and includes infec-
haemoptysis. a Bilateral perihilar nodular consolidation is seen, tion, including atypical infections and pneumocystis pneumonia if
which is most marked in both midzones. b The chest CT of the same there is a history of immunocompromise
782 M. Antonelou et al.
Case Study
Case 1 Case 2
A 33-year-old woman presents with progressively worsen- A 67-year-old Bangladeshi man with a background of
ing dyspnoea of 2 days. Her medical history was signifi- type 2 diabetes, hypertension and benign prostatic hyper-
cant for systemic lupus erythematosus. A PD catheter was plasia presented to a district general hospital with com-
placed 8 weeks prior, and she began PD. She started on plaints of feeling unwell and dark urine for 10 days despite
continuous ambulatory PD (CAPD) with 6 hours dwell a week’s course of co-amoxiclav from his GP. His urine dip-
time and 4–5 exchanges per day. She initially tolerated PD stick showed +3 protein, +3 blood, his renal US showed
well while on 2.2 L fill volumes; however, over the last normal-sized kidneys and his CXR bilateral alveolar shad-
2 days, her drain volume had reduced to 1.8 L. Physical owing. His creatinine was 500 μmol/L with no baseline
examination was remarkable for right-sided basilar crack- value available out of hours. He was treated with intrave-
les with no other signs of fluid overload. nous co-amoxiclav for presumed partially treated UTI and
Her presentation CXR demonstrated the presence of chest consolidation. Over the next 2 days, he became
large right-sided pleural effusion (. Fig. 44.6a). Right- hypoxic, and his urine output reduced. His anti-GBM titre
sided thoracentesis was performed; the pleural fluid analy- was positive, and he was transferred to a tertiary renal cen-
sis is shown in . Table 44.3. tre for plasma exchange and immunosuppressive treatment.
Pleural-fluid glucose concentration that is greater than The peak incidence of anti-GBM disease is in the third
that of serum is most probably due to pleuroperitoneal and sixth decades, and there is a male preponderance. If
leak. untreated, anti-GBM disease is life-threatening, with irre-
. Figure 44.6b shows resolution of the pleural effu- versible kidney damage and respiratory failure. Over 50%
sion after drainage of the peritoneal fluid. CT peritoneog- of patients present beyond the point at which renal recov-
raphy can confirm the diagnosis as contrast material leaks ery is possible. In particular, renal recovery at 1 year in
from the peritoneal into the right pleural space. patients that presented with dialysis-dependent renal fail-
PD-related hydrothorax is an important complication ure has been reported to be only 17% [34]. In addition,
of PD with incidence of 1.6–10%. despite the widespread availability of diagnostic tests,
a b
. Fig. 44.6 a Moderate right pleural effusion with atelectasis in the right midzone and volume loss in the right lower lobe b which
resolves after the peritoneal fluid is drained
44
Respiratory Medicine and the Kidney
783 44
recommended. Some guidelines recommend the specificity [39]. An example of such question-
use of interferon gamma release assays, but the evi- naires used in clinical practice is the STOP-Bang
dence for this in patients with CKD is limited [36]. score for assessment of obstructive sleep apnoea
In many units, assessment for latent TB includes (OSA) [40].
history of previous not adequately treated TB or The diagnosis of sleep-disordered breathing is
suggestive CXR findings of previous TB, close based upon the presence or absence of related symp-
contact with TB or immigration from a highly toms, as well as the frequency of respiratory events
endemic country. during sleep as measured by polysomnography.
For patients undergoing renal transplanta-
tion, treatment of latent TB could be considered
if transplanted in a highly endemic country or if 44.3 Summary
the organ donor is from a highly endemic country.
2. Guidelines recommend that all patients with Pulmonary and renal physiology are intimately related
CKD at stage 5 or 4 with progressive disease likely in both health and disease. Collaboration between the
to require renal replacement therapy within two specialties is essential to not only aid management
6 months should be considered for transplanta- and monitoring of common conditions that affect
tion [37, 38]. A minority of patients with ESRF patients with chronic kidney disease but also offer a sig-
are deemed unsuitable for transplantation. nificant diagnostic value in the setting of inherited and
Respiratory considerations and contraindications acquired renal diseases.
to renal transplantation include:
5 Active infection such as TB
5 Active pulmonary malignancy References
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May 2019. et al. Value of the tuberculin skin testing and of an interferon-
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et al. Long-term outcomes in patients with incident chronic www.renal.org/guidelines
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787 45
Contents
References – 796
n Learning Objectives tural changes seen in ageing are evident from studies of
1. To understand the challenges posed by the ageing tissue from living donor kidneys, which demonstrate
CKD population typical features such as tubular atrophy, glomeruloscle-
2. To appreciate that physiological and psychosocial rosis, interstitial fibrosis and athero- and arteriosclerosis
differences impact on the management of older (. Figs. 45.3 and 45.4). When added to the accrued
patients with kidney disease, necessitating an indi- damage from diseases, such as diabetes and hyperten-
vidualised approach to their management sion, these result in an increased risk of CKD. There is
3. To recognise that frailty is often the greatest predic- also an increased predisposition to acute kidney injury
tor of patient outcome in the elderly rather than due to toxicity from renally excreted drugs and isch-
the modality or adequacy of renal replacement aemic insults.
therapy The relationship between increasing age and preva-
lence of CKD is based on an estimated GFR (eGFR)
cut-off of 60 ml/min/1.73 m2, as defined by the Kidney
45.1 Introduction Disease Improving Global Outcomes (KDIGO) guide-
lines. This does not acknowledge the decline in kidney
The World Health Organization (WHO) estimates that function with physiological ageing. In the original studies
by 2050 the proportion of the world’s population over of age-related GFR changes in healthy subjects, a sequen-
the age of 60 will have nearly doubled from that in 2015, tial reduction in GFR from 122.8 ± 16.4 ml/min/1.73 m2
from 12% to 22%. In the UK the number of people over to 65.3 ± 20.4 ml/min/1.73 m2 was found in patients in
60 is expected to reach 18.5 million by 2025. This will their 20s and 80s, respectively [5]. In a series of over 1000
result in an increasingly polymorbid population (75% of healthy American kidney donors, GFR declined by 8 ml/
75-year-olds in the UK have more than one long-term decade after the age of 45 [6]. GFR is typically estimated
condition [1], 30% with CKD; . Fig. 45.1) and expo- using the MDRD and CKD-EPI equations, both of
nential rises in healthcare usage. which were formulated using a study population under
the age of 70. Additionally, they assume unvarying mus-
cle mass, despite body composition changing with age.
45.2 Ageing and Chronic Kidney Disease It is likely that we have neither a reliable nor vali-
(CKD) dated method of estimating GFR in the older popula-
tion and that our standard cut-offs for CKD should be
Ageing is associated with senescence of tissues. In the age adjusted. That said, the KDIGO eGFR cut-off was
kidneys this results in an approximately 50% reduction determined by a large meta-analysis looking at mortal-
in functional nephron mass by the age of 70 when com- ity, cardiovascular risk, risk of end-stage renal disease
pared to 29–30-year-olds (. Fig. 45.2), with a parallel and progressive CKD, and a subgroup analysis of
decline in glomerular filtration rate (GFR). The struc- >65-year-olds included in the study showed similar
60%
male female
Point prevalence of CKD stage 3-5
48.61%
50%
44.75%
41.66%
40%
33.16%
27.86%
30%
17.65%
20%
13.09%
10% 6.89%
45 0.18% 0.79% 2.69%
0.71%
2.79%
3.08%
0.01% 0.17%
0%
18-24 24-34 35-44 45-54 55-64 65-74 76-84 85+
Age
. Fig. 45.1 Estimated CKD stage 3–5 prevalence amongst 38,262 adults in England between 1998 and 2003. (Reproduced using data from
Stevens et al. [2])
Ageing and the Kidneys
789 45
120
Medulla volume
100
Kidney volume
Cortex volume
80
Age
. Fig. 45.2 Effect of age on total kidney, cortical and medullary vol- volume relatively stable until about 50 years of age. (Modified from
umes based on histology from living kidney donors. Cortical volume O’Neill et al. [3])
declines, whereas medullary volume increases, making total kidney
Macroscopic changes
- Reduction in cortical
mass
m >>medulla
- Calcifications
C
Renal cysts
- R
Chronic inflammation Glomerular changes
- Reduction in number
of glomeruli
Impaired repair - Glomerulosclerosis
mechanisms - Changes
g to podocytes
p y
Oxidative stress
Endothelial dysfunction
Tubular changes
- Tubular atrophy
Vascular changes - Interstitial fibrosis
- Atherosclerosis - Tubular diverticulae
- Intimal/medial
hypertrophy
Other factors
- Impaired regenerative capacity
- Increased EPO production
- Reduced EPO response to anaemia
- Reduced vitamin D activation
. Fig. 45.3 Ageing-related changes in the kidney. (Adapted from Bolignano et al. [4])
increases in risk in all the aforementioned categories at emphasis on reducing cardiovascular risk by controlling
an eGFR less than 60 ml/min/1.73 m2. hypertension, diabetes and hyperlipidaemia. These ther-
apeutic targets are generally derived from clinical trials
that exclude older patients (and thus lack a solid evi-
45.3 Ageing and the Management dence base to support their implementation in this pop-
of Chronic Kidney Disease (CKD) ulation) and have end points that are not as relevant (or
even detrimental) to their care. For example, major
The management of CKD has evolved over the last CKD trials, such as AASK [7] and REIN2 [8], included
decade to focus on targets for the management of com- patients only up to the age of 70, with a mean age of
plications, such as anaemia and mineral bone disease, 54 years old.
and with planning and preparing for dialysis or trans- Older patients are often polymorbid and may suffer
plantation in its later stages. There is also increasing from one or more of the ‘geriatric syndromes’, making
790 S. M. Y. Chong et al.
a b
. Fig. 45.4 Renal histology showing normal kidney histology in a of the tubules in b. (Images courtesy of the Royal Free Hospital Lon-
young a and old b patient using haematoxylin and eosin staining. Note don, Histopathology Department)
the thickening of the vessel wall, sclerosed glomerulus and flattening
application of standardised care challenging. In addi- 45.4 End-Stage Renal Failure (ESRF)
tion, many of these syndromes occur more commonly and Renal Replacement Therapy
and severely in the context of CKD and frequently coex-
Decisions in the Elderly
ist. These include cognitive impairment and delirium,
falls, polypharmacy, depression, immobility and frailty.
Starting dialysis therapy in later life does not carry the
Frailty (a phenotype partly defined by weight loss, mus-
same mortality benefit seen in younger patients
cle weakness and fatigue) is especially associated with
(. Fig. 45.5). However, within each age cohort, there is
adverse outcomes in geriatric populations [9].
a wide degree of variation in life expectancy, with no
Several factors should be considered when applying
validated method of predicting good outcomes on dialy-
standardised treatment targets to elderly patients, one
sis (although high frailty scores and low BMI have been
being the potential harmful impact of interventions: for
associated with increased mortality in elderly dialysis
example, aggressive blood pressure control can lead to
patients [16]). Choices regarding dialysis become
postural hypotension and falls. Treatment priorities are
increasingly difficult in the context of mild to moderate
often different in the ageing population: these may
cognitive impairment, when judgements about ‘quality
include maintaining mobility and independence, allevi-
of life’ come into question, and complex family and eth-
ating symptoms and suffering and maintaining social
ical issues need to be considered.
relationships. Furthermore, whilst hospital admission to
Whilst there appears to be a modest survival benefit
expedite investigations and instigate aggressive treat-
with dialysis (. Fig. 45.6), there are many potential
ment may improve outcomes for a younger patient,
drawbacks, including the tolerability of treatments,
elderly patients will decondition rapidly and have higher
increased hospital attendance and admissions and an
45 risks of delirium and hospital-acquired infections, lead-
increased likelihood of dying in hospital. Some studies
ing to prolonged hospital stays, pressure sores, low
have suggested an increase in symptom burden upon
mood and reduced functional status at discharge
starting dialysis, with a stepwise decline in functional
(. Table 45.1).
ability with each hospital admission.
Ageing and the Kidneys
791 45
. Table 45.1 Challenges of managing CKD in an ageing population
Hypertension, salt and Frequent presentation with isolated systolic hyperten- Treatment may increase falls due to postural
water management sion (ISH) with preserved or low diastolic BP due to hypotension or increase fatigue and confusion
increased vascular stiffness; it is clear that ISH carries Predisposition ischaemic renal injuries, due to
similar CV risks [1]; however, reducing diastolic BP will age-related vasculopathy, leading to acute
reduce cardiac perfusion and lead to increased CV kidney injury (AKI) and hyperkalaemia with
events when lowered excessively (i.e. <60 mmHg) Renin-Angiotension system (RAS) blockade
Good RCT evidence of benefit in terms of mortality,
CV outcomes and CKD progression on patients >80
[10]. However, other studies suggest BP control in this
group may in fact cause harm [11]
Immobility may affect ability to monitor change in
weight and may mask fluid accumulation
Diabetes control Visual impairment, loss of dexterity and memory loss Under-recognition or awareness of hypoglycae-
may hinder ability to monitor blood sugar levels mia
Often poor eating habits which may make insulin dose Increased frequency of hospitalisation
prediction difficult
Cardiovascular risk RAS blockade As above
management Pre-existing vascular changes in ageing will predispose
to ischaemia from RAS inhibitor-induced reduction in
glomerular blood flow
Beta blockers Treatment may increase falls due to postural
No study has demonstrated clear benefit of beta hypotension
blockade in hypertension treatment in the elderly,
although does have benefit in heart failure or cardiac
ischaemia
Aspirin therapy Increased risk of bleeding, particularly upper
Mortality benefit seen in a large trial but was associated gastrointestinal bleeds
with a twofold higher risk of non-fatal major bleeding
complications [12]
Anticoagulation Increased risk of bleeding, particularly upper
Large trials of older individuals demonstrate superiority gastrointestinal bleeds and catastrophic
of novel oral anti-coagulant drugs (NOACs) to warfarin intracranial bleeds. In this group, this can
[13–15] in reducing cerebrovascular events and also frequently lead to prolonged hospital stays,
reducing need for hospital attendance for monitoring; significant morbidity and irreversible loss of
however, most studies excluded patients with an eGFR function
<25
Poor mobility may result in infrequently attendance for
international normalised ratio (INR) monitoring
Polypharmacy may result in altered efficacy of the
anticoagulants
Older individuals are prone to falls and head injuries
CKD mineral bone May have swallowing difficulties or poor appetite, May worsen bowel symptoms such as constipa-
disease affecting compliance with phosphate binders tion
May be housebound and therefore likely to have lower
levels of vitamin D
Whilst it is suggested that most elderly patients this group, including better assessment tools to predict
would choose quality of life over longevity, it is not clear outcomes on dialysis, such as frailty scores, which will
what strategy is best to achieve this goal. Further trials help guide clinicians, patients and families in decision-
are needed to ascertain the right treatment options in making. One such strategy may be to incorporate the
792 S. M. Y. Chong et al.
100
95
90
Percentage survival
85
80
75
70
65
90 day 1 year after 1 year
60 survival 90 day survival survival
55
18-34
35-44
45-54
55-64
65-74
75-84
85+
18-34
35-44
45-54
55-64
65-74
75-84
85+
18-34
35-44
45-54
55-64
65-74
75-84
85+
Age group
. Fig. 45.5 UK renal registry data on unadjusted survival of incident RRT patients by age (2014 cohort). (Open access article by Methven
et al. [17])
80
70
Dialysis
60
50 Medical management
Median survival (months)
40
30
20
10
0
GFR at start
<6
6-<9
<6
6-<9
<6
6-<9
<6
6-<9
9->12
9->12
9->12
9->12
Age
60 65 75 85
. Fig. 45.6 Mortality difference between patients randomised to mortality benefit compared to medical management, whereas start-
dialysis therapy compared with medical management in different age ing dialysis at an eGFR of <6 had a greater mortality benefit, albeit
groups, subdivided by eGFR at initiation of therapy. This data sug- a difference of only 19–26 months. (Reproduced using data from 73
gests that initiating dialysis at a higher eGFR results in a diminished 349 US veterans from Tamura et al. [18])
comprehensive geriatric assessment (GCA) into the pro- 45.5 Ageing and Transplantation
cess. The GCA is a validated tool, which has been ben-
eficial in the assessment of elderly surgical candidates 45.5.1 Patient and Allograft Outcomes
and may be a useful adjunct when making these deci-
45 sions. There has also been increasing use of augmented There is an overall increased survival in older patients
dialysis strategies, such as reduced frequency dialysis, after kidney transplantation compared to those who
which has been shown to improve quality of life for remain on dialysis [19]. However, special considerations
patients rather than regimes with aim to achieve the should be made when considering transplantation in an
standard targets of dialysis adequacy (. Table 45.2). older individual (. Fig. 45.7). As older recipients are
Ageing and the Kidneys
793 45
Pros Improved solute clearance Retained independence Improved quality of life Better focus on symptom
and ultrafiltration Assisted service available May allow return to social management
Readily available Minimal haemodynamic activities, travel and work Least invasive to lifestyle
No training required for compromise Reduced dietary and fluid Few hospital visits
patient/carer More physiological restrictions Improved recognition of
Short treatment time Treatment often tailored dying and advanced care
to suit lifestyle planning
Cons Requires frequent hospital Noisy machines/ Increased perioperative risks due No life expectancy benefit
attendance disturbed sleep to comorbidities
Need for vascular access Risk of peritonitis Increased mortality in initial
Increased infection risk Long duration of post-operative period
from indwelling vascular treatment Exposure to immunosuppression
catheters Poor solute clearance and and increased infection/malig-
Rapid fluid and electrolyte unreliable ultrafiltration nancy risk
shifts Catheter dysfunction Frequent hospital visits
Requires systemic antico- Change to physical Risk of perioperative complica-
agulation appearance tions
Dietary and fluid restric- Requires space for
tions storage of PD fluid
Dietary and fluid
restrictions
more likely to die with a functioning graft, some argued 45.5.2 Rejection
that older donor kidneys or extended criteria donor
(ECD) kidneys should be preferentially offered to older Acute rejection rates are overall lower in older transplant
recipients. In Europe, the Eurotransplant Senior recipients, likely due to decreased immunocompetence.
Program (ESP) initiative is aimed at reducing waiting However, preventing acute rejection is critical in older
times for older patients. Kidneys from donors >65 years KTRs as rejection can have a greater impact on long-term
of age are allocated to recipients >65 years of age within graft survival in the older compared to younger recipients.
a small geographical area to minimise cold ischaemic
time. The 15-year outcome from this showed that despite
a higher complication rate (mainly due to atherosclerotic 45.5.3 Comorbidities and Frailty
vascular disease of the recipient and donor), the patient in the Older KTR
and allograft survival are comparable with younger
patients. However, both the patient and allograft sur- Frailty increases risks of adverse post-operative out-
vival in older kidney transplant recipients (KTRs) who comes and is a predictor of prolonged hospital stays and
received ECD kidneys are worse when compared to early hospital readmission. It has also been identified to
those who received standard criteria donors (SCD) or be the best predictor of 30-day post-operative complica-
living donor kidneys, even when adjusted for other tions independent of age and is an independent risk fac-
donor and recipient factors and pre-transplant dialysis tor for mortality.
vintage. Renal function at 1 year is similarly worse in
older KTRs, who had received an ECD kidney, as com-
pared to a SCD or living donor kidney [20, 21]. Overall, 45.5.4 Immunosuppressive Therapy
SCD and living donor transplantation is preferred for
older patients, but ECD transplantation should be The innate and adaptive immune systems change with age,
offered to those without a living donor who otherwise as do the pharmacokinetics and pharmacodynamics of
will have a very long wait for a SCD kidney. immunosuppressive drugs. Older KTRs have been found to
794 S. M. Y. Chong et al.
require significantly lower doses of cyclosporine to achieve immunosuppressive therapy in older KTRs is clearly sig-
similar plasma drug concentrations than young recipients nificant, but few studies have looked into the impact of
[22]. High calcineurin inhibitor (CNI) peak levels have these drugs in this age group. Ideally, age-specific immuno-
nephrotoxic potential that can hasten graft failure espe- suppressive protocols should be developed to optimise both
cially in ECD kidneys. Age-related reduction in hepatic and the patient and graft survival and reduce overall morbidity.
renal clearance is compounded by factors, such as frailty,
comorbidity and polypharmacy, resulting in drug interac-
tions and changes in availability and distribution. For 45.6 Individualisation of Treatment
instance, mycophenolate mofetil (MMF) clearance and Palliati ve Care
decreases with falling renal function, albumin levels and
haemoglobin – all of which are affected in older transplant Older patients benefit from an individualised and multi-
45 recipients. MMF usage is also associated with a higher inci- disciplinary approach to care. The treatment priorities
dence of opportunistic infections (viral, fungal and myco- of an older patient often centre around social needs and
bacterial) [23] in the elderly. The clinical implication of quality of life rather than the standard outcomes of
Ageing and the Kidneys
795 45
mortality and disease progression that is often used to their prognosis and information about the choices avail-
guide treatment. Some centres in the USA, such as able to them. High-quality palliative care should be
Mount Sinai in New York, have pioneered a multidisci- accessible at all stages of patient care, and systems in
plinary geriatric renal service for patients over the age of place to recognise patients who are struggling or declin-
60 with geriatric syndromes, which focuses on both dial- ing on dialysis, and for providing opportunities to dis-
ysis and non-dialysis therapies and addresses many of cuss withdrawal. Anticipatory prescribing for symptom
the geriatric syndromes and symptom management. control should be adapted to take renal function into
Their main focus is on improving quality of life, main- account and an end of life care plan built around an
taining independence and avoiding hospital attendances. individual’s needs and wishes should be made accessible
The National Service Framework for Renal Services to everyone involved in their care, including family
calls for renal patients to have a timely evaluation of members (see Palliative Care chapter).
Case Study
Tips and Tricks ing RAS blockade. However, all the major heart
failure trials included large numbers of older
1. Consider how therapeutic interventions might patients and suggested that they would have the
confer no benefit to, and even adversely affect, same benefit as a younger cohort, which may on
elderly patients. balance mean that ACE/ARB therapy would be
2. Always assess fall risk, including a postural BP preferred where possible.
measurement, before up-titrating BP medications, 2. Evidence supports the use of NOACs rather than
and avoid intensive blood pressure control in very warfarin. Apixaban is the favoured choice due to
frail patients, especially if non-ambulant and par- the lowest proportion of renal clearance (27%)46
ticularly if the pretreatment diastolic BP is low. and superiority to warfarin in stroke/VTE preven-
3. The use of frailty scores and taking into consider- tion seen in the ARISTOTLE trial and, more
ation BMI and comprehensive geriatric assess- importantly, reduced risk of major bleeding (HR
ment can be a useful tool in guiding decisions 0.5).29
regarding renal replacement therapy. 3. The best patient and graft survival outcomes in
4. Changes in the ageing immune system, pharmaco- older KTRs are in those who receive living donor
kinetics and pharmacodynamics of immunosup- kidneys. However, older patients who receive
pressive drugs used necessitates careful ECD kidneys still have better outcomes than
consideration when prescribing immunosuppres- those who remain on dialysis.
sion for older recipients. 4. The major cause of graft loss in older KTRs is
5. A comprehensive evaluation of prospective older patient death with a functioning allograft. CVS
transplant recipients should include not only pre- disease and infection remain the predominant
morbid conditions but also baseline cognition and cause of death in older KTRs. A majority of
physical function. infections occur in the first 6 months post trans-
6. Consider additional treatment goals such as inde- plantation.
pendence and quality of life when managing
elderly patients.
References
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? Chapter Review Questions B. Epidemiology of multimorbidity and implications for health
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5. Davies DF, Shock NW. Age changes in glomerular filtration rate,
KTRs? effective renal plasma flow, and tubular excretory capacity in
adult males. J Clin Invest. 1950;29:496–507.
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v Answers clinical characteristics associated with glomerular filtration rates
1. Not necessarily: The European Society of in living kidney donors. Kidney Int. 2009;75:1079–87.
Hypertension and the American Heart 7. Wright JT Jr, Bakris G, Greene T, et al. Effect of blood pressure
Association both advise that it is the degree of BP lowering and antihypertensive drug class on progression of
hypertensive kidney disease: results from the AASK trial.
control rather than the agent that had the greatest
JAMA. 2002;288:2421–31.
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trial, lisinopril was less effective than chlorthali- for renoprotection in patients with non-diabetic chronic renal
45 done at improving cardiovascular end points.
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9. Fried LP, Tangen CM, Walston J, et al. Frailty in older adults:
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799 46
Contents
References – 810
The Renal Patient in Critical Care - The ICU: Renal Interface
801 46
n Learning Objectives going emergency surgery. It is important to distinguish
The learning objectives of this chapter are to under- mortality rates in ICU admissions of patients with
stand that established end-stage renal failure from those of patients
1. Outcome predictors, e.g. APACHE, SOFA scores, presenting in acute kidney injury (KDIGO 3) requiring
used in critical care tend to overestimate mortality renal replacement therapy, in whom in-hospital mortal-
in dialysis patients and should be used with cau- ity is nearly fourfold greater [2]. Illness severity scores in
tion. critical care (e.g. APACHE II and III and SAPS II) also
2. Patients with end-stage renal disease (ESRD) tend to overestimate illness severity amongst patients on
have a better ICU and hospital mortality when long-term renal replacement therapy (RRT) and should
compared with patients with AKI requiring renal therefore be used with caution for prognostication in
replacement therapy. patients with ESRD. Thus, patients with ESRD fre-
3. End-of-life informed decision-making in elderly quently benefit from admission to ICU despite multiple
dialysis patients prior to hospitalisation could pre- co-morbidities [3].
vent unnecessary, aggressive medical interventions
and improved use of conservative care pathways.
4. Care of patients with ESRD requires good com- 46.2 Patient-Led Care
munication between both the intensive care and
nephrology teams from vascular access to medica- As inclusion in long-term renal replacement therapy
tion prescriptions. (RRT) programmes has increased worldwide, so have
5. Renal patients in critical care are at higher risk of the age, co-morbidity and frailty of included patients.
muscle wasting and require early intensive rehabili- Advanced care planning for severe illness amongst
tation. frailer patients is crucial. Fewer than 10% patients on
RRT report having spoken about goals and values and
wishes in the context of their illness, despite almost 90%
46.1 Introduction wanting to do so. Likely reasons for this disparity are
physician concerns they will upset their patient, uncer-
With the increase in prevalence of chronic kidney dis- tainty about predicting outcomes, lack of training and
ease and the availability of long-term renal replacement insufficient time to broach the subject. The penalty for
therapy, the proportion of patients with pre-existing missing such end-of-life conversations results in elderly
renal dysfunction developing acute critical illness and dialysis patients undergoing invasive procedures and
necessitating admission to critical care has progressively aggressive treatments focussed on prolonging life when
increased. In the UK, the requirement for an ICU bed is survival may not be consistent with their personal pref-
fourfold greater amongst renal patients than the general erences. Where such discussions do occur, there is an
population. Renal patients also have a higher ICU read- enhanced quality of life for the patient and their family,
mission rate, longer hospital stay and greater overall an enhanced goal-consistent care with greater use of
hospital mortality [1]. palliative care facilities and an increased likelihood of
The management of the ‘critically ill chronic renal death out of the hospital setting, mostly without an
patient’ has thus become an everyday challenge for both increase in patient anxiety or distress [4].
nephrologists and intensive care specialists. The aim of
this chapter is to describe the common problems encoun-
tered when managing renal patients admitted to critical 46.3 Common Problems in Patients
care and cover aspects of physiology affected by critical with ESRD on ICU
illness leading to an acquired functional disability,
focussing on the specific interaction related to pre- 46.3.1 Access
existing renal failure. This then offers a roadmap to
recovery and rehabilitation planning in these patients. Arteriovenous fistulae and grafts are inappropriate
Whilst renal patients are admitted to the ICU for means of access for continuous renal replacement ther-
diverse reasons, several predictable frequent causes are apy (CRRT) as prolonged needle placement can damage
found in the literature. Cardiogenic pulmonary oedema, the access and relatively low flow speeds increases the
sepsis and management post-cardiac arrest typically risk of thrombosis. Instead, a temporary dialysis cathe-
account for most admissions to critical care in ESRD, ter should be placed for the initiation of RRT. Good
respectively. Predictably, patients with ESRD admitted communication between the nephrology and critical
for elective surgery have a lower mortality when com- care team is vital for information regarding previously
pared with non-surgical admissions and patients under- known central venous stenosis that can maximise suc-
802 K. Lane et al.
cess and minimise complications particularly when perfusion pressure to avoid exacerbating neurological
prompt vascular access is urgently required. If the dysfunction [7].
patient is likely to require prolonged ICU admission, the Peritoneal dialysis (PD) may be continued in estab-
temporary catheter should be replaced with a cuffed lished patients during critical illness. However, difficulty
tunnelled dialysis catheter to prevent multiple catheter fine-tuning fluid shifts, a tendency for hypo-osmolar
insertions, as it is imperative to preserve existing venous hyponatraemia due to the inability to excrete a free-
access in an obtunded patient with few remaining access water load, intra-abdominal pressure considerations,
options. Subclavian vein dialysis catheter placement impaired nutrition and thermoregulation have limited
should be carefully considered, and placement of its use, and usually temporary extracorporeal renal ther-
peripherally inserted central venous catheters (PICC) apy is established in the acute setting unless in extreme
remains controversial in patients with ESRD, as this site circumstances in patients unable to have CVVH due to a
carries the highest risk of subsequent central vein steno- complete lack of vascular access. In addition, technical
sis [5]. In addition, due consideration is necessary prior aspects and a thorough understanding of the PD pre-
to placement of temporary venous access on an ipsilat- scription are factors that play key roles in achieving
eral iliac vein to a functioning renal transplant to reduce adequate PD. Notwithstanding, when the recovery
risk of graft thrombosis or unintentional arterial injury phase of critical illness starts, patients who were on
and thus this site is best avoided. maintenance IHD or PD therapies prior to ICU admis-
Pre-existing tunnelled haemodialysis catheters sion can restart, with intermittent therapies facilitating
should not be used for routine drug administration to mobilisation and rehabilitation. An exception is breach
minimise infection and thrombosis risk, although in of the peritoneal cavity due to acute abdominal injury,
extremis, they can provide a useful means of immediate leading to the inability to perform PD and requirement
wide bore access. Communication between ICU and for conversion to extracorporeal therapy.
nephrology staff is important to ensure the line is locked
with appropriate antibacterial anticoagulant agent e.g.
sodium citrate (DuraLock-C™) after use, as many ICUs 46.3.3 Nutrition in ICU
may use sodium chloride 0.9% alone to lock lines.
Malnutrition, often a chronic problem in patients with
end-stage renal disease, is exacerbated in the setting of
46.3.2 Renal Replacement Therapy acute illness. Calculation of energy and protein require-
for Critically Ill Patients with ESRF ments is complicated during critical illness, particularly
when a patient requires RRT. Some RRT fluids contain
There are no prospective comparative studies of CRRT energy substrates (citrate, glucose, lactate) that must be
over intermittent HD (IHD) for the patients in ESRF on accounted for to prevent overfeeding and problems with
ICU. Therefore, the decision regarding the chosen glycaemic control. Citrate-mediated filtration can pro-
modality is often a pragmatic one based on staff exper- vide an additional 300 kcal/day to a patient. The use of
tise and equipment availability. IHD requires access to concentrated renal feeds (e.g. Nepro®HP – which also
an online water supply that meets stringent water purity contains the highest protein concentration of the sup-
standards and is provided by a reverse osmosis (RO) sys- plements – Abbot Laboratories Ltd) in patients unable
tem. The necessary piping is usually unavailable in the to self-feed can minimise volume overload. Water-
ICU; however, IHD can be provided using a portable soluble vitamin loss may also be severe during CRRT,
RO connected to a purpose-built water connection at particularly in those with suboptimal enteral absorp-
the bedside [6]. Shared protocols detailing patient tion. In such circumstances, parenteral supplementation
cohorts suitable for either IHD and continuous veno- may be required. No supplementation of fat-soluble
venous haemofiltration (CVVH) or CVVH only on the vitamins is usually required.
ICU should be discussed and agreed between the inten-
sive care and nephrology teams. The advantage of IHD
is that existing vascular access can be used without the 46.3.4 Electrolyte Abnormalities
need for additional temporary access; however, in situa-
tions of haemodynamic instability and multi-organ fail- 46.3.4.1 Hyperkalaemia
ure, CRRT is preferable to minimise further alterations The management of a patient with ESRD and severe
in blood pressure and fluid shifts. Similarly, in the con-
46 text of acute brain injury or elevated intracranial pres-
hyperkalaemia can be challenging. Over ninety percent
of potassium excretion occurs via the kidneys, with the
sure, e.g. in trauma or patients with fulminant hepatic remainder occurring via the gut. Priorities of care are to
failure, CRRT is recommended for maintaining cerebral stabilise the myocardium where there is evidence of car-
The Renal Patient in Critical Care - The ICU: Renal Interface
803 46
diac conduction abnormality, whilst preparing an urgent monitoring of ECG morphology can be a useful guide.
means of RRT to reduce total body potassium concen- It is important to ensure that post-IHD hypokalaemia
tration. Hyperkalaemia leads to suppression of impulse (whilst awaiting equilibration of total body potassium
generation by the sino-atrial node and reduced conduc- that may well remain high) is not overzealously treated
tion by the AV node and Purkinje system. This results in by the critical care team (used to supplementing potas-
bradycardia, conduction blocks and ultimately cardiac sium to achieve a target of 4–4.5 mmol/L). Conversely,
arrest if left untreated. it may be necessary to replace sustained significant
The ideal initial treatment for severe hyperkalaemia hypokalaemia and hypophosphataemia, induced by
in ESRD is high-flow haemodialysis or haemodiafiltra- CRRT.
tion to rapidly reduce serum potassium to a safer level,
followed by a gentler and gradual removal of potassium, 46.3.4.2 Hypocalcaemia
all of which should be done in an environment with Patients with advanced CKD may have hypocalcaemia
close continuous cardiac monitoring and regular reas- due to altered calcium-phosphate balance and impaired
sessment of blood biochemistry, preferably with point- vitamin D activation. If treated with sodium bicarbon-
of-care testing. Frequently, there are locally determined ate for the management of acidosis or hyperkalaemia,
practical limitations that preclude optimal care. For exacerbated hypocalcaemia can worsen precipitating
example, a physician may need to decide whether rapid tetany, seizures and cardiac arrhythmias. In addition, the
haemodialysis of a patient with an established func- use of citrate anticoagulation for RRT may exacerbate
tional fistula or graft on an inpatient haemodialysis unit underlying hypocalcaemia due to the chelation of serum
(albeit with less ability to monitor the patient and fewer calcium. Treatment of hypocalcaemia is with bolus and/
nursing staff) would overall be safer than the inherent or infusion of calcium gluconate or chloride through a
delay of ICU admission, temporary dialysis catheter large vein to avoid thrombophlebitis. Coincident hypo-
insertion and slower potassium removal of CRRT, magnesaemia may also require treatment.
despite the presence of a higher nurse-to-patient ratio
enabling closer monitoring and better access to point-
of-care testing. Regardless of location, a patient should
46.4 Medication in the ICU in Patients
receive close cardiac monitoring for several hours after
HD. Blood glucose concentration must also be closely with ESRD
observed in patients who have received insulin to tempo-
rise hyperkalaemia to ensure hypoglycaemia is treated 46.4.1 Drug Dosing
promptly. If a patient has sustained a hyperkalaemic
cardiac arrest, subsequent ICU admission is strongly Drug dosing in a critically ill patient is complex. In the
advised. case of antimicrobials, under- and overdosing can have
Insufficiently expedient institution of RRT to remove significant adverse consequences for the patient.
potassium can lead to rebound hyperkalaemia in Alterations in extracellular volume, protein binding and
patients with ESRD and minimal renal function: potas- renal and hepatic function can also significantly alter the
sium moved intracellularly with insulin therapy leaks concentration of drugs and their efficacy. Drug removal
back into the extracellular space where it remains due to frequently varies with modality of renal replacement
the lack of renal function. Therefore, it is important to therapy, blood flow rate, filter surface area and age.
monitor closely for rebound. More recently, sodium zir- There is large individual variability in vancomycin phar-
conium cyclosilicate and Patiromer have been recom- macokinetic and pharmacodynamic target attainment
mended for acute life-threatening hyperkalaemia in in ICU patients. As a result, it is essential to seek the
adults in emergency care alongside standard care expert advice of a critical care renal pharmacist.
described above [8]. These may have a key role in avoid- Therapeutic drug monitoring should be used for antimi-
ing the need for RRT in patients with recovering AKI or crobials particularly aminoglycosides and glycopeptides
permitting safe transfer of dialysis patients from institu- to prevent toxicity in patients with reduced renal func-
tions that lack dialysis facilities to a dialysis unit thus tion.
avoiding the need for ICU admission and acute vascular
access.
Some propose that high potassium gradients and 46.4.2 Rationalisation of Medication
consequent rapid potassium shifts put the patient at
higher risk of myocardial arrhythmias than hyperkalae- Multiple medications, though may be indicated and be
mia per se [9]. There are no studies to guide serum potas- of benefit, increase the burden of polypharmacy in
sium reduction targets in hyperkalaemia, but serial chronic kidney disease. However, on admission to ICU,
804 K. Lane et al.
PERSISTENT
PERSISTENT INFLAMMATORY
ACUTE
INFLAMMATORY CATABOLIC
CHRONIC SYNDROME
CRITICAL
CATABOLIC CRITICAL
ILLNESS SYNDROME
ILLNESS
CHRONIC
CRITICAL
ILLNESS
PATIENT JOURNEY
5 As discussed above, acute illness scores often overes- dysfunction are specifically at risk of muscle wasting
timating mortality in ESRD. and the functional consequences of low muscle mass
5 Clinical frailty is associated with both mortality and because of interactions between predisposing factors
morbidity in the critically ill [14] and patients with and the physiology of critical illness.
ESRD often fulfil frailty criteria.
5 Newly emerging intermediate syndromes such as
chronic critical illness and persistent inflammatory 46.8 Baseline Muscle Mass and Function
catabolic syndrome are likely to exist in patients
undergoing ward-based therapy post intensive care Low baseline muscle mass and quality are associated
discharge (. Fig. 46.1). with both critical illness mortality and subsequent
5 The overall prevalence of delirium on the inpatient decreased independence. This is unsurprising, given
hospital setting is estimated between 14 and that, all things being equal, muscle mass is the major
24% [15]. determinant of muscle function. Both loss of muscle
mass and function are well described in chronic stable
kidney disease, which places these patients at high risk
of subsequent functional disability [17].
46.7 Skeletal Muscle Mass Increasingly the critical care community is aware
that the presence of pre-existing chronic diseases
Acute skeletal muscle wasting occurs rapidly in critical results in a differential trajectory of recovery from
illness and is related to severity of illness: Greater organ those without. Patients with renal disease therefore
dysfunction results in greater muscle wasting, with rates will require a combination of different rehabilitation
of 2–3% loss per day [16]. This is underpinned by altered strategies and different recovery goals compared to
protein homeostasis. In the acute phase, muscle protein previously healthy individuals. Defining this popula-
synthesis is depressed and recovery variable over time. tion is crucial for the development of clinical pro-
In chronic critical illness, rates of muscle protein break- grammes, and the clinical definitions of frailty are
down are seen to rise. Associated with this quantitative being increasingly demonstrated to be useful in doing
loss is a qualitative loss; myonecrosis is seen in up to so. . Figure 46.2 demonstrates the impact of pre-
40% of patients, with an associated fasciitis, likely fur- existing clinical frailty on discharge destinations of
ther contributing to loss of function. Patients with renal critical illness survivors [14].
806 K. Lane et al.
. Fig. 46.2 Meta-analysis of discharge destination studies in critically ill patients with and without clinical frailty. From Muscedere Inten-
sive Care Medicine 2017 [14]
46.9 Altered Protein Homeostasis (. Fig. 46.3). These barriers include lack of education
regarding the importance of mobilisation, unfounded
Muscle mass is maintained by protein homeostasis, a safety concerns and poor teamworking [21].
balance between muscle protein synthesis and muscle A major step forward is the realisation amongst cli-
protein breakdown. In humans, protein synthesis is the nicians that mobilisation is a therapeutic intervention
process primarily affected by stimuli, both adverse and and encouraging this, e.g. in sitting patients out of bed
favourable. In the acute phase of critical illness, muscle for meals, will improve patient outcomes.
protein synthesis is depressed and recovers variably
over time. In chronic critical illness, rates of muscle
protein breakdown are seen to rise patients with renal 46.11 Inflammation
disease who are then at further at risk of the conse-
quences and drivers of altered protein homeostasis, Systemic inflammation suppresses muscle protein syn-
with decreased protein synthesis having been described thesis, as does intramuscular inflammation. Whilst both
in stable chronic kidney disease [18]. The same factors occur during critical illness, persistent low-grade inflam-
affect both acute and chronic decreased muscle protein mation occurs in survivors and is seen post-hospital dis-
synthesis and need to be addressed for muscle mass to charge [22]. In addition to the immunosuppressive
be gained. effects, persistent inflammation represents a major
physiological barrier to physical recovery, in that it
impedes muscle protein synthesis and amino acid
46.10 Immobilisation uptake by skeletal muscle, rendering exercise and nutri-
tional interventions ineffective. Post-intensive care,
In bed-rest models, a week of immobilisation results in a patients with chronic kidney disease have multiple
decrease in muscle protein synthesis and an appreciable causes for persistent inflammation. This may be related
reduction of muscle mass. Importantly this predisposes to critical illness (persistent unexplained inflammation),
the patient to further, accelerated muscle mass loss and secondary to new infections, the result of systemic
affects skeletal muscle metabolism. Reversing the effects inflammatory diseases common in this population or
of immobilisation (acutely) requires resistance exercise, lastly as a feature of chronic kidney disease. Regardless
the simple provision of nutrition alone cannot do so. of the aetiology, a cause for such inflammation needs to
Whilst the exact amount of time required will vary be ascertained and treated to allow recovery of normal
between patients, it is likely to be in the order of minutes protein homeostasis.
per day [19]. This can be seen in the clear differences
between patients mobilised early versus those who are
not in randomised controlled trials; return to indepen- 46.12 Age
dent functionals status occurred in 59% in the interven-
46 tional group compared with only 35% in the control Elderly patients demonstrate anabolic resistance, whilst
group [20]. Incorporating mobilisation into daily care is basal muscle protein synthetic rates are similar to that of
not straightforward, with multiple barriers existing younger patients, their synthetic response to resistance
The Renal Patient in Critical Care - The ICU: Renal Interface
807 46
Barriers Enablers
Diagnosis & illness severity, age & • Sedation, delirium & pain management
comorbidities • Patient goal setting & family involvement
Sedation, delirium & pain • Sleep
Pt psychological state (e.g. motivation)
Poor culture, teamwork, & leadership • Develop positive culture, MDT team meetings
Lack of expertise & skill training • Interprofessional expertise / skill training
Need for physician orders prior to rehap • Ward rounds & site visits to est programs
• Routine mobility orders
• Designated leaders & discipline champions
Motivations & beliefs regarding the benefit • Education re: importance & benefit of PA
/ harm of PA interventions • Positive experiences / storytelling of success
Lack of funding & access to PT services • Automatic referral pathways for PA interventions
Lack of equipment, resources & staffing • Illustrate cost saving benefit / business case
Lack of time & competing priorities • Dedicated equipment & staffing
• Coordination of schedules within MDT
• Mobility protocol, ABCDE bundle & mobility team
. Fig. 46.3 Barriers and enablers of mobilisation. From Parry et al. Intensive Care Medicine 2017 [21]
exercise amino acid intake is blunted, in addition is the 46.14 Interventions to Increase Anabolism
blunting of muscle protein breakdown to insulin [23]. and Recovery
Elderly patients thus require either more frequent (exer-
cise) or greater concentrations (amino acids) to achieve Neither trials of increased nutritional delivery in acute
a similar synthetic response. Whilst age is a non- critical illness nor early exercise has delivered improve-
modifiable risk factor, it remains an important factor in ments in functional outcomes or mortality. Once func-
rehabilitation and recovery planning. Separate, tailored tional deficits are established, they have proven to be
interventions are likely to be needed, unlike in younger difficult to reverse or ameliorate emphasising the need
individuals. for novel approaches to primary prevention. Therefore,
patients with chronic kidney disease admitted as in-
patients should be treated as being (by definition) at
46.13 Acidosis risk of muscle wasting in the same fashion as the elderly
and those suffering from chronic obstructive pulmo-
The effect of metabolic acidosis on muscle mass and nary disease.
protein homeostasis in patients with kidney disease has Mobilisation and resistance exercise should be part
been well described, as has the reversal of these effects of the daily in-patient routine, with an ‘opt-out’
with therapeutic sodium bicarbonate [24]. Metabolic approach taken by the clinical team as opposed to
acidosis impairs muscle protein synthesis, and whilst requiring a daily prescription. Amino acid intake and
trial data are conflicting as regards the response to aci- specifically essential amino acids are required for muscle
dosis derangement in adults, this is likely to be an over- protein synthesis. Exercise without amino acids is a cata-
simplification. No single intervention is likely to correct bolic stimulus and detrimental to patients. In the absence
muscle protein homeostasis in the setting of the com- of specific data pertaining to nutrition and muscle gain
plex physiology of chronic renal disease. Rather, a com- post critical illness, clinical practise should be in line
plex or multifaceted intervention is likely to be needed. with the kidney disease outcomes quality initiative,
Correction of acute or chronic metabolic acidosis is delivering 0.6 g protein/kg/day in non-dialysed patients
most likely to be part of this. and 1.2/kg/day for patients undergoing haemodialysis
808 K. Lane et al.
[25]. Ideally this would be timed to occur post exercise to 46.16 Anticipation of Deterioration (the
maximise the synergistic effects on muscle protein syn- ICU Outreach): Renal Interface
thesis. In the elderly patient, this would be even more
efficient if delivered in equitable portions across the day, Whilst some risks for readmission and adverse outcomes
again maximising synthetic opportunities. are fixed and intrinsic to the renal patient, some risks may
be modifiable. Therefore, it is good practice to identify
and intervene early in patients at risk of deterioration
46.15 The Role of Sleep and Delirium through use of a SBAR or I-PASS multidisciplinary
in Facilitating and Preventing handover on the renal ward (. Fig. 46.4). Evidence for
Rehabilitation effective resident handovers is associated with a reduction
in medical error rate of 23% from a pre-intervention
On discharge from ICU, patients frequently suffer from period to the post-intervention period [30]. Similarly, it is
disturbed sleep. This is multi-factorial, because of high important to ensure robust processes are in place for post-
levels of noise, poor light management within the ICU, discharge review of ICU survivors to renal wards who are
lack of direct sunlight or routine, pharmacological treat- often frail and at risk of subsequent readmission.
ment and delirium [26]. The culmination of this is a
combination of reversed sleep/wake cycles, poor con-
centration and engagement with staff and rehabilita- 46.17 Conclusion
tion. Whilst hyperactive delirium is commonly
recognised, hypoactive delirium is not and often mis- In summary, rehabilitation strategies for patients who
taken for sleep, contributing to the issues surrounding survive critical care remain suboptimal. Many experi-
sleep deprivation listed above. ence significant and persistent physical, cognitive and
Patients with stable kidney disease suffer from both post-traumatic problems after discharge. For patients
alterations in normal sleep patterns and quality [27] with complex co-morbidities such as ESRD, the after-
with a high incidence of delirium [28]. The addition of
a critical illness therefore represents an acute-on-
chronic effect, which, in addition to affecting patients’
health-related quality of life, will prevent engagement I-PASS
with rehabilitation and therefore impede recovery. BETTER HANDOFFS. SAFER CARE.
Several measures have been proposed to improve sleep
quality. Fundamental to this is the environmental set I Illness Severity • Stable, “watcher,” unstable
up, light and noise regulation on the ward needs to be
enforced, as does the timings of nursing observations P Patient • Summary statement
and drug rounds, ensuring that these occur early in the Summary • Evens leading up to
admission
evening [26].
• Hospital course
A daily routine and diary are useful aid in orienta- • Ongoing assessment
tion and structure provision, as is exposure to direct • Plan
sunlight. The use of earplugs and sleep masks can aid
uninterrupted sleep and transition to deeper stage sleep
and rapid-eye movement sleep, both necessary for well- A Action List • To do list
being. Lastly, patients should be screened regularly for • Time line and ownership
delirium. In the setting of a high-acuity patient, the
Confusion Assessment Method for the ICU (CAM- S Situation • Know what’s going on
ICU) score would seem useful in capturing those with Awareness and • Plan for what might happen
both hyper- and hypoactive delirium. Using the CAM- Contingency
Planning
ICU assessment tool, patients are screened for an acute
change or fluctuating course of mental status together
with inattention and either altered consciousness or dis- S Synthesis by • Receiver summarizes what
Receiver was heard
organised thinking [29]. If the above criteria are met, the • Asks questions
patient is CAM-ICU positive and requires management • Restates key action/to do
46 of delirium, a goal in its own right, in addition to facili- Items
tating rehabilitation. A full discussion on the patho-
physiology, incidence and management of delirium is
beyond the scope of this chapter, though it is of clear . Fig. 46.4 Elements of the I-PASS mnemonic. From Waltz et al.
relevance. Curr Pediatr Rep 2019 [30]
The Renal Patient in Critical Care - The ICU: Renal Interface
809 46
care needs are even more fraught with a greater likeli- multidisciplinary team, with the full spectrum of clinical
hood of long-term difficulties. Therefore, optimisation skills (from medical to occupational therapy) needed to
of recovery as a goal of therapy rather than just survival offer a fully holistic approach to patients with such com-
has gained increasing importance with the role of the plex rehabilitation needs.
Case Study
? Chapter Review Questions 3. Arulkumaran N, Annear NMP, Singer M. Patients with end-
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patients? ments for hyperkalaemia: patiromer and sodium zirconium
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haemodialysis suffer from different regimens of potassium
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1. Hutchison CA, Crowe AV, Stevens PE, Harrison DA, Lipkin and sepsis. Am J Respir Crit Care Med. 2008;177(11):1242–7.
GW. Case mix, outcome and activity for patients admitted to 23. Wilkes EA, Selby AL, Atherton PJ, et al. Blunting of insulin
intensive care units requiring chronic renal dialysis: a secondary inhibition of proteolysis in legs of older subjects may contrib-
46 analysis of the ICNARC Case Mix Programme Database. Crit ute to age-related sarcopenia. Am J Clin Nutr. 2009;90(5):1343–
Care. 2007;11(2):1–14. 50.
2. Chan O, Ostermann M. Outcomes of chronic hemodialysis 24. Stein A, Moorhouse J, Iles-Smith H, et al. Role of an improve-
patients in the intensive care unit. Crit Care Res Pract. ment in acid-base status and nutrition in CAPD patients. Kidney
2013;2013:715807. Int. 1997;52(4):1089–95.
The Renal Patient in Critical Care - The ICU: Renal Interface
811 46
25. National KF. K/DOQI clinical practice guidelines for chronic 29. Gusmao-Flores D, Salluh JI, Chalhub RÁ, Quarantini LC. The
kidney disease: evaluation, classification, and stratification. Am confusion assessment method for the intensive care unit (CAM-
J Kidney Dis. 2002;39(2 Suppl 1):S1–266. ICU) and intensive care delirium screening checklist (ICDSC)
26. Bion V, Lowe A, Puthucheary Z, Montgomery H. Reducing for the diagnosis of delirium: a systematic review and meta-anal-
sound and light exposure to improve sleep on the adult intensive ysis of clinical studies. Crit Care. 2012;16(4):R115.
care unit: an inclusive narrative review. J Intensive Care Soc. 30. Walz A, Emrath E, Mack E. Communication in the PICU: hand-
2017:1–9. offs of care. Curr Pediatr Rep. 2019;7:123–9.
27. Iliescu EA, Coo H, McMurray MH, et al. Quality of sleep and
health-related quality of life in haemodialysis patients. Nephrol Patient Information and Guidelines
Dial Transplant. 2003;18(1):126–32.
Booklet for patients advanced kidney disease planning for end-of-life
28. Murray AM, Pederson SL, Tupper DE, et al. Acute variation in
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cognitive function in hemodialysis patients: a cohort study with
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repeated measures. Am J Kidney Dis. 2007;50(2):270–8.
dnacpr_info_entry_pg_30.pdf
813 47
Contents
References – 825
5 Previous cancer in the recipient (3–4 times more diagnosed at a later stage compared to the general popu-
likely to die of cancer post-transplant). lation and has a worse prognosis, including for common
5 Viral infections: >50% of PTLD cases are EBV- cancer types such as breast, colon, lung and prostate
related (positive donor to negative recipient increases cancer [17]. Outcomes are unsurprisingly tumour spe-
PTLD risk 20-fold [13]); HHV8, HPV, hepatitis cific; for example, following renal transplantation 5-year
viruses and Merkel cell polyomavirus are also carci- survival from colorectal cancer is 27% compared to 75%
nogenic. in the general population, and transplant recipients with
5 Increased dialysis vintage. breast cancer have a 40% excess mortality compared to
5 Use of T-cell depleting induction agents. the general population [18]. In a Dutch study of 12,805
5 Maintenance immunosuppression dose. renal transplant recipients, 7% were diagnosed with can-
cer, of whom 81% died from cancer, with 69% dying
with a functional graft. The median survival following a
47.4 Renal Disease Impact on Cancer cancer diagnosis was 2.1 years compared to 8.3 years in
matched controls without cancer [19].
Prognosis
Impaired renal function is associated with worse prog-
nosis in cancer patients and impacts cancer treatment. 47.5 Malignancy as a Cause of Renal
Unfortunately, cancer outcomes are significantly worse Disease
for patients with even modest impairment of renal func-
tion. An eGFR less than 60 mL/min/1.73m2 is a signifi- There are a multitude of diagnostic possibilities when a
cant independent risk factor for death from cancer, with patient with malignancy presents with renal dysfunction
cancer-specific mortality increasing 18% for every (. Fig. 47.1). Causes can be categorised into three major
10 mL/min/1.73m2 of eGFR decline [14]. AKI during groups: (i) directly tumour-related, due to direct renal
treatment is associated with reduced treatment dose involvement (e.g. due to renal cancer or lymphomatous
intensity, reduced progression-free survival and infiltration) or obstructive nephropathy from retroperito-
increased overall mortality [15, 16]. neal lymph nodes or pelvic malignancy; (ii) treatment-
In addition, renal transplantation is associated with related, due to direct renal toxicity from exogenous agents
poorer cancer outcomes. Post-transplantation, cancer is such as chemotherapy or treatment-related complications
816 O. Lucas et al.
achieved using standard calculations of creatinine clear- used with caution in renal impairment due to potentially
ance or nuclear medicine tests such as chromium-51 nephrotoxic effects, and dose reduction may be required.
EDTA clearance. Close monitoring throughout the Second-line treatments include calcitonin, steroids
course of treatment is essential with prompt reaction to (sometimes used in lymphoma to reduce calcitriol pro-
deteriorating renal function. This should include con- duction) and denosumab. Denosumab is a human
sideration of other causes of renal dysfunction (e.g. gas- monoclonal antibody which blocks osteoclast formation
trointestinal losses, infection, NSAIDs) and then dose through the inhibition of RANK-ligand, and is used for
adjustment or treatment delay or cessation as appropri- refractory hypercalcaemia or if bisphosphonates are
ate. CKD stage V, haemodialysis and peritoneal dialysis contraindicated due to severe renal impairment.
patients require special consideration with regard to vol-
ume status and electrolyte management. For this reason, 47.5.2.2 Tumour Lysis Syndrome
multidisciplinary team working is crucial. Chemotherapy Tumour lysis syndrome (TLS) is an important and often
dosing advice can be found in the renal drug handbook preventable cause of AKI and constitutes a medical
for patients with CKD, haemodialysis and peritoneal emergency. It occurs when there is mass lysis of tumour
dialysis [36]. cells, either spontaneously or in response to treatment,
leading to hyperuricaemia, hyperkalaemia, hyperphos-
phataemia and hypocalcaemia. It is much more com-
47.5.2 Endogenous Toxins mon in haematological than non-haematological
and Paraneoplastic Renal malignancies, but can occur in solid tumours (e.g. meta-
Dysfunction static germ cell tumours). The incidence varies depend-
ing on the definition used, but approximately 10% of
47.5.2.1 Hypercalcaemia patients with acute lymphocytic leukaemia (ALL)
develop severe uric acid nephropathy, as do roughly 5%
Hypercalcaemia is common in cancer, occurring in up to of patients with non-Hodgkin’s lymphoma (NHL), with
30% of all cancer patients during the clinical course of half of these becoming anuric. Both uric acid and phos-
their disease. It is most common in later-stage malig- phate are thought to play a role in the AKI associated
nancy and is generally associated with poorer prognosis. with cell lysis, and a spot urinary urate/creatinine ratio
The estimated yearly prevalence of hypercalcaemia for of >1 is suggestive of the diagnosis. Risk factors are
all cancers is 1.46% to 2.74%, and it is four times more shown in . Table 47.2 and clinical markers in
prevalent in stage IV cancer [37]. It is most commonly . Table 47.3.
associated with multiple myeloma, lung cancer and
renal cell carcinoma but is also regularly encountered in
cancers of the head and neck, breast, ovary and colon . Table 47.2 Risk factors for tumour lysis syndrome
[37]. It is frequently caused by excessive tumour secre-
tion of parathyroid hormone-related protein, but is also 1. Patient factors
caused by bone metastasis-related release of osteoclast a. Increasing age, acidic urine, hypotension and renal
activating factors and by excessive production of cal- impairment
citriol [38].
b. Concomitant nephrotoxic medications
Hypercalcaemia can cause acute and chronic renal
disease. Renal manifestations of hypercalcaemia 2. Inadequate supportive care
include nephrogenic diabetes insipidus, renal vasocon- a. Dehydration
striction, distal renal tubular acidosis, nephrolithiasis
b. No allopurinol or rasburicase prophylaxis
and tubular dysfunction [39]. It can also cause nephro-
calcinosis due to calcium oxalate or calcium phosphate 3. High tumour burden
deposition in the tubulointerstitium, causing acute or a. Bulky tumour
chronic kidney injury, sometimes with progressive renal b. Extensive metastases
dysfunction [40].
Treatment of the underlying cancer is important in 4. High cell lysis potential
correcting hypercalcaemia. Additional therapies are a. Rapidly proliferating tumour – LDH is a surrogate marker
often also required, particularly if severe. The mainstay for this
of acute hypercalcaemia treatment is intravenous fluids b. High cancer cell sensitivity to therapy
and bisphosphonate therapy. Bisphosphonate therapy
c. Intensity of therapy
can be continued regularly for long-term control.
47 Pamidronate and zoledronate are both used and gener-
ally take 2–4 days to take effect. Of note, both need to be
d. High white blood cell count
Oncology and the Kidney
819 47
The incidence of TLS has been dramatically reduced
. Table 47.3 Clinical markers of tumour lysis syndrome
by prophylaxis with pre-hydration and urate reduction
1. Hyperuricaemia (uric acid >0.4 mmol/L)
treatments. Allopurinol (a xanthine oxidase inhibitor)
inhibits the oxidation of hypoxanthine to xanthine (and
2. Hyperphosphataemia (serum phosphate >1.5 mmol/L in
then to urate) and is used in prophylaxis. Rasburicase
adults; >2.1 mmol/L in children)
(recombinant urate oxidase) catalyses the oxidation of
3. Rapid onset hyperkalaemia (serum potassium >6.0 mmol/L) urate to allantoin (5–10x more soluble) which is excreted
4. Hypocalcaemia (corrected calcium <1.75 mmol/L; ionised harmlessly by the kidney. It reduces urate levels within
calcium <0.3 mmol/L) 4 hours and can be used both as prophylaxis and treat-
5. Raised lactate dehydrogenase ment. As allopurinol prevents the formation of urate
(which is the substrate for rasburicase), they should not
6. Acute kidney injury
be prescribed together. Rasburicase is significantly more
expensive but appears much more effective; in one ran-
domised controlled trial, rasburicase reduced urate by
86% compared to 12% with allopurinol, and it has been
. Table 47.4 Lymphoproliferative causes of glomerular shown to result in better renal function and reduced
deposition diseases need for dialysis [41]. Hypersensitivity reactions are not
infrequent, anti-oxidase antibodies can be induced with
1. Light chain cast nephropathy repeated treatments and it is contraindicated in G6PD-
2. AL amyloid deficient patients.
3. Monoclonal immunoglobulin deposition disease (MIDD)
47.5.2.3 Paraneoplastic Phenomenon
a. Light chain deposition disease in Lymphoproliferative Disorders
b. Heavy chain deposition disease Acute kidney injury can also occur as a paraneoplastic
4. Cryoglobulinaemia (type 1 and type 2)
phenomenon related to lymphoproliferative disorders.
This is often in association with multi-organ dysfunc-
5. Macroglobulinaemia-monoclonal IgM Waldenstrom’s or tion and may be the presenting feature before the under-
multiple myeloma
lying diagnosis is made. An example of this is Castleman’s
6. Immunotactoid GN (0.1% of biopsies) disease, which is a non-neoplastic B-cell proliferative
7. Fibrillary GN (1% of biopsies) disorder associated with renal and systemic effects
related to excess IL-6 production. This condition may
8. Monoclonal gammopathy (POEMSa)
precede the onset of NHL.
aPOEMS polyneuropathy, organomegaly, endocrinopathy,
monoclonal gammopathy and skin involvement
Immunoglobulin-Related Renal Disease
Acute kidney injury and CKD are common accompani-
ments to endogenous, pathological immunoglobulin
TLS may occur spontaneously in patients with a production either via glomerular deposition (see
heavy burden of disease, but more typically occurs 7 Chap. 50 on Amyloid) or secondary to the toxic
3–7 days after treatment, though severe hyperkalaemia effects of excess light and heavy chains (see 7 Chap. 49
may be present earlier. Without treatment there is a risk on myeloma). In short, light chains, heavy chains and
of fulminant hyperkalaemia, arrhythmias, seizures and immunoglobulins can form casts, crystals, fibrils or
anuric renal failure, with oligo-anuric patients being granular deposits in the kidney; these conditions are
particularly at risk of these life-threatening complica- termed monoclonal gammopathies of renal significance.
tions. Appropriate treatment includes supportive care Glomerular disorders secondary to lymphoprolifera-
and intense monitoring of high-risk patients, in con- tive disorders (LPD) are relatively common, and whilst
junction with rasburicase (see below). There is no evi- there is overlap, they can be divided into (a) glomerular
dence that alkalinisation of the urine is helpful (urate is deposition diseases secondary to abnormal production
more soluble with higher pH), possibly because xan- of immunoglobulin components (. Table 47.4) and (b)
thine, hypoxanthine and calcium phosphate are less sol- paraneoplastic glomerulonephritides without apparent
uble in alkaline urine. There are no trials to support excess of immunoglobulin production.
early dialysis but urate and phosphate are rapidly cleared Patients with glomerular deposition diseases may
by haemodialysis, and so there is a logical argument for present with AKI or other renal syndromes such as
early renal replacement therapy (RRT). In a patient with nephrotic syndrome (secondary to renal amyloid, mem-
pre-existing renal failure, it is important to anticipate branoproliferative glomerulonephritis (MPGN) or
metabolic mayhem and thus prepare for timely RRT. membranous nephropathy), rapidly progressive glomer-
820 O. Lucas et al.
ulonephritis (fibrillary GN) or just sub-acute renal Fibronectin glomerulopathy, collagenofibrotic glo-
impairment. Clinically, nephrotic syndrome occurs in merulopathy, TMA, systemic lupus erythematosus
1–2% of patients with chronic lymphocytic leukaemia and diabetes mellitus can all be associated with organ-
(CLL), predominantly associated with an MPGN pat- ised deposits, and the distinguishing features are cov-
tern, but membranous nephropathy, minimal change ered in an excellent review by Guillermo and
nephropathy, amyloid deposition, focal segmental glo- Turbat-Herrera [42].
merulosclerosis (FSGS), crescentic glomerulonephritis
and light chain deposition disease can all occur. MPGN Glomerulonephritis in Lymphoproliferative
is usually associated with cryoglobulinaemia, but may Disease
be associated with neither cryoglobulins nor comple- Glomerulonephritides are well documented in associa-
ment activation but instead with IgG deposition in the tion with lymphomas and chronic leukaemias, and
form of immunotactoid glomerulonephritis. rarely occur in association with acute leukaemia. As
As well as non-haematological causes, cryoglobu- described above, glomerulonephritis secondary to glo-
linaemia has been associated with NHL, Hodgkin’s lym- merular deposition of excess immunoglobulin prod-
phoma (HL), CLL, multiple myeloma (MM), chronic ucts is common. Paraneoplastic glomerulonephritis
myelocytic leukaemia (CML), Waldenstrom’s macro- without apparent excess of immunoglobulins can also
globulinaemia (WM), Castleman’s disease, myelodys- occur in association with haematological malignancies
plasia, thrombotic thrombocytopaenic purpura (TTP) (. Table 47.6). Management is focussed on identifying
and cold agglutinins. Thus the presence of any mono- and treating the underlying haematological malig-
clonal cryoglobulin requires full haematological assess- nancy. Remission rates for secondary glomerulone-
ment. Cryoglobulinaemia secondary to LPD tends to be phritides are good if the underlying driver is successfully
predominantly type 1, which less frequently presents cured.
with vasculitis and purpura compared with types 2–3 Minimal change nephropathy (MCN) is the classic
but more commonly presents with veno-occlusive dis- glomerulonephritis associated with HL and NHL,
ease. occurring in about 1% of cases. FSGS is also associated
The pattern of deposition on electron microscopy but at a tenth of the frequency of MCN. As patients
may help to differentiate the underlying pathology: with MCN secondary to lymphoma are often steroid
amyloid, cryoglobulin, fibrillary and immunotactoid resistant, it is important to reassess all steroid-resistant
glomerulonephritis all have a fibrillary pattern, whereas patients with MCN for underlying lymphoma. The
light and heavy chain deposition diseases have a granu- diagnosis of lymphoma may not be apparent for months
lar pattern. Distinguishing immunoglobulin deposition after the appearance of nephrotic syndrome.
can be difficult, and it is important to ensure that Congo Approximately 70% of patients presenting with MCN
red staining and electron microscopy are done and secondary to lymphoma have constitutional symptoms
fibrils are measured. Differentiating characteristics of (e.g. fever, night sweats), and 90% have an acute phase
immunoglobulin deposition diseases are shown in response; these signs and symptoms can be used to aid
47 . Table 47.5. diagnosis [43].
Oncology and the Kidney
821 47
phritis, IgA nephropathy and IgA vasculitis can also
. Table 47.6 Glomerulonephritis associated with lymphop-
roliferative disorders without apparent paraprotein produc-
occur [44].
tion Cancer-associated membranous nephropathy is most
commonly associated with lung and gastric carcinomas
Lymphoproliferative disorder Type of glomerulonephritis but also with renal carcinoma, prostate cancer and thy-
moma, amongst others. In a series of patients with mem-
Hodgkin/non-Hodgkin Minimal change, FSGS
lymphomas branous nephropathy, cancer was found in approximately
10%, with risk factors for finding cancer including
CLL/hairy cell leukaemia MPGN with or without
age >65 years and a >20 pack year smoking history [45].
cryoglobulin, membranous
Thromboembolic disease occurred in 25% of cancer-
T cell lymphoma (Sezary IgA associated membranous nephropathy compared to 7% in
syndrome, mycosis
primary membranous nephropathy. Findings suggesting
fungoides)
a secondary cause of membranous nephropathy include
Chronic myelomonocytic Various glomerulonephritides negative immunostaining for M-type phospholipase A2
leukaemia
receptor (PLA2R) and thrombospondin type 1 domain-
Myelofibrosis/polycythaemia FSGS (secondary) containing protein 7A (THSD7A) antigens, negative
rubra vera/essential serum PLA2R and THSD7A antibodies and a prefer-
thrombocythaemia
ence towards a mixed IgG1, IgG2 and IgG3 subclass
staining pattern, rather than IgG4 dominant [46].
It is important to screen for malignancy in all patients
with glomerulonephritis and clinical or pathological
features suggestive of a secondary cause. There are no
Chronic lymphocytic leukaemia and hairy cell leu- formal screening guidelines and screening should be
kaemia (HLL) are predominantly associated with driven by a patient’s individual risk factors; [43] a small
MPGN and monoclonal production of immunoglobu- study of patients with membranous nephropathy also
lin with or without cryoglobulinaemia (see section highlighted a potential role for 18F-fluorodeoxyglucose
Glomerulonephritis in Lymphoproliferative Disease positron emission tomography/computed tomography
above) but also, to a much lesser extent, membranous (FDG-PET/CT) in identifying occult malignancy [47].
glomerulonephritis which may show a fibrillary pattern Treatment is aimed at the underlying malignancy, and
in the sub-epithelial deposits. the development of proteinuria following successful
treatment should prompt investigations for potential
Hyperviscosity recurrence.
In addition to direct infiltration and cryoglobulin depo-
sition, Waldenstrom’s macroglobulinaemia (and IgM 47.5.2.5 Renal Vein Thrombosis
multiple myeloma) may result in hyperviscosity syn- Cancer causes a hypercoagulable state, which in turn
drome and thus risk of renal arteriovenous thrombosis increases the risk of renal vein thrombosis. This can
of any sized vessel, including an acute glomerular capil- cause acute kidney injury or chronic kidney disease.
lary thrombosis. As with all the above disorders, the pri- Renal cell carcinomas can extend into the renal veins
mary aim is to identify any underlying haematological and can be associated with tumour thrombus in 4–25%
disorder and treat this directly rather than the resultant of cases [48].
secondary renal disease.
47.5.2.6 Cancer-Associated Thrombotic
47.5.2.4 Glomerulonephritides in Solid Microangiopathy
Cancers Cancer-associated thrombotic microangiopathy (TMA)
In addition to the range of glomerulonephritides asso- is characterised by microvascular thrombosis, thrombo-
ciated with lymphoproliferative disorders, paraneo- cytopaenia and resultant end-organ ischaemic damage,
plastic glomerulonephritis can rarely be associated commonly affecting the kidneys. It can be caused by
with solid tumours. Membranous nephropathy is the malignancy itself (particularly in mucinous adenocarci-
most frequently reported solid tumour-associated nomas and widely disseminated malignancy), or it can
paraneoplastic glomerulonephritis, although minimal be a complication of cancer therapy (see Sect. 47.5.1 on
change disease, membranoproliferative glomerulone- chemotherapy and targeted agents) [49].
822 O. Lucas et al.
47
Oncology and the Kidney
823 47
Case Study
a b
Urine protein creatinine ratio following diagnosis
2000
Lobectomy
Relapse
1600
1200
mg/mmol
800
400
0
0 1 2
Years
. Fig. 47.3 a Spiculated lesion in the right lower lobe suspicious of recurrent lung carcinoma; b protein creatinine ratio change
from diagnosis, through lobectomy, and cancer recurrence
824 O. Lucas et al.
41. Goldman SC, Holcenberg JS, Finklestein JZ, et al. A random- raphy in detecting hidden malignancies at the time of diagnosis
ized comparison between rasburicase and allopurinol in children of membranous nephropathy. Oncotarget. 2016;7(9):9645–51.
with lymphoma or leukemia at high risk for tumor lysis. Blood. 48. Aeddula HRMNR. Renal vein thrombosis. StatPearls Publish-
2001;97(10):2998–3003. ing; 2019.
42. Herrera GA, Turbat-Herrera EA. Renal Diseases With Orga- 49. Govind Babu K, Bhat GR. Cancer-associated thrombotic micro-
nized Deposits: An Algorithmic Approach to Classification and angiopathy. Ecancermedicalscience. 2016;10:649.
Clinicopathologic Diagnosis. 2010;134(4):512–31. 50. Bach AG, Behrmann C, Holzhausen HJ, et al. Prevalence and
43. Plaisier E. Ronco P. Screening for Cancer in Patients with Glo- patterns of renal involvement in imaging of malignant lympho-
merular Diseases. 2020;15(6):886–8. proliferative diseases. 2012;53(3):343–8.
44. Lien Y-HH, Lai L-W. Pathogenesis, diagnosis and management 51. Schwartz JB, Shamsuddin AM. The effects of leukemic infil-
of paraneoplastic glomerulonephritis. Nat Rev Nephrol. trates in various organs in chronic lymphocytic leukemia. Hum
2011;7(2):85–95. Pathol. 1981;12(5):432–40.
45. Lefaucheur C, Stengel B, Nochy D, et al. Membranous nephrop- 52. Toriihara A, Kitazume Y, Nishida H, Kubota K, Nakadate M,
athy and cancer: epidemiologic evidence and determinants of Tateishi U. Comparison of FDG-PET/CT images between
high-risk cancer association. Kidney Int. 2006;70(8):1510–7. chronic renal failure patients on hemodialysis and controls. Am
46. De Vriese AS, Glassock RJ, Nath KA, Sethi S, Fervenza FC. A J Nucl Med Mol Imaging. 2015;5(2):204–11.
Proposal for a Serology-Based Approach to Membranous 53. Coppolino G, Bolignano D, Rivoli L, Mazza G, Presta P, Fuiano
Nephropathy. 2017;28(2):421–30. G. Tumour markers and kidney function: a systematic review.
47. Feng Z, Wang S, Huang Y, Liang X, Shi W, Zhang B. A follow- Biomed Res Int. 2014;2014:647541.
up analysis of positron emission tomography/computed tomog-
47
827 48
Contents
References – 840
48
n Learning Objectives becoming increasingly common in non-endemic regions,
1. Chronic kidney disease is an increasingly prevalent for example, there are over 12,000 sufferers of sickle cell
complication of sickle cell disease in developed disease living in the UK and approximately 72,000 in the
countries. USA. Twenty-five percent of babies born with SCD
2. Patients should be screened for risk factors and worldwide are born outside of sub-Saharan Africa [1].
early signs of renal damage and managed appro- Renal involvement in SCD is well recognised, and
priately. chronic kidney disease (CKD) secondary to sickle cell
3. Renal replacement therapy including renal trans- nephropathy (SCN) is becoming more prevalent as the
plantation should be considered early in patients life expectancy of patients with SCD improves.
with sickle cell disease approaching end-stage kid- Undoubtedly, environmental factors play a role in dis-
ney disease. ease severity as well as co-inherited genes and other risk
4. Other red cell disorders associated with acute or factors for the development of chronic kidney disease
chronic intravascular haemolysis are associated (CKD). The onset is insidious and microalbuminuria,
with both acute kidney injury and chronic kidney an early manifestation of SCN, reaches a prevalence of
disease. approximately 60% in those over 45, although only
4–12% of patients with SCD will develop the serious
and life-threatening complication of end-stage renal
48.1 Haemoglobinopathies disease.
48
patients with sickle cell disease tend to have reduced sys- lin-1 (ET-1) release results in vasoconstriction but also
temic vascular resistance and hence lower mean arterial promotes natriuresis via stimulation of ET type b
pressure when compared with age- and ethnicity- receptors in the renal collecting ducts [10]. Although
matched controls [6]. hyposthenuria is reversible by blood transfusion until
Although it is not clear whether early or prolonged the age of 10, after this age it becomes irreversible and
hyperfiltration is pathogenic in the aetiology of CKD, it is associated with a permanently damaged microvas-
is very common; 71% of adults were found to have an culature.
estimated GFR (eGFR) ≥140 ml/min/1.73m2 in a cross- SCD is also associated with both proximal and distal
sectional study [7]. Although only a small proportion of tubular abnormalities. The increase in sodium and water
these patients develop end-stage renal disease (ESRD), loss from the collecting ducts leads to a reactive increase
GFR does begin to decline in most people with SCD in sodium and water reabsorption by the proximal
over the age of 30, and in a study of an elderly cohort of tubule. This reabsorption of sodium is the driving force
patients in Jamaica those who had died over the age of for the reabsorption of other solutes, such as phosphate
60, chronic renal failure was cited as the major cause of and β2-microglobulin, often causing hyperphosphatae-
death in 43%, making CKD the most frequent fatal mia. Other solutes have a marked increase in proximal
complication in this age group [8]. Although this is cir- tubular secretion, such as creatinine and uric acid. Up to
cumstantial evidence, in CKD due to SCN it is probable 30% of the total creatinine excretion can arise from
that hyperfiltration plays a role in the pathogenesis of tubular secretion, and so creatinine-based formulas for
progressive renal dysfunction. GFR can significantly overestimate renal function.
Cystatin C has been demonstrated to be a more accurate
Microalbuminuria and Proteinuria surrogate marker of renal function in both adults and
The appearance of albumin in the urine is an early man- children with SCD, and hence its use is more likely to
ifestation of SCN. It can be detected from late child- detect early decline in renal function [11].
hood onwards and is detectable in approximately 28% In contrast, impaired medullary perfusion can cause
of patients in the 15–26 age group, 38% in the 26–35 s, distal tubule dysfunction, leading to acidosis that arises
50% in the 36–45 s and >60% in the over 46 s [7]. In from diminished availability of ammonium.
some patients, microalbuminuria can develop into Hyperkalaemia is a common phenomenon in patients
heavier proteinuria (protein: creatinine ratio with SCD and has been attributed to hyperchloremic
(PCR) >50 mg/mmol) occasionally reaching the metabolic acidosis linked to a type IV renal tubular aci-
nephrotic range. Although full-blown nephrotic syn- dosis or resistance of the distal tubule to aldosterone [2].
drome is uncommon (at about 4%), when it does occur
it is associated with a very poor renal prognosis. One Haematuria
rare cause of sudden-onset nephrotic syndrome that has Haematuria is common both in SCD and SCT. It can
been described in patients with SCD is recent infection range from microscopic and painless, through visible
with human parvovirus B19 (HPV B19). In cases that and painless to visible and painful. It is usually self-
have been biopsied early, the collapsing variant of focal limiting but can occasionally be severe enough to require
segmental glomerulosclerosis (FSGS) has been found transfusion. Small microinfarcts are often the cause of
(with or without evidence of direct HPV B19 infection). minor bleeding, but full renal papillary necrosis (RPN)
Although the nephrotic syndrome per se spontaneously with sloughing of the ischaemic papilla can lead to
resolves without the need for corticosteroids, it is often severe haemorrhage and obstruction and may be com-
followed by persistent proteinuria and slowly progres- plicated by superadded infection. RPN can sometimes
sive renal dysfunction [9]. be diagnosed by ultrasonography, but CT urography (or
intravenous urography if CT is unavailable) and direct
Tubular Abnormalities ureteroscopy have a much higher diagnostic rate
Hyposthenuria (inability to concentrate urine under (. Fig. 48.2). The management of haematuria is usu-
conditions of water deprivation) is a common phe- ally conservative and limited to good hydration, pain
nomenon in people with SCD and often leads to relief and antibiotics if necessary. Patients with sickle
enuresis in children and marked dehydration. It is cell disease also have an increased susceptibility to bac-
caused by sickling in the vasa recta leading to micro- terial infections due to impaired immunity from auto-
thrombi, infarction and collateral formation of blood splenectomy and an opsonic antibody deficiency.
vessels. As a consequence, there is a defect in the coun- Bacteriuria was found to be present in 26% of children
tercurrent exchange mechanism leading to insufficient with SCD presenting with fever in Nigeria and UTI
trapping of solute in the inner medulla and abnormal- complicated pregnancy in 12% of mothers with SCD in
ities in renal water conservation. Increased endothe- a large UK cohort [12, 13].
Red Cells and the Kidney
831 48
Progressive Chronic Kidney Disease
As life expectancy of patients with SCD increases, pro-
gressive CKD is becoming an increasingly large prob-
lem. Although hypertension is less common in patients
with SCD than in an age- and ethnicity-matched cohort,
when it is present, it has a marked impact on the rate of
progression of CKD [17]. Other predictors of progres-
sive CKD include haematuria; high levels of haemoly-
sis; inheritance of the Bantu, or Central African
Republic; β-globin gene cluster haplotype; and younger
age at onset of CKD. New insights in to co-inheritance
genetic modifiers in both Afro-Caribbean patients and
those with SCD can also help us to stratify patients
according to risk of progression of CKD [18].
48
stones. This differential should be considered when Therapies for Treating Sickle Cell Disease
investigating a patient with SCD and new-onset protein- Sickle cell nephropathy is a chronic complication of
uria or haematuria. Although we don’t investigate every SCD; therefore, strategies designed to alleviate the sever-
patient with SCD and microalbuminuria (ACR >3.5 mg/ ity of SCD are likely to impact upon the development of
mmol), patients with a protein to creatinine ratio >50 mg/ SCN.
mmol should be evaluated for other causes of CKD, and Blood transfusions, either intermittent or regular,
if any of these investigations are positive or the patient’s are an established treatment for the management of
signs and symptoms do not conform to those expected both acute and chronic complications of sickle cell dis-
within the natural history of SCN as described above, ease and are regularly used for stroke prevention, in the
they should be referred for further renal or urological treatment of acute chest crisis and pulmonary in hyper-
evaluation. In particular, patients with sudden onset of tension. However, there is little evidence for the benefits
nephrotic syndrome, warrant renal biopsy to look for of long-term blood transfusions for the prevention of
causes other than SCN [15]. renal complications. In a recent comparison of children
with SCD on chronic transfusion programmes com-
Imaging pared to non-transfused cohorts, it was concluded that
Imaging should always be considered in the diagnosis of chronic transfusion is associated with a lower prevalence
visible haematuria as described above. Renal iron depo- of albuminuria [25]. Previous studies, however, found no
sition has been noted on magnetic resonance scans in difference in the number of children receiving chronic
patients with SCD but appears not to be related to liver transfusion when comparing those with microalbumin-
iron concentration, a marker of total body iron load. uria to those without [26].
Renal iron does appear to be correlated with markers of Hydroxycarbamide (HC, also known as hydroxy-
haemolysis but has not been shown to be associated urea) is a cytotoxic, antimetabolite approved for use in
with renal dysfunction or degree of albuminuria [22]. SCD. Although it has pleotropic effects, it primarily acts
Simple renal cysts occur more frequently, are more to increase levels of foetal haemoglobin which serve to
abundant and develop at a younger age in patients with dilute the levels of HbS and reduce risk of polymerisa-
SCD than ethnically matched controls, though the sig- tion. Clinical benefits include lower rates of pain, acute
nificance of this is unknown [23]. chest syndrome and need for blood transfusion. Long-
term usage has been associated with improved growth
Renal Histology and development in children and reduced overall mor-
There is no pathognomonic lesion that defines tality and morbidity in adults [27, 28]. Although some
SCN. Glomerular hypertrophy with distended capillar- small studies have suggested that it may also be effica-
ies is universally found but is not confined to those who cious both in the treatment of children with established
have developed microalbuminuria or proteinuria. Focal SCN and also in preventing its onset, the BABY HUG
and segmental glomerular sclerosis (FSGS) is the most study (a phase III randomised, placebo-controlled,
common lesion associated with proteinuria but is not double-blind study of 193 patients starting HC in
specific to SCN. Other lesions that have been noted on infancy between 9 and 17 months) was unable to prove
biopsy include thrombotic microangiopathy (TMA) and this [29]. Subsequent prospective observational data col-
membranoproliferative glomerulonephritis (MPGN), lected from the Hydroxyurea Study of Long-Term
lesions also not exclusive to SCN [24]. The only fre- Effects (HUSTLE) has demonstrated a reduction in
quently demonstrated interstitial lesion is the presence hyperfiltration in children treated at the maximum toler-
of abundant haemosiderin granules in proximal tubular ated dose over a 3-year period, but no change in albu-
epithelial cells. As with all causes of progressive CKD, minuria was detected. [3]
interstitial fibrosis and tubular atrophy predominate in The only curative treatment currently available for
the later stages. sickle cell disease is allogeneic haematopoietic cell trans-
plantation (HCT). It is usually reserved for children
48.1.2.6 Management of Sickle Cell with major complications such as stroke and is not
Nephropathy widely available. Although it is probable that HCT
The management of sickle cell nephropathy can be recipients who have a good outcome are likely to be pro-
divided into specific therapies, targeting sickle cell dis- tected from developing SCN, most published studies
ease and the general management of chronic kidney dis- exclude those with established renal disease from receiv-
ease. ing this treatment. One small study evaluating the use of
Red Cells and the Kidney
833 48
HCT in 10 adults with SCD included three patients with Management of Advanced Chronic Kidney
renal dysfunction. After an average of 30 months of Disease
follow-up, it was noted that HCT neither exacerbated Despite optimal treatment as outlined above, a propor-
nor ameliorated the progression of renal disease [30]. tion of patients with SCN will develop progressive
There have also been case reports describing HCT as CKD. Chronic anaemia and tissue hypoxia are strong
safe in adults with end-stage renal disease (ESRD) and a drivers for erythropoietin (epo) synthesis, and SCD
promising study demonstrating safety of non- patients with normal kidney function often have epo
myeloablative peripheral blood stem cell transplanta- levels well-above the normal range. However, as the
tion (PBSCT) in patients with chronic organ damage GFR falls, their ability to produce sufficient levels of
including ESRD [31]. endogenous epo also begins to decline. Erythropoiesis-
Whilst not a treatment for SCD per se, good man- stimulating agents (ESAs) can be useful, particularly in
agement of acute and chronic pain is of paramount combination with HC in patients who are intolerant of
importance to patients and clinicians alike. Conflicts HC alone due to reticulocytopenia. Patients with CKD
over choice and frequency of medications frequently stage 3–4 often require very high doses of ESAs to have
lead to a loss of trust and break down of relations, and an impact on haemoglobin (Hb) levels. Although Hb
so it is vitally important to plan and have mutual agree- targets should be lower than in the general CKD popu-
ment of pain management strategies in advance. The lation (<10 mg/dl) due to the increased risk of triggering
added burden of CKD has implications for the use of vaso-occlusive crises, they are still rarely achieved, and
numerous analgesics including non-steroidal anti- most patients become transfusion dependent by the
inflammatory drugs (NSAIDs) and opiate-based medi- time they reach end-stage renal disease (ESRD). It is
cations. NSAIDs are effective and generally often beneficial to continue ESA therapy after the com-
well-tolerated painkillers. They have the advantage of mencement of dialysis, however, as this can prolong the
not causing drowsiness or constipation and are not interval between red cell transfusions and minimise the
habit-forming. They should however be avoided in risk of iron overload [15, 33].
patients with CKD 3–5 (though can be used in patients In patients who develop progressive renal dysfunc-
on dialysis in moderation). Their mechanism of action tion secondary to SCN, the rate of decline can be quite
results in inhibition of prostaglandin synthesis, mole- rapid once the GFR falls below 40 ml/min/1.73m2, and
cules that are intricately involved in maintaining border- so timely preparation for renal replacement therapy
line renal perfusion, and therefore they accelerate decline (RRT) is very important. Multiple admissions to hospi-
in GFR and medullary ischaemia. Opiates are often tal often result in very poor peripheral veins, so access
required for pain relief in SCD and should not be with- planning needs to be commenced early and with expert
held if indicated. In advanced CKD, however, accumu- input. Outcome data for patients with SCN on dialysis
lation secondary to reduced excretion can occur, and so are few, but Powars reported that ESRD is associated
careful monitoring of dose and side effects is required. with a very poor prognosis as not only was the average
Advance pain-management planning involving both age of those reaching ESRD very young (23.1 in those
haematologists and nephrologists is the ideal situation. with HbSS disease) but also the mean time to death after
reaching ESRD was only 4 years despite being on hae-
Therapies for Treating Chronic Kidney Disease modialysis [34]. More recently, a Saudi Arabian study
In common with other causes of proteinuric CKD, it reported that those with SCD and ESR D suffered more
seems logical to attempt aggressive treatment of hyper- infectious complications, lived on average for only
tension and reduction of proteinuria with blockade of 27 months after commencing RRT and were signifi-
the renin-angiotensin system. Although studies cantly younger when they died compared to patients
designed to demonstrate the benefit of ACE inhibition with ESRD of other causes [35]. A larger-scale compar-
in SCN have been small and short term, the results of ison using the US Renal Data System looking at all
these have been positive in reducing proteinuria and patients who commenced RRT in the 1990s found that
hyperfiltration [32]. In our own practice, we generally not only was SCN an independent risk factor for death,
recommend the introduction of an ACEi or angioten- worse even than diabetes, but also patients with SCD
sin receptor blockers (ARBs) when a patient has a uri- were much less likely to receive a kidney transplant [36].
nary protein/creatinine ratio persistently above 100 mg/ More recently, a 5-year study of patients with SCD
mmol. We have noticed an additional benefit reported receiving haemodialysis in France reported similar find-
by patients that when prescribed these medications they ings [37].
experience a reduction in their frequency of nocturia, Despite there being may be many obstacles in the
presumably due to the reduction in GFR that these path to kidney transplantation, it is probably the modal-
drugs impart. ity that offers the best outcome for patients with SCD
834 C. C. Sharpe
48
requiring RRT. Although long-term graft and patient borne in mind when considering the management of
survival are not quite as good as for patients with other acute rejection. Patients with ESRD receiving RRT
causes of renal failure, the prognosis for individuals experience very few painful crises, probably due to severe
with SCN is far better after transplantation with a pro- anaemia and relatively frequent blood transfusions.
jected 7-year survival of 67% (vs. 83% for other African Following transplantation delayed graft function (DGF)
American) when compared with a 10-year survival of is common, but once renal function improves, there is a
only 14% for those who remain on dialysis [38]. significant rise in the haemoglobin, which is often
accompanied by an increase in the number of painful
Management of the Transplanted Patient crises experienced by the patients [39]. Acute intra-renal
In our experience, the major complications following sickling has been demonstrated as a cause for a sudden
transplantation in patients with SCD are sepsis, an deterioration in renal function post-transplantation in
increase in painful crises and acute renal sickling. homozygote SCD and, interestingly, also in heterozy-
Although we do not specifically tailor induction and gotes (. Fig. 48.3) [40]. To minimise the risk of DGF,
maintenance immunosuppression for these patients, VOC and recurrent SCN, we now recommend patients
their increased susceptibility to infection should be with SCD receive regular exchange blood transfusion
a b
c d
. Fig. 48.3 Acute sickle glomerulopathy in a kidney transplant. a biopsy of a kidney transplant demonstrating glomerular capillary tufts
congested with sickle shaped red blood cells. a silver stain, b haematoxylin and & eosin, c Picro-Mallory Trichrome, d toluidine blue
Red Cells and the Kidney
835 48
(EBT) with a view to reducing the HbS to <30% as soon exposes patients to more blood than top-up transfusion
as they are placed on the cadaveric waiting list (or pre- alone, we have not found it to be associated with an
operatively in living donor transplantation), and we increased level of anti-HLA antibodies or an increased
continue this for the life of the transplant. Although this rate of rejection [41].
Case Studies
48
Tips and Tricks 48.2 Other Red Cell Disorders
1. Prescribing ACEi or ARBS in the evening can 48.2.1 Thalassaemia
reduce nocturia resulting in a better night’s sleep.
2. Creatinine-based formulas for estimation of GFR
There are two genetic loci for α-globin and thus 4 genes
(e.g. MDRD) overestimate renal function in
in diploid cells. Defects of all four α-genes results in
patients with SCD due to enhance proximal tubu-
hydrops foetalis and death. Alpha-thalassaemia resulting
lar excretion of creatinine. Relative change rather
from defects of 1 or 2 α-globin genes results in very mild
than absolute values may detect changes in renal
or subclinical disease and can in some circumstances be
function earlier.
protective against haemolysis when co-inherited with
3. Patients who choose not to have blood transfu-
β-globin abnormalities [7]. Defects in 3 α-genes leads to
sions (e.g. Jehovah’s Witnesses) may need paren-
haemoglobin H disease. In general, this disease is rela-
teral iron to maximise the effect of ESA therapy.
tively mild with affected individuals having stable hae-
4. When using the MDRD formula to estimate renal
moglobins of around 90 g/l. However, sudden acute
function in advanced CKD, the 1.2 multiplication
haemolysis can occur, often in combination with acute
factor applied in Afro-Caribbean patients may
infection, and may lead to acute kidney injury [42].
overestimate renal function in patients with SCD
Beta-thalassaemia syndromes are characterised by
due to their relatively low muscle mass. If in
genetic abnormalities in beta-globin chain synthesis. In
doubt, measure the true GFR using a gold stan-
β-thalassaemia major, synthesis of β-globin chains is
dard method.
severely impaired as both genes are affected, whilst
5. When making decisions regarding dialysis modal-
α-chain synthesis remains normal. This imbalance in glo-
ity, consider the benefits of an AV fistula if regu-
bin chain synthesis results in ineffective erythropoiesis
lar EBT is to be recommended. Patients who
and severe anaemia. Affected individuals require regular
choose peritoneal dialysis may still benefit from
transfusion to survive, resulting in chronic iron overload
the formation of an AVF for this reason.
and the necessity for ongoing iron chelation therapy.
Although red cell survival is reduced, intravascular
haemolysis is not a feature of this disease, and so the toxic
Conclusion
effects of free heme are not manifest. However, shortened
Good communication between the haematologists and
red cell lifespan, rapid iron turnover and tissue deposition
nephrologists caring for patients with SCN is impera-
of excess iron are major factors responsible for chronic
tive. Timely management can minimise the risk of pro-
organ failure. Cardiopulmonary and reticuloendothelial
gression of CKD, whilst advanced planning in those
dysfunction are common, but direct kidney involvement is
approaching ESRD increases the well-being of the
less apparent. Although renal failure per se is uncommon,
patient whilst they are on dialysis and prepares them
tubular abnormalities are detectable in many patients, even
for transplantation. This not only reduces early com-
in childhood, and are probably related to renal iron depo-
plications but also maximises graft function and long-
sition. One recent 10-year follow-up has concluded that
term outcomes. As there is little evidence base for the
long-term renal functional decline is uncommon in patients
best way to manage these patients, decisions should be
with normal tubular function. However, in those with evi-
made in discussion with the patient and the multidis-
dence of tubular damage in childhood (elevated phospha-
ciplinary team on a case-by-case basis. Some of the
turia and high levels of uricuria) the rate of decline of
choices available together with their pros and cons are
GFR in adulthood is greater than in those with normal
highlighted in . Table 48.1.
tubular function and greater than that expected for age
Red Cells and the Kidney
837 48
. Table 48.1 Treatment options for patients with SCN; their pros and cons
Commencing ACEi or ARB for Reduces proteinuria and may reduce risk of New medication for life in a young person
proteinuria in a young person with progression to CKD based on evidence in Risk of hyperkalaemia so needs monitoring
an eGFR>90 and BP other proteinuric renal diseases Little research undertaken in this patient group
<130/80 mmHg Reduces nocturia
Commencing hydroxycarbamide May improve foetal Hb levels and reduce No evidence that HC reduces progression of
for progression of CKD in intrarenal sickling and hypoxia CKD in SCD
patients without frequent VOC May improve patient Well-being May have unwanted side effects
Commencing ESAs to improve May improve Hb and Well-being May not work, needs high doses
Hb in patients with eGFR<60 ml/ May allow a higher dose of HC to be tolerated May need extra iron supplementation if
min ferritin low (i.e. in patients who have had a low
number of blood transfusions)
May cause VOC if Hb rises too high (rare)
Commencing EBT on patients on HbS% kept below 30 improves fitness for Increased exposure to blood risks, increase in
the waiting list for a cadaveric surgery and reduces intercurrent illness and anti-HLA antibodies and a positive cross-
renal transplant suspension from the list match
No need for top-up transfusion or EBT High use of a precious resource
immediately prior to surgery Good venous access needed for effective EBT
Reduced risk of DGF and early intra-renal (AVFs should be used if needled by experience
sickling staff)
May lead to reduced iron overload in patients
who require frequent top-up transfusion
Commencing EBT on patients Removes the risk of frequent painful crises Increased exposure to blood risks an increase in
post renal transplant Reduces intrarenal sickling and may improve anti-HLA antibodies and a positive cross match
the longevity of the graft Patients may become highly sensitised and
difficult to retransplant in the future
May lead to iron overload if continued for
years
ACEi angiotensin converting enzyme inhibitor, ARB angiotensin receptor blocker. HC hydroxycarbamide, VOC vaso-occlusive crisis,
EBT exchange blood transfusion. AVF arteriovenous fistula, DGF delayed graft function, HLA human leucocyte antigen, CKD chronic
kidney disease, SCD sickle cell disease, ESA erythropoiesis stimulating agent
alone [43]. Although iron chelation is an important aspect One rare complication of chronic, severe anaemia
of management for patients with β-thalassaemia, many (due to thalassaemia or other red cell disorders) is over-
chelators (deferoxamine (iv or sc) or deferiprone (oral)) stimulation of the bone marrow leading to extra-
require normal renal function for the chelated iron to be medullary haematopoiesis (EMH). This usually occurs
excreted. Deferasirox is an orally active and hepatically in the reticuloendothelial system but can occasionally
excreted iron chelator frequently used in patients with iron occur in other tissues including the kidney. Renal lesions
overload. Unfortunately, it is nephrotoxic and can lead to may be asymptomatic but can be complicated by spon-
renal dysfunction or the Fanconi syndrome in patients taneous haemorrhage requiring treatment. EMH can be
with clinical or subclinical renal impairment and so is not avoided by adequate red cell transfusion and iron sup-
licenced for use in patients with established kidney disease. plementation where indicated.
838 C. C. Sharpe
48
. Table 48.2 Haemolytic anaemias known to be associated
48.3.1 Paroxysmal Nocturnal
with kidney disease. AKI: acute kidney injury, CKD: chronic Haemoglobinuria
kidney disease
48.3.1.1 Epidemiology and Pathogenesis
Haemolytic anaemia Associated Associated
with AKI with CKD Paroxysmal nocturnal haemoglobinuria (PNH) is a rare
condition with a prevalence in the region of 16 pmp in
Acute transfusion haemolysis Yes No the UK and a mean age of onset of approximately 34,
Autoimmune Yes No though it can occur at any age [45]. It is an acquired
haematopoietic disorder that arises from a somatic
Paroxysmal cold haemoglo- Yes No
binuria (PCH)
mutation of the phosphatidylinositol glycan class A
(PIG-A) gene in one or more haematopoietic stem cells,
Glucose-6-phospahte Yes No followed by non-malignant clonal expansion. This leads
dehydrogenase (G6PD)
deficiency
to a deficiency of glycosylphosphatidylinositol (GPI)-
anchored molecules including CD55 (decay accelerating
Drug reactions Yes No factor) and CD59 (inhibitor of membrane reaction) in
Insect/snake bite Yes No the plasma membrane. These are important regulatory
Malaria Yes Yes
proteins that inhibit the formation of the complement
membrane attack complex and thus prevent complement-
Paroxysmal nocturnal Yes Yes mediated cell lysis. PNH red bloods cells are conse-
haemoglobinuria (PNH)
quently more susceptible to both intravascular and
extravascular haemolysis and the resultant cell-free hae-
moglobin leads to the clinical manifestations of the dis-
ease as it exceeds the capacity of the body’s natural
48.3 Haemolytic Anaemias scavenging molecule, haptoglobin to remove it from the
circulation.
There are many causes of haemolytic anaemia, some of
which result in acute and/or chronic kidney disease 48.3.1.2 Clinical Manifestations
(. Table 48.2). Free heme-containing proteins cause Paroxysmal nocturnal haemoglobinuria is typically
renal injury via a number of mechanisms including oxi- characterised by episodic haemolytic anaemia in associ-
dative stress, vasoconstriction (through scavenging of ation with dark discoloration of the urine in the absence
nitric oxide), chronic inflammation and haemosiderin of red cells, most notably in the first urine voided in the
deposition. ABO incompatible blood transfusion used morning. It is of varying severity and occurs either in
to be the most common cause of haemolysis-associated isolation (classic PNH) or in association with aplastic
AKI, but this is becoming increasingly rare with the anaemia or myelodysplastic syndrome. Other clinical
advent of robust blood banking and dispensing prac- manifestations include venous thrombosis often affect-
tices. However, usually insignificant and untested for ing the hepatic and mesenteric veins, episodic dyspha-
antibodies may rarely cause acute haemolysis if a patient gia, abdominal pain and kidney disease, both acute and
is unwittingly transfused with incompatible blood. [44] chronic.
Autoimmune haemolytic anaemia, if severe, may
also cause AKI, though other concurrent conditions 48.3.1.3 Renal Disease
such as dehydration or sepsis are often exacerbating fea- When the binding capacity of haptoglobin is exceeded,
tures. Paroxysmal cold haemoglobinuria (PCH) is a self- haemoglobin dimers circulate in the plasma and are fil-
limiting, postinfectious, cold-agglutinin-mediated form tered by renal glomeruli. The dimers are resorbed in the
of haemolytic anaemia, which occurs in children, is proximal tubules and degraded, and the iron is stored as
occasionally associated with AKI and needs to be dis- ferritin in the epithelium of the proximal tubules. Severe
tinguished from paroxysmal nocturnal haemoglobin- and sudden haemolysis often occurs in conjunction with
uria. Other causes of haemolysis associated with kidney gastroenteritis and the combination of heavy haemoglo-
injury include malaria, paroxysmal nocturnal haemo- binuria and dehydration can lead to AKI. Management
globinuria, glucose-6-phosphate dehydrogenase defi- is thus supportive including rehydration, and the kidney
ciency, drug reactions and snake and insect bites. injury is usually self-limiting [46].
Red Cells and the Kidney
839 48
effected haematopoietic clone. Specific tests for PNH
a
include the Ham test in which complement is activated
by reducing the pH of fresh serum to 6.4, leading to red
blood cell lysis. The gold standard test, however, involves
detection a population of cells deficient in the GPI-
anchored proteins CD55 and CD59 using monoclonal
antibodies followed by flow cytometry [47]. Renal biopsy
invariably demonstrates haemosiderosis with iron depo-
sition in the proximal tubular cells (. Fig. 48.4). Other
features may include interstitial inflammation and fibro-
sis [48]. The renal iron deposition can also be clearly
identified by magnetic resonance imaging (MRI), which
typically shows reversed renal cortex-medulla differen-
tiation on T(1)-weighted images and substantial loss of
cortical signal intensity on both T(1)- and T(2)-weighted
b
images [49].
48.3.1.5 Treatment
Although a proportion of patients (10–15%) go into
spontaneous remission, the only curative treatment for
the remaining patients is haematopoietic cell transplan-
tation. However, the treatment of PNH has been trans-
formed over the last 10 years by the development of
eculizumab, a humanised monoclonal antibody that
binds to the C5 component of complement and inhibits
terminal complement activation. This drug not only
improves the signs and symptoms associated with the
disease but also improves life expectancy, although there
is a subgroup of patients whose response to treatment is
suboptimal. Eculizumab has specifically been shown to
improve or stabilise kidney function in patients with
. Fig. 48.4 a x600 H&E. Golden-coloured haemosiderin in the
cytoplasm of the tubular epithelial cells of a patient with intravascu- established renal disease secondary to PNH and is also
lar haemolysis. b x400 Perls-stained section to demonstrate the iron effective at managing other manifestations of the disease
in the haemosiderin-laden tubular epithelial cell cytoplasm. The iron in patients on renal replacement therapy [50].
granules are stained blue in this preparation
48
a list of drugs to be avoided in patients with G6PD,
. Table 48.3 Drugs to be avoided in patients with G6PD
deficiency
though this is not exhaustive [54, 55].
48
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843 49
Multiple Myeloma
and the Kidney
Ritika Rana, Paul Cockwell, and Jennifer Pinney
Contents
References – 858
Multiple Myeloma and the Kidney
845 49
n Learning Objectives
1. All patients with unexplained AKI should be Monoclonal protein (M protein) or monoclonal immuno-
screened for a monoclonal protein (paraprotein). globulin (MIg) or paraprotein: Abnormal Ig or its com-
This screen should include serum protein electropho- ponents (heavy chain or light chain) present in the serum
resis and a serum or urinary free light chain assay. or urine; produced by an abnormal monoclonal prolifera-
2. A monoclonal gammopathy can produce renal dis- tion of a plasma cell or another cell of B-cell lineage.
ease regardless of the quantity of paraprotein or
whether the underlying cause is benign or malignant.
3. Paraprotein-related renal diseases can present as
AKI, progressive proteinuric renal disease, and/or Dysproteinaemia: An abnormality of the monoclo-
as Fanconi syndrome. nal Ig content of blood.
4. Prompt commencement of chemotherapy is crucial
in MM and AKI, and patients with MGRS usually
require chemotherapy.
Monoclonal disease: A monoclonal protein is pres-
ent in the blood or urine, and there is tissue damage
49.1 Introduction associated with that protein.
CH
Multiple Myeloma and the Kidney
847 49
intact Ig, changes in involved serum FLC levels are a better The range of haematological disorders that can
marker of early disease response than intact (clonal) Ig. produce MGRS includes MGUS (although this is con-
Given the important role of kidneys in the clearance fusing as by definition it is not MGUS), smouldering
of FLCs, in patients with a low GFR, the normal serum multiple myeloma (SMM), smouldering Waldenström
free light chain (sFLC) ratio shifts up, because κFLC is macroglobulinemia (WM), monoclonal B-cell lympho-
differentially retained as it has a lower MW: this means cytosis (MBL), low-grade chronic lymphocytic lym-
that the upper limit of the normal range for the sFLC phoma (CLL), and other low-grade lymphomas.
ratio in a patient receiving dialysis treatment is 3.17. The The International Kidney and Monoclonal Gam-
normal range ratio in normal kidney function is 0.26– mopathy (IKMG) research group has proposed a clas-
1.65 [11]. sification system for MGRS-associated lesions based
on immunofluorescence (IF) and the ultrastructural
appearance of in situ deposits, categorised as organised
49.5 Paraprotein-Related Renal Disease and non-organised (. Fig. 49.3). This emphasises that
MGRS can only be fully assessed by pathology depart-
The clonal proliferation of plasma cells or other cells of ments that have available IF for a full panel of antibod-
B-cell lineage can be malignant or non-malignant. The ies and electron microscopy (EM).
paraprotein produced in these cells can result in a diverse The deposition of the MIg can occur in the glom-
range of renal disorders. Whilst most paraprotein-related eruli, the tubulointerstitium, and/or the vasculature,
renal disease is due to the direct effects of the MIg LCs, with glomerular capillaries and mesangium, being a pre-
it can also be due to intact Ig or HC Ig. Occasionally ferred site for deposition [12]. LC deposition in the kid-
(e.g. C3 glomerulopathy), the renal disease is due to a ney is most commonly seen, deposition of the whole Ig
distal effect of a MIg. The classification of paraprotein- is less frequent, and monoclonal HC deposition is rare.
related renal disease is shown in . Fig. 49.2. MGRS may be underappreciated in clinical practice
since patients with renal dysfunction often have other
plausible explanations for their deteriorating renal
function, and the monoclonal protein is considered
49.5.1 Monoclonal Gammopathy of Renal coincidental rather than causal [13]. Also, the disease
Significance-Associated Renal spectrum is wide with manifestations ranging from labo-
Disease ratory results suggestive of a tubulopathy (e.g. Fanconi
syndrome) to proteinuria and renal impairment, which
The term MGRS is used to describe a B-cell lineage is often progressive.
clonal proliferation with: 1) one or more renal lesions If a monoclonal protein is detected in patients with
caused by the produced MIg and 2) a clone that does unexplained renal dysfunction or urinary abnormalities
not cause tumour complications or meet current haema- (proteinuria or haematuria), a complete haematologic
tological criteria for immediate specific therapy. Most workup must be carried out if a renal biopsy then shows
of these patients have a low-grade clone consistent with a MGRS-associated renal lesion. A critical aspect of the
that seen in MGUS; however, unlike in MGUS, the renal biopsy is to correlate the specific Ig found in the
monoclonal protein causes end-organ damage. The renal kidney with the circulating paraprotein to ensure a direct
lesion is a consequence of the physico-chemical proper- link between the MG and renal lesion is established [14].
ties of the clone rather than the nature of the underlying Treatment of MGRS-associated kidney disease is
clonal lymphoproliferation. Renal disease secondary to often indicated to preserve or restore kidney function
MGRS is termed an MGRS-associated renal lesion. and prevent recurrence after kidney transplantation.
Non-malignant clonal
Malignant clonal proliferation. proliferation.
(Myeloma, WM, CLL) (MGRS related)
848 R. Rana et al.
Organized Non-organized
PGNMID
Light Chain Proximal
Alg Amyloidosis Immunotactoid GN
Tubulopathy
C3 glomerulopathy
with monoclonal
Monoclonal Fibrillary Cryoglobulinemic GN Crystal storing gammopathy
GN Type I and II histiocytosis
Crystaloglobulin GN
. Fig. 49.3 Classification of MGRS-associated renal lesions based noglobulin amyloidosis, GN glomerulonephriti, MIDD monoclonal
on the ultrastructural appearance of deposits. (Adapted with per- immunoglobulin deposition disease, PGNMID proliferative glomer-
mission from Bridoux et al. (2015). Ig immunoglobulin, AIg immu- ulonephritis with monoclonal immunoglobulin deposits)
The choice of chemotherapy regimen depends on the Later oncogenic events include the following: muta-
nature of underlying B-cell clone; i.e. lymphocytic or tions or expression-mediated activation of oncogenes,
plasmacytic in origin [15]. The renal response strongly loss of function of onco-suppressor genes, overexpres-
correlates with the nature of the haematologic response, sion of anti-apoptotic proteins, secretion of various
and rapid suppression of Ig secretion with chemother- cytokines, growth factors, and chemokines. Each of
apy is required to improve outcomes [15]. For patients these processes may have a role in supporting cancer cell
who have progressed to end-stage renal failure, kidney growth, survival, and resistance to therapies and occur in
transplantation may be an option for those with a sus- the bone marrow [18]. Genetic, epigenetic, and biological
tained haematologic response [16]. events occurring in the cancer clones and bone marrow
microenvironment all play a role in pathogenesis [18].
49.6 Pathogenesis of MM
49.7 Evolution and Development of
Myeloma is a genetically complex disease and intra-clonal Myeloma
heterogeneity is a common feature [17]. A plasma cell
becomes malignant through an accumulation of genetic MM almost always evolves from MGUS. Patients with
hits across different cellular pathways, leading to dysregu- MGUS have a 1% per year lifelong rate of malignant
lation of the intrinsic biology of the cell over time [18]. transformation; therefore, most individuals with MGUS
There appears to be interplay between tumour cell do not develop MM. The risk of progression is related
genetics and the local microenvironment. The first to the concentration of the monoclonal protein, sFLC
oncogenic events may occur in the germinal centre ratio, BM plasmacytosis, proportion of phenotypically
during somatic hypermutation and isotype switching, clonal plasma cells, and presence of immune paresis [20,
and the plasma cell differentiates into a long-lived cell 21]. The monitoring strategy for a patient with known
[19]. These initial mutations also occur in premalignant MGUS will be determined by risk of progression.
plasma cell dyscrasias (MGUS and SMM), suggesting The incidence of MGUS increases with age and is
they are necessary but not especially causative in the present in 3% of white individuals = > 50 years old [22].
pathogenesis of MM. About 80% of MM originates from non-IgM intact
Multiple Myeloma and the Kidney
849 49
. Table 49.1 International Myeloma Working Group diagnostic criteria and classification for monoclonal gammopathy of
undetermined significance and smouldering multiple myeloma
Non-IgM Serum monoclonal protein (non-IgM type) <30 g/L 1% per year MM, solitary plasmacy-
MGUS Clonal bone marrow plasma cells <10% toma, immunoglobulin-
Absence of end-organ damage, i.e. CRAB lesions or amyloidosis that related amyloidosis
can be attributed to the plasma cell proliferative disorder
IgM Serum IgM monoclonal protein <30 g/L 1·5% per year Waldenström macroglobu-
MGUS Bone marrow lymphoplasmacytic infiltration <10% linaemia, immunoglobulin-
No evidence of anaemia, constitutional symptoms, hyperviscosity, related amyloidosis
lymphadenopathy, hepatosplenomegaly, or other end-organ damage
that can be attributed to the underlying lymphoproliferative disorder
Light Abnormal FLC ratio (<0·26 or >1·65) 0·3% per year Light chain MM,
chain Increased level of the appropriate involved light chain (increased κ FLC immunoglobulin light chain
MGUS in patients with ratio >1·65 and increased λ FLC in patients with amyloidosis
ratio <0·26)
No immunoglobulin heavy chain expression on immunofixation.
Absence of end-organ damage such as CRAB lesions or amyloidosis
that can be attributed to the plasma cell proliferative disorder
Clonal bone marrow plasma cells <10%
Urinary monoclonal protein <500 mg/24 h
Smoulder- Both criteria must be met: 10% per year MM
ing MM Serum monoclonal protein (IgG or IgA) ≥30 g/L or urinary monoclo- in the first
nal protein ≥500 mg per 24 h and/or clonal bone marrow plasma cells 5 years
10–60%
Absence of myeloma defining events or amyloidosis
Ig MGUS and 20% from light chain only (LCO) Ig 49.8 Diagnosis
MGUS [23].
LCO MGUS has a lower rate of evolution to MM The IMWG updated the diagnostic criteria for MM in
compared to intact Ig producing MGUS [24]. When IgM 2015 (7 Box 49.1). The revised criteria comprise the
MGUS evolves into a disease, this is usually to WM; presence of clonal plasma cells and either a myeloma
rarely IgM MGUS can progress to IgM myeloma [25, 26]. defining event of one or more of the classic ‘CRAB’ fea-
The diagnosis of MGUS requires the absence of end- tures of hypercalcemia, renal failure, anaemia, and/or
organ damage attributed to the clone of B-cell lineage or destructive bone lesions or evidence of a heavy tumour
the monoclonal gammopathy produced by the clone. burden defined by one or more of >60% plasma cells on
SMM is an intermediate asymptomatic clinical stage BM biopsy, sFLC ratio of >100, or >1 focal bone lesion
between MGUS and MM, and patients have a 10%/year on MRI scan [28].
risk of progression to MM within the first 5 years of These criteria allow for the recognition and treat-
diagnosis, which then progressively reduces but never ment of high-risk patients (i.e. patients with 80% risk of
disappears; therefore, SMM requires more frequent progression of SMM to MM within 2 years), in whom
monitoring than MGUS [27]. treatment would clearly be beneficial before serious end-
It is important to note that not all patients with organ damage has occurred.
myeloma precursor diseases will develop overt MM. Refer The requirement for monoclonal protein as a part of
to . Table 49.1 for International Myeloma Working diagnostic test criteria is not mandatory as 3% of MM
Group (IMWG) definition and diagnostic criteria for patients have non-secretory MM (NSMM) character-
MGUS and SMM. ised by no M-protein in the serum or urine on immuno-
For MM, the diagnosis requires either a myeloma fixation at the time of diagnosis; 30% of these patients
defining event (see 7 Box 49.1) or a heavy tumour bur- with NSMM have a normal FLC assay, despite clearly
den. having MM as defined by other criteria.
850 R. Rana et al.
49 Box 49.1 Revised International Myeloma Working Group Diagnostic Criteria for Multiple Myeloma. Repro-
duced with Permission from Rajkumar et al. (2014)
Definition of multiple myeloma: 5 Clonal bone marrow plasma cell percentage* ≥60%.
Clonal bone marrow plasma cells ≥10% or biopsy- 5 Involved: uninvolved serum free light chain
proven bony or extramedullary plasmacytoma7 * and any ratio > =100§.
one or more of the following myeloma defining events: 5 >1 focal lesions on MRI studies. Each focal lesion
Evidence of end-organ damage that can be attributed must be 5 mm or more in size.
to the underlying plasma cell proliferative disorder, spe- 5 *Clonality should be established by showing κ/λ-light
cifically: chain restriction on flow cytometry, immunohisto-
5 Hypercalcaemia: serum calcium >0·25 mmol/L chemistry, or immunofluorescence
(>1 mg/dL) higher than the upper limit of normal 5 †Measured or estimated by validated equations
or >2·75 mmol/L (>11 mg/dL). 5 ‡If bone marrow has less than 10% clonal plasma
5 Renal insufficiency: creatinine clearance <40 mL per cells, more than one bone lesion is required to distin-
min† or serum creatinine >177 micromol/L (>2 mg/dl). guish from solitary plasmacytoma with minimal mar-
5 Anaemia: haemoglobin value of >20 g/L below the row involvement
lower limit of normal, or a haemoglobin value 5 §These values are based on the serum Freelite assay
<100 g/L. (The Binding Site Group, Birmingham, UK). The
5 Bone lesions: one or more osteolytic lesions on skele- involved free light chain must be ≥100 mg/L. The
tal radiography, CT, or PET-CT7 ‡. involved free light chain, either κ or λ, is the one that
is above the normal reference range; the uninvolved
Any one or more of the following biomarkers of malig- free light chain is the one that is typically in or below
nancy: the normal range.
49.9 Prognostic Factors The IMWG criteria has been recently updated to
clarify that only renal failure caused by light chain cast
Prognosis in MM can be stratified by the International nephropathy (based on typical histological changes
Staging System (ISS) and chromosomal abnormalities or presumptive diagnosis based on the presence of
[29]. The ISS incorporates beta 2 microglobulin (B2M), high involved FLC levels, >1500 mg/l) is regarded as a
serum albumin, and reflects tumour burden, renal function myeloma defining event. The IMWG threshold for cast
(as a function of B2M renal clearance), and patient fitness. nephropathy is higher than that recommended by the
BM karyotype, translocations, chromosome number, and International Kidney and Monoclonal Gammopathy
gene expression profiling also have prognostic value [30]. (IKMG) Research group (>500 mg/L). The published
Although detection of any cytogenetic abnormality literature indicates that the threshold sFLC at which
is considered to suggest higher-risk disease, the specific there is a risk of MCN by the involved LC is 500 mg/L.
abnormalities considered poor risk are cytogenetically A renal biopsy should be reserved for diagnostic
detected chromosomal 13 or 13q deletion, t(4;14) and uncertainty, such as patients with an involved FLC
del17p, and detection by fluorescence in situ hybridiza- level <500 mg/L and or heavy albuminuria, which may
tion of t(4;14), t(14;16), and del17p [31]. indicate the presence of a different renal pathology (e.g.
Detection of 13q deletion by fluorescence in situ AL amyloidosis) (. Fig. 49.4).
hybridization only, in the absence of other abnormali-
ties, is not considered a high-risk feature.
49.11 Impact of Kidney Disease
on Prognosis
49.10 Definition of Renal Failure in MM
The survival of patients who present with impaired
The IMWG recommends using estimated glomerular fil- kidney function has been improved by the use of novel
tration rates (eGFR) for the evaluation of renal function agents, in particular regimens that included the protea-
in patients with MM with a stable creatinine. An eGFR some inhibitor bortezomib [32].
threshold of less than 40 ml/min/1.73m2 has now been Dialysis has a major impact on the survival of
adopted to define renal impairment in MM consistent patients with MM; however, survival is improving in
with evidence of renal end-organ damage that fulfils the patients with MM who require dialysis with a median
diagnostic criteria. overall survival of 14 months [4]. Over 50% of patients
Multiple Myeloma and the Kidney
851 49
. Fig. 49.4 Algorithm for
evaluation of suspected Suspected paraprotein-related
paraprotein-related kidney kidney disease
disease. (SPE serum protein
electrophoresis, sFLC serum free
light chain, UPEP urine protein
electrophoresis, UIFE urine
immunofixation) SPE and sFLC (If sFLC not
available use UPEP/UIFE).
Check urine albumin excretion.
who present with AKI and require dialysis now recover further compromising renal function [34]. The reduced
independent renal function with an associated improve- tubular clearance of FLC further increases their con-
ment in survival [33]. centration in the tubules and contributes to the vicious
cycle that results in MCN (. Fig. 49.6). This lesion can
quickly progress to end-stage renal disease [34].
49.12 Pathogenesis of MM and Kidney An involved free light chain level in excess of 500 mg/l
Disease can cause MCN [35]. However, most patients with lev-
els >500 mg/L will not develop the lesion and require
Many patients with newly diagnosed MM have mild to serum levels of several g/L of the involved LC before
moderate renal impairment, which is usually transient MCN develops. The threshold for cast formation is
and reversible. This is generally a consequence of dehy- dependent on the structural features of the involved LC
dration, infection, hypercalcemia, use of contrast agents, and cofactors that increase the likelihood of cast for-
and /or prescription of non-steroidal anti-inflammatory mation including low pH, dehydration, hypercalcemia,
drugs (NSAIDs). With more severe AKI, the dominant NSAIDs, diuretics, and radiological contrast media.
lesion is MCN; for patients who have dialysis-dependent Light chain endocytosis may also cause acute tubu-
AKI, MCN is present in 90%. lar necrosis; aggregation of light chains after endocyto-
Serum FLCs are normally freely filtered by the sis may initiate a cascade resulting in tubular cell death
glomerulus and reabsorbed in the proximal tubule via [34]. Light chains may lead to functional impairment
receptor-mediated endocytosis. MCN develops when of tubular cells, in which case Fanconi syndrome may
an excessive load of the involved FLC overwhelms the present. Focal loss of microvilli and inhibition of Na-K-
capacity of the tubular cells to catabolise them, with ATPase may lead to reabsorption defects [36].
subsequent significant level in the tubular fluid of distal Some myeloma patients also have a urine con-
nephron segments. Here, FLCs bind to Tamm-Horsfall centration defect, probably due to tubulo-interstitial
protein (uromodulin), a glycoprotein synthesised by changes, and nephrogenic diabetes insipidus due to
the cells in the medullary thick ascending limb of the unresponsiveness to ADH, thus further promoting
loop of Henle to form tubular casts (. Fig. 49.5). Light dehydration [37].
chains interact through their complementary determin- Hypercalcemia is an important common cause of
ing region with a specific binding site on Tamm-Horsfall renal impairment in MM. Hypercalcemia impairs renal
protein to form aggregates and casts that subsequently concentrating ability. It causes vasoconstriction of renal
lead to the tubular obstruction of the distal tubule and vasculature and enhances diuresis, which may result in
the thick ascending loop of Henle. hypovolemia and prerenal azotemia [34]. Concentrated
Tubular obstruction increases intraluminal pressure, urine and reduced urine flow enhance cast formation,
reduces GFR, and reduces interstitial blood flow, thus thus leading to further renal damage [34].
852 R. Rana et al.
49
those historically reported. However, patients in these 49.14.7 Preventing and Managing Bone
49 studies received novel chemotherapy (usually bortezo- Disease
mib based) and assessed the relationship between FLC
level and renal function in dialysis-dependent patients Bone destruction and hypercalcaemia are very common
treated with chemotherapy and HCO dialysis. in MM. Hypercalcemia is a consequence of osteoclast-
Two randomised controlled trials have been recently mediated osteolysis and inhibition of osteoblast
completed: the MYRE and EuLITE studies both reported function. Intravenous bisphosphonates are a critical
no difference in renal recovery at 3 months in patients component of supportive care; in addition to treatment
treated with HCO-HD compared to HF-HD. There of hypercalcaemia, bisphosphonates reduce skeletal-
was an increase in overall renal recovery in the MYRE related events and have anti myeloma properties [42].
study, but not in the EuLITE study, where there was an Bisphosphonates are recommended for all MM patients
increased mortality reported by 2 years in patients who requiring therapy, which should be continued with active
received HCO-HD. disease and reassumed after disease relapse.
There is not sufficient evidence of benefit to support To prevent bone disease in patients with myeloma,
the use of HCO-HD in routine clinical practice. zoledronic acid should be offered. If zoledronic acid is
contraindicated or not tolerated, disodium pamidronate
should be given. If zoledronic and disodium pamidro-
49.14.4 Supportive Care nate are contraindicated, not tolerated or not suitable
sodium clodronate should be offered [8].
Careful attention to fluid and electrolyte, infection, drug The UK MRC IX trial showed that zoledronic acid
use, and bone management is mandatory. An individu- was associated with better outcomes than clodronate;
alised approach is required for provision of support- however, it should be avoided in patients with an eGFR
ive care. For example, whilst a high oral fluid intake is <30 ml/min/1.73m2.
important for the dilution of light chains to decrease the At present, intravenous pamidronate at an adjusted
likelihood of ongoing cast formation and direct tubular dose should be used for the management of hypercal-
toxicity, in patients with oligo-anuria or pre-existing car- caemia and to facilitate immediate bone stabilization in
diac disease this may require reassessment. patients with an eGFR <30 ml/min/1.73m2. If the kidney
function does not subsequently improve to an eGFR of
≥30 ml/min/1.73m2, a dialogue with haematology col-
49.14.5 Fluid Balance and Acid-Base Status leagues is recommended to produce an individualised risk
assessment that can then be discussed with the patient.
As long as there are no contraindications, then the aim
should be to maintain a urine output of 3 L a day. Salt
loading should be avoided, as increased tubular NaCl 49.14.8 Preventing Infection
concentrations can precipitate cast formation. Loop
diuretics are contraindicated as they both increase intra- Patients with MM are at increased risk of infections, as
tubular sodium and lower intra-tubular pH. Animal and a consequence of disease-related immunodeficiency as
in vitro studies have indicated that casts are more likely well as anti-myeloma therapy. Humoral immunity can
to precipitate with a more acidic milieu. be overestimated by not accounting for the M-protein
Maintenance of adequate hydration, tissue oxygen- when interpreting the levels of intact Ig isotype. For
ation, avoidance of infection, and timely commencement example, patients with an intact IgG clone may have
of dialysis treatment should prevent the development of ‘normal IgG’ levels, but the major component of IgG
systemic acidosis. may be clonal with no useful biologic activity, and there
may be profound depression of humoral immunity.
Patients with MM develop suboptimal antibody
49.14.6 Drugs responses; however, they should be offered seasonal influ-
enza and pneumococcal vaccination. Patients with hypo-
Drugs that can decrease renal perfusion are contraindi- gammaglobulinemia and recurrent infections should be
cated, and all medications should be justified as clinically considered for intravenous Ig replacement therapy.
appropriate for the patient. Drugs should be adjusted Antiviral prophylaxis is recommended after treatment
for renal impairment; clinicians often overlook that with bortezomib or other proteasome inhibitors, in those
most drug dose adjustments based on kidney function on immunomodulatory drugs and high-dose steroids as
utilise the Cockroft-Gault calculation, not MDRD. In these are associated with reactivation of varicella zoster.
patients with rapidly progressive AKI, there should be Antibacterial prophylaxis is commonly included in dexa-
an assumption that the GFR is <15 mls/min/1.73m2 . methasone containing and multi agent regimens.
Multiple Myeloma and the Kidney
855 49
Consider testing for hepatitis B, hepatitis C, and HIV a potential diagnosis and recognise the urgency in prompt
before starting treatment for MM. treatment will optimal care be delivered. It is important
to emphasise that involvement of a speciality is depen-
dent on a specific indication and involvement can occur
49.14.9 Managing Peripheral Neuropathy anywhere from diagnosis through to end-of-life care.
There is evidence that the diagnosis of MM may be
Peripheral neuropathy is an important toxicity of both tha- delayed when the initial presentation of the patient is to
lidomide and bortezomib occurring in up to 50% of patients a nephrologist [44]. The multidisciplinary team who may
[43]. Peripheral neuropathy from thalidomide is cumula- be involved in the diagnosis and management of MM
tive, dose dependent, and usually permanent. Peripheral are shown in 7 Box 49.2.
neuropathy from bortezomib is related to dose, schedule,
and mode of administration and mostly reversible [29].
Patients receiving bortezomib who develop neuropathic Box 49.2 Multidisciplinary and Medical Spe-
pain should be considered for switching to subcutaneous cialty Involvement in the Diagnosis and Manage-
injections and/or dose reduction. Those on a drug other ment of MM
than bortezomib should be considered for dose reduction. Multidisciplinary specialists
Prompt dose reductions are required with development of 5 Haematology clinical nurse specialists.
neuropathy of any grade with thalidomide. 5 Dialysis nurses.
5 Research nurses.
5 Pharmacists.
49.14.10 Preventing Thrombosis 5 Physiotherapists.
5 Occupational therapists.
Immunomodulatory drugs (thalidomide, lenalidomide) 5 Social workers.
when combined with steroids result in a marked increase 5 Psychologists.
in thromboembolic events. The rate of venous thrombo-
embolism in these regimes ranges from 20 to 40% with- Medical specialties
out prophylaxis [29]. 5 General practitioners.
For people with myeloma who are starting immu- 5 Haematologists.
nomodulatory drugs, thromboprophylaxis with either 5 Nephrologists.
low-molecular-weight heparin at a prophylactic dose or 5 Neurosurgeons (to manage spinal cord compres-
vitamin K antagonists at a therapeutic dose to maintain sion).
an INR of 2–3 should be offered. 5 Clinical oncologists (radiotherapy to bone lesions).
If low-molecular-weight heparin or vitamin K antag- 5 Palliative care specialists.
onists are contraindicated, low-dose aspirin should be 5 Pain control specialist.
considered [8].
Full anticoagulation should be considered in patients
with nephrotic syndrome or heavy proteinuria, espe-
Tips and Tricks
cially when commencing immunomodulatory drugs.
1. If the sFLC results do not fit with the clinical pic-
ture, discuss with the laboratory about the possi-
49.14.11 Managing Fatigue bility of antigen excess.
2. In new patients presenting with AKI who have an
If other treatable causes have been excluded, consider abnormal sFLC (>500 mg/L), commence dexa-
erythropoietin analogues adjusted to maintain steady state methasone treatment following discussion with
of haemoglobin at 110–120 g/litre, to improve fatigue in haematology colleagues. Do not delay treatment
people with myeloma who have symptomatic anaemia [8]. whilst waiting for further diagnostic tests.
3. IF is required to rule out MGRS, many institu-
tions don’t routinely offer this test, and samples
49.15 Multidisciplinary Working in MM may need to be sent to an alternative laboratory.
Always liaise with histology colleagues if you are
Although MM is a haematological malignancy, it may performing a biopsy to look for MGRS to ensure
present to a variety of specialties and when diagnosed the relevant test is requested. In addition, ensure
will often require the input of a multidisciplinary team. that EM assessment is performed.
Only when all members of this team are aware of MM as
856 R. Rana et al.
Case Study
49
Case 1 5 MM commonly affects elderly people, acting as a
An 86-year-old African American man with a previous chronic disease for the rest of the patients’ life;
diagnosis of cardiomyopathy with congestive cardiac fail- patients may subsequently die of unrelated dis-
ure, chronic obstructive pulmonary disease, and prostate eases.
cancer presented to the hospital with pneumonia and AKI 5 With prompt disease-specific management patients can
requiring dialysis. recover independent renal function, although this may
On presentation, he had a haemoglobin of 109 g/L not be to their previous baseline.
(normal range 130–180 g/L), and serum calcium level was 5 Myeloma has good disease outcomes for the very old
normal. His urine dipstick was negative for blood and and therefore full treatment may be indicated.
showed a trace of protein, and ACR was 8 mg/mmol. A
renal tract USS was normal. Case 2
A myeloma screen showed an IgA Kappa paraprotein A 67-year-old Caucasian man was admitted with a
on immunofixation, and clonal Ig quantitation was 2-month history of weight loss and left flank pain. On pre-
5.88 g/L. Serum Ig levels were normal; sFLC results sentation, he had stage 3 AKI (MDRD eGFR 3 ml/min,
showed evidence of FLC clonality with LC of 852.0 mg/l, creatinine 1500 micromol/l) and required dialysis.
λ LC of 18.59 mg/l, and a κ:λ ratio of 45.83. Haemoglobin was 81 g/L (haematinics normal), and cal-
Immunology profile revealed a negative ANCA and cium was normal. Urinalysis showed 2 + protein and 3+
ANA, and complement levels were normal. A skeletal sur- blood and ACR 11.3 mg/mmol. The renal tract USS was
vey didn’t show any lytic lesions; BM trephine biopsy normal.
showed a 20% clonal population of plasma cells consistent An IgA lambda paraprotein was present on immuno-
with a diagnosis of MM. fixation, and clonal immunoglobulin quantitation was
He was started on weekly bortezomib- (Velcade), cyclo- 26 g/L. Serum Ig showed immunoparesis (IgG 2.04 g/L,
phosphamide-, and dexamethasone-based chemotherapy IgA 27 g/L, IgM 0.02 g/L), and sFLC results showed evi-
(VCD). At 1 month post presentation, he recovered inde- dence of free LC clonality with κ LC of 15 mg/l, λ LC of
pendent renal function to an eGFR of 25 ml/min/1.73 m2. 5835 mg/l, and a κ:λ ratio of 0.003. ANCA, ANA, and
The patient completed four cycles of VCD with a very complement levels were normal.
good partial response (VGPR) (IgA paraprotein fell from A BM trephine biopsy showed neoplastic plasma cells
5.8 g/L to 0.4 g/L and κ LC fell from 852 mg/l to 80 mg/l); accounting for 60–70% of the cellularity, and skeletal sur-
however, he developed a painful ulcer on the tip of the left vey did not reveal any lytic lesion.
hallux, which was slow to heal. He received five cycles of VCD chemotherapy with a
For cycle 5, he was switched to fortnightly bortezomib VGPR (IgA paraprotein fell from 26.6 g/L to 0.5 g/L, and
and dexamethasone; however, his chemotherapy had to be serum free lambda light chain level fell from 5835 mg/l to
discontinued because of increasing foot pain, and as there 39 mg/l).
was a concern this could be neuropathic. Despite stopping Within a month of starting chemotherapy, patient
the chemotherapy, his symptoms did not improve. recovered independent renal function (to an eGFR 35 ml/
He was then seen in the vascular clinic as an arterial min/1.73m2) and reached a long-term steady state (of
duplex scan of left lower limb revealed >75% stenosis of eGFR 75 ml/min/1.73m2) at 8 months post presentation.
left superficial femoral artery and occluded anterior tibial The patient underwent an ASCT after completing five
artery. A MRI foot ruled out osteomyelitis or any lytic cycles of VCD and is currently ten post-transplant and in
lesion. Given his frailty and comorbidities, the vascular remission.
team decided to manage him conservatively. This case illustrates that:
His renal function slowly continued to improve (to an 5 Patients present with nonspecific symptoms and often
eGFR 40 ml/min/1.73 m2 at 8 months post presentation); how- there is a delay in presentation.
ever, he was becoming increasingly frail with time. From the 5 ASCT is not a curative procedure but extends the
haematological perspective, he continued to be in remission. length of time disease is controlled for, typically for 2
He developed gangrene in left hallux secondary to and a half years to 3 years.
peripheral vascular disease and died 15 months later sec- 5 The renal response depends on the quality of the hae-
ondary to pneumonia. matologic response, and rapid suppression of Ig secre-
This case illustrates that: tion with chemotherapy improves outcomes.
Multiple Myeloma and the Kidney
857 49
4. Frailty, performance status measures, and comor- 16. Herrmann SM, Gertz MA, Stegall MD, Dispenzieri A, Cosio
49 bidities are used to determine eligibility for stem FC, Kumar S, et al. Long-term outcomes of patients with
light chain amyloidosis (AL) after renal transplantation with
cell transplant.
or without stem cell transplantation. Nephrology Dialysis
5. Novel chemotherapy agents especially bortezo- Transplantation. 2011;26(6):2032–6.
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32. Uttervall K, Duru AD, Lund J, Liwing J, Gahrton G, Holmberg 39. Clark WF, Stewart AK, Rock GA, Sternbach M, Sutton DM,
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861 50
Contents
References – 874
Amyloidosis and the Kidney
863 50
n Learning Objectives
. Table 50.1 Systemic amyloidoses commonly associated
1. To understand the basis of amyloidosis, its clinical with kidney involvement
presentation, renal involvement, associations and
management. Amyloid Fibril precursor Note
type
50
. Fig. 50.1 Molecular events leading to amyloidosis. Interaction antisense oligonucleotides (ASO). Small molecules capable of stabi-
of the misfolded protein with the extracellular environment may lising the amyloid precursor and preventing its misfolding and aggre-
result in proteolytic cleavage and binding to matrix components, gation (diflunisal, tafamidis) are being tested in patients with ATTR
such as glycosaminoglycans (GAGs) and collagen, that facilitate amyloidosis. Inhibitors of proteases (secretase) and compounds
aggregation. Several lines of evidence support a role for extracellular interfering with the binding of GAGs to amyloid proteins (eprodis-
chaperones in the in vivo clearance of aggregation-prone extracellu- ate) are being evaluated in trials. SAP can be cleared from amyloid
lar proteins. Serum amyloid P component (SAP) binds to amyloid deposits by using small palindromic drugs (CPHPC). The clearance
fibrils and protects them from reabsorption. The organ dysfunction of amyloid deposits can be promoted and accelerated by specific
may result from the combined action of the cytotoxic pre-fibrillar antibodies through passive and active immunotherapy. Small mole-
aggregates and of the amyloid deposits. Several new therapeutic cules, such as iododoxorubicin and doxycycline, have shown to be
approaches have been recently developed. The synthesis of the amy- able to disrupt the amyloid fibrils and have been tested in clinical
loid protein can be silenced using RNA interference (siRNA) or trials
clinical presentation among different ethnic groups and are remarkably consistent regardless of the constitu-
geographic areas [3]. ent polypeptide.
Amyloid deposition may occur in almost any organ. The exact incidence of AA amyloidosis is unclear, but
Nonetheless, specific amyloidogenic proteins tend favour it accounts for 4% of the cases of amyloidosis seen at
deposition in defined organs, for example, the kidney for major referral centres. It is always a complication of
fibrinogen Aα chain and leukocyte chemotactic factor 2 inflammation, and the list of chronic disorders that
and the joints and bones for wild-type β2-microglobulin. can be complicated by AA amyloidosis is summarised
In AL amyloidosis there is some evidence that the physi- in 7 Box 50.1. In industrialised countries, inflamma-
cochemical characteristics (amino acid composition and tory arthritides used to underlie 60%, but this is falling
conformation of the variable region) of the LC may be in the era of effective biologics [10]. For unexplained
the most significant factor in determining the type and reasons the incidence of AA amyloid is much lower in
location of organ dysfunction. the USA than in Europe. The median latency between
the onset of inflammation and diagnosis of amyloid
is approximately 17 years, but this varies from less
50.3 Epidemiology than a year to decades. The median age at diagnosis
is 50 years, but presentation in childhood, although
Systemic amyloidosis is a rare disease accounting for becoming less common, is still recognised. As with all
approximately 1 in 2000 deaths in the UK and presum- types of amyloidosis, AA appears slightly commoner
ably other developed countries [7]. Although cases of in men who account for 56% of the largest character-
amyloidosis have been reported in children, it is pre- ised series [11].
dominantly a disease of mid to late life and accounts for
4% of adult renal biopsies and 1.6% of patients starting
dialysis. 50.3.3 Dialysis-Related Amyloidosis (DRA)
50.5 Investigations has become the gold standard for identifying the amy-
loid fibril protein [19].
The diagnosis of amyloidosis relies on a high index of
50 clinical suspicion. Amyloid can be asymptomatic until
50.5.2 Imaging Amyloid Deposits
a relatively late stage and then present with highly vari-
able or non-specific symptoms. Amyloidosis should
be suspected in any patient with the following: non- 50.5.2.1 SAP Scintigraphy
diabetic nephrotic syndrome; non-ischemic cardiomy- SAP concentrates specifically in amyloid deposits of all
opathy, particularly if the echocardiogram suggests types. Radiolabelled SAP scintigraphy has been used
concentric hypertrophy; increased NT-proBNP in the since 1988 in the UK for diagnosis and quantitative
absence of primary heart or renal disease; hepatomegaly monitoring of amyloid deposits [20]. This safe, non-
or increased alkaline phosphatase without an imaging invasive method provides information on the presence,
abnormality; peripheral and/or autonomic neuropathy; distribution and extent of visceral amyloid deposits, and
unexplained facial or neck purpura; and macroglossia. serial scans monitor progress and response to therapy
Any patient with suggestive features should undergo (. Fig. 50.5). The method is not informative about
a biopsy to look for presence of amyloid deposits. amyloid deposition in the moving heart and is not com-
Identification of amyloid should prompt a series of mercially available.
investigations to determine the amyloid fibril protein
and organ involvement/dysfunction (. Table 50.3). 50.5.2.2 Imaging the Heart
The classical two-dimensional Doppler echocardio-
graphic appearance of cardiac amyloidosis is of con-
50.5.1 Histology centric biventricular wall thickening with a restrictive
filling pattern. Amyloid causes diastolic dysfunction
The diagnosis of amyloidosis requires histological with well-preserved contractility until a very late stage.
confirmation (. Fig. 50.4). Subcutaneous fat biopsy The ECG in advanced disease may show small voltages
(taken by aspiration of abdominal subcutaneous fat and pathological ‘Q’ waves (pseudo-infarct pattern).
under local anaesthetic using a 14 gauge needle), screen- The finding of abnormal gadolinium kinetics particu-
ing rectal biopsy and labial salivary gland biopsy are larly global late gadolinium enhancement on cardiac
between 60 and 80% sensitive. There have been con- magnetic resonance imaging has a high sensitivity and
cerns that organ biopsies in patients with amyloidosis specificity for cardiac amyloidosis and has substantially
carry an increased risk of haemorrhage, although firm contributed to diagnosis [21]. Scans following injec-
evidence of this is lacking. Congo red staining of amy- tion of technetium-99 m-labelled 3,3-diphosphono-1,2-
loid produces pathognomic apple green birefringence propanodicarboxylic acid (99Tc-DPD), an established
when viewed under cross-polarised light, and negatively bone tracer, are sensitive for detecting presence of car-
stained electron microscopy reveals 8–15 nm diameter diac ATTR amyloid deposits [22].
rigid, non-branching fibrils composed of twisted proto-
fibrils of indeterminate length. 50.5.2.3 DNA Analysis
The main protein constituting the amyloid deposit Hereditary amyloidoses are rare and often overlooked.
can often be identified by immunohistochemistry, Although all types are dominantly inherited, pen-
although this may be unreliable in AL and hereditary etrance and expressivity are highly variable, and there
amyloidosis [18]. Laser microdissection (LMD)- and is frequently no obvious family history. DNA analysis
tandem mass spectrometry (MS)-based proteomic anal- is mandatory in all patients with systemic amyloidosis
ysis can confirm the amyloid protein composition and whose fibril type cannot be confirmed by immunohis-
Amyloidosis and the Kidney
869 50
. Table 50.3 Investigation and staging of patient discovered to have amyloid deposits
BJP Bence Jones protein; sFLC serum free light chain; pp. paraprotein; SAA serum amyloid A protein; CRP C-reactive protein; MRI
magnetic resonance imaging; MEFV familial Mediterranean fever gene; TNFRSF1A TRAPS gene; MVK mevalonate kinase gene
870 J. D. Gillmore and H. J. Lachmann
a b
50
. Fig. 50.4 Sections of renal biopsy stained with Congo red viewed rial are seen within the glomeruli. b Pathognomonic apple green bire-
under x10 magnification. a Amorphous deposits of eosinophilic mate- fringence of amyloid deposits when viewed under cross-polarised light
best assessment is multimodality including bio- 16. Gillmore JD, Lachmann HJ, Rowczenio D, Gilbertson JA,
markers such as BNP, easily available tests includ- Zeng CH, Liu ZH, et al. Diagnosis, pathogenesis, treatment,
and prognosis of hereditary fibrinogen a alpha-chain amyloi-
ing ECG and echocardiography and specialised
dosis. J Am Soc Nephrol. 2009;20:444–51.
50 cardiac MRI and DPD scintigraphy.
5. The aim of treatment is to obtain an early, com-
17. Lobato L. Portuguese-type amyloidosis (transthyretin amyloi-
dosis, ATTR V30M). J Nephrol. 2003;16:438–42.
plete and sustained clonal response with minimal 18. Arbustini E, Morbini P, Verga L, Concardi M, Porcu E, Pilotto
treatment-related toxicity. Treatment is best han- A, et al. Light and electron microscopy immunohistochemi-
cal characterization of amyloid deposits. Amyloid. 1997;4(3):
dled by multidisciplinary teams, and choice of
157–70.
agents is highly individual depending on the spe- 19. Vrana JA, Gamez JD, Madden BJ, Theis JD, Bergen HR 3rd,
cific underlying clonal disorder, organ function, Dogan A. Classification of amyloidosis by laser microdissec-
presence of neuropathy and performance status. tion and mass spectrometry-based proteomic analysis in clini-
cal biopsy specimens. Blood. 2009;114:4957–9.
20. Hawkins PN, Myers MJ, Epenetos AA, Caspi D, Pepys
MB. Specific localization and imaging of amyloid deposits
References in vivo using 123I-labeled serum amyloid P component. J Exp
Med. 1988;167:903–13.
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Engl J Med. 2003;349:583–96. Harding I, et al. Cardiovascular magnetic resonance in cardiac
2. Obici L, Raimondi S, Lavatelli F, Bellotti V, Merlini amyloidosis. Circulation. 2005;111:186–93.
G. Susceptibility to AA amyloidosis in rheumatic diseases: a 22. Rapezzi C, Quarta CC, Guidalotti PL, Pettinato C, Fanti S,
critical overview. Arthritis Rheum. 2009;61:1435–40. Leone O, et al. Role of (99m)Tc-DPD scintigraphy in diagnosis
3. Saraiva MJ. Hereditary transthyretin amyloidosis: molecu- and prognosis of hereditary transthyretin-related cardiac amy-
lar basis and therapeutical strategies. Expert Rev Mol Med. loidosis. JACC Cardiovasc Imaging. 2011;4(6):659–70.
2002;2002:1–11. 23. Rowczenio DM, Noor I, Gillmore JD, Lachmann HJ, Whelan
4. Chiti F, Dobson CM. Protein Misfolding, Amyloid Formation, C, Hawkins P, et al. Online registry for mutations in hereditary
and Human Disease: A Summary of Progress Over the Last amyloidosis including nomenclature recommendations. Hum
Decade. Annu Rev Biochem 2. 2017;86:27–68. Mutat. 2014;35(9):E2403–E12.
5. Pepys MB. Serum amyloid P component. In: Haeberli A, 24. Gillmore JD, Lovat LB, Persey MR, Pepys MB, Hawkins
editor. Human Protein Data. Weinheim: Wiley-VCH Verlag PN. Amyloid load and clinical outcome in AA amyloidosis in
GmbH; 1997. relation to circulating concentration of serum amyloid a pro-
6. Bodin K, Ellmerich S, Kahan MC, Tennent GA, Loesch A, tein. Lancet. 2001;358:24–9.
Gilbertson JA, et al. Antibodies to human serum amyloid 25. Vaxman I, Gertz M. Recent advances in the diagnosis, risk
P component eliminate visceral amyloid deposits. Nature. stratification, and Management of Systemic Light-Chain
2010;468:93–7. Amyloidosis. Acta Haematol. 2019;141(2):93–106.
7. Pinney JH, Smith CJ, Taube JB, Lachmann HJ, Venner CP, 26. Muchtar E, Dispenzieri A, Leung N, Lacy MQ, Buadi FK,
Gibbs SD, et al. Systemic amyloidosis in England: an epide- Dingli D, et al. Depth of organ response in AL amyloidosis is
miological study. Br J Haematol. 2013;161(4):525–32. associated with improved survival: grading the organ response
8. Kyle RA, Gertz MA. Primary systemic amyloidosis: clini- criteria. Leukemia. 2018;32:2240–9.
cal and laboratory features in 474 cases. Semin Hematol. 27. Gertz MA, Leung N, Lacy MQ, Dispenzieri A, Zeldenrust
1995;32(1):45–59. SR, Hayman SR, et al. Clinical outcome of immunoglobu-
9. Wechalekar AD, Lachmann HJ, Goodman HJ, Bradwell A, lin light chain amyloidosis affecting the kidney. Nephrol Dial
Hawkins PN, Gillmore JD. AL amyloidosis associated with Transplant. 2009;24:3132–7.
IgM paraproteinemia: clinical profile and treatment outcome. 28. Pinney JH, Lachmann HJ, Bansi L, Wechalekar AD, Gilbertson
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10. Lane T, Pinney JH, Gilbertson JA, Hutt DF, Rowczenio DM, lowing chemotherapy. J Clin Oncol. 2011;29(6):674–81.
Mahmood S, et al. Changing epidemiology of AA amyloidosis: 29. Palladini G, Hegenbart U, Milani P, Kimmich C, Foli A, Ho
clinical observations over 25 years at a single national referral AD, et al. A staging system for renal outcome and early mark-
Centre. Amyloid. 2017;24(3):162–6. ers of renal response to chemotherapy in AL amyloidosis.
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Sabin CA, Gillmore JD, et al. Natural history and outcome in 30. Havasi H, Doros G, Sanchorawala V. Predictive value of the
systemic AA amyloidosis. N Engl J Med. 2007;356:2361–71. new renal response criteria in AL amyloidosis treated with high
12. Schwalbe S, Holzhauer M, Schaeffer J, Galanski M, Koch KM, dose melphalan and stem cell transplantation. Am J Hematol.
Floege J. Beta 2-microglobulin associated amyloidosis: a van- 2018;93:E129–32.
ishing complication of long-term hemodialysis? Kidney Int. 31. Wechalekar AD, Whelan C. Encouraging impact of doxycy-
1997;52:1077–83. cline on early mortality in cardiac light chain (AL) amyloidosis.
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Pathol. 2016;29(4):416–20.
875 51
Thrombotic Microangiopathies
Neil S. Sheerin
Contents
References – 886
Thrombotic Microangiopathies
877 51
n Learning Objectives
1. The combination of thrombocytopenia and micro- In a patient with thrombotic microangiopathy endo-
angiopathic haemolysis with a normal clotting thelial dysfunction leads to the formation of thrombi
screen is highly suggestive of a TMA. in small vessels, platelet consumption, and mechani-
2. TMAs can present with a wide range of clinical cal damage to erythrocytes (microangiopathic hae-
features including neurological involvement and molysis).
acute kidney injury. Haemolytic uraemic syndrome (HUS) is a form of
3. In patients with a suspected TMA, it is important TMA that is caused by Shiga toxin in 90% of cases
to investigate thoroughly to identify the cause of with the remaining cases (atypical HUS) most com-
the TMA. monly due to excessive complement activation.
4. TMAs should be treated as an emergency as they Kidney injury is the most common clinical feature.
can be rapidly fatal. Thrombotic thrombocytopenic purpura (TTP) is a
5. The treatment required will depend on the clini- form of TMA due to an inherited or acquired defi-
cal features at presentation, but urgent plasma ciency in ADAMTS13 which leads to the accumulation
exchange should be considered until TTP has been high molecular weight multimers of von Willebrand
excluded. factor on the surface of endothelial cells and the for-
mation of platelet-rich thrombi. Neurological disease
is the most common clinical feature.
51.1 Introduction
are also damaged as they pass over activated endothe- infected with STEC suggesting that other genetic or
lium and through partially occluded vessels leading to environmental factors are important in determining
microangiopathic haemolysis. whether HUS develops.
The initial step is to diagnose the presence of a STEC O157 can be identified after culture from the stool
TMA. This is based on the clinical presentation and the or from a rectal swab (which is a useful technique to
presence of the characteristic biochemical and haemato- obtain cultures in children or after diarrhoea has
logical changes which are summarised in . Table 51.3. stopped). It is possible to test for the presence of Shiga
Once this has been established, the next step is to iden- toxin, and the gene encoding Shiga toxin can be detected
tify the cause of the TMA. by polymerase chain reaction. Infection can be con-
firmed by measuring the serological response to the
O-serotype of Shiga toxin-producing E. coli; however, it
51.5.1 Thrombotic Thrombocytopenic is not possible to test for all serotypes. Renal biopsy is
Purpura rarely necessary to confirm the diagnosis, but when per-
formed arteriolar and glomerular capillary thrombosis
The diagnosis is made by testing ADAMTS13 activ- is seen, with glomerular capillaries congested with frag-
ity, with severe deficiency (<5–10% activity), being mented erythrocytes. Acute tubular injury and mesan-
associated with the disease. ADAMTS13 activity can giolysis are commonly seen.
This is a rare form of HUS complicating infection with 51.9.2 Malignancy and its Treatment
Streptococcus pneumonia (septicaemia, pneumonia with
empyema and meningitis) accounting for 5% of child- HUS- and TTP-like syndromes are associated with dis-
hood HUS [24]. Patients are usually young (<2 years), seminated adenocarcinoma (gastric, colonic, breast, and
and the disease is associated with a high mortality prostate) and haematological malignancies, and the
884 N. S. Sheerin
TMA can pre-date the diagnosis of malignancy. In addi- resolve with measures such as calcineurin inhibitor
tion drugs used in the treatment of these cancers can withdrawal.
cause a TMA including mitomycin, gemcitabine,
platinum-based drugs, tyrosine kinase inhibitors, and
VEGF inhibitors (. Table 51.1). It can be difficult to 51.9.6 Bone Marrow Transplantation
determine whether the TMA is due to malignancy or its
51 treatment. There is some evidence of a response to The development of a TMA has been reported in 10–40%
steroids and plasma exchange. of patients following allogeneic bone marrow transplan-
tation. There are several factors that could contribute to
this including graft versus host response, calcineurin
51.9.3 Drug-Induced TMA inhibitor use, chemotherapy, and infection. Defects in
complement regulation have also been reported and com-
The development of a TMA has been reported in asso- plement activation can be demonstrated in some cases.
ciation with the use of a range of drugs in addition to These observations have led to the use of eculizumab in
those used for the treatment of cancer (. Table 51.1). this situation although evidence that this should be part
For some drugs this appears to be a direct effect on the of the management of this condition is still lacking.
endothelium as is the case for Interferon-β [25] and beva-
cizumab [26], while in the case of quinine, the TMA is
due to the development of autoantibodies against plate- 51.9.7 Autoimmune Disease
let glycoproteins. The TMA induced by clopidogrel [27]
and ticlopidine [28] leads to the production of antibodies TMA is seen in patients with systemic lupus erythema-
against ADAMTS13 and a TTP-like disease which tosus (SLE) and scleroderma renal crisis. In patients
responds to plasma exchange. In some drugs the exact with anti-phospholipid antibody syndrome (APS), par-
mechanism of TMA development is unknown, and man- ticularly catastrophic APS, antibodies bind to and acti-
agement is supportive with the withdrawal of the caus- vate platelets and endothelial cells leading to a
ative drug. pro-thrombotic state and a TMA. TMAs have also been
described in patients with primary glomerular diseases
including IgA nephropathy, FSGS, and ANCA-
51.9.4 Malignant Hypertension associated vasculitis.
Case Study
Case 1 Case 2
A 27-year-old man presented with severe abdominal pain. A 58-year-woman presented to her local hospital with a
A diagnosis of pancreatitis was made was based on a 2-hour history of drowsiness and slurring of her speech.
raised amylase and pancreatic inflammation evident on She was initially diagnosed as having had a CVA, but her
imaging. No gall stones were identified and the patient admission blood demonstrated severe thrombocytopenia
did not drink alcohol. On admission he was thrombocy- (platelets 9 x 109/ml) and evidence of haemolysis with anae-
topenic with a platelet count of 62 x 109/l, his haemoglo- mia (haemoglobin 97 g/l, LDH unmeasurable due to hae-
bin was low (109 g/l), and he had evidence of fragmentation molysis, and fragmentation on the blood film). A diagnosis
on his blood film. His coagulation screen was normal. He of TTP was made, and she was transferred to the closest
was managed conservatively and the symptoms and labo- hospital where plasma exchange was available. By the time
ratory abnormalities resolved. He presented again she arrived, her level of consciousness had fallen, and she
9 months later again with pancreatitis and laboratory required ventilation to protect her airway. Blood for
findings of thrombocytopenia and microangiopathic hae- ADAMTS13 activity was taken and plasma exchange (1.5
molytic anaemia. x plasma volume initiated). She was given pulsed methyl-
Screening was performed for a genetic abnormality in prednisolone. On day 3 she remained ventilator dependent.
complement regulation, and a pathogenic variant in The frequency of plasma exchange was increased to twice
CD46 was identified making a diagnosis of complement- daily, and she started a course of rituximab. After 7 days
mediated aHUS most likely. This case demonstrates that her platelet count started to improve; plasma exchange fre-
TMAs can affect and organ and should be considered in quency was reduced to daily and finally stopped on day 18
patients presenting with thrombocytopenia and haemoly- after admission following normalisation of her platelet
sis. Although disseminated intravascular haemolysis can count and weaning from the ventilator. She was finally dis-
occur during the severe inflammatory response associated charged from the hospital for further rehabilitation.
with pancreatitis, the normal clotting screen in this case This case demonstrates how rapidly TTP can cause severe
makes it unlikely. neurological disease, which can be fatal without treat-
886 N. S. Sheerin
ment, and highlights the importance of rapid initiation of had acute kidney injury with a serum creatinine of
plasma exchange. It also demonstrates that after the acute 340 μmol/l and oligoanuria. He was started on peritoneal
phase, patients can be left with residual neurocognitive dialysis. STEC culture was negative but Shiga toxin PCR
impairment. was positive. He remained dialysis dependent for 6 days
and required blood transfusion on 2 occasions. Twelve
51 Case 3 days after admission, he was discharged from the hospital
A 5-year-old boy developed abdominal pain and bloody with no neurological deficit and improving renal function.
diarrhoea 5 days after visiting a petting farm. The diar- This case is characteristic of STEC infection with a diar-
rhoea resolved, but 9 days after the onset of diarrhoea, he rhoeal illness preceding the onset of HUS. It emphasises
presented with pallor and reduced consciousness. He has a the importance of STEC testing in all cases and potential
seizure in the emergency room and required ventilation. for neurological involvement. The good outcome is normal
He was thrombocytopenic (platelets 43 x 109/l) and anae- after the acute phase, but these children require long-term
mic (haemoglobin 76 g/l) with evidence of haemolysis. He monitoring because of the risk of CKD and hypertension.
Contents
References – 914
892 H. Blakey et al.
n Learning Objectives with CKD are at high risk for maternal and foetal mor-
1. Chronic kidney disease, even CKD stage 1, is asso- bidity and mortality. Their management is complex, and
ciated with substantially increased risk of adverse successful outcomes are optimised by thorough pre-con-
pregnancy outcome including pre-eclampsia, pre- ception counselling and collaborative antenatal care in
term delivery, and low birth weight. The risks are dedicated renal-obstetric specialist clinics. This chapter
greater with an increasing severity of CKD and explores maternal and foetal outcomes in women with
proteinuria. CKD and offers guidance on optimal pregnancy man-
2. Pregnancy frequently unmasks hitherto undiag- agement.
52 nosed CKD. Persistent proteinuria (PCR >30 mg/
mmol) and/or a serum creatinine >75 μmol/l identi-
fied before 20 weeks suggests CKD. 52.1.1 Physiological Changes in Pregnancy
3. Contraception and pre-conception counselling
are essential. Pregnancy planning should include Normal pregnancy results in profound changes in renal
substituting medications known to be teratogenic – and cardiovascular physiology. These changes are mir-
including mycophenolate – for safer alternatives rored in women with chronic kidney disease (CKD),
and optimizing underlying disease control. albeit to a diminishing extent with the greater severity
4. During pregnancy, patients should be reviewed of CKD reflecting reduced renal reserve, and this may
regularly by an obstetrician and nephrologist underlie frequent adverse pregnancy outcomes. It is
with experience in managing patients with renal important to recognise these changes in order to appro-
disease in pregnancy ideally in a dedicated joint priately interpret the results of laboratory tests during
renal-obstetric clinic. It is important to establish pregnancy; the normal upper limit for serum creatinine
close links with obstetricians and gynaecologists falls to <75 μmol/l, normal serum sodium concentration
in your hospital but also with other obstetric units falls by 5 mmol/l, and women develop a compensated
within the catchment of the renal unit. Clear refer- respiratory alkalosis manifest by a fall in serum bicar-
ral guidelines and rapid access are important both bonate.
for the management of patients with CKD or renal
replacement therapy but also for the diagnosis and
follow-up of patients presenting to obstetricians 52.1.2 Cardiovascular Physiology
with renal disease. in Normal Pregnancy [2]
5. All women with CKD should be offered low-
dose aspirin from 12 weeks of pregnancy (unless Substantial vasodilatation leading to reduced systemic
otherwise contraindicated) to mitigate the risk of vascular resistance occurs within 4 weeks of conception
pre-eclampsia. Low molecular weight heparin pro- reaching a nadir at 40–50% below baseline in the mid sec-
phylaxis is indicated for patients with nephrotic ond trimester which is maintained until delivery. There
range proteinuria. is a contemporaneous increase in cardiac output of 40%
(due to an increase in stroke volume in early pregnancy
and increased heart rate later on). Consequently, in nor-
52.1 Introduction mal pregnancy blood pressure (BP) falls in the first and
second trimesters (sometimes allowing withdrawal of
Chronic kidney disease (CKD) is often clinically silent antihypertensives), returning to pre-pregnancy levels
until renal function declines to less than 25% of normal. in the third trimester. There is no physiological change
CKD stages 1 and 2 (normal or mildly impaired renal in cardiac ejection fraction or normal range for central
function with abnormal albuminuria or structural kid- venous pressure or pulmonary capillary wedge pressure
ney damage) affect roughly 3% of women of childbear- during the antenatal period. In later pregnancy, inferior
ing age, whilst stages 3–5 (GFR <60 ml/min) affect just vena cava compression by the gravid uterus may lead to
less than 1% of women in this age group [1]. Enhanced ‘supine hypotension’.
antenatal monitoring in pregnancy and increased com- Plasma and extracellular fluid volume progressively
plication rates offer an opportunity to identify women rises from conception reaching 40 to 50% over baseline
with hitherto unrecognised CKD in early pregnancy. by 32 weeks. There is a lesser increase in red cell mass
Furthermore, around 20% of women who develop of 20 to 30%, driven by enhanced renal erythropoietin
severe early-onset (<30 weeks) pre-eclampsia (PET) have production resulting in mild dilutional anaemia. A mild
underlying CKD as the predisposing cause. Whilst live degree of peripheral oedema is common in normal
birth outcomes have improved, pregnancies in women pregnancy.
Pregnancy and the Kidney
893 52
52.1.3 Renal Haemodynamic and Structural 52.2 Tubular Changes
Changes [2, 3]
52.2.1 Electrolyte Balance
Glomerular filtration rate (GFR) rises within 1 month
of conception, peaks 40–50% above baseline levels by Total body sodium increases by 3–4 mmol/day result-
the early second trimester, and is sustained at this level ing in a net positive balance of 900–1000 mmol over
until 1–2 weeks postpartum. The rise in GFR (hyperfil- the whole gestation (total body potassium increases by
tration) is mediated by elevated renal plasma flow (RPF) 320 mmol). Exquisite tubular control of sodium bal-
in the first two trimesters resulting from both pre- and ance is achieved in pregnancy, despite the net increase of
post-glomerular arteriolar dilatation and not by glo- sodium filtration resulting from a 50% gestational rise in
merular hypertension. This may explain why multiple GFR. A fine balance of natriuretic factors (raised GFR,
pregnancy in women with normal kidney function or atrial natriuretic peptide, and progesterone) versus anti-
those with CKD 1 and 2 is not associated with renal natriuretic factors (aldosterone, deoxycorticosterone,
damage. However, in the third trimester, RPF falls but and tubuloglomerular feedback) is felt to achieve this
GFR remains elevated: maintained by a modest increase critical homeostatic task.
in glomerular permeability and reduced intraglomerular As a consequence of resetting of the hypothalamic
oncotic pressure. osmostat, plasma osmolality falls by 10 (standard devia-
The mechanism of pregnancy-induced systemic and tion 3) mOsmol/kg in normal pregnancy reflecting a fall
renal vasodilatation is incompletely understood, but the in plasma sodium by 5 (2) mmol/l. This change occurs
ovarian vasodilator hormone relaxin appears to mediate early in pregnancy and correlates closely with increased
the upregulation of NO-dependent vasodilation via the production of human chorionic gonadotrophin.
NO-endothelin-B pathway [2]. Enhanced urate excretion in the first two trimesters of
Neither the MDRD nor the Cockcroft-Gault for- pregnancy leads to a fall in serum urate. In the third tri-
mulae are accurate in estimating GFR in pregnancy mester, serum urate is restored to pre-pregnancy levels.
and should not be used. In an individual, GFR can be This must be considered if urate levels are being consid-
tracked across pregnancy by serial creatinine measure- ered as part of the assessment of pre-eclampsia (PET).
ments.
and foetal outcomes over the last 40 years, and the focus
. Table 52.1 Definitions of hypertension and its severity in
of advice for women with CKD is now shifting. Pre- pregnancy [6]
pregnancy counselling should be offered to all women
with CKD to allow shared and informed decision- Definition Presenta- Significant Prevalence
making and an individualised management plan centred tion Protein- (%)
around their underlying disease aetiology, baseline renal uriaa
function, obstetric history, and other comorbidities. It
Chronic <20 weeks No 2
is optimally provided in a dedicated combined clinic led hypertension
52 by an obstetrician and nephrologist who have experience
Gestational >20 weeks No 4–8
of looking after women with renal disease in pregnancy.
hypertension
In this setting, the nephrologist and obstetrician learn
to speak the same language and recognise each other’s Pre-eclampsia >20 weeks Yes 4.1**/1.7***
(PET)
anxieties in the care of these patients. Moreover, the vast
majority of women attending these clinics find them ben- PET superim- >20 weeks Yes <1
eficial in their pregnancy decision-making process [4]. posed on
chronic
Counselling should cover:
hypertension
1. Contraceptive advice
2. How pregnancy might affect maternal kidney func- Hypertension severity Systolic BP Diastolic BP
(mmHg) (mmHg)
tion
3. How kidney disease might affect pregnancy out- Mild 140–149 90–99
comes Moderate 150–159 100–109
4. Optimal timing of pregnancy to improve maternal/
Severe >160 >110
foetal outcomes:
In general, women with slowly progressive renal
**First pregnancy, ***second pregnancy
disease may be best advised to plan pregnancy ear- aSignificant proteinuria is >300 mg in a validated 24 h urine
lier (rather than waiting a potentially long time before collection or urine PCR >30 mg/mmol
transplant is deemed necessary), and women with
relapsing and remitting disease such as lupus have
more favourable outcomes if pregnancy is delayed women and are a major cause of maternal morbidity
until a period of disease quiescence. Those with rapidly and a leading cause of maternal death worldwide. In a
progressing renal disease or on dialysis may have better large meta-analysis of over 795,000 pregnancies, chronic
pregnancy outcomes if they wait to conceive until after hypertension was found to be strongly associated with
a potential renal transplant (if likely to occur within adverse pregnancy outcomes including pre-eclampsia
the timeframe of being of childbearing age). (incidence 25.9%; 95% C.I. 21.0–31.5%), Caesarean
5. Modification of drug therapy to those known to be section (41.4%; 35.5–47.7%), preterm delivery (28.1%;
safe in pregnancy 22.6–34.4%), and perinatal death (4.0%; 2.9–5.4%) [5].
6. Assessment of comorbidity, e.g. diabetes, cardiopul- Specific management of chronic essential or gestational
monary disease, renal/bladder structure hypertension is beyond the scope of this chapter, but
7. General preparation for pregnancy: guidelines are available from the UK National Institute
5 Folic acid (400ug daily or 5 mg OD in those with for Health and Clinical Excellence [6].
diabetes mellitus, a previous child with a neural
tube defect, or a BMI >30 g/m2) at least 3 months
prior to conception until 12 weeks of pregnancy. 52.5 Blood Pressure Targets
5 Smoking cessation.
5 Weight loss (targeting an ideal BMI). There have been historic concerns that overzealous BP
lowering during pregnancy for women with chronic
essential or gestational hypertension may adversely affect
52.4 Hypertension in Pregnancy foetal growth by reducing placental blood flow. However,
a more recent meta-analysis of 49 RCTs showed that anti-
The definitions of hypertension and classification of hypertensive treatment for pregnant women with mild
severity are listed in . Table 52.1. BP measurement to moderate hypertension did not result in harm to the
should be taken in a sitting position using a validated foetus [7]. These findings have been corroborated by the
oscillometric device or manual reading to Korotkov 2015 Chronic Hypertension in Pregnancy Study (CHIPS)
5. Hypertensive disorders in pregnancy affect 10% of [8], which assigned 987 pregnant women with chronic
Pregnancy and the Kidney
895 52
. Table 52.2 Impact of ‘tight’ vs ‘less tight’ BP control on . Table 52.3 Antihypertensive agent use in pregnancy
pregnancy outcomes. Data from [8]
Drug Dose Comments
Outcome ‘Less ‘Tight’ Odds ratio
tight’ control Labetalol 100–400 mg First line unless
control diastolic orally twice to 4 contraindications,
diastolic BP <85 times daily (max e.g. asthma. Reduced
BP <100 n = 488 dose 1200 mg/ half-life in pregnancy
n = 493 day)
CKD. However, the continuation of ACEi or ARB in the only definitive treatment is delivery of the baby,
the second and third trimester is associated with a spe- without which the maternal condition will deteriorate.
cific fetopathy comprising oligohydramnios, neonatal The pathophysiology of PET remains poorly under-
renal failure, neural tube defects, and cardiac abnormal- stood, although abnormal maternal and foetal immune
ities and should be avoided [11]. One American study responses to pregnancy are likely to contribute. It is widely
involving almost half a million pregnancies revealed an accepted that the placenta plays a central role in disease
increased risk of congenital malformations in hyper- initiation, with placental mal-perfusion and ischaemia
tensive women exposed to ACEi in the first trimester. arising from abnormal placentation within the uterine
52 However, the magnitude was the same as those receiv- wall. This may promote abnormal placental secretion
ing other antihypertensives or no BP treatment at all. of angiogenic factors leading to altered vascular endo-
It therefore appears that hypertension per se in the first thelial growth factor (VEGF) signalling. In PET, there is
trimester is associated with an increased risk of birth increased expression of anti-angiogenic soluble fms-like
defects with no additional adverse impact of ACEi in tyrosine kinase-1 (sFlt-1) and reduced serum placental
the first trimester [11]. growth factor (PlGF) which act via functional VEGF
As a rule, women with hypertension receiving ACEi deficiency to cause endothelial dysfunction (hyperten-
who are considering pregnancy should be stabilised on sion) and podocyte injury (proteinuria). A high ratio of
antihypertensives known to be safe in pregnancy before sFlt-1 to PIGF has been associated with an increased risk
conception. Some women may take some considerable of PET [13], and abnormal levels may precede the clinical
time to conceive and those denied ACEi pre-pregnancy onset of PET by several weeks. A recent study found a low
may consequently suffer an unnecessary renal decline, sFlt-1/PIGF ratio was associated with a low risk of devel-
particularly those with proteinuric CKD. Women who opment of PET in the short term in cases where PET was
have a strong indication for the use of ACEi, such as clinically suspected [14]. NICE have since issued clinical
those with CKD and proteinuria, may be carefully guidance recommending the use of sFlt-1/PIGF assay
counselled to continue on the ACEi until conception, at in tandem with clinical review to help rule out PET in
which point they should be converted to labetalol, long- women suspected to have PET between 20 and 34 weeks
acting nifedipine, or methyldopa. +6 days gestation (NICE DG23): 7 https://www.nice.
org.uk/guidance/dg23/chapter/1-Recommendations. It
should be noted that this assay is not currently widely
52.8 Pre-Eclampsia available, and cannot be used for confirming or ruling
in a diagnosis of PET. PlGF has also been reported as
a promising biomarker for predicting the development
of PET in those with CKD [15]. PlGF did not correlate
Pre-eclampsia (PET) is defined as de novo develop- with serum creatinine in study participants; however, the
ment of hypertension (BP >140/90) and either pro- sample size and number of women with severe CKD were
teinuria (>300 mg/24 hrs) or evidence of limited, so further study is required to assess the predic-
thrombocytopenia, renal insufficiency, impaired liver tive value in women with CKD and whether the underly-
function, pulmonary oedema, or cerebral symptoms ing renal impairment is a confounding factor and affects
(including visual disturbance) after 20 weeks’ gesta- the interpretation of results.
tion [12].
. Fig. 52.1 Relative risk of pregnancy outcomes for women treated with low-dose aspirin for primary prevention of pre-eclampsia. (Repro-
duced with permission from [17])
898 H. Blakey et al.
device which has far greater precision than manual read- [20]. Some women with CKD have urinary tract abnor-
out. Moderate proteinuria detected early in pregnancy fre- malities (such as renal stone disease, reflux nephropathy,
quently progresses to heavy proteinuria, sometimes into bladder dysfunction, and autosomal dominant poly-
the nephrotic range in the third trimester (see . Fig. 52.2). cystic kidney disease) which substantially increase their
Pregnancy is a thrombophilic state, and heavy protein- risk. Meta-analysis demonstrates that antibiotic treat-
uria substantially increases thromboembolic risk. In this ment is highly effective in eradicating asymptomatic
setting, daily subcutaneous low molecular weight hepa- infection and preventing pyelonephritis, and treatment
rin (LMWH) (prophylactic dose) continued until 6 weeks is associated with higher birth weight [21].
postpartum is recommended. The threshold level of Urine should be sent for culture at each antenatal
proteinuria to initiate treatment is unclear, though many visit, and those with evidence of asymptomatic bacte-
authorities treat when proteinuria >2 g/24 h (PCR >200). riuria are treated empirically with antibiotics to reduce
Monitoring anti-factor Xa activity may improve safety in their risk of ascending infection and adverse pregnancy
CKD (samples taken 3 hours after dose). outcome. Strict prophylaxis from infection is vital in
A high index of suspicion for a venous thrombo- those with a history of recurrent UTI or abnormal uri-
embolic disease should be maintained in these women nary tract anatomy. The mainstay is the bladder toilet
during pregnancy. The risks of foetal radiation exposure comprising at least 3 litre daily oral fluid intake, double
from V/Q or CTPA scanning are small when balanced micturition, and post-coital voiding. Those women with
against the risk of undiagnosed pulmonary embolism or predisposing factors or who suffer more than one ante-
blind treatment. Women treated with low-dose aspirin natal infection or persistent asymptomatic bacteriuria
and LMWH are at high risk of symptomatic oesopha- after two or more antibiotic courses should also receive
geal reflux or peptic ulceration and should receive oral nocturnal prophylactic antibiotics until 6 weeks postpar-
ranitidine which appears safe from the second trimester. tum. Cefalexin 250 mg nocte is effective and safe in all
Those women receiving long-term LMWH and/or ste- trimesters or, if allergic to beta lactam antibiotics, nitro-
roids should receive calcium/vitamin D3 supplements as furantoin 50 mg nocte (the latter should be suspended
prophylaxis from bone mineral loss. around 36 weeks due to risk of haemolytic anaemia
in some babies). Where possible, quinolones or genta-
micin (risk of neonatal deafness) should be avoided if
52.10.3 Urinary Tract Infection safer alternatives exist, based on antibiotic sensitivities.
Co-amoxiclav use late in pregnancy may increase the
Pregnant women are at increased risk of UTI. Mechanical risk of necrotising enterocolitis in preterm babies.
compression from the gravid uterus can impede ureteric
outflow, and progesterone-mediated smooth muscle
relaxation leads to reduced ureteral peristalsis, ureteric 52.10.4 Renal Tract Obstruction Versus
dilatation, and urinary stasis. Asymptomatic bacteriuria Physiological Hydronephrosis
is common (incidence 2–10% in normal pregnancy). If
left untreated, up to one-third will go on to develop cys- Differentiating physiological hydronephrosis in preg-
titis or pyelonephritis, which has been strongly associ- nancy from ureteric obstruction can be challenging. In
ated with preterm delivery and poor perinatal outcomes general, physiological hydronephrosis is asymptomatic,
Pregnancy and the Kidney
899 52
whereas acute obstruction is often associated with loin
a
pain and tenderness. Pregnancy-related hydronephro-
sis tends to be right-sided and occurs from the second
trimester onwards, whereas pathological hydronephro-
sis can affect either side and in any stage of pregnancy.
Ureteric calculi are the commonest cause of urinary
tract obstruction in pregnancy, associated with non-
visible haematuria and renal colic, whilst urine in healthy
women rarely contains red cells. A significant increase in
plasma creatinine is suggestive of unilateral obstruction.
Imaging techniques may be helpful in differentiating.
Ultrasonography is the first-line imaging modality for
suspected obstructive uropathy in pregnancy, although
up to 40% of nephrolithiasis cases may be missed if this
is used alone. Measuring renal artery resistive index (RI)
derived by Doppler ultrasound can be a useful adjunct;
an RI >0.7 in the setting of unilateral hydronephrosis
is suggestive of obstruction if contralateral RI is <0.7.
Magnetic resonance urography (MRU) can be helpful
(see 7 Case 52.43.1 and . Fig. 52.3a and b). Recent evi-
dence shows this to be safe in pregnancy, even in the first
trimester, although gadolinium contrast has been asso- b
ciated with birth defects and increased risk of stillbirth
and should not be used at all [22]. Although MRU does
not adequately image calculi, a ureteric filling defect or a
level of ureteric ‘cut-off’ above the pelvic brim is sugges-
tive of a stone. Faced with a critically ill pregnant woman
with tender hydronephrosis, not settling with antibiot-
ics, prompt relief of obstruction either by percutaneous
nephrostomy (with antibiotic cover) or retrograde stent
insertion (in the mid trimester of pregnancy) is required
and can be lifesaving for the foetus and the mother.
52.12.1 Identification of Women with CKD analysis reported no significant difference in long-term
in Pregnancy adverse renal outcomes between pregnant women with
mild CKD and non-pregnant controls with CKD (OR
Routine monitoring of urinalysis and BP in pregnancy 0.96; 95 CI 0.69 to 1.35) [26]. Adverse renal outcomes
frequently identifies previously unrecognised CKD were broadly defined however as doubling of creatinine,
(see 7 Case 52.43.2). Persistent proteinuria (PCR >50% decline in GFR, or reaching ESRD.
>30 mg/mmol) and/or a serum creatinine >75 μmol/l Moderate to Severe Renal Impairment (CKD Stages
identified before 20 weeks gestation is suggestive of 3–5).
52 CKD. Investigation by repeat serum creatinine, full More advanced CKD pre-pregnancy and heavy pro-
blood count, tests of soluble immunology (antinuclear teinuria (>1 g/24 h) appear to be strong predictors of
antibody, complements 3 and 4, antineutrophil cyto- an irreversible decline in renal function associated with
plasmic antibody), and baseline renal ultrasound is indi- pregnancy.
cated. These findings put the pregnancy at high risk for In a landmark retrospective study, women who
complications and thus the need for enhanced antena- started pregnancy with moderate CKD (creatinine
tal monitoring and postpartum follow-up. Neither the 124–168 μmol/L) had a 40% risk of deteriorating renal
MDRD nor Cockcroft-Gault equations accurately pre- function during pregnancy, which persisted postpartum
dict eGFR. Serial creatinine measurements should be in half [27]. Two-thirds of those with severe CKD (ante-
used instead to avoid the risks of underestimating the natal creatinine >177 μmol/l) suffered a decline in renal
degree of renal impairment. function in the third trimester which persisted postpar-
tum. A third deteriorated to the point of requiring dialy-
sis. A subsequent prospective study confirmed adverse
52.13 Role of Renal Biopsy in Pregnancy pregnancy outcomes of 49 women with moderate/severe
pre-pregnancy CKD (mean creatinine 186 μmol/L and
In pregnancy, proteinuria presenting for the first time GFR 35+/−12 ml/min). Mean GFR fell from 35 before
after 20 weeks gestation is generally due to PET. Renal to 30 ml/min after pregnancy (p < 0.001). However,
biopsy risks complications including foetal compro- the rate of decline of GFR before and after pregnancy
mise. A meta-analysis of renal biopsies performed in remained the same for this group. Those women with
pregnancy suggested an increased risk of complications a pre-pregnancy GFR <40 ml/min and heavier protein-
compared with non-pregnant patients [24]. However, uria (>1 g/24 h) had an increased risk of accelerated
this analysis included historic series where biopsy was deterioration in GFR post-pregnancy and progressed
performed for the diagnosis of PET. Renal biopsy is more rapidly to dialysis [28].
technically difficult and uncomfortable for the patient A more recent Italian cohort study reported similar
after 20–24 weeks gestation. In highly selected cases outcomes [29], although the numbers of women stud-
of undiagnosed progressive kidney disease (before foe- ied with advanced renal impairment remain small and
tal viability, <26 weeks), early onset of nephrotic syn- lack comparison with non-pregnant control groups. It is
drome (<20 weeks), or unexplained AKI (<26 weeks), therefore unclear whether the decline seen in renal func-
renal biopsy has a similar complication risk to the non- tion is due to pregnancy alone or following the natural
pregnant state. Histological diagnosis beneficially affects underlying disease course.
care in over one-third of cases, being safer than blind
therapy [25]. Pregnant women with stable CKD and
proteinuria or those presenting after 26 weeks should be 52.15 Effect of Maternal CKD on Pregnancy
observed carefully. In this situation renal biopsy should Outcomes
be deferred until stable postpartum [25].
CKD has been widely reported as an independent risk
factor for adverse maternal and foetal outcomes in preg-
52.14 Effect of Pregnancy on Maternal nancy in recent meta-analyses [26] and cohort studies
Kidney Function [29]. Zhang et al. reported significantly increased risks
of pre-eclampsia (OR 10.36, 95% CI 6.28 to 17.09) and
Mild Renal Impairment (CKD Stages 1–2). Caesarean section (OR 2.67, CI 2.01 to 3.54) in preg-
Pregnancy in women with stages 1 and 2 CKD pre- nancy with CKD, compared to pregnancies in women
pregnancy or first trimester creatinine <110 μmol/l without CKD. Moreover, there were significantly
with low-level proteinuria (<1 g/24 hours) and absent/ increased odds of adverse foetal events for pregnan-
well-controlled hypertension appears to have little or no cies in CKD, including preterm delivery (OR 5.72, 95%
long-term adverse effect on renal function. A 2015 meta- CI 3.26 to 10.03), small for gestational age/low birth
Pregnancy and the Kidney
901 52
Pre-eclampsia
0 20 40 60 80 100 0 20 40 60 80 100
Rate of complications (%) Rate of complications (%)
Controls CKD stage 2 CKD stage 4–5 Controls CKD stage 2 CKD stage 4–5
CKD stage 1 CKD stage 3 CKD stage 1 CKD stage 3
. Fig. 52.4 Effect of maternal CKD on pregnancy outcome. Reproduced with permission from [4]. (Data taken from two cohort studies:
[15, 29])
weight babies (OR 4.85, 95%CI 3.03 to 7.76), and fail- stage 1 is associated with adverse pregnancy outcome,
ure of pregnancy (stillbirth, foetal death, and neonatal even when hypertension, proteinuria, and systemic dis-
death) (OR 1.80, 95%CI 1.03 to 3.13) [26]. Absolute ease are absent (OR 1.88, 95%CI 1.27–2.79). This raises
outcomes vary between studies, given differing cohort the suggestion that renal disease itself presents a “base-
sizes, the heterogenous nature of renal disease, and line risk” in pregnancy, regardless of CKD severity [29].
local factors such as variance in thresholds for early
delivery and referral to neonatal intensive care. Despite
this, all adverse maternal and foetal outcomes become 52.16 How Should CKD be Managed
increasingly prevalent as renal function worsens – see in Pregnancy?
. Fig. 52.4.
In pregnant women with CKD, proteinuria All women with CKD or those identified with CKD in
(>1 g/24 hours) and hypertension are associated with pregnancy should be referred promptly to an established
adverse pregnancy outcomes, independently of renal renal-obstetric clinic to plan antenatal care. Assessment
disease severity. Proteinuria >1 g/24 h increases the need of renal function, degree of proteinuria (ACR or PCR),
for neonatal intensive care (RR of 4.2), and hyperten- haemoglobin, urine dip and culture, BP measurement
sion is associated with an increased risk of preterm (24 h ambulatory BP can be helpful), and baseline renal
delivery (RR 7.2) and Caesarean section (RR 5.7) [30]. ultrasound should be performed. All women with CKD
Interestingly, however, one study reported that CKD should be offered daily low-dose aspirin, given their
902 H. Blakey et al.
52.18.1 Pregnancy in Women with Systemic ity in patients with lupus; more so in those with lupus
Lupus Erythematosus nephritis (even for those women with preserved renal
function). Patients with active lupus (of any manifesta-
Lupus is predominantly a disease affecting women of tion), active lupus nephritis, and/or hypertension have
childbearing age. Its management in pregnancy therefore particularly high risk of adverse outcome. . Table 52.6
requires special consideration. There remains a signifi- presents results from a recent meta-analysis. Ideally,
cant risk of foetal and maternal morbidity and mortal- pregnancies should be planned in periods of quiescent
Pregnancy and the Kidney
903 52
be stopped at least 3 months prior to conception and
. Table 52.6 Lupus and risk of adverse pregnancy
outcome. (Data from [53])
switched to an alternative agent such as azathioprine if
necessary. Cyclophosphamide is associated with signif-
Lupus factor Pregnancy outcome Odds icant teratogenic and abortifacient effects and should
ratio not be used. Rituximab crosses the placenta especially
in the third trimester and has been associated with neo-
Active or flaring lupus Pre-eclampsia 12.7 natal B cell depletion and should probably be avoided
Emergency caesarean 19.0 in pregnancy. Antihypertensive medication may also
Early foetal loss 3.0
need modification as discussed previously.
6. Antiphospholipid antibodies: these have been shown
Preterm delivery 5.5
consistently to increase both the rate of pregnancy
Active lupus nephritis Any adverse maternal 5.3 loss (typically after 10 weeks) and the risk of pre-
outcome eclampsia. There appears to be a hierarchy of effect
Hypertension Pre-eclampsia 4.8–7.3 with the presence of lupus anticoagulant being asso-
ciated with more adverse events than anticardiolipin
Use of glucocorticoids Preterm birth 3.5
≥10–20 mg/day antibodies alone. In addition, higher titres of
antiphospholipid antibodies increase the risk of
adverse outcomes as does a history of previous
thromboembolic events or pregnancy loss.
disease when maternal and foetal outcomes are signifi-
7. Lupus serology: women with high levels of anti-
cantly improved.
dsDNA antibodies or low complement are at greater
In the pregnant woman with lupus nephritis, there
risk of adverse pregnancy outcomes than patients with
are various factors to consider:
quiescent serology, but the presence of active disease
1. Lupus itself does not appear to affect fertility (but
with active serology gives by far the worst outcomes. It
prior the use of cyclophosphamide and/or advanced
should be noted that complement levels are naturally
CKD may do). Appropriate contraception should be
raised in pregnancy so that trends in complement lev-
discussed with all women of childbearing potential.
els should be monitored in addition to absolute values.
Combined oral contraceptives are probably best avoided
8. Anti-Ro/SSA antibodies: these antibodies are associ-
in this group because of increased risks of hypertension
ated with neonatal lupus and two main foetal com-
and venous thromboembolic complications.
plications:
2. Lupus activity: maternal and foetal outcomes are
(a) Cutaneous neonatal lupus.
significantly worse when lupus is active at concep-
(b) Cardiac complications such as heart block
tion. This applies to renal and non-renal manifesta-
(around 1–2%) or endocardial fibroelastosis.
tions and emphasises the need for early and frank
discussion with all female patients of childbearing
Higher antibody titres and a history of cutaneous
potential of the importance of planning pregnancy.
neonatal lupus in a previous pregnancy appear to be
3. Background CKD: as with all pregnancies in women
associated with an increased risk of cardiac compli-
with CKD, the degree of chronic damage caused by
cations. All lupus patients with the presence of anti-
previous active disease is an important factor and
Ro/SSA antibodies should undergo foetal heart rate
can influence maternal and foetal outcomes.
auscultation weekly from 16 weeks.
4. Flares: it remains unclear whether pregnancy itself
The use of hydroxychloroquine in anti-Ro-posi-
increases the risk of lupus flare in the antenatal or
tive mothers with a previous child affected by car-
early postnatal period. The risk is increased by any
diac neonatal lupus has been shown to significantly
lupus activity within 6 months of conception, his-
reduce the risk of cardiac neonatal lupus in a subse-
tory of multiple flares, and discontinuation of
quent pregnancy [32].
hydroxychloroquine.
9. Other organ damage from lupus: pulmonary hyper-
5. Medication: see the British Society of Rheumatology
tension appears to be associated with antiphospho-
guideline on prescribing drugs in pregnancy and breast-
lipid syndrome and can be fatal in pregnancy even
feeding for detailed guidance [31]. Glucocorticoids,
with specialist management.
azathioprine, hydroxychloroquine, ciclosporin, and
tacrolimus appear to be safe to use in pregnancy.
Mycophenolate mofetil has been shown to be associ- Bearing in mind the above factors, we recommend that
ated with various congenital abnormalities, particularly all patients with lupus nephritis receive joint renal-
of the heart, palate, and face (which may be difficult to obstetric pre-pregnancy counselling with experienced
detect on a foetal ultrasound scan). It should ideally practitioners to enable tailored advice of individual risk
904 H. Blakey et al.
of both maternal and foetal outcomes. In addition, this 52.18.2 Diagnosis of Lupus Nephritis
allows: for the First Time in Pregnancy
1. Discussion about lupus activity and planning ther-
Presents Its Own Challenges
apy to achieve quiescence in preparation for preg-
nancy. Best outcomes result in those women with
Occasionally a patient will present with an active urinary
quiescent disease for >6 months on pregnancy safe
sediment and positive lupus serology for the first time
drugs. Where there is uncertainty about activity of
in pregnancy. We would recommend a full immunology
lupus nephritis (such as the presence of persistent
screen in any patient presenting with proteinuria prior
52 proteinuria), a pre-pregnancy renal biopsy is helpful
to 20 weeks and at any stage when proteinuria is associ-
as a guide.
ated with haematuria or appears not to be typical for
2. Medication changes:
pre-eclampsia. The decision to perform a renal biopsy
(a) Transfer from mycophenolate, cyclophospha-
can then be a difficult one. Real-time, ultrasound-guided
mide, or rituximab when the disease is felt to be
biopsy up to foetal viability can be very useful, both to
quiescent to azathioprine with a period of obser-
confirm a renal diagnosis allowing appropriate intensity
vation.
of treatment and to provide informed counselling to a
(b) Cessation of ACE inhibitors or ARB and trans-
woman. After viability, ‘blind’ treatment of assumed
fer to either labetalol or nifedipine for control of
lupus nephritis may be required with induction of pre-
hypertension if necessary. This also allows re-
term delivery if a significant deterioration of renal (or
establishment of a new baseline for proteinuria
extra-renal) parameters occur that require treatment
prior to pregnancy which makes interpretation of
contraindicated in pregnancy.
any subsequent rise in pregnancy easier (allowing
for a further physiological rise). In patients with
significant proteinuria, one may recommend the 52.19 Pregnancy in Women Treated by
continuation of ACEi or ARB until conception to
Dialysis
allow anti-proteinuric benefit to continue.
(c) Discussion around the use of folic acid for pre-
Fertility in women treated by chronic dialysis is mark-
vention of neural tube defects and low-dose
edly reduced due to the complex interplay of biological
aspirin from conception to reduce the risk of
and psychosocial factors, including decreased libido and
pre-eclampsia in this high-risk group.
disturbances of the hypothalamic-pituitary-gonadal
(d) Hydroxychloroquine should be offered to (or
hormonal axis (hyperprolactinaemia occurs in 70–90%),
continued in) all women with lupus in preg-
leading to irregular periods, anovulation, or amenor-
nancy. It reduces the risk of lupus flare and is
rhoea. Conception rates for women on dialysis have
also of benefit to anti-Ro-positive mothers in
been reported as 1.4 pregnancies per 1000 patients per
reducing the risk of cardiac neonatal lupus (as
year, compared with the national rate of approximately
discussed above).
76 per 1000 patients per year [4]. Conception on perito-
neal dialysis is 3 times less common than on haemodi-
3. Consideration of the need for low molecular weight alysis.
heparin. This should be used at a prophylactic dose A recent meta-analysis reported an increase in the
(with factor Xa monitoring): number of successful pregnancies in dialysis patients
(a) In all cases of significant proteinuria (PCR or over the last 15 years (574 pregnancies in 543 patients
ACR ≥200) whenever it develops in pregnancy. reported from 2000 to 2014) [33].
(b) When there is a previous history of venous Pregnancy outcomes have also improved over the
thromboembolic disease. last 3 decades as a consequence of more intensive dialy-
(c) When there is a history of significant pregnancy sis regimes, advances in obstetric/neonatal care, and a
loss in the presence of antiphospholipid anti- reduction in therapeutic termination. Conception rates
bodies. and outcomes (including live birth rates) for women
(d) In patients currently anticoagulated with warfa- who progress to dialysis during pregnancy are superior
rin – patients should be switched to LMWH in to those already established on dialysis prior to preg-
pregnancy. The evidence for safety of direct nancy [34]. Nevertheless, pregnancy in women treated
orally acting anticoagulants is unclear, and by dialysis is arduous, associated with high maternal
patients should be converted pre-conception to and foetal morbidity, and pregnancy outcomes remain
alternative agents. comparatively poor. See . Table 52.7.
Pregnancy and the Kidney
905 52
hypotensive episodes, and no requirement for anticoag-
. Table 52.7 Foetal and maternal outcomes in meta-
analysis of pregnancies in women treated by dialysis. (Data
ulation. However, reported outcomes between treatment
from [33]) modalities are similar. Peritonitis has been associated
the with onset of spontaneous labour, and by the third
Pregnancy outcome Incidence (%) trimester, peritoneal space for dialysis fluid is limited
even on automated nocturnal treatment, often leading
Preterm delivery 83 (median gestational age
to reduced appetite. We do not recommend immediate
(<37 weeks) 33 weeks)
switch of dialysis modality in early pregnancy but sug-
Low birth weight/IUGR 32 gest the formation of AV fistula early in the second tri-
Requirement for NICU 60 mester to enable easy conversion to haemodialysis later
care in pregnancy if problems are encountered.
Stillbirth/neonatal death 18
Surviving infants 83
52.20.2 Haemodialysis
Maternal perinatal 0.4
mortality The literature is almost certainly influenced by publica-
tion bias in favour of successful outcomes and under-
reporting of spontaneous miscarriage. An attempt at
52.19.1 Diagnosis of Pregnancy rationalisation of contemporaneous data has been made
recently in a systematic review of 126 heterogeneous
Diagnosis of early pregnancy in dialysis patients is dif- studies of pregnancies (n = 574) in patients receiving
ficult. Amenorrhoea or irregular periods are common, haemodialysis or peritoneal dialysis (n = 543), reported
and urine pregnancy tests are often unreliable. Serum between 2000 and 2014 [33].
beta-HCG levels may be elevated in the absence of preg- Rates of adverse foetal outcomes, including low birth
nancy. Trans-abdominal or the more sensitive transvagi- weight (p = 0.017) and preterm delivery (p = 0.044), were
nal ultrasound is the most reliable pregnancy test in this significantly reduced in those women undergoing more
population and allows assessment of gestation. intensive dialysis schedules. Incidence of maternal peri-
natal mortality was low (0.4%). Maternal complications
such as pre-eclampsia, hypertension, and anaemia are
52.19.2 Pre-Pregnancy Counselling commonplace; however, exact incidence is difficult to
define due to heterogeneity of studies and differences in
Many women assume that it is impossible to conceive on definitions.
dialysis. It is good practice to counsel women of fertile age Polyhydramnios is widely reported and may underlie
treated by dialysis for the risks of pregnancy and routinely the high rate of spontaneous premature labour precipi-
offer contraceptive advice. Any woman contemplating tating delivery. It is suggested that foetal osmotic diure-
pregnancy should be offered combined renal-obstetric sis secondary to high maternal urea may be the cause.
pre-conception counselling in a unit experienced in the An inverse correlation between pre-dialysis urea and
care of such pregnancies and be managed under the super- successful outcome has been reported, leading to a rec-
vision of a joint renal-obstetric antenatal service through- ommendation to keep pre-dialysis urea <17 mmol/l [35].
out pregnancy. For most women, delaying pregnancy until The incidence of polyhydramnios and premature
after a successful renal transplant with much improved labour may be reduced by better solute control achieved
prospects of a successful outcome is the optimum pre- by more prolonged dialysis. A recent cohort study com-
conception advice. Pregnancy, even if unsuccessful, may pared outcomes of 22 pregnancies in women receiving
lead to HLA sensitisation – reducing opportunities for intensive haemodialysis (mean 43 hours per week) with
subsequent transplantation, especially spousal donation. outcomes from 70 pregnancies of patients receiving
‘standard’ dialysis (mean 17 hours per week). The inten-
sive dialysis group had a significantly higher live birth
52.20 Pregnancy Outcomes rate (86.4% vs 61.4%, p = 0.03) and a longer median
duration of pregnancy (36 weeks vs 27 weeks, p = 0.002).
Furthermore, a dose-response was found, with a longer
52.20.1 Peritoneal Dialysis duration of dialysis therapy associated with improved
pregnancy outcomes [36].
It therefore appears that increasing hours of dialysis,
There are some theoretical advantages of peritoneal
whether by daily or nocturnal dialysis, is associated with
dialysis over haemodialysis in pregnancy, including
better outcomes. The logistics of such therapy should
more gentle fluid, electrolyte and toxin removal, reduced
906 H. Blakey et al.
be discussed with any woman undertaking pregnancy lar morbidity in babies born small for gestational age.
on dialysis and can be particularly difficult in those who Moreover, there may be a potential risk of renal impair-
already have caring responsibilities for other children or ment in children born to dialysing mothers [37].
who remain in employment. We would recommend the In summary, pregnancy in the dialysis patient is
commencement of intensive dialysis therapy from the increasingly common and appears to have better out-
second trimester and earlier if feasible. comes than previously noted – probably related to the
provision of more frequent dialysis and better mater-
nal and neonatal care. Nevertheless, pregnancy in this
52 52.21 Guidelines for Management group of patients will require a considerable time com-
of Pregnancy in Haemodialysis mitment from the patient and medical staff, and preg-
nancy outcomes are less favourable than for those with
Patients
a functioning transplant or with less severe CKD. Most
women should be advised to defer pregnancy until after
1. Offer contraceptive advice and pre-conception
successful renal transplantation when a maternal and
counselling for all women of childbearing age
foetal outlook is improved. Pregnancy may however be
receiving dialysis.
a reasonable option in the highly motivated, counselled
2. Intravenous iron (after the first trimester) and ESA are
patient within an experienced environment.
widely used and are not associated with foetal abnor-
malities. Maintain haemoglobin 95–110 g/L. Monitor
BP closely. ESA dose increase of 50–100% is usually
required. 52.22 Pregnancy Following Renal
3. Folic acid and water-soluble vitamin supplementa- Transplantation
tion are advised.
4. Dialysis dose: increase dialysis frequency to 6 times/ Renal transplantation rapidly restores fertility in women
week in early second trimester providing a mini- with ESRD, offering for many the first opportunity to
mum of 20 hours/week, keeping pre-dialysis urea conceive with a good chance of a successful pregnancy
below 17moml/l. There may be benefits in longer outcome. Nevertheless, these pregnancies are complex
hours or daily nocturnal dialysis. and at high risk for foetal and maternal complications.
5. Maintain BP <140/90 to 130/80 mmHg. At least 50% of transplant pregnancies reported in the
6. Avoidance of intra-dialytic hypotension with care- literature are unplanned. Best outcomes are most likely
ful and regular reassessment of dry weight. if early effective contraceptive advice is given on dis-
7. Anticoagulation: low molecular weight heparin charge post-transplantation, and women considering
does not cross the placenta and is not associated pregnancy are advised in a joint renal-obstetric pre-
with increased antepartum haemorrhage. pregnancy counselling clinic. Appropriate antenatal
8. Treatment with daily low-dose aspirin from care is best provided in a joint antenatal clinic managed
12 weeks to reduce risk of pre-eclampsia. by renal and obstetric doctors with significant experi-
9. Dialysate: try to mimic pregnancy physiology. ence in this area see 7 Case 52.43.3.
Reduce dialysate sodium to 135 mmol/l, bicarbon-
ate to 25 mmol/l, and calcium to 1.25 mmol/l. Serum
phosphate levels frequently fall below normal on 52.23 The Evidence Base and Sources
intensive treatment requiring dialysate phosphate of Guidance
supplementation and/or supplementary dietary
advice. The evidence base to counsel women in guiding preg-
10. Regular review by an experienced renal-obstetric nancy management remains incomplete but has
multidisciplinary team to allow appropriate mater- improved considerably recently. Many small single
nal and foetal monitoring and discussions with centre retrospective case series which may suffer from
regard to optimal timing of delivery. selection bias have been collated in a large meta-analysis
11. Meticulous management of other comorbidities [38]. The US National Transplant Pregnancy Registry
such as diabetes, cardiovascular disease, and employed voluntary submission, but three prospective
immune-related conditions by experienced teams. registries collecting data on almost all transplants (two
from the UK and one from Australia/New Zealand)
The long-term outcome of children born to mothers on have also been published [39–41] as well as a recent
dialysis remains unknown. The immediate risks associ- study reporting pregnancy outcomes from all kidney
ated with prematurity are well characterised, and there transplant patients in England using Hospital Episode
is some evidence for increased long-term cardiovascu- Statistics data [42]. UK Kidney Association, American
Pregnancy and the Kidney
907 52
Society of Transplantation Clinical Practice Guidelines There is increasing evidence that mycophenolic acid
and European Best Practice Guidelines advise clinicians (MPA) and mycophenolate mofetil (MMF) are terato-
[43, 44]. genic. Reports in renal transplant pregnancies identify
a greater than expected first trimester spontaneous mis-
carriage rate of 40% (10–15% in the general popula-
52.24 The Timing of Pregnancy in Relation tion). In addition, an embryopathy comprising cleft lip
to Transplantation and palate, ear, and cerebral abnormalities is reported in
a quarter of exposed pregnancies [45], which may be dif-
Guidelines recommend deferring pregnancy until at ficult to detect on the foetal ultrasound scan. All women
least 12 months post-transplantation. By this time, should be counselled for the risks of congenital abnor-
immunosuppressant doses should be at their nadir, and mality at the time of transplantation and should practice
the risks of rejection and opportunistic infection (in secure contraception and undergo pre-pregnancy coun-
particular cytomegalovirus which can affect the foetus) selling if they wish to conceive. Women taking MMF or
are remote. Meta-analysis however does not support MPA should be advised to stop at least 3 months before
a clear cut-off in the timing of conception post-preg- planned conception (ideally 6 months) to enable transfer
nancy. The live birth rate for pregnancies <2y, 3–4y, to alternative therapy (usually azathioprine) and assess-
and >4y post-transplant were reported to be 80%, 76%, ment of stability, before attempting conception. There
and 75% respectively, whereas obstetric complications is a small but definite increased risk of rejection during
were significantly greater in earlier pregnancies [38]. In this period, and this must be discussed.
practice it is best to wait for stable well-preserved kid-
ney function after conversion to treatment known to be
safe in pregnancy. 52.26 Men and Mycophenolate
the likelihood that some women have had previous peri- 52.29 Foetal Outcomes
toneal dialysis-related peritonitis (although results rely
on voluntary submissions and may be subject to report- Foetal outcomes are listed in . Table 52.9 . As compared
ing bias). with the general population, the adjusted odds ratio for
preterm delivery is 12.7 [40]. The mean gestational age at
birth is 36 weeks, being remarkably consistent between
52.28 Maternal Outcomes of Pregnancies different registry series and meta-analyses. Over half of
in Renal Transplant Recipients births are premature (<37 weeks), and consequently a sig-
52 nificant proportion is born with low birth weight (<2.5 kg)
Pregnancies progressing beyond the first trimester have a and is small for their gestational age (birth weight < tenth
greater than 95% chance of a successful outcome with a centile). Many babies born to renal transplant recipients
live birth [39]. However, maternal complications such as will therefore require neonatal intensive care.
pre-eclampsia and gestational diabetes are substantially Kidney transplant recipients with a GFR >90 appear
increased for renal transplant recipients when compared to have less favourable pregnancy outcomes than non-
to the general population (adjusted odds ratio for pre- transplanted patients with CKD stage 1. However, this
eclampsia is 6.3 [40]). More than half of pregnancies are effect levels out when only CKD stage 1 patients with pro-
delivered by Caesarean section, with the risk increasing gressive or immunologically mediated diseases (such as
if delivery is prior to 37 weeks. Maternal outcomes are lupus and diabetes) are compared with kidney transplant
listed in . Table 52.8 and provide important informa- patients. Outcomes are comparable between transplant and
tion for counselling transplant recipients contemplating non-transplanted patients of all other CKD stages [46].
pregnancy.
The UKOSS study importantly demonstrates a
significant rise in serum creatinine in the third tri- 52.30 Long-Term Effect of Pregnancy
mester which is exaggerated in women with a poor on Graft and Patient Survival
pregnancy outcome [40]. The cause of the rise is
unexplained but is likely to result from a physiologi- Case-control studies show no evidence of an adverse impact
cal decline in GFR rather than the adverse impact of of pregnancy on graft and patient survival in women with
superimposed PET. Proteinuria develops or increases preserved kidney transplant function. However, those with
in around a third of women sometimes to near more significant pre-pregnancy renal dysfunction are more
nephrotic levels [40]. likely to suffer pregnancy-related decline [47].
Despite immunological tolerance shown to the foetus, The UK Transplant Registry identifies higher pre-
the reported incidence of rejection during pregnancy pregnancy creatinine and systolic BP at conception with
is similar to that in non-pregnant transplant recipients, adverse transplant outcome. The odds ratio for preterm
2–4% [38–40]. In early pregnancy, this is associated birth in those women with a creatinine of <150 mmol/l
with volume depletion and failure to absorb immuno- at conception is 0.2 as compared to those with a serum
suppression due to hyperemesis. Physiological hydro- creatinine of >150. It appears that hypertension (even
nephrosis of the transplant is common in pregnancy, when controlled) has an even greater association with
but ureteric obstruction by the gravid uterus is thank- preterm birth (30-fold increased risk) as compared with
fully rare. Unexplained transplant dysfunction before normotensive transplant recipients [40].
28 weeks gestation should include consideration of
renal biopsy as this may be safer than blind antirejec-
tion treatment. PET may explain transplant dysfunc- 52.33 Delivery
tion later in pregnancy. Any decision must be carefully
considered and the risk/benefit ratio discussed with the The pelvic transplant kidney does not impair vaginal
pregnant woman. delivery, nor is there evidence of damage to the trans-
plant in the process. Nevertheless, two-thirds of deliv-
eries are by Caesarean section. Delivery should be
52.32 Factors Affecting Live Birth Rate ‘covered’ with IV steroids and IV hydration.
It is advisable for obstetricians to plan Caesarean sec-
Risk factors for adverse pregnancy outcome (live birth tion delivery in advance by a discussion with the trans-
or delivery <32 weeks) include: plant surgeon, particularly where there may be anatomical
1. Maternal age <20 or >35 years. challenges including simultaneous pancreas-kidney trans-
2. African-Caribbean ethnicity. plantation or those with abnormal urinary drainage.
910 H. Blakey et al.
. Table 52.10 Comparison of forms of contraception with reference to women with CKD. (Reproduced with permission from [4])
tive contraception. The spermicide, nonoxynol-9, alters 52.42 Contraception for Patients
periurethral microbial flora and may lead to recurrent with Lupus Nephritis and Renal
urinary tract infections in those with predisposing fac-
Transplant Recipients
tors such as reflux nephropathy or bladder dysfunction.
Long-acting reversible contraception includes depot
Women with lupus nephritis are often denied oestrogen-
progestogens, depot medroxyprogesterone acetate
containing COC or intrauterine device/system contra-
(DMPA) requiring 3-monthly deep IM administration,
ception. Historic literature has led to the belief that
and etonogestrel (Nexplanon®) inserted subdermally by
oestrogens lead to a flare of lupus and may increase BP
52 a trained operator, providing contraception for 3 years.
and that the IUD/S may not be effective or are associ-
The alternatives, intrauterine devices include copper coil
ated with a high risk of pelvic infection in the setting
or levonorgestrel releasing intrauterine system (LNG-
of immunosuppression. These fears appear largely
releasing IUS, Mirena®). In our experience, these long-
unfounded. A single blind study of 162 women with
acting forms are forms are preferred by many women
SLE and mild/quiescent disease randomised patients to
with CKD not contemplating pregnancy after coun-
COC, POP, or copper IUD. No pregnancies occurred
selling because of high efficacy and convenience. The
over 12 months, and the incidence of lupus flare was the
Mirena IUS is associated with light menses or amenor-
same across all groups. No episodes of PID occurred in
rhoea and can be inserted in nulliparous women. Over
those treated with the IUD [51]. A second randomised
80% of women in the general population remain satis-
study of COCs vs placebo (exclusions included moder-
fied with these methods after 12 months.
ate/high anticardiolipin antibodies, lupus anticoagulant
or history of thrombosis) in women with inactive or sta-
ble SLE [52] confirmed no increased risk of lupus flares
52.41 Oral Contraceptives with use of the COC. As such, women with mild or sta-
ble lupus can be safely treated with either the COC (in
The traditional progesterone-only ‘mini pill’ is effec- the absence of thrombotic risk factors, which includes
tive if taken within a 2-hour window each day. Efficacy nephrotic syndrome) or IUD/S.
in practice is reduced and may not be adequate for In renal transplant recipients, the use of progesto-
women requiring a high level of security from preg- gens may alter CNI metabolism. Both increases and
nancy. Desogestrel 75 mcg (Cerelle, Cerazette®) has a reductions in levels have been reported, which should
different mechanism of action including inhibition of therefore be monitored and doses adjusted accord-
ovulation and has a 12-hour window of administration ingly. A small uncontrolled cohort study of COC use
without loss of effectiveness. This is effective and well in renal transplant recipients using the COC pill or
tolerated in women with CKD, including those immu- patch demonstrated contraceptive efficacy. However,
nosuppressed, although it can lead to irregular uterine 30% of women required alteration of antihypertensive
bleeding. therapy. No comparator group was included so causa-
In the general population, combined oral contra- tion is unproven. The COC should not be used as first-
ceptives (COCs) are the most commonly used form of line in transplant recipients. However, in those who have
reversible hormonal contraception and are well tolerated controlled BP, with no other contraindication who have
and highly effective and have a long history of safety. been intolerant or do not wish to use alternative meth-
However, many women with CKD, especially those with ods, we cautiously allow their use in this population.
treated hypertension, are advised against their use. Oes- The risk of pregnancy in this setting usually outweighs
trogens should be avoided in those women at greater the risks of COC.
risk of venous thromboembolic disease (including those The IUD/S is widely used in another immunosup-
with antiphospholipid syndrome and nephrotic syn- pressed population, those with HIV, and is not associated
drome). The evidence of a hypertensive effect in women with an increased risk of pelvic infection or unplanned
with CKD is limited, and experience suggests that any pregnancy. The LNG-releasing IUS is appropriate for
change in BP can be offset by a dose increase in antihy- use in selected women post-renal transplantation. We
pertensive treatment. As such the use of COC in women tend to avoid the use of DMPA because of the poten-
with CKD and controlled hypertension should not be tial risk of exacerbating post-transplant osteoporosis
considered an absolute contraindication. although good evidence for this is lacking.
Pregnancy and the Kidney
913 52
Contraception Tips and Advice
4. The LNG-IUS is effective and safe for women
1. Contraceptive advice is an essential component of with kidney disease receiving immunosuppres-
care of women with CKD. sion including those with SLE or transplant
2. There are few additional absolute contraindications recipients.
to most forms of contraception in this population. 5. Where there is no increased risk of vascular
3. Desogestrel POP (Cerazette) is well tolerated by thrombosis, the COC can be safely used in women
many patients with CKD and highly effective with with inactive or low activity SLE and is not asso-
less demanding compliance issues (12-hour window). ciated with an increased risk of lupus flare.
Case Study
Case 1: Obstructive Uropathy and AKI in Pregnancy due to rising proteinuria. A renal biopsy post-pregnancy
A 35-year-old nulliparous female presented at 28 weeks showed focal and segmental glomerulosclerosis.
pregnant with acute onset right flank pain. Blood tests
revealed a stage 1 AKI (creatinine rise from a baseline of Case 3: Pregnancy in a Renal Transplant Recipient
50 to 90) and urine dipstick showed 4+ blood and 2+ leu- A 28-year-old female with a background of ESRD second-
cocytes. ary to membranous nephropathy treated with a living
An abdominal ultrasound was performed which donor kidney transplant. Her baseline graft function was
showed right-sided hydronephrosis. Given ongoing pain good (creatinine 85, eGFR 70), she had no proteinuria
and AKI, an MRU was requested. This showed right-sided (ACR <1), and blood pressure was normal with no require-
hydronephrosis (see . Fig. 52.3a) and dilation of the right ment for antihypertensive medication. She expressed a
ureter to the level of the pelvic inlet where it narrowed. wish to conceive at 9 months post-transplant and was
Beyond this there was an apparent filling defect at the VUJ, referred to the joint renal-obstetric pre-pregnancy counsel-
suggestive of a calculus (see . Fig. 52.3b with an arrow ling clinic. She was advised to wait until at least 1-year
showing filling defect). post-transplant prior to conceiving, but mycophenolate
The patient was treated with intravenous fluid and immunosuppression was switched to azathioprine in prep-
antibiotics and the stone spontaneously passed. The AKI aration. Tacrolimus and prednisolone were continued.
resolved soon after and the pregnancy was able to continue On confirmation of pregnancy at 12-month post-trans-
to term. plant, this patient was commenced on 75 mg aspirin as pre-
eclampsia prophylaxis. Pregnancy initially progressed well
Case 2: Newly Diagnosed Chronic Kidney Disease with no change in graft function or blood pressure, and
in Pregnancy monthly monitoring took place in a joint renal-obstetric ante-
A 32-year-old female with no past medical history was natal clinic. Gestational diabetes was diagnosed at 28 weeks
referred to renal antenatal clinic at 19 weeks pregnant with after an abnormal glucose tolerance test, and treatment with
heavy proteinuria (PCR 350) and invisible haematuria (3+ metformin, and later insulin, was initiated.
on dipstick). Blood pressure was mildly elevated Pregnancy continued uneventfully until around 32 weeks
(142/96 mmHg), so she was treated with labetalol. There gestation, when creatinine began to rise to reach a peak of
were no other clinical features of pre-eclampsia, and the 120, and there was evidence of proteinuria (PCR 50–70).
proteinuria was attributed to probable underlying renal Blood pressure remained well controlled. She was admitted
disease. to the antenatal ward for closer monitoring and steroid
Blood tests showed normal renal function (creatinine treatment for foetal lung maturation in the event of prema-
55, GFR >90 ml/min), albumin 30, negative ANA, ANCA ture delivery being required. Tacrolimus levels were slightly
and paraproteins, and normal complements and dsDNA. low, so the dose was increased. A transplant ultrasound scan
Careful discussion took place around the risks and was also carried out which showed normal graft perfusion
benefits of doing a kidney biopsy. Given that immunology and no evidence of obstruction. There was no further dete-
was all negative and there was no evidence of lupus or vas- rioration in proteinuria or renal function so she was dis-
culitis, the decision was made to hold off biopsying in charged from the hospital but kept under thrice weekly
pregnancy. She was managed instead with prophylactic outpatient monitoring for blood pressure, blood, and urine
low molecular weight heparin (given the nephrotic range testing and underwent planned delivery at 37 weeks gesta-
proteinuria) and low-dose aspirin for pre-eclampsia pro- tion. The deterioration in renal function and proteinuria
phylaxis. Induced delivery took place at 38 weeks gestation were attributed to probable superimposed pre-eclampsia.
914 H. Blakey et al.
? Questions References
1. A 32-year-old female with a background of CKD
secondary to lupus nephritis attends the nephrol- 1. Coresh J, et al. Prevalence of chronic kidney disease in the
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2038–47.
nant. She has a baseline creatinine of 140 and an
2. Odutayo A, Hladunewich M. Obstetric nephrology: renal
eGFR of 42. Urine ACR is 150. Her medication hemodynamic and metabolic physiology in normal pregnancy.
list includes mycophenolate mofetil, predniso- Clin J Am Soc Nephrol. 2012;7(12):2073–80.
lone, ramipril, and hydroxychloroquine. 3. Williams D, Davison J. Chronic kidney disease in pregnancy. Br
52 The patient wishes to know what the risks are
4.
Med J. 2008;336(7637):211–5.
Wiles KS, Nelson-Piercy C, Bramham K. Reproductive health
to her health from pregnancy. What would you
and pregnancy in women with chronic kidney disease. Nat Rev
advise? Nephrol. 2018;14(3):165–84.
2. This patient also wishes to know what the poten- 5. Bramham K, et al. Chronic hypertension and pregnancy out-
tial risks could be to the baby. What would you comes: systematic review and meta-analysis. BMJ. 2014;348:
tell her? g2301.
6. National Institute for Health and Care Excellence (NICE).
3. Which of her current medications can be contin-
Hypertension in pregnancy: diagnosis and management. 2011
ued and which would you stop? [cited 2018 24/7/2018]; Clinical guideline (CG107)]. Available from:
4. Which additional medication(s) would you con- https://www.nice.org.uk/guidance/cg107/resources/hypertension-
sider starting on confirmation of pregnancy? in-pregnancy-diagnosis-and-management-pdf-35109334011877.
7. Abalos E, Duley L, Steyn DW. Antihypertensive drug therapy
for mild to moderate hypertension during pregnancy. Cochrane
v Answers
Database Syst Rev. 2014;2:CD002252.
1. CKD is an independent risk factor for adverse 8. Magee LA, et al. Less-tight versus tight control of hypertension
maternal outcomes in pregnancy, including sig- in pregnancy. N Engl J Med. 2015;372(5):407–17.
nificantly increased odds of developing pre- 9. Magee LA, et al. The CHIPS Randomized Controlled Trial
eclampsia and requirement for Caesarean delivery. (Control of Hypertension in Pregnancy Study): Is Severe
Hypertension Just an Elevated Blood Pressure? Hypertension.
The presence of proteinuria and hypertension
2016;68(5):1153–9.
increase the risks further. There is also an 10. Butalia S, et al. Hypertension Canada’s 2018 guidelines for
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tion post-pregnancy. Successful pregnancy is 2018;34(5):526–31.
however possible and should ideally be planned in 11. Li DK, et al. Maternal exposure to angiotensin convert-
ing enzyme inhibitors in the first trimester and risk of mal-
a period where lupus has been quiescent for a
formations in offspring: a retrospective cohort study. BMJ.
period of at least 6 months. Regular antenatal 2011;343:d5931.
monitoring by a nephrologist and obstetrician 12. Roberts JM, et al. Hypertension in pregnancy report of
will be required. the American college of obstetricians and gynecologists’
2. There are increased risks of adverse foetal out- task force on hypertension in pregnancy. Obstet Gynecol.
2013;122(5):1122–31.
comes in pregnancy in women with CKD. The
13. Levine RJ, et al. Circulating angiogenic factors and the risk of
risks increase incrementally with increasing sever- preeclampsia. N Engl J Med. 2004;350(7):672–83.
ity of renal impairment and include preterm 14. Zeisler H, et al. Predictive value of the sFlt-1:PlGF ratio
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and low birth weight. 2016;374(1):13–22.
15. Bramham K, et al. Diagnostic and predictive biomarkers for
3. Mycophenolate: stop at least 3 months prior to
pre-eclampsia in patients with established hypertension and
conceiving and switch to azathioprine. chronic kidney disease. Kidney Int. 2016;89(4):874–85.
Prednisolone and hydroxychloroquine – continue. 16. Piccoli GB, et al. Pre-eclampsia or chronic kidney disease? The
Ramipril – consider continuing until confirmation flow hypothesis. Nephrol Dial Transplant. 2013;
of pregnancy given underlying proteinuria. 17. Askie LM, et al. Antiplatelet agents for prevention of pre-
eclampsia: a meta-analysis of individual patient data. Lancet.
Alternatively could be switched to labetalol.
2007;369(9575):1791–8.
4. Folic acid should be commenced in the pregnancy 18. Visintin C, et al. Management of hypertensive disorders during
planning period. Aspirin 75 mg daily from pregnancy: summary of NICE guidance. BMJ. 2010;341:c2207.
12 weeks gestation as pre-eclampsia prophylaxis. 19. Rolnik DL, et al. Aspirin versus placebo in pregnancies at high
Consider the need for low molecular weight hepa- risk for preterm preeclampsia. N Engl J Med. 2017;377(7):
613–22.
rin if urine ACR rises to a nephrotic range.
Pregnancy and the Kidney
915 52
20. Wing DA, Fassett MJ, Getahun D. Acute pyelonephritis in 37. Abou-Jaoude P, et al. What about the renal function during
pregnancy: an 18-year retrospective analysis. Am J Obstet childhood of children born from dialysed mothers? Nephrol
Gynecol. 2014;210(3):219 e1–6. Dial Transplant. 2012;27(6):2365–9.
21. Smaill FM, Vazquez JC. Antibiotics for asymptomatic bac- 38. Deshpande NA, et al. Pregnancy outcomes in kidney trans-
teriuria in pregnancy. Cochrane Database Syst Rev. 2015;8: plant recipients: a systematic review and meta-analysis. Am J
CD000490. Transplant. 2011;11(11):2388–404.
22. Ray JG, et al. Association Between MRI Exposure During 39. Sibanda N, et al. Pregnancy after organ transplantation: a report
Pregnancy and Fetal and Childhood Outcomes. JAMA. from the UK Transplant pregnancy registry. Transplantation.
2016;316(9):952–61. 2007;83(10):1301–7.
23. Nevis IF, et al. Pregnancy outcomes in women with chronic 40. Bramham K, et al. Pregnancy in renal transplant recipi-
kidney disease: a systematic review. Clin J Am Soc Nephrol. ents: a UK national cohort study. Clin J Am Soc Nephrol.
2011;6(11):2587–98. 2013;8(2):290–8.
24. Piccoli GB, et al. Kidney biopsy in pregnancy: evidence for 41. Wyld ML, et al. Pregnancy outcomes for kidney transplant
counselling? A systematic narrative review. Bjog-an Inter J recipients. Am J Transplant. 2013;13(12):3173–82.
Obstet Gynaecol. 2013;120(4):412–27. 42. Sarween N, et al. pregnancy outcomes in renal transplant
25. Day C, et al. The role of renal biopsy in women with kidney recipients in England over 15 years. Nephrol Dial Transplant.
disease identified in pregnancy. Nephrol Dial Transplant. 2016;31:6–6.
2008;23(1):201–6. 43. McKay DB, et al. Reproduction and transplantation: report
26. Zhang JJ, et al. A systematic review and meta-analysis of out- on the AST Consensus Conference on Reproductive Issues and
comes of pregnancy in CKD and CKD outcomes in pregnancy. Transplantation. Am J Transplant. 2005;5(7):1592–9.
Clin J Am Soc Nephrol. 2015;10(11):1964–78. 44. Transplantation E.E.G.O.R. European best practice guidelines
27. Jones DC, Hayslett JP. Outcome of pregnancy in women for renal transplantation. Section IV: Long-term management
with moderate or severe renal insufficiency. N Engl J Med. of the transplant recipient. IV.10. Pregnancy in renal transplant
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28. Imbasciati E, et al. Pregnancy in CKD stages 3 to 5: fetal and 45. Sifontis NM, et al. Pregnancy outcomes in solid organ trans-
maternal outcomes. Am J Kidney Dis. 2007;49(6):753–62. plant recipients with exposure to mycophenolate mofetil or
29. Piccoli GB, et al. Risk of adverse pregnancy outcomes sirolimus. Transplantation. 2006;82(12):1698–702.
in women with CKD. J Am Soc Nephrol. 2015;26(8): 46. Piccoli GB, et al. Outcomes of pregnancies after kidney trans-
2011–22. plantation: lessons learned from CKD. A comparison of
30. Piccoli GB, et al. Pregnancy and chronic kidney disease: a challenge transplanted, nontransplanted chronic kidney disease patients
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31. Flint J, et al. BSR and BHPR guideline on prescribing drugs Transplantation. 2017;101(10):2536–44.
in pregnancy and breastfeeding-Part I: standard and biologic 47. Levidiotis V, Chang S, McDonald S. Pregnancy and mater-
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32. Izmirly PM, et al. Maternal use of hydroxychloroquine 48. Bramham K. et al. Breastfeeding and tacrolimus: serial moni-
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1217–22. 53. Andreoli L, et al. EULAR recommendations for women’s
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917 VIII
Contents
References – 930
Microscopic
Haematuria
No further
evalutaion needed
Is there any evidence suggesting
glomerular bleeding:
• Albuminuria
• Acutely high Se Cr
• Hypoalbuminaemia
• Dysmorphic RBCs
• RBC casts
• WBC casts
• New or worsening HT
• New or worsening Oedema
No Yes
Yes No
. Fig. 53.1 This is one example of an evaluation pathway for adults robust method for identifying patients at risk of renal disease or con-
with asymptomatic non-visible (microscopic) haematuria. There are versely urological causes of haematuria so patients can be rapidly
many alternative versions of this; the principle is to embed a simple, referred appropriately and also avoid unnecessary investigations
922 S. Camilleri et al.
haematuria (see Chap. 2 on urine analysis), and it is the least invasive screening tool is phase-contrast micros-
commonly accepted that visible haematuria should be copy; if the RBC are predominantly dysmorphic, then
referred to a urologist for initial assessment (there are the cause is likely to be the underlying glomerular lesion,
some caveats here, see below) [4]. Investigation of non- but if predominantly lower tract, it should provoke uro-
visible haematuria is complicated by the facts that (a) logical assessment.
dipsticks are very sensitive (so guidelines usually recom- The need for radiological evaluation of the upper
mend ignoring ‘trace’ and frequently 1+) and (b) auto- urinary tract in patients with asymptomatic micro-
mated urine microscopy for RBC may be falsely negative scopic haematuria (AMH) is supported by all guide-
if RBCs have time to haemolyse. Thus, for asymptom- lines (see the end of chapter), but the recommended
atic non-visible haematuria 2–3 positive dipsticks are modality varies between them. The American Urology
recommended before referral having excluded urinary Association (AUA), American College of Radiology
53 tract infection. Conventionally, patients over 40 are Appropriateness Criteria, and European Association of
referred for upper tract imaging and cystoscopy to Urology (EAU) choose multiphase CT urogram as the
exclude a urological cause. What needs to be built into preferred study (highest sensitivity and specificity). The
the urology and nephrology pathways is the identifica- CUA microscopic haematuria guidelines recommend
tion of patients who are at increased risk of renal disease renal ultrasonography as the first-line imaging method,
and malignancy, respectively. Therefore, for patients with CT urography used in cases where additional tests
referred to urology, it would be very helpful to know that are needed for abnormal or inconclusive findings [7].
as part of the urological assessment: In summary, confirmed asymptomatic non-visible
1. eGFR is >60mls/min (or no significant drop in haematuria is a non-specific sign with both urological
eGFR). and nephrological causes. Nephrologists need to refer
2. Urine albumin/creatinine ratio (ACR) or protein/ patients at increased risk of malignancy, and urologists
creatinine ratio (PCR) is less than 30 or 50, respec- need to establish clear pathways to identify patients with
tively. increased risk of renal.
3. Blood pressure <140/90.
4. Microscopy performed* [5, 6].
53.3 Renal Stones
*Given that glomerular haematuria is distinct from non-
glomerular haematuria and that dipstick positive hae- The assessment and management of renal stones
maturia without red blood cells might indicate a pigment is covered in Chap. 55 However, in the context that
nephropathy the addition of confirmatory microscopy there is a steadily growing incidence of stone forma-
or, ideally, phase-contrast microscopy to the end (or tion (4.4% increase in 5 years in the UK) [8] result-
beginning) of a negative one-stop shop might genuinely ing in roughly a 10% lifetime risk of stones in Western
improve the pathway. With or without this addition, countries and with recurrence rates after an initial
convincing non-visible haematuria should be consid- symptomatic stone event reported to be from 30 to
ered for nephrology review and in patients who trigger 50% within 10 years of the first presentation, this is
on the three screening tests above as being increased risk an increasingly common problem [6, 7]. Therefore, it
of renal disease, there needs to be a system for efficient is important to consider the ability of urologists and
nephrology referral. nephrologists to efficiently manage such patients.
Conversely, nephrologists need to be adept at spot- While some urologists have a specialist interest in met-
ting and confirming new haematuria in existing patients, abolic stone disease, for most patients there is merit in
requesting the appropriate imaging and referring. For a referring to a specialized metabolic stone clinic with
small subset of patients, such as those with aristolochic multidisciplinary review including radiology, dietetics,
acid nephropathy, analgesic nephropathy, large exposure urology, and nephrology [9]. There are different mod-
to cyclophosphamide, or those with renal tumour syn- els for this, but the most efficient ones probably don’t
dromes, there needs to be a clear plan for urological sur- involve nephrologists and urologists sharing the same
veillance that follows the patient whether they have consultation.
transitioned to dialysis or transplant or to another The key to investigation is deciding who is a low-risk
nephrologist. There will also be patients (particularly stone former and who is a high-risk stone former. It is
older patients and smokers) with chronic renal haematu- generally accepted that even low-risk first-time stone
ria (such as IgA nephropathy) who may have increased former should undergo a basic minimum metabolic
haematuria. Thus, when possible it would be efficient to evaluation, usually at the time of presentation in the
screen out patients with glomerular haematuria to avoid emergency department. . Fig. 53.2 shows how patients
unnecessary cystoscopy. As alluded to above, perhaps are assigned to either low- or high-risk groups and their
Urology Renal Interface
923 53
. Fig. 53.2 Offers one
structure for the investigation of Stones
stones based on risk. Patients
who are low-risk stone formers
will usually be managed in Past h/o
yes no
nephrolithiasis
isolation by urologists but will
need a robust system for
reviewing results and offering
• urinalysis +/- culture
• Se electrolytes (incl Ca
good-quality advice on lifestyle • Se urate
changes or medical intervention. Basic Se Cr
evaluation • FBC
High-risk stone formers may • CRP
need a referral to a metabolic • Imaging
clinic that can address risk • Stone analysis if stone available
factors for stone formation and
management in more detail. This
• First stone below the age of 30
may be run by a urologist, • Family h/o stone formation
nephrologist, or biochemist but Risk factors
• Multiple stones at presentation/follow-up
needs clear referral guidelines • Biochemical abnormalities
present • Anatomical abnormalities
and protocols that can be • Genetically determined stone formation eg
replicated cystinuria
• Drug-induced stone formation eg indinavir
• Environmental factors eg high ambient
temperatures or lead exposure
management thereof based on the EAU urolithiasis guidance. We also have a responsibility to develop a sys-
guidelines (7 https://uroweb.org/guideline/urolithiasis/ tem that reliably communicates between both speciali-
stone/#3). ties and offers a consistent, reliable, and patient-centred
The reason for mentioning these screening tests in service.
this chapter is that anecdotally, basic and in-depth
screening is frequently not achieved, and not all patients
are referred appropriately. 53.4 Obstruction
There may also be other stone forming patients who
warrant discussion or referral to nephrologists such as those The causes and management of urinary tract obstruc-
with a single kidney, recurrent infections, nephrocalcinosis, tion is covered in Chap. 57. Clearly it remains a common
sarcoidosis, and chronic gastrointestinal problems resulting and important problem, and while the vast majority of
in malabsorption, oxalate stones, and dehydration. urinary tract obstruction is managed by urologists and
Typically, nephrologists offering long-term meta- radiologists, nephrologists are frequently involved in
bolic follow-up strive to encourage weight loss, appro- managing patients who develop AKI/CKD or urosepsis
priate dietary changes, and management of in this context. Given that even relatively brief episodes
CKD. Urologists have a critical role in (see . Fig. 53.3 of obstruction may cause nephron loss, obstruction
resolving acute obstruction or recurrent stone-related and sepsis is a very bad combination compounding
UTIs very much in collaboration with nephrologists renal injury. Nephrologists have a key role in support-
and microbiologists (. Fig. 53.4). In short, nephrolo- ing and promoting rapid management of obstruction,
gists and urologists should make a point of formally particularly as such patients often present to non-renal
liaising to agree to practice and audit adherence to specialists.
924 S. Camilleri et al.
53
A.i
Right pleural
thickening
b
. Fig. 53.5 FDG-PETCT imaging at a time of diagnosis and b following 1 year of treatment with weaning doses of prednisolone and
maintenance methotrexate
pathway for MDT management of these patients is previously. He underwent emergency haemodialysis,
highly recommended (see . Fig. 53.5).. and following CT imaging demonstrating evidence of
A Caucasian male in his 50s was under investigation RPF, bilateral ureteric stents were placed with good kid-
for a cough and pleural thickening. On the day of an ney function back to baseline after 4 weeks. An IVC fil-
elective pleural biopsy, his serum creatinine was found ter was placed following confirmed PEs during the
to be 1100umol/L despite being 102umol/L only 4 weeks admission, likely caused by external IVC compression
926 S. Camilleri et al.
Screening
Dipstick and MSU
Access to previous microbiology results
History and Perineal examination
Pre and post-micturition bladder scan
Flow studies
Multi-disciplinary review
Consistent, evidence-based life-style guidance Protocol guided imaging Further urological intervention
Radiology
Consistent, evidence-based treatment or Nuclear Medicine
prophylaxis of UTI Urodynamics
VCMG
53.7 Renal Tumour Syndromes ron mass and the risk of progressive CKD and end-
stage renal failure [12].
Most urological cancers are diagnosed and managed The patient below presented at 34 with a renal cell
solely by urologists [12]. However, there are several renal cancer (RCC) of the left kidney and underwent a left
tumour syndromes (see below) that often first present nephrectomy. She was lost to follow-up but presented in
to urologists. It is important to have a system that can a different country with hypertension and non-visible
identify such patients and have a referral pathway for haematuria. The presence of a clear cell renal carcinoma
syndromes with multi-organ involvement, usually to a at 34 is suspicious of a genetic renal tumour complex.
renal geneticist. Imaging of the remaining kidney demonstrated a sig-
Renal tumours with genetic predisposition: nificantly abnormal kidney with at least two masses with
5 Von Hippel-Lindau disease. the characteristic of RCCs and multiple simple cysts
5 Birt-Hogg-Dubé syndrome. (. Fig. 53.6). Von Hippel-Lindau syndrome was sus-
5 Hereditary papillary renal carcinoma,
5 Hereditary leiomyomatosis and renal cell carcinoma.
5 Succinate dehydrogenase-associated renal cancer.
5 Tuberose sclerosis complex.
5 BAP1 tumour predisposition syndrome.
5 MiTF-associated cancer syndrome.
pected and while awaiting genetic testing a cerebellar with elderly comorbid patients with CKD and renal
haemangioblastoma was diagnosed on screening MRI. tumours. The role of the nephrologist is no less critical
As a part of a multidisciplinary review, the masses in optimising renal function and assessing these patients
were monitored, and the patient was counselled and pre- for renal replacement therapy. Urologists, on the other
pared for dialysis (including the formation of a fistula hand, commonly run a low clearance pathway for such
and vaccinations) with a clear plan for delayed trans- patients with eGFR <45 mL/min/1.73m2 involving the
plantation. This case illustrates the critical importance use of DMSA scans to help decide on nephron-sparing
of coordinating care, in this case among several speciali- surgery versus radical nephrectomy.
ties.
Similarly, some patients with large angiomyolipomas
53 will be in greater need of radiologist and urologist fol- 53.8 Renal Haemorrhage
low-up (. Fig. 53.7(a–c)) or more need of a nephrolo-
gist (. Fig. 53.7(d)). Renal haemorrhage is relatively common in the set-
Beyond the relatively rare renal tumour syndromes, ting of trauma (rarely requiring nephrology input) but
urologists are increasingly and more commonly, faced thankfully uncommon in the spontaneous or postrenal
d e
Urology Renal Interface
929 53
Tips and Tricks
53.9 Summary
Contents
References – 957
Urinary Tract Infection
935 54
n Learning Objectives There is a genuine clinical utility in dividing UTIs
1. To identify the risk factors for and the impact of this way in terms of patient risk and overall manage-
UTIs. ment. Moreover, it is also useful to divide urinary tract
2. To illustrate the different sorts of UTI and differ- infection into anatomical location: balanitis, urethritis,
ent clinical presentations. prostatitis, cystitis, and pyelonephritis, all of which can
3. To appreciate the difference between uncompli- also be divided into acute or chronic.
cated and complicated UTI in terms of manage- The definition and diagnosis of UTIs are not
ment. always straightforward, for example, a poorly taken
4. To consider options for stream-lining referral and sample may be contaminated with perineal bacteria,
assessment of patients with recurrent, persistent, whilst a delayed or un-refrigerated can yield a spuri-
and complicated UTIs. ous result. Asymptomatic bacteriuria (ASB) is defined
5. To inspire enthusiasm among nephrologists to as the growth of bacteria from a well-taken sample in
teach, lead, and research in this area. the absence of symptoms with or without associated
pyuria. This commonly occurs in several patient groups
including the elderly, pregnant women, transplant, and
54.1 Introduction diabetic patients.
The laboratory definition of UTI derives from work
Urinary tract infection (UTI) in vulnerable groups is in asymptomatic women with ≥105 colony-forming
responsible for considerable morbidity and mortality, units (cfu)/ml, and counts below this or 104 are rarely
but even in healthy individuals ‘uncomplicated’ UTIs reported by laboratories. There is however good evi-
(cystitis or pyelonephritis in a healthy woman) are dence that ≥102 cfu is an appropriate diagnostic thresh-
responsible for a considerable health care burden [1]. In old in symptomatic patients. These groups include
2011 UTIs were responsible for 8.6 million visits a year acutely symptomatic young women with counts of a
in the USA, symptoms lasting an average of 6 days with single isolate (>102 cfu/mL), men (≥ 103 cfu/ml), renal
2–4 days of reduced activity and an estimated cost to transplant recipients (≥102 cfu/mL), and children (a
the US economy of $2–4 billion per year. Patients with carefully voided sample of ≥104 or ≥ 103 cfu/mL of a
complicated UTIs and recurrent urosepsis in the setting single species).
of urological abnormality, transplantation, and antimi- Recent antibiotics may inhibit culture; fastidious
crobial resistance, are often seen by nephrologists and organisms may not grow or may be overwhelmed by
can represent a considerable challenge. Care pathways other organisms with standard techniques. Urinary
for these patients are often haphazard, without a clear catheters, ileostomies, and urostomies will inevitably
structure, with patients commonly suffering care that is be colonised with bacteria and result in ‘positive’ cul-
more disjointed than it should be. tures. Patients with neutropenia may have no pyuria,
whilst pyuria may be caused by non-infectious disease.
Urethritis and vaginitis can mimic the symptoms of
54.2 Diagnosis and Definition cystitis, and symptoms of upper and lower UTI are
often minimal in the elderly and immunocompro-
Bacterial UTIs are classically divided into ‘uncompli- mised. In short, urine cultures need to be interpreted
cated’, where patients are otherwise healthy individuals thoughtfully to avoid over or underdiagnosis and
with no underlying structural or neurological lesions of treatment.
the urinary tract with no other systemic diseases predis- Distinguishing recurrent UTI (rUTI) from relapsed
posing the host to bacterial infection and ‘complicated’ UTI is very important. rUTI is defined as the occurrence
(essentially everyone else, i.e. UTIs in men, pregnancy, of two more UTIs within 6 months or three or more
diabetics, transplantation, and anyone with an anatomi- infections within a 12-month period. This can be a rein-
cally or functionally abnormal urinary tract). fection where recurrence occurs with a different organ-
Complicated UTI also occurs in patients in whom ism or the same organism, however, with sterile urine
there may be residual inflammatory changes following on culture in between episodes. In contrast a relapse is
recurrent infection or instrumentation, obstruction, defined as a recurrent UTI with the same organism from
stones, or anatomical or physiological abnormalities or an intracellular uroepithelial organism usually occur-
pathological lesions. These interfere with the drainage ring within 2 weeks. One in three women are known to
of urine in part of the tract which encourages prolonged have an acute UTI by the age of 24, and around 25%
colonisation. Examples include acute and chronic pyelo- of these women are likely to have a recurrence within
nephritis and perinephric, renal, and emphysematous 6 months. Recurrences are common in sexually active
abscesses. or postmenopausal women. Recurrences are either due
936 G. Rajakaruna et al.
54.4 Urethritis, Urethral Syndrome, 54.6 Interstitial Cystitis (IC) and Overactive
and Vaginitis Bladder (OAB) Complex
These conditions may be misdiagnosed as cystitis Interstitial cystitis and OAB form a spectrum of chronic,
on the basis of dysuria. Symptoms more suggestive poorly understood conditions that can cause profound
of urethritis are the predominance of dysuria, with and disabling lower urinary tract symptoms (LUTS). IC
less frequency and urgency, often more gradual onset is associated with mast cell infiltrate and may be associ-
and more common in a sexually active patient, espe- ated with sterile pyuria, forming an important part of the
cially with new partner(s). If urethritis is secondary to differential for recurrent UTI reviewed by Moutzouris
Chlamydia trachomatis or Neisseria gonorrhoeae, then it [2]. From the nephrologist’s point of view, it is important
is often associated with pyuria and should be detected to exclude other pathologies such as low-grade chronic
by urinary antigen testing. Additional pathogens such infection (especially in diabetics) which can present with
as mycoplasma genitalium may be detected using a ure- IC/OAB symptoms, malignancy, stones, and other phys-
thral specimen at a sexually transmitted disease clinic iochemical causes such as radiation cystitis or ketamine-
visit. Culture negative or low bacterial count bacteri- induced inflammation. An index of suspicion is required
uria associated urethritis/acute urethral syndrome is and early referral for cystoscopy and to a sympathetic
often not associated with pyuria is a poorly understood specialist.
condition with a variety of aetiologies including auto-
immune (e.g. Bechet’s syndrome, Wegener’s granuloma-
tosis), mycobacterial, viral (e.g. Adenovirus) trauma, 54.7 Epidemiology of Bacterial Cystitis
chemical, foreign body, strictures, and stones/crystallu- and Pyelonephritis
ria. Occasionally viral infections such as herpes simplex
can present with culture-negative urethritis and can In infancy bacteriura occurs in 1–2%, more commonly
respond to prophylactic acyclovir. As a chronic condi- in boys for the first 3 months and more likely to be asso-
tion, it is often difficult to diagnose and treat; referral to ciated with bacteraemia and pyelonephritis. After this
a urologist or genitourinary medicine colleague with a time girls are more commonly affected with a pre-school
specialist interest is worth considering. incidence of 4.5% compared to 0.5% in boys in whom
Vaginitis is another cause for dysuria misdiagnosed UTI is very likely to be associated with a significant con-
as UTI, and it is important to specifically ask about vag- genital abnormality.
inal discharge (the absence of which has a good negative In adults 84% of uncomplicated UTIs occur in
predictive value). Symptoms are often felt to be exter- women with 3% of American women seeking medical
nal and as with urethritis frequency and urgency may be help for this per year. Fifty percent of women experi-
absent. Candida, gonorrhoea, chlamydia, mycoplasma, ence at least one symptomatic UTI in their lifetime and
and herpes simplex are all common causes. 20–25% of these having a recurrence within 6 months.
Urinary Tract Infection
937 54
For a woman having a first-degree female relative with a pital patients, an indwelling catheter has a 10% risk of
history of UTI is a significant risk factor (OR ~ 2.5–4). UTI. Urinary tract infection is also very frequent in
With increasing age, comorbidity, and institution- transplant recipients commonly exceeding 50% in the
alization, the incidence of UTI increases dramatically first year of transplantation with the highest risk in the
with the female/male ratio reducing significantly. In first few weeks.
postmenopausal women alone, the annual risk of UTI The risk factors for urinary tract infection are shown
is around 10% with 5–15% of women over 60 having in . Table 54.1 and explain much of the increase in old
recurrent UTIs. UTIs are the commonest nosocomial age and transplant recipients. In short, anything that
infection (40%). Instrumentation is an important and reduces or circumvents the normal physiochemical bar-
potentially modifiable risk factor; a one off urinary riers and innate immunity of the urinary tract becomes
catheterisation carries a 1% risk of UTI, but for hos- a significant risk factor.
. Table 54.1 Risk factors for urinary tract infection and potential preventative interventions
Acute uncomplicated pyelonephritis in women is (class II) genotype, and (c) Dr. fimbriae which binds to
roughly 3 per 1000 person-years [3] with a peak age of decay-accelerating factor virulence in pregnancy and is
15–34. The host risk factors for acute and chronic pyelo- associated with APN in pregnancy. While interesting,
nephritis are almost identical to that of lower urinary organisms are not routinely screened for these virulence
tract infection, but diabetes, stones, pregnancy, and uri- factors; however, it does have clinical relevance in that
nary tract abnormalities including transplantation are sexual partners often have the same uropathogenic bac-
prominent. Emphysematous pyelonephritis (EPN) and teria, and in the absence of good infection control, these
xanthogranulomatous pyelonephritis (XPN) also have a organisms can be transmitted from patient to patient in
very strong female predominance and a peak incidence the hospital setting.
in the sixth decade both being highly associated with
diabetes (95% of EP) and stones [4].
Both lower and upper UTIs are almost exclusively the 54.9 Host Defences and the Urinary
result of ascending infection of periurethral organisms, Microbiome
54 predominantly the patient’s own bowel organisms with
over 85% of infections being due to gram-negative bacilli. Most of our protection from UTIs comes from physio-
The vast majority (75–95%) of infections in uncompli- chemical barriers and, when infection occurs, the innate
cated upper and lower UTI are due to Escherichia coli. immune system. Acquired immunity (antibodies or
The remainder are due to other gram negatives (Klebsiella cell-mediated) seems to count for very little in the way
pneumoniae, Proteus mirabilis, Citrobacter, Pseudomonas of defence or cure of UTIs. Our understanding of the
aeruginosa, and other Enterobacteriaceae) or gram posi- host defences is continuously evolving with the evidence
tives (Staphylococcus saprophyticus, Enterococci, Group emerging regarding the urine microbioma. Contrary
B streptococci, Staphylococcus aureus). It is important to our previous understanding that ‘urine is sterile’, it
to note that along with an increasing risk of resistance, is now known that the normal urinary bladder has a
this pattern of uropathogens significantly alters in compli- microbiome and there are several commensal organisms
cated UTIs with a marked increase in other enterobacte- in a healthy person’s uroepithelium. Although it would
ria such as Pseudomonas (especially related to catheters), be commonly assumed that these organisms are likely to
Proteus (especially related to stones), and enterococci. be associated with bowel flora, in females these microbi-
Staphylococcus aureus infection can result from ascend- ota seem to be associated with vaginal flora. The impli-
ing infection, but particularly in the setting of APN, it cations for the existence of a commensal microbiota are
is critical to exclude a haematogenous source. Multiple not clear. However, it is thought that these commen-
infections from a variety of different gut organisms sug- sals might outcompete pathogens and may play a role
gest repeated urinary tract introduction or, rarely, an ana- in regulation and maintenance of epithelial junctions,
tomical connection between the gut and urinary tract. On priming epithelial defences including immune defences,
the other hand, multiple infections with the same organ- degradation of harmful compounds, and prevention
ism suggest a persistent nidus of infection or an organ- of recurrent superficial bladder cancer, necessary for
ism particularly adept at causing UTIs, e.g. UPEC. A very proper development of the urinary tract, including the
small proportion of upper and lower UTIs are secondary uroepithelium, immune system, and peripheral nervous
to mycobacteria, fungal, and viruses (BKV, CMV, HSV system within the bladder and surrounding tissues.
and adenovirus) in the immunocompromised (7 Chap. 94 . Figure 54.1 shows the impact of impairing local bar-
Infections complications of transplantation). riers in the perineum on the propensity to UTI.
As shown in . Table 54.2, there are a variety of
antimicrobial peptides and anti-adhesion molecules as
54.8 Bacteria Virulence natural defences. In acute cystitis there may be a direct
invasion of the uroepithelial cells, with the formation of
Some UPEC have virulence factors that facilitate infec- intracellular bacterial colonies, which are semi-protected
tion or avoid host defences. They include adhesins such from antibiotics and the innate immune system and sub-
as P, Type 1 and Dr. fimbriae, haemolysin, and factors sequently cause reinfection. In response, the superficial
that disrupt the integrity of the uroepithelium, impair umbrella cells of the bladder wall exfoliate in part trig-
ureteric peristalsis, complement resistance, and promote gered by FimH bacterial adhesion. Macroscopically
iron sequestration. Some pathogens have multiple viru- APN causes either focally or a diffuse enlargement of the
lence factors with some specifically facilitating cystitis kidney and localised bacterial infection, this may result
but not APN with others promoting APN. Specifically in a lobar nephronia (see . Fig. 54.2) intra-renal abscess,
three virulence factors are associated with APN; (a) man- perinephric abscess, or papillary necrosis* (*in predis-
nose resistant P fimbriae (>90% of APN), (b) papGAP posed individuals (diabetes, sickle cell disease and anal-
Urinary Tract Infection
939 54
. Fig. 54.1 The importance of
normal mucosal barriers in
preventing UTI. This renal
transplant recipient had been
free of UTIs since transplanta-
tion but was treated with topical
imiquimod cream (arrow) for
vaginal intra-epithelial neopla-
sia. This resulted in significant
local inflammation and for 9
months she suffered recurrent
severe UTIs reflected in
recurrent deterioration in renal
function (y-axis creatinine in
μmol/L), despite prolonged
courses of appropriate antibiot-
ics. UTIs stopped with cessation
of imiquimod and topical
oestrogen cream
Urine:
High osmolality Ability to produce a concentrated high osmolality, acid urine with high flow rates is impaired in
almost all forms of AKI and CKD. The presence of glycosuria, a nutrient for bacteria as well
as impairing the function of neutrophils is an important risk factor in diabetic patients
Low pH Potentially impaired in CKD and renal tubular acidosis
Urine flow
Urine voiding Complete bladder emptying is a crucial mechanism for controlling or eradicating bacteria
hence the excess of UTI in male patients with BPH and incomplete voiding or those with
bladder diverticulae, reflux to transplant or native kidneys. Bacteria can also commonly
sequester in stones
Urinary tract mucosa (antibacterial The role of the mucosal barrier is illustrated by the increased incidence of UTIs in post-meno-
peptides and cytokines) pausal women and in those with local inflammation (see . Fig. 54.1)
Anatomical barrier of male urethra Both the male and female urethra offer an important defence against ascending infection,
which is completely out flanked by instrumentation or catheterisation
FimH-mediated exfoliation of Shedding of infected ‘umbrella cells’ of transitional epithelium
superficial epithelial cells
Urinary inhibitors of bacterial adhesion:
Tamm-Horsfall protein (uromodulin) The impact of AKI or CKD is unknown but it seems likely that production of urinary
inhibitors such as uromodulin may be impaired in this setting and urine concentrations of
uromodulin are significantly reduced in older patients with a UTI
Mucopolysaccharides
Lactoferrin
Blood group P secretor status
Antimicrobial peptides α and β defensins, Catlicidin, Pentraxin related peptide-3 (PTX-3), Ribonuclease-7, Hepcidin
Innate immunity:
Neutrophils (TLR4/CD14 pathway, Neutropenia is a significant risk factor especially in the progression of lower UTI to systemic
IRF-3, CXCR1) sepsis. Functional impairment of neutrophils and other aspects of innate immunity by steroids
may also result in greater severity of UTI rather than increased risk
(continued)
940 G. Rajakaruna et al.
Urine:
Cytokines (IL-6, IL1β) IL-6 produced by renal tubular epithelial cells is likely to be reduced in CKD and AKI
54
1. Increasing daily fluid intake by 1.5 L 1. Voiding after intercourse 1. Cranberry juice
2. Controlling blood glucose in diabetics 2. Avoiding sequential anal and vaginal intercourse 2. D-mannose
3. Antibiotic prophylaxis (regularly or post-coital) 3. Avoiding prolonged holding of urine 3. Intravesical
4. Vaginal oestrogen 4. Habitual double micturition in patients with hyaluronic acid
5. Avoidance of spermicides modest post-micturition residuals or those who
6. Avoiding disruption of normal vaginal microbiota have significant reflux
with harsh cleansers
7. Methenamine hippurate
tors including local resistance profiles. Co-amoxiclav 20–35% to 1–4%) and pre-procedure prophylaxis before
and fluoroquinolones both offer highly effective pro- urological intervention likely to draw blood, treat-
phylaxis but are not recommended as first line due to ment is mandatory. In other words treatment depends
the risks of resistance and altered bowel flora, whilst on the perceived risk; in healthy women while 50% of
resistance develops quickly to fosfomycin (3 g every patients with ASB resolve spontaneously, the 50% that
10 days). There is no convincing evidence that rotat- do develop cystitis rarely progresses to severe disease,
ing antibiotics (changing prophylactic antibiotics peri- so observation of ASB is reasonable unless the patient
odically) are beneficial; however, it may be helpful in has a history of recurrent severe UTIs. Similarly, in the
preventing the long-term use of nitrofurantoin (which elderly ASB there is no strong evidence that treatment
can rarely cause neuropathy and pulmonary fibrosis) is beneficial. UTI is very common in renal transplan-
especially in patients with renal impairment. Antibiotic tation, associated with detrimental effects, but there
prophylaxis always carries the risk of the development is no evidence that treatment of ASB is helpful in this
of antibiotic resistance and no lasting post-prophylaxis setting. For other patients at risk of complicated UTI,
54 difference in rUTIs. Prophylaxis is also effective in such as those with abnormal anatomy, treatment greatly
patients carrying out intermittent self-catheterisation. depends on the individual assessment. . Tables 54.4a,
In a randomised open-label study using daily prophy- b, c, d shows treatment options for UTIs.
lactic antibiotics vs control for 1 year, a 48% reduction
in UTIs (1·3 cases per person-year (95% CI 1·1–1·6) ver-
sus 2·6 (2·3–2·9) (control) incidence rate ratio of 0·52 54.17 Special Groups
(0·44–0·61; p < 0·0001) = 22 minor adverse events in
prophylaxis group) was seen however with increased 54.17.1 Pregnancy
antimicrobial-resistant rates. NICE guidance in 2018
offers a very useful approach to individuals with recur- Progesterone-induced dilatation of the collecting sys-
rent UTI [11]. tem with decreased peristalsis partial obstruction from
the gravid uterus contribute to a high (1–2%) rate of
pyelonephritis [18]. 80–90% of pyelonephritis occurs
54.16 Antibiotic Treatment in the last two trimesters and more commonly on the
right (50% and 25% on the left and 25% bilateral) [18,
There are a few guiding principles for the treatment of 19]. ASB in early pregnancy is an important predictor
UTI: the quality of the diagnosis and sample is impor- with less than 1% of patients without ASB going on
tant before commencing treatment, not everyone needs to develop pyelonephritis later in pregnancy compared
treatment, and poor renal function significantly limits the to 20–40% of those with untreated bacteriuria early in
penetration, usefulness, and safety of some antibiotics. pregnancy [19]. APN in pregnancy is associated with
An up-to-date appreciation of local levels of antibiotic
resistance, previous resistance patterns in your patient,
and a close liaison between nephrologist and microbiolo-
. Table 54.4a Treatment of asymptomatic bacteriuria (ASB)
gist are extremely important. It is critical to distinguish
between uncomplicated and complicated UTI in terms
Contaminated Contaminated samples (mixed growth,
of treatment length, follow-up, and exclusion of revers- sample multiple epithelial cells no pyuria) should
ible predisposing factors. Nice guidance for the treat- not be treated
ment of uncomplicated lower urinary tract infection
Healthy There is little convincing evidence for
[11] is a very helpful guideline and is broadly similar to women treating ASB in healthy women (despite a
European and North American recommendations that 50% chance of progressing to cystitis)
aim to promote antibiotic stewardship and reduce collat-
Elderly Treatment of ASB in the elderly should be
eral damage from antibiotics. Antibiotic recommenda- avoided as it makes no difference to
tions for uncomplicated lower UTI in a woman from this morbidity or mortality
guideline are 3 days of either nitrofurantoin (if eGFR
Indwelling Long-term indwelling catheters, urostomies,
>45 ml/min), trimethoprim, pivmecillinam, or a single catheters and ileal loops are universally contaminated
dose of fosfomycin. The caveat being that choice should with bacteria often associated with pyuria.
be informed by local resistance patterns [11]. Culture and treatment with antibiotics are
Asymptomatic bacteruria (ASB) often should not unnecessary when the patient shows no sign
of infection, and treatment is likely not only
be treated (especially if likely to be contaminated, cath-
to fail to clear colonisation but almost
eter, urostomy or ileal loop-related samples), whereas guaranteed to generate increasing resistance
in other groups such as pregnancy (where treatment of
Urostomy/ileal loop
ASB reduces the rate of subsequent pyelonephritis from
Urinary Tract Infection
945 54
. Table 54.4b Asymptomatic bacteruria special cases . Table 54.4d Treatment of acute pyelonephritis
Pregnancy Treatment of ASB in pregnancy shown to Antimicrobial prescribing in acute pyelonephritis in non-preg-
reduce subsequent APN from 20–35% to nant women and men aged more than 16 years:
1–4% screening and treatment is mandatory
with post-antibiotic follow up in pregnancy Most patients can be managed at home but need thoughtful
assessment and early review. For those who are clinically sick
Prior to Compelling evidence that treatment or should be admitted to a place of safety and if AKI associated with
urological prophylaxis directed at ASB in patients prior sepsis then should have urgent renal imaging (within 12 hours) to
intervention/ to urological surgery reduces the risk of exclude obstruction. The choice of antibiotics will depend on local
surgery urosepsis (not routine catheterisation) protocols, resistance patterns and in some cases availability.
Typical oral treatment options in the UK are the following:
Neutropenia It is unclear if treatment of ASB in the
neutropenic patient is beneficial 1. Cefalexin: 500 mg twice or three times a day (up to 1 to 1.5 g
three or four times a day for severe infections) for 7 to 10 days
Transplanta- ASB is common with a high conversion to
tion transplant pyelonephritis and high levels of 2. Co-amoxiclav (only if culture results available and
antibiotic resistance. However there is currently susceptible) 500/125 mg three times a day for 7 to 10 days
no evidence showing the benefit of treating 3. Trimethoprim (only if culture results available and
ASB. Stent removal should be considered susceptible) 200 mg twice a day for 14 days
urgently in the context of ASB. Anecdotally,
ASB in patients with complex anatomy such as 4. Ciprofloxacin (consider safety issues): 500 mg twice a day
augmented bladders or reflux may behave for 7 days
differently and require more thought.
If the patient is nable to take oral antibiotics, or severely unwell
Complex The role of treating ASB is unclear; there is a treatment should initiated intravenously and rapidly. In the case
uroanatomy high risk of conversion to symptomatic of a sick patient it is critical to discuss local resistance patterns
complicated UTI in this group but little or previous recent cultures with microbiology department.
evidence that treatment of ASB has long-term Typical IV treatment options in the UK are the following:
benefits and these patients often have resistant
Co-amoxiclav (only in combination or if culture results available
organisms
and susceptible) 1.2 g three times a day
1. Cefuroxime 750 mg to 1.5 g three or four times a day
2. Ceftriaxone 1 to 2 g once a day
. Table 54.4c Common treatment options for uncompli-
cated cystitis 3. Ciprofloxacin (consider safety issues) 400 mg twice or three
times a day
Treatment of uncomplicated cystitis. Typical first line treatment 4. Gentamicin initially 5 mg/kg to 7 mg/kg once a day,
options for cystitis in women with normal anatomy. subsequent doses adjusted according to serum gentamicin
Choice depends on knowledge of local resistance patterns. concentration
Nitrofurantoin 100 mg twice daily for 3 days 5. Amikacin initially 15 mg/kg once a day (maximum per
dose 1.5 g once a day), subsequent doses adjusted
Co-trimoxazole 960 mg twice daily for 3 days according to serum amikacin concentration (maximum
15 g per course)
Fosfomycin 3 g single dose
Remember also that readmission within 1–2 weeks of finishing
Pivmecillinam 400 mg twice a day for 3 days
antibiotics strongly suggests a persistent and deep-seated
infection which requires imaging and careful consideration
increased risk of preterm delivery and small-for-dates Pyonephrosis and emphysematous pyelonephritis
infants (although it is not clear if this is causal) and These are medical emergencies
sepsis syndrome with leaky lungs, stressing the impor-
tance of screening patients for ASB early in pregnancy. Radiological, microbiological and surgical liaison essential
Consequently, aggressive treatment with good support- High dose, broad-spectrum intravenous antibiotics and rapid
ive care is important; however, antibiotic choices are lim- drainage (usually radiological) of obstructed system has best
ited somewhat. Fluoroquinolones and aminoglycosides outcome followed by antibiotics and nephrectomy compared to
medical treatment alone. Minimum of 2 weeks treatment
are relatively contraindicated in pregnancy (although
are probably safe), and sulfonamides should be avoided
in the third trimester due to the risk of the grey baby
syndrome. It is important to liaise with microbiology, and it can be challenging to differentiate physiological
but intravenous third generation cephalosporins or dilatation from obstruction. If the patient’s condition is
temocillin are reasonable first-line options assuming no not rapidly improving, then sequential ultrasound scan-
previous resistance. Imaging by ultrasound is urgent, ning sometimes helps to identify progressive dilatation.
946 G. Rajakaruna et al.
54.17.2 Transplantation tis (ATPN)(18.7% in one study) [20]. There are several
possible explanations for the high frequency of APN in
UTI post-transplant is incredibly common and accounts transplants but near-universal reflux (85%) to the trans-
for 40–50% of infectious complications commonly affect- plant kidney, the use of stents and catheters and the high
ing >50% of transplant recipients, the majority of which prevalence of abnormal urinary tracts probably all con-
occur within the first few months and with a high (30– tribute. The high incidence of ASB is a key element as
40%) recurrence rate. . Table 54.5 shows the risk fac- in pregnancy the presence of ASB is a very strong risk
tors for post-transplant UTI which have little to do with factor for APN (RR 12–26). It is important to remember
immunosuppression but mostly involve breaches of the that hospitalized deceased donor kidneys may well have
normal physicochemical barriers. Not only the rate of been exposed to bacteriuria and urosepsis with potential
ASB (50%) and cystitis high post-transplant but there is donor transmission. Patients receiving transplants abroad
a high conversion rate to acute transplant pyelonephri- may come from areas with high levels of multi-resistant
organisms, and there is an argument for prompt screening
54 of urine or stool in patients from high-risk areas.
. Table 54.5 Reported risk factors for urinary tract Clinically UTI in transplant recipients may present
infection post –transplant with classical LUTS and in the case of acute transplant
pyelonephritis (ATPN), a tender kidney, fever, and sepsis
Risk Factor Possible intervention (7% presenting with septicaemia). However, in immuno-
suppressed patients, the presentation can be subclinical
Donor infection Culture perfusion fluid and donor
urine presenting with unexplained graft dysfunction, and a
high index of suspicion is required before giving a short
Female
course of antibiotics for a presumed lower urinary tract
Old age Impairment of normal physiochemi- UTI. Having ruled out the obstruction with an USS,
cal barriers and innate immunity sometimes a CT scan (ideally with contrast) will pick
History of reflux Thorough urological assessment up enlargement, perinephric stranding, or a nephronia,
pre-transplant alternatively a CT gallium (not requiring ionic contrast)
UTIs pre-transplant Full urological assessment pre- may identify ATPN in a patient with recurrent UTIs.
transplant The impact of UTI post-transplant has not been abso-
lutely clear partly because many studies have been based on
ADPKD (native Consider native nephrectomy if
kidneys still in situ) recurrent serious UTIs positive cultures rather than clinical disease. It is increas-
ingly clear however that ATPN undoubtedly results in fre-
Diabetes Exclude autonomic bladder and it
quent admission, temporary deterioration in function, late
seems sensible to attempt tight
diabetic control renal scarring, and poorer long-term patient survival [21].
ATPN is an independent risk factor for reduced function,
Long period on Possibly related diseased underused
rejection, and increasing evidence of graft dysfunction
haemodialysis bladder
pre-transplant and graft loss [22, 23]. A Spanish study demonstrated 89%
1-year graft survival in those patients with ATPN com-
Deceased donor
pared to 96% in those without [24]. Another study dem-
Delayed graft Possibly related toduration of onstrated worse 5-year graft and patient survival following
function catheter, length of hospitalization or early ATPN [25]. It is also clear that rUTIs in RTRs have
impairment of innate immunity
increased antimicrobial drug resistance, and inadequately
Acute rejection Possibly related to the effect of high dose treating UTI in RTRs is an effective way of generating
steroids on the innate immune system. multi-drug resistant organisms [26].
Chronic viral infection A meta-analysis of six studies demonstrated signifi-
Reflux to transplant Occasionally use of native ureter
cantly less bacteriuria and 60% less bacteraemia in trans-
helpful plant patients receiving UTI prophylaxis in the early stages
of a transplant [27]. This data is striking when one con-
Ureteric stent Consider early (2 weeks) removal,
with rapid removal if ASB or
siders the universally high rates of antibiotic resistance
symptomatic UTI in transplant recipients (frequently 100% for Septrin
and >50% for beta-lactams and ciprofloxacin). In practical
Indwelling catheter Earliest possible removal
terms almost all patients will receive Pneumocystis jirovecii
Dual kidney Sfbfn prophylaxis with Septrin, whether adding in a second agent
transplant for the early transplant period is beneficial is not clear. Nor
Surgical manipula- Screening for ASB and appropriate is the optimum duration of prophylaxis clear or whether
tion of the Graf prophylaxis long-term prophylaxis for all transplant recipients is help-
ful but the pragmatic approach adopted by most units is to
Urinary Tract Infection
947 54
stop prophylaxis with Septrin when pneumocystis is felt to Patients should be offered streamlined pathways for
be lower risk and offer UTI prophylaxis only to those who acute deteriorations.
declare themselves to have recurrent UTIs.
There is no clear guidance on screening but given
the strong association of ASB with subsequent ATPN 54.19 Infected Renal Cysts
we routinely send MSUs each visit for the first 3 month
and on any subsequent visit if the patient has symptoms Infection of renal cysts is relatively common in patients
or the dipstick is suggestive of a UTI. However, a study with polycystic kidney disease when the MSU may be
done by Origuen [28] have shown that there is no benefit negative and can be difficult to distinguish from a haem-
in treatment of asymptomatic bacteruria in renal trans- orrhage into a cyst. Macroscopic haematuria, flank pain,
plant patients. 112 patients with asymptomatic bacteruria and lower urinary tract infection recurring after treatment
two months post renal transplant randomised to receive or pyrexia of unknown origin are common presenta-
treatment have shown no difference in occurrence of tions. Contrast CT scan may help the diagnosis but often
TPN at 2 years and current guidance is not to treat ASB fails to distinguish between infection, bleed, or chronic
in transplant recipients. Advice on the treatment of clini- changes, and treatment is often empirical. Considering
cal UTIs in transplant recipients is not evidence based. diagnostic aspiration of the offending cyst if the infection
Our policy is to accelerate ureteric stent removal in any is not responding to treatment bearing in mind that whilst
new transplant with ASB or overt UTI and investigate for
fluoroquinolones have good penetration, other antibiot-
correctable risk factors such as poor bladder emptying in ics, e.g. aminoglycosides and beta-lactams, have poor
patients with recurrent, severe or later UTI. A study done penetration into renal cysts and may result in treatment
looking early stent removal at 5 days without cystoscopy failure. Some success has been claimed for the injection
post-transplant vs late removal at 6 weeks post-trans- of antibiotics into a single infected cyst. More commonly,
plant with cystoscopy in 227 patients showed that stent particularly in patients suffering recurrent post-trans-
related complications were significantly higher in the late plant, UTI then native nephrectomy may be curative, but
versus early stent removal groups (36 of 126 [28.6%] vs. 6 getting the correct kidney is crucial; it is not a small oper-
of 79 [7.6%]; p < 0.001) with a UTI incidence of 31 of 126 ation, and UTIs may continue post-operatively.
(24.6%) in the late group compared with 6 of 79 (7.6%)
UTIs in the early group (p = 0.004) suggesting that early
removal is a sensible manoeuvre [25, 29]
If clinically the patient has cystitis and is well, then 54.20 Renal and Perinephric Abscesses
a 5-day course of antibiotics is probably appropriate,
but if there is a suggestion of ATPN, then 14 days of Both renal and perinephric abscesses may occur secondary
treatment is probably reasonable. Relapse and readmis- to haematogenous spread or as a complication of APN, but
sion following an inadequate course of antibiotics are renal abscess is more likely to be due to the former (there-
not infrequent with transplant UTI. It is important to fore search for distant source) and perinephric abscess the
note that any patient returning within 2–3 weeks of latter. In either case culture of Staphylococcus aureus or
their last day of antibiotics is likely to have a persistent, Candida species should provoke a fingertip search for the
inadequately treated infection and requires rapid resolu- primary source. Both renal and perinephric abscesses may
tion of the anatomical cause and if the patient has a present as loin pain, fever, rigors, and tenderness in the
deep nidus, then a longer course of antibiotics may be costovertebral angle, or subacutely as a PUO, anaemia,
required. and a raised acute phase response. A positive urine cul-
Due to the high rates of resistance to ciprofloxacin and ture is highly likely with an untreated perinephric abscess
amoxicillin-clavulanic acid, we do not use these as first line although less so with a renal abscess and commonly nega-
in transplant patients sick enough to require admission. tive if a patient has already received a course of antibiotics
for presumed APN rapidly responding to treatment. CT
scanning is the imaging of choice and should be consid-
54.18 Infections and Complex Uroanatomy ered early in a patient with presumed APN not respond-
(See 7 Chapter 56) ing to treatment. Perinephric abscess is usually contained
within Gerota’s fascia but can infiltrate locally into the
Urosepsis can be a significant problem in patients diaphragm (hiccups), lung, psoas, and pelvis. Most renal
with complex uroanatomy. Recurrent infection, mul- abscesses respond to appropriate parenteral antibiotics
tiple drug resistance, and a high rate of progression to without the need for percutaneous drainage, but the bigger
acute and chronic pyelonephritis are common. This is the abscess, the less likely conservative management will be
a complex and challenging area, and patients should effective and percutaneous (especially if culture negative),
be reviewed in with MDT meetings involving a special- or sometimes surgical drainage should be considered if the
ist urologist, radiology, and urology nurse specialists. patient is failing to respond to treatment.
948 G. Rajakaruna et al.
54.23 Malakoplakia
54.31 Management
54.37 Summary
Case Study
400
350
300
250
mg/L
200
150
100
50
. Fig. 54.11 CRP of a patient admitted with AKI on CKD secondary to UTI. The admission point is shown by the arrow with
preceding CRPs
Urinary Tract Infection
955 54
Case 3
A renal transplant recipient with a past history of poste-
rior urethra valves was seen in the clinic with a rising cre-
atinine (. Fig. 54.14) (dashed arrow). Biopsy and imaging
at this stage revealed no obvious acute cause although it
was in the context of high tacrolimus levels and persis-
tent asymptomatic bacteruria (E. coli). Things appeared
to settle, and then after missed appointments, the patient
represented (solid arrow) with a marked deterioration in
renal function and low tacrolimus levels. An urgent renal
biopsy demonstrated a florid bacterial pyelonephritis. A
. Fig. 54.12 Klebsiella pneumoniae resistance profile following
MRI scan (. Fig. 54.15) done at the time demonstrated
6 months of recurrent UTI with multiple courses of antibiotics
multiple areas of inflammation and oedema consistent
quickly on appropriate antibiotics. Some urine cultures with pyelonephritis. At no stage did the patient have any
were negative some demonstrated an increasingly resis- symptoms, fever or graft tenderness and indeed remained
tant Klebsiella pneumoniae which eventually procured the very well with CRPs no greater than 30. Although cur-
resistance profile shown in . Fig. 54.12. Despite normal rent guidelines do not recommend treating ASB (except in
ultrasound imaging, the fact that her symptoms recurred pregnancy) it is important to be vigilant in patients with
within 2 weeks of stopping antibiotics with the same but persistent pyuria and ASB, and ensure that there is not an
increasingly resistant organism is highly suggestive of an ongoing nidus of infection in the kidney.
inadequately treated nidus of infection. A CT PET scan
(. Fig. 54.13) identified a focus of infection in the trans- Case 4
plant kidney. She was treated with 6 weeks of IV temocillin A 65-year-old man presented with PCP as an AIDS-defining
in the community and had no further UTIs for 18 months. illness. He had a CD4 count of 20 and mildly abnormal
This illustrates a couple of key points, firstly it is very renal function with a creatinine of 100mcmol/L. He was
easy to generate multi-resistant uropathogenic bacteria treated with co-trimoxazole and ARVs including tenofo-
in ‘complicated’ UTI. Secondly the index of suspicion vir. At a follow-up clinic 5 weeks following ARV, he com-
that there is a persistent infection should be very high if plained of bilateral loin pain and fevers. His creatinine has
956 G. Rajakaruna et al.
400
300
200
100
Case 5
A man in his 40s who had reached ESRD secondary to
recurrent UTI, pyelonephritis, and scarring presented
with a failing transplant secondary to recurrent epi-
sodes of urosepsis with different but increasingly resis-
tant organisms. His native kidneys had previously been
removed, but this failed to stop the infections. An ultra-
sound and cross-sectional imaging revealed no obvi-
ous nidus and his bladder appeared to empty well on
USS. However, VCMG demonstrated gross reflux to his
failing transplant and some pooling of urine in the blad-
der at the end of micturition as urine from the renal pel-
vis returned to the bladder. Given the loss of his native
and transplant kidneys to recurrent urosepsis, his trans-
plant kidney was surgically removed before relisting.
Subsequent transplantation has been free from urosepsis
. Fig. 54.15 MRI of the transplant kidney demonstrating het- demonstrating the importance of identifying and resolv-
erogenous cortex with multiple wedge-shaped areas of oedema
ing problematic drainage problems.
and inflammation consistent with ongoing infection
Urinary Tract Infection
957 54
? Questions tomy is appropriate, the patient can often be sta-
1. What are the key virulence factors for UPEC bilized by a period of radiological drainage and
causing acute pyelonephritis? antibiotics.
2. Is it recommended to start antibiotics whenever 5. First, establishing a diagnosis of fungal UTI is
asymptomatic bacteruria detected? paramount as in the majority of cases, candiduria
3. When to recommend antibiotic prophylaxis for does not represent infection but rather contamina-
patients with recurrent UTI? tion. Generally, fungal UTIs are rare in healthy
4. Is it sufficient to treat a case of emphysematous community-based individuals and more commonly
pyelonephritis with broad-spectrum antibiotics? found in hospitalized patients. Community-
5. What is the diagnostic and therapeutic approach acquired Candida infections are most common
for a case with fungal UTI? amongst patients with diabetes mellitus, those who
are bedridden, and patients receiving antimicrobial
v Answers therapy. Infection is associated with typical and
1. Pathogens can have virulence factors that facili- indistinguishable symptoms of cystitis, prostatitis,
tate infection or avoid host defences. Some spe- epididymo-orchitis, or APN. Asymptomatic candi-
cifically facilitate cystitis while others promote duria in a previously healthy individual should be
APN. Specifically three virulence factors are asso- verified on a second carefully collected urine speci-
ciated with APN: (a) mannose resistant P fimbriae men. If absent then ignore. While for persistent
(>90% of APN), (b) papGAP (class II) genotype, candiduria in a previously healthy individual
and (c) Dr. fimbriae which binds to decay- search for a predisposing condition such as diabe-
accelerating factor virulence in pregnancy and is tes, urological abnormality, or catheter (which
associated with APN in pregnancy. should be changed). The removal of a precipitating
2. No, not all patients with asymptomatic bacteruria cause or treatment of underlying conditions is usu-
should be treated, and treatment depends on the per- ally sufficient, and in the absence of any obvious
ceived risk. Treatment is mandatory in pregnancy abnormality in a well patient, it is reasonable to
and pre-procedure prophylaxis before urological monitor. In the presence of a susceptible individual
intervention, whereas ASB should not be treated if such as a critically ill patient or an immunocom-
likely to be contaminated, catheter, urostomy, or promised patient, candiduria should be regarded as
ileal loop-related samples. In healthy women, obser- a marker of potential invasive candidiasis. In
vation of ASB is reasonable unless the patient has a selected patients, a renal ultrasound should be car-
history of recurrent severe UTIs. Similarly, in the ried out to rule out the presence of hydronephrosis/
elderly ASB, there is no strong evidence that treat- obstruction, a focal mass in the collective system.
ment is beneficial. UTI is very common in renal Further investigations with CT or MRI may be
transplantation, but there is no evidence that treat- required to demonstrate the presence of a renal
ment of ASB is helpful in this setting. abscess, fungal balls, or non-functioning kidneys.
3. Antibiotic prophylaxis is highly effective at reduc-
ing the frequency of recurrent UTIs, yet carries
risk of inducing bacterial resistance. First, behav- References
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implanted. If not effective or appropriate, vaginal 1. Hooton TM. Clinical practice. Uncomplicated urinary tract
oestrogen can be considered for postmenopausal infection. N Engl J Med. 2012;366(11):1028–37.
2. Moutzouris D-A, Falagas ME. Interstitial cystitis: an unsolved
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4. No, antibiotics alone (without drainage) are not 4. Pontin AR, Barnes RD. Current management of emphysema-
tous pyelonephritis. Nat Rev Urol. 2009;6(5):272–9.
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tis, as such approach is associated with a RR of agement in primary care. BMJ. 2006;332(7533):94–7.
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spectrum antibiotics plus rapid medical drainage pelvis and renal tract combined with a plain film of abdomen
(large bore nephrostomy) helps to improve the in young women with urinary tract infection: can it replace
intravenous urography? A prospective study. Br J Radiol.
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drainage and surgical nephrectomy needs to be 7. Sandler CM, Amis ESJ, Bigongiari LR, Bluth EI, Bush WHJ,
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9. Somani BK, Nabi G, Thorpe P, Hussey J, Cook J, N’Dow J. Is factors, and survival. Transplant Proc. 2016;48(7):2298–300.
percutaneous drainage the new gold standard in the manage- 26. Britt NS, Hagopian JC, Brennan DC, Pottebaum AA, Santos
ment of emphysematous pyelonephritis? Evidence from a sys- CAQ, Gharabagi A, et al. Effects of recurrent urinary tract
tematic review. J Urol. 2008;179(5):1844–9. infections on graft and patient outcomes after kidney trans-
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LG, et al. International clinical practice guidelines for the 27. Green H, Rahamimov R, Gafter U, Leibovitci L, Paul
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959 55
Contents
References – 980
Renal Stone Disease
961 55
n Learning Objectives a cause of urinary tract obstruction. Stone formers of
1. To understand that renal stone disease is a symp- all types:
tom and therefore an underlying diagnosis should 1. Are at increased risk of developing CKD compared
be sought. to non-stone formers (over 8-year follow-up) [10].
2. To know the modifiable risk factors for stone dis- 2. Have lower bone mineral density when compared
ease and how to treat them. with the general population [11].
3. To allow the reader to design an optimum clini- 3. Are associated with a higher incidence of metabolic
cal pathway in their clinical setting to identify and syndrome and increased cardiovascular risk [12],
treat rarer types of stone disease. with a 30% increased risk of myocardial infarction
over a 9-year period [13].
55.1 Introduction
55.2 Presentations
There has been a progressive increase in the global inci-
dence of urinary tract stone disease, for reasons stated Stone disease is unusual in that the first presentation is
below, and as a consequence results in a considerable rarely to a nephrologist. Patients with acute renal colic
burden of disease. The combination of urinary tract may present to A&E, “recurrent urinary tract infections”
stones, diabetes, anatomical abnormalites or urinary may be a presentation of ureteric stone disease in general
tract infection can be particularly damaging and diffi- practice, and stones found incidentally on imaging may be
cult to manage. This chapter covers the causes and man- referred directly to a urologist. Patients who have suffered a
agement of renal stones and emphasises the important previous stone are more likely to recognise the symptoms.
role of nephrologists working together with urologists
to provide and efficient and patient-centred service.
55.2.1 Common Presentations
. Table 55.1 More common genetic causes of calcium renal stone disease in adults
Primary Cal- Autoso- Alanine-glyoxylate Previously liver Progressive chronic kidney Combined
hyperoxal- cium mal aminotransferase 1 biopsy showing disease; systemic deposition kidney-liver
uria type oxa- recessive (AGT1 – Liver decreased AGT1 (oxalosis) when plasma transplantation.
1 (80% of late enzyme which function. oxalate >30 μM childhood Trials of specific
PH) converts glyoxylate Nowadays presentation, urinary oxalate siRNA knockdown
to glycine) mutation analysis >0.7 mmol/24 h, 100% technologies are in
of AGXT gene calcium oxalate stones progress. These
target genes involved
in oxalate produc-
tion
Primary Cal- Autoso- Hydroxypyruvate Mutation Milder phenotype than type 1 Low oxalate diet
hyperoxal- cium mal reductase analysis of disease
uria type oxa- recessive (GRHPR – Con- GRHPR gene
2 (10% of late verts glyoxylate to
PH) glycolate)
Primary Cal- Autoso- 4-Hydroxy-2- Mutation May present in adulthood; Low oxalate diet
hyperoxal- cium mal oxoglutarate analysis of urinary oxalate 0.4–
uria type oxa- recessive aldolase HOGA1 gene 0.7 mmol/24 h
3 (5–10% late
of PH)
Familial Cal- Autoso- Impaired activity Mutation Normal anion gap metabolic Potassium citrate
distal renal cium mal of H-ATPase analysis acidosis
tubular phos- domi- pump or AE1
acidosis phate nant/ chloride-
autoso- bicarbonate
mal exchanger
recessive
Treatments
Bisphosphonates reduce hypercalciuria due to bone loss
and can be used if GFR >30 ml/min. They have the
advantage of also inhibiting the crystallisation of cal-
cium salts.
It is worth noting that vitamin D itself, given as 25-
OH vitamin D (e.g. cholecalciferol) without a calcium
supplement, does not usually increase hypercalciuria. An
important exception is CYP24A1 loss of function (which
is often undiagnosed) (see . Table 55.3). Restricting
dietary calcium intake is never recommended.
. Fig. 55.1 Light microscopy of 2,8-dihydroxyadenine crystals.
Kindly provided by Vidar Edvardsson, MD and Runolfur Palsson,
Thiazide diuretics reduce hypercalciuria by induc-
MD, Landspitali-The National University Hospital of Iceland, and ing a mild volume depletion which encourages proximal
the APRT Deficiency Programme of The Rare Kidney Stone Con- tubular sodium and hence calcium reabsorption. They
sortium should be used only once a primary cause of hyper-
964 S. H. Moochhala and R. Unwin
Monogenic disease Causative gene Location of defect Inheritance Clues in addition to stone disease
Dent disease CLCN5 Proximal tubule X-linked Proximal tubulopathy, progressive CKD,
recessive predominantly calcium phosphate stone type
Hypophosphataemic SLC34A1 Proximal tubule Autosomal Phosphate wasting
nephrolithiasis/osteoporo- (sodium dominant
sis phosphate
co-transporter)
Familial hypomagnesae- CLDN16, Thick ascending Autosomal Renal magnesium wasting, nephrocalcinosis
mia, hypercalciuria, CLDN19 limb of Loope of recessive on imaging
nephrocalcinosis (claudins 16 and Henle; distal
(“FHHNC”) 19) tubule
Bartter syndrome Various Thick ascending Autosomal Hypokalaemic alkalosis, presentation in
limb of Loope of recessive infancy
Henle
Autosomal dominant CASR (calcium- Parathyroid gland; Autosomal Stone formation usually only noted during
hypocalcaemia sensing receptor) thick ascending dominant inappropriate treatment with calcium/vitamin
limb of Loope of D
Henle
Vitamin D-induced CYP24A1 (loss Mitochondria Autosomal Unexpectedly high native vitamin D level,
hypercalcaemia of function) recessive hypercalciuria, suppressed PTH with either
hypercalcaemia or normocalcaemia, high
1,25-dihydroxy vitamin D. treat with
fluconazole
Renal Stone Disease
965 55
calciuria has been excluded. Their tendency to cause 55.3.6 Mechanisms of Calcium Stone
increased urinary potassium loss results in mild potas- Formation
sium deficiency which can reduce the urinary excretion
of citrate (a stone inhibitor). This effect can be lessened The three main mechanisms have some overlap between
by combination with amiloride. them:
1. The free particle theory. Crystals spontaneously pre-
cipitate in supersaturated urine.
55.3.5 Hyperoxaluria 2. The fixed particle theory. Crystals adhere to dam-
aged tubular cell membranes.
Hyperoxaluria is usually secondary to increased gut 3. Randall’s plaque theory. Calcium phosphate is
absorption: deposited in papillary interstitium, causing damage
5 Dietary, due to excessive intake of oxalate-rich to overlying epithelium, to which calcium oxalate
foods, e.g. chocolate, tea, bran, nuts, also spinach, can then adhere.
and rhubarb.
5 Enteric hyperoxaluria refers to increased intestinal These mechanisms are balanced by inhibitors of cal-
absorption of oxalate due to: cium stone formation:
5 Inappropriately low calcium diet (sometimes, but 1. Citrate. Hypocitraturia is the most easily measured
incorrectly, advocated in hypercalciuria). and is currently the most clinically modifiable inhibi-
5 Malabsorption due to small intestinal or pancreatic tor. Citrate occurs naturally in fruit and fruit juices
exocrine disease or surgery, e.g. inflammatory bowel and is metabolised to bicarbonate. It is easily replaced
disease, ileal resection, and Roux-en-Y gastric bypass orally as potassium citrate, e.g. in the management
for obesity. Malabsorption increases free fatty acid of distal renal tubular acidosis and sometimes in the
availability in the colon. The excess fatty acids pref- medullary sponge kidney.
erentially complex with dietary calcium, reducing the 2. Magnesium. Although can sometimes participate in
calcium available for complexing with oxalate in the stone formation.
colon which is the main site of oxalate absorption. 3. Pyrophosphate. A structural analogue of bisphos-
5 Megadose vitamin C (rare). phonates.
5 Ethylene glycol toxicity (rare). 4. Tubular proteins such as uromodulin (. Fig. 55.2).
Calcium
Oxalate
Supersaturation
pH
Uric acid
Acute hyperphospha- Acute phosphate nephropathy (due to sodium phosphate bowel prep), tumour Intracellular; cortical
turia lysis syndrome or medullary
Hypercalciuria + Primary hyperparathyroidism (20% have nephrocalcinosis), sarcoidosis, vitamin Medullary
hypercalcaemia D, or milk-alkali syndrome
Hypercalciuria + Tubulopathies (dRTA, MSK) Medullary
normocalcaemia
Rarer tubulopathies (all causes listed in “genetic causes of calcium stones” table Medullary
above)
Hyperoxaluria Primary or secondary hyperoxaluria (see above) Medullary
Structural or other Severe disease of the renal cortex (chronic glomerulonephritis, renal allograft Cortical
diseases rejection, renal cortical necrosis), renal tuberculosis
Drugs Analgesic nephropathy (chronic papillary necrosis) Medullary
Nephrocalcinosis always requires investigation The high recurrence rate, rising incidence, number of
because (a) there is a high likelihood of finding an procedures, and associated costs justify preventative
underlying metabolic defect and (b) progression of strategies:
the underlying disease process may cause renal failure. 5 64% of young adult stone formers had a single meta-
The calcium deposits are composed of calcium phos- bolic risk factor, and 27% had more than one, the com-
phate or calcium oxalate (the latter known as “oxalo- monest being hypercalciuria and hypocitraturia [14].
sis” especially if systemic) and once present are usually 5 Screening reduces healthcare costs, by around £2000
permanent, even if the cause is treated. The largest per avoided surgical episode [16] as well as indirect
nephrocalcinosis registry [15] found that 97% of nephro- costs (reduced sick pay, etc).
calcinosis affected the medulla and that these correlated 5 The European Association of Urology (EAU) guide-
with metabolic causes, most of which are also causes of lines [17] recommend that first-time, solitary stone
calcium renal stone disease. The remaining 3% (cortical) formers should have a basic metabolic screen and
comprised structural causes. estimation of renal function. For recurrent stone
It is usually asymptomatic, but symptoms can occur formers/high-risk patients a more complete evalua-
due to the underlying cause or of hypercalcaemia itself tion is recommended.
(if present) or due to consequences including calcium
renal stone disease and sometimes polyuria (medul- In many cases screening results will identify only sub-
lary nephrocalcinosis affects concentrating ability) tle abnormalities. Validated algorithms (e.g. APCaOx,
(. Table 55.4). EQUIL, Psf) have been developed which combine
parameters to quantify the risk of recurrence in these
patients. But even with this information, clinical evalu-
55.5 Clinical Assessment ation of underlying conditions, diet, lifestyle, and medi-
cation is required in order to provide meaningful advice
The aims of management are to treat the stone and to to the individual patient.
institute longer-term measures to reduce recurrence.
Symptoms Lower urinary tract symptoms May indicate current stone as well as UTIs. UTI is a risk factor
for struvite stones if urine is alkaline
Chronic immobilisation/spinal injury Hypercalciuria from bone loss; urinary stasis if neurogenic
bladder
Stone Age of the first onset before age 30 Young age is suggestive of a genetic cause
history
Unilateral or bilateral stone disease Bilateral more likely to suggest an underlying metabolic or
genetic cause
Past Number, type, and timing of previous stone Severity and consequences of recurrence; staghorn calculi
surgical and episodes and procedures suggest cystine or struvite stones
medical
Bowel surgery or inflammation (esp. May lead to secondary hyperoxaluria; also low urinary volume
history
ileostomy),malabsorption and acidic urine pH if high ileostomy losses
Gastric banding/bariatric surgery causing small May lead to secondary hyperoxaluria
bowel malabsorption
Anatomical renal tract abnormalities, e.g. MSK is associated with biochemical and anatomical risk factors.
medullary sponge kidney, horseshoe kidney, single Horseshoe kidney may increase risk but also causes technical
functioning kidney, PUJ obstruction difficulties with urological treatment. Obstruction of a single
functioning kidney will have more severe consequences
Obesity/insulin resistance; gout Associated with decreased urine pH, hence increased uric acid
and mixed urate-calcium oxalate stone risk
Hypertension Associated with high salt diets causing hypercalciuria
Social Job Deliberate restriction of fluid intake e.g. taxi drivers; working in
history hot conditions, e.g. cooks
Betel nut chewing; chronic laxative or antacid abuse Increased calcium and alkali absorption (“milk-alkali syn-
drome”) leading to calcium phosphate stones (calcium hydroxide
is often added to betel nuts or “paan”)
Regular strenuous exercise; frequent air travel Increased free water loss
Family First degree relatives affected Increased risk of monogenic stone disorder
history
Drugs and Excessive vitamin D supplements Avoid in sarcoidosis. But the correction of hypovitaminosis D is
supplements not associated with increased stone risk
Protease inhibitors Risk of crystallisation
Vitamin C in megadoses Metabolised to oxalate
Losartan Commonly used drug which is uricosuric (not a class effect)
would cause underestimation of these metabolites. Most ral criteria (see . Table 55.4) must be agreed, with a
laboratories require separate acidic and plain collec- mechanism for follow-up of basic screening tests previ-
tions. ously requested in the urology clinic. There should pref-
erably also be a system for longer-term follow-up of
z Serum Biochemistry outcomes via the urology follow-up clinic, with re-referral
Urea and electrolytes (baseline renal function), venous to a nephrologist if indicated. For most patients only two
bicarbonate, and chloride (looking for hyperchloraemic clinic visits would normally be needed: an initial visit and
metabolic acidosis); serum calcium, magnesium, phos- a review with the results of screening tests. Further review
phate, parathyroid hormone, and vitamin D; serum visits may be indicated for certain patients, for example, if
urate; serum glucose (features of metabolic syndrome). an underlying tubular disorder is diagnosed.
Additional tests include coeliac serology and haema- Benefits of the medical stone clinic:
tinics (if malabsorption suspected or diarrhoea present) 5 Identification of high-risk patients (e.g. those with
and exclusion of autoimmune causes (if dRTA suspected). an extensive family history of stone disease, bowel
surgery, known underlying metabolic disorder).
z Analysis of Stone or Fragments 5 Increase in patient empowerment and understand-
55 The gold standard is infrared spectroscopy with sup- ing – in the case of recommended lifestyle/dietary
portive wet chemistry [21], but this is often not possible changes, patients will need to understand and main-
or available. Clues may be obtained from: tain these recommendations long-term.
5 Urine microscopy – looking for the presence of clas- 5 Allow a genetic diagnosis to be made (e.g. cystinuria,
sic crystalluria. Some crystals are always abnormal primary hyperoxaluria).
(calcium phosphate crystals; hexagonal cystine crys- 5 Improve diagnosis of rarer stone types.
tals are pathognomonic of cystinuria). However, cal- 5 Decide whether specific nephrological follow-up is
cium oxalate and urate crystals can be a feature of indicated, e.g. for CKD or a tubular disorder.
normal urine. 5 Assist urologists in determining risk (and hence fol-
5 Radiology evidence – Hounsfield unit (HU) density low-up arrangements) in specific cases, e.g. single
on non-contrast CT KUB can differentiate between functioning kidney.
“soft” (e.g. urate) and “hard” (calcium) stones. Uric
acid stones have a density of around 200–400 HU,
while calcium oxalate monohydrate stones may have 55.5.4 Interpretation of Results
values of >1000 HU [22]. Plain KUB or the scout and Assessment of Risk
film from a CT KUB may show whether stones are
radio-opaque or not and whether staghorn calculi Urinary pH
are present.
55.5.4.1 Consistently High Urinary pH
Further Radiological Investigations Look for:
Anatomical and functional abnormalities of the uri- 5 Renal tubular acidosis (perform urinary acidification
nary tract can also predispose to stone formation (see testing).
section above) or can increase the likelihood of stone 5 Recurrent urinary infection with a urea-splitting
complications (such as obstruction of a single function- bacterium (perform MSU).
ing kidney). With the increasing use of non-contrast CT 5 Systemic alkalosis, e.g. chronic vomiting.
and ultrasound, anatomical abnormalities may be more 5 Ongoing alkali treatment.
readily noted.
55.5.4.2 Consistently Low Urinary pH
Further Specific Investigations This is an increasingly common finding, especially in
After interpretation of the above results, further investi- obesity and metabolic syndrome. These conditions are
gations may include: themselves associated with an increased risk of all stone
5 Urinary acidification testing. formation (see above), so it is common for acidic urine
5 Screening for tubular proteinuria. to be associated with calcium oxalate (but not calcium
5 Genotyping (RTA, PH, cystinuria). phosphate) stones, as well as uric acid stones, or a mix-
ture of these types.
Note: variability in urine biochemistry occurs mainly due to physiological variations in day-to-day excretions but also due to under−/
over-collection by the patient and differences in quality assurance between laboratories
. Table 55.8 Comparison of imaging modalities and current usage in urinary tract stone disease
55
. Table 55.9 Pharmacotherapy
Thiazide diuretics Increase tubular reabsorption of Calcium Indapamide 2.5 mg/day; Dose-dependent hypokalaemia,
calcium leading to reduced urinary stones chlorthalidone 25–50 mg/ hyperglycaemia, hyperlipidae-
excretion; increase magnesium day; hydrochlorothiazide mia, and
excretion 50 mg/day [26] Hyperuricaemia, all of which
can impact on stone risk
Magnesium Works as an oxalate binder in the Calcium 500 mg/day Diarrhoea can be a problem
supplements gut oxalate and if severe will negate the
beneficial effect
Potassium citrate (a) Alkalinises urine, (b) citrate is Uric 20 mmol tds (either as Over-alkalinisation promotes
itself a calcium stone inhibitor, (c) acid, liquid or tablets where the formation of calcium phos-
alkalinising effect increases tubular cystine available, e.g. Urocit-K, phate stones, even in calcium
reabsorption of urinary calcium Effercitrate) oxalate stone formers
Sodium As above, but used where potassium Uric Standard doses Contributes to dietary sodium
bicarbonate salts not indicated or not available acid, load
cystine
Pyridoxine Reduces oxalate production in type Calcium 300 mg/day
1 primary hyperoxaluria (certain oxalate
mutations only)
Allopurinol/ Xanthine oxidase inhibitors Uric Standard doses Allopurinol given during very
febuxostat acid high uric acid excretion can
result in xanthinuria and
xanthine stones
D-penicillamine Cystine chelators which increase Cystine Standard doses D-Penicillamine can cause
Tiopronin cystine solubility by forming a bone marrow side effects, rash,
(2-mercapto- disulphide complex nephrotic syndrome
propionylglycine)
Captopril (but
not other ACE
inhibitors)
Tamsulosin α 1 (alpha −1) receptor blocker used Any Standard doses Postural hypotension
as “medical expulsive therapy”,
relaxing urinary tract smooth
muscle
Renal Stone Disease
975 55
55.7.2 Combined Approaches for Particular eating disorders. In the latter, the resulting metabolic
Stone Types acidosis results in an appropriate increase in urinary
ammonium production to buffer the excess acid. In
z Uric Acid Stone Formers less developed countries, these stones may occur due
Low purine-containing diet (commonest purine sources to insufficient dietary phosphate resulting in increasing
are meat, fish, seafood, pulses, and beer), alkali treat- urinary ammonium production rather than phosphate
ment (aim for urinary pH >6.2) with high fluid intake to buffer acid.
(aim for urine output >2.5 L/day). Add allopurinol if
still forming stones.
55.7.3 Surgical Treatment of Ureteric
z Infection Stones (Calcium Phosphate or Magnesium
Ammonium Phosphate)
and Renal Stones
Cranberry juice is advisable since it is the only fruit juice
55.7.3.1 Stones in the Ureter
that acidifies the urine, whereas all others alkalinise the
urine. Prolonged antibiotic therapy may be needed since All patients with a ureteric stone should be referred for
stones and fragments may contain organisms. Recurrent urgent urological review even if they are asymptomatic,
infections can sometimes be due to an obstructing stone as there is a high chance of progressing to obstruction
of any type, so in this case, a full metabolic screen should and/or infection and management is nicely covered in
be performed after the infection has been cleared. UK guidelines [27].
Treatment options are:
z Cystine Stones 5 Direct treatment of the stone. Lithotripsy (SWL) is
As urinary pH becomes more alkaline, insoluble cystine the first choice for proximal ureteric stones less than
is more likely to dissociate to its more soluble ion. A uri- 10 mm, and ureteroscopy for distal ureteric stones
nary pH of >7.5 and urine output of >3 L/day (spread greater than 10 mm [17]. In all other cases, options
throughout the day) is optimal in reducing the urinary will be determined by local expertise.
concentration of cystine to prevent precipitation. This 5 If obstruction or infection is suspected, or if direct
can be augmented by: treatment is not possible, then decompression of the
5 Titration of fluid and alkali therapy to maintain kidney should be performed as an interim measure,
urine cystine concentration of <1 mmol/L (prefera- via either a percutaneous nephrostomy (under local
bly <0.5 mmol/L). anaesthetic) or JJ stent (a stent with two coiled ends
5 If necessary, the addition of a chelating agent which placed in the ureter).
combines with cystine forming a soluble disulphide 5 Medical expulsive therapy with either a calcium chan-
complex (see table above) while maintaining fluid nel blocker or alpha blocker (to relax the smooth mus-
and alkali therapy. cle of the distal ureter and bladder trigone) is an option
for lower ureteric stones. If the stone has not passed
z Xanthine Stones within 6 weeks, then definitive treatment is required.
These require dilution with large amounts of fluid and
consumption of a low purine diet. Xanthine oxidase 55.7.3.2 Stones in the Kidney
catalyses the conversion of hypoxanthine to insoluble Staghorn calculi, symptomatic stones, and those caus-
xanthine and of xanthine to uric acid. Stones occur due ing obstruction should always be treated. Increasingly,
to a build-up of xanthine caused by allopurinol ther- kidney stones are an incidental finding on imaging for
apy in patients with high urate production of any cause other indications. Unlike ureteric stones, they are often
(hence stop allopurinol) or rarely due to a deficiency of asymptomatic or present subacutely with nagging back
endogenous xanthine oxidase. or flank pain. It is unclear whether small asymptomatic
2,8-Dihydroxyadenine Stones
kidney stones should be observed or actively treated. A
z
study looking at 300 men with a mean stone diameter of
Stones formed from this metabolite are effectively
10.8 mm over 3 years showed 77% progressed and 26%
treated with allopurinol or febuxostat.
required surgical intervention [28]. All patients with
z Ammonium Urate Stones kidney stones should be offered the urological review to
In developed countries, this rare stone type is either consider the benefits of treatment or to allow urological
an infection stone or a marker of laxative abuse or follow-up (. Table 55.10).
976 S. H. Moochhala and R. Unwin
a b
. Fig. 55.4 Small left lower pole stone (arrow) visualised on differ- a posterior acoustic shadow (dark streak running vertically down
ent imaging modalities. a Axial non-contrast CT KUB is the most underneath the stone, marked with an asterisk). c The stone is diffi-
accurate at demonstrating the dense (i.e. white) stone. b The same cult to visualise on plain film. Overlying faeces/bowel gas and adja-
stone is seen as a hyperechoic (i.e. bright) focus on ultrasound, with cent venous phleboliths can mask or mimic stones
978 S. H. Moochhala and R. Unwin
55
Case Study
kAcknowledgements 13. Rule AD, Roger VL, Melton LJ, 3rd, Bergstralh EJ, Li X,
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981 56
Congenital Anomalies
of the Kidneys and Urinary
Tract
Melanie M. Y. Chan, Angela D. Gupta, Dan Wood, and John O. Connolly
Contents
References – 991
n Learning Objectives
1. CAKUT is the leading cause of CKD and ESRD Anomalies of Duplex collecting system,
in children and adolescents with the median age the collecting ureteropelvic junction
patients require RRT of 31 years. system and obstruction (UPJO), ectopic
2. The pathogenesis of CAKUT is complex with a ureter ureter, megaureter, ureterocele,
vesicoureteral reflux (VUR)
monogenic cause identified in approximately 20% of
patients. Environmental factors including maternal Lower urinary Bladder exstrophy, bladder
diabetes, obesity, and exposure to teratogens such as tract malforma- aplasia, posterior urethral valves
tions
ACE inhibitors are also thought to contribute.
3. Patients with CAKUT may have undergone mul-
tiple reconstructive and corrective surgeries as a
child including bladder augmentation, ureteric
reimplantation, and Mitrofanoff formation. It is
essential that nephrologists are familiar with the 56.2 Epidemiology
long-term management and possible complications
associated with such conditions. CAKUT occur in approximately 3–6 per 1000 live
4. Management of patients with CAKUT requires births and collectively account for 20–30% of all con-
genital anomalies detected antenatally [1]. CAKUT
56 joint nephrology and urology multidisciplinary
input with particular focus on the transition usually occur in isolation although non-renal anoma-
between paediatric and adult services. lies are seen in 30%, and it has been associated with
over 200 different syndromes. Renal tract malforma-
tions account for up to 50% of all childhood CKD
56.1 Introduction and are the leading cause of paediatric ESRD [2], plac-
ing a huge socioeconomic and educational burden on
Congenital anomalies of the kidneys and urinary tract patients and their families. However, CAKUT is not
(CAKUT) encompass a diverse range of developmental just a paediatric disease; the median age for patients
malformations (7 Box 56.1) and are an important cause of requiring renal replacement therapy (RRT) is 31 years,
chronic kidney disease (CKD) and end-stage renal disease and as a group, they make up 4–5% of adults requiring
(ESRD) in children and young people. Although the major- RRT [3, 4].
ity of CAKUT occur as isolated malformations, a signifi-
cant number of patients will have familial inheritance, and
many cases occur as part of multisystem syndromes. With 56.3 Pathogenesis
improvements in foetal screening and early urological man-
agement, the number of adults with CAKUT as a cause The embryonic kidney is derived from the intermediate
of CKD is likely to increase. Patients with CAKUT pres- mesoderm and proceeds through three distinct devel-
ent a variety of clinical and management problems and are opmental phases; the pronephros, mesonephros, and
often cared for as part of a multidisciplinary team – involv- metanephros (7 Box 56.2). The lower urinary tract
ing a range of healthcare professionals. This is particularly forms from the endodermal cloaca which develops into
important for young people making the transition from the urogenital sinus (early bladder and urethra) and rec-
paediatric care to adult follow-up. tum. Urine is produced from 9 weeks, and nephrogen-
esis continues until approximately 36 weeks. Disruption
of the tightly regulated process of renal and urinary
Box 56.1 Congenital anomalies of the kidneys tract development results in the many differing clinical
and urinary tract manifestations of CAKUT, depending on the timing
and location of the disruption. Environmental factors
Renal parenchy- Renal agenesis, renal dysplasia, such as pre-gestational maternal diabetes mellitus [5]
mal malforma- renal hypoplasia, multicystic
and obesity [6] have been shown to disrupt normal renal
tions dysplastic kidney
development.
Abnormal renal Ectopic kidney, pelvic kidney,
embryonic horseshoe kidney, crossed fused
migration renal ectopia
Congenital Anomalies of the Kidneys and Urinary Tract
983 56
Mesonephros: develops in the 5th week in a cranial-caudal direction as 20 paired tubules that form an ‘interim’ kidney.
Regresses by week 10 except for the mesonephric duct which contributes to the formation of the bladder
and male genital system.
Metanephros: forms the permanent kidney from the metanephric mesenchyme and ureteric bud (caudal mesonephric
duct) in week 6–10 of embryogenesis. Reciprocal interactions between the metanephric mesenchyme and
ureteric bud result in branching morphogenesis and mesenchymal to epithelial transition to form nephrons
and the urinary collecting system. The metanephros migrates from the pelvis to the lumbar region in the
8th week and starts to produce urine by week 9.
Mesonephric duct
Metanephric
mesenchyme
Ureteric bud
HNF1B Renal cysts, early-onset diabetes mellitus, hypomagnesaemia, abnormal liver function tests, hyperuricaemia and
early-onset gout, pancreatic hypoplasia, genital tract malformations, autism spectrum disorder.
PAX2 Renal hypodysplasia, optic coloboma, adult-onset FSGS.
EYA1 Branchio-oto-renal (BOR) syndrome: renal anomalies, deafness, branchial anomalies, pre-auricular pits.
SIX5
SALL1 Townes-Brocks syndrome: imperforate anus, dysplastic ears, thumb malformations, renal anomalies.
GATA3 HDR syndrome: hypoparathyroidism, sensorineural deafness, and renal anomalies.
56
dilation of the urinary tract that is characteristic of children will develop some degree of CKD, usually
this syndrome is primarily caused by replacement of associated with a lack of coordination between the
smooth muscle with fibrous tissue leading to aperi- detrusor and external sphincter. Detrusor overac-
staltic ureters. Urodynamics are often difficult to tivity causes high functional bladder pressures with
interpret because of gross VUR, but typically there is uncontrolled contractions against a closed sphincter,
a low-pressure bladder. With late presentation, some resulting in upper tract damage. Low bladder pres-
patients have detrusor instability. Surgical interven- sures with incomplete bladder emptying and urinary
tion may be indicated to optimize urinary drainage sphincter incompetence can also result in urinary
and prevent recurrent UTIs. Approximately 50% of stasis and recurrent infections. Early initiation of
patients who survive infancy will develop CKD with clean intermittent self-catheterization and the use of
the severity and timing dependent on the degree of anticholinergics or botulinum toxin type A for high
associated renal dysplasia present. pressure or hyperreflexic bladders can help to pre-
5 Bladder exstrophy is a rare but significant congeni- serve renal function and promote continence.
tal anomaly which occurs in 1 in 20,000–33,000 live 5 Urofacial or Ochoa syndrome is an extremely rare
births. The male to female ratio is 2:1 and offspring of autosomal recessive disease characterized by facial
affected individuals have an increased risk of 1 in 70 grimacing when attempting to smile and a neuro-
indicating some genetic predisposition. It is charac- pathic bladder. They are at risk of CKD.
terized by an open, ‘inside-out’ bladder which is fused
with the lower abdominal wall and an open exposed
dorsal urethra, requiring surgical reconstruction of 56.6 Diagnosis and Monitoring
the abdominal wall, bladder, bladder neck, and in a
male infant, the penis. The reproductive, digestive, By the time an adolescent with CAKUT is seen in adult
and urinary tracts as well as the abdominal wall and services, the diagnosis has usually been made, any cor-
pelvic muscles are often affected. Occasionally, the rective surgery is completed, and it is assumed that the
more severe condition, cloacal exstrophy, is found; urinary tract is not obstructed. It is important however
this is associated with other anomalies of the bowel that this be reviewed periodically and any increase in
or kidneys and may include neuropathic damage as a the frequency or severity of urinary tract infections or
result of sacral agenesis or myelomeningocele. Only sudden decline in renal function should prompt further
a third of patients empty their bladder via the ure- investigation for the presence of stones, obstruction, or
thra with the remainder requiring a urinary diversion dysfunctional bladder emptying (. Box 56.4). Patients
(see . Fig. 56.1). Long-term renal outcomes are with dysfunctional bladder emptying will commonly
generally good. carry out clean intermittent self-catheterization, and
5 Neuropathic bladder dysfunction can occur in adherence to this should be confirmed. Routine moni-
patients with spina bifida, especially when associated toring of renal function, blood pressure, and proteinuria
with myelomeningocele. Approximately 30–40% of should also be carried out in line with CKD guidelines.
Congenital Anomalies of the Kidneys and Urinary Tract
987 56
56.7.2 Ileal Conduit (Urostomy)
Box 56.4 Investigations used to monitor clinical
status in CAKUT The ureters are attached to an isolated segment of ileum
Investigation Indication and urine drains into a stoma bag. The ileal conduit is
free flowing with rapid urinary transit and no reservoir
Ultrasound of Diagnosis of CAKUT (see . Fig. 56.2). Metabolic complications are much
kidneys, ureters and Exclude obstruction less common, but hyperchloraemic metabolic acidosis
bladder Assess residual volume can still occur as the bowel exchanges sodium and chlo-
(<100mls post-micturition)
ride for potassium and bicarbonate. Long-term com-
CT KUB Exclude stones plications of conduits include strictures, obstruction,
99Tc-labeledMAG3 Assess outflow obstruction calculi, vitamin B12 deficiency, and malignancy at the
dynamic isotope intestinal-ureteral anastomosis [14].
scan
+/− furosemide
99Tc-labeled DMSA Assess renal scarring and 56.7.3 Neobladder (Bladder
static isotope scan divided function Reconstruction)
Urodynamics Bladder dysfunction
with videocystomet- Assess free urine flow rate Bowel is used to augment or completely replace the native
rogram (VCMG) (>15 ml/s), end filling bladder. A Mitrofanoff channel using appendix or small
pressures, bladder capacity
and compliance
bowel may also be necessary to allow bladder drainage.
This provides a continent, cutaneous channel for catheter-
Loopogram Exclude obstruction in ization. Complications include infection, mucus produc-
patients with ileal conduits
tion, kidney stones, and CKD. Lifelong follow-up is needed
51Cr-EDTA isotopic Assess GFR in patients with to detect medical or surgical complications. Excess mucus
GFR reduced muscle mass, production can be treated with regular bladder washouts.
e.g. spina bifida
56.8 Complications
Without careful bladder management progressive, kid- Recurrent UTIs may be associated with urinary stasis,
ney damage will be seen in the first 5 years of life in vesicoureteral reflux, stones, obstruction, or inadequate
30–40% of children. This can be dramatically reduced self-catheterization. An increase in the frequency or sever-
or delayed by ensuring the native or reconstructed blad- ity of UTIs should prompt investigation for stones or
der is compliant, has low pressure, and provides good obstruction including CT KUB, renal ultrasound, and
drainage. Clean intermittent self-catheterization plays a post-micturition residual volume. Patients with recon-
central role and anticholinergic medication offers addi- structed bladders often have abnormal urinalysis and
tional benefit by improving bladder capacity [13]. positive urine cultures and should be advised to increase
fluid intake and the frequency of self-catheterization if
they have any signs of cloudy or offensive urine. Only
56.7.1 Ureterosigmoidostomy symptomatic infections should be treated with antibiotics.
56
cystoplasties and ileal conduits (5–30%) because of function and blood pressure who were followed up for
the alkaline environment. Upper tract stones must 30 years reported an increased risk for ESRD (HR 5.19)
be suspected if UTIs recur or become more frequent; [17], highlighting the importance of long-term follow-
there is a sudden onset of severe pain and renal func- up for patients even with normal renal function as an
tion suddenly deteriorates or there is an unexplained adolescent.
sterile pyuria.
. Fig. 56.3 A suggested algorithm for pre-transplant assessment of a patient with CAKUT and abnormal lower urinary tract
990 M. M. Y. Chan et al.
56
Case Study 1
A 25-year-old man is referred to general nephrology level. HbA1c is mildly elevated at 50 mmol/mol. Urine
clinic with hypertension and proteinuria following a PCR is 50 mg/mmol and a renal ultrasound shows bilat-
recent diagnosis of type 2 diabetes mellitus for which he eral cystic dysplastic kidneys. He is diagnosed with
takes metformin. He was previously fit and well and is CAKUT. Given his diabetes, renal cysts, and blood test
asymptomatic. On specific questioning he mentions that abnormalities, a blood sample is sent for sequencing and
his mother also has type 2 diabetes which was diagnosed dosage analysis of HNF1B, and a heterozygous patho-
at a similar age and he has no other siblings as his mother genic variant is reported. The results are explained to
unfortunately suffered multiple miscarriages. There is him, and he is counselled that any future offspring will
nothing significant to find on clinical examination except have a 50% chance of inheriting the variant but that the
for an elevated blood pressure of 146/95. Blood tests clinical manifestations of HNF1B-related disease are
show normal renal function with mildly elevated liver highly variable. He continues to be followed up annually
function tests, hypomagnesaemia, and a raised urate in the renal clinic for his CKD.
17. Calderon-Margalit R, Golan E, Twig G, Leiba A, Tzur D, Afek kidney transplant recipients. Transplantation. 2011;92(11):
A, et al. History of childhood kidney disease and risk of adult 1237–43.
end-stage renal disease. N Engl J Med. 2018;378(5):428–38. 19. Neild G, Dakmish A, Wood S, Nauth-Misir R, Woodhouse
18. Foster BJ, Dahhou M, Zhang X, Platt RW, Samuel SM, Hanley C. Renal transplantation in adults with abnormal bladders.
JA. Association between age and graft failure rates in young Transplantation. 2004;77(7):1123–7.
56
993 57
Contents
n Learning Objectives
. Table 57.1 Causes of dilated but non-obstructed and
1. To review the causes and impact of acute and causes of obstructed but non-dilated upper tract
chronic obstruction
2. To review the management of obstructed urinary Common causes of dilated but non-obstructed kidneys
tracts and appreciate some of the pitfalls
Pregnancy Physiological dilatation (effects of
3. To establish the robust communication and proto- obstruction progesterone) and superimposed from the
cols to ensure rapid diagnosis and management of gravid uterus. R > L kidney
aUTO
Extra-renal Very common cause of apparent dilatation
pelvis/ but the absence of dilated calyces key
Definition parapelvic cyst
Acquired UTO is classified according to duration (acute Vesicoureteric Associated with (sometimes grossly)
or chronic) and by location (lower or upper tract). There reflux chronically dilated ureters
is limited data on the incidence of acquired UTO, and
Renal trans- Typically mildly dilated in the setting of
part of the reason for this comes from the difficulty in plant or ileal unrestricted reflux (may lessen post-
accurately defining cases. Absolute acute lower urinary conduit loop voiding)
tract obstruction is clear-cut but, despite being frequent,
Megacalyces/ Congenital abnormalities mimicking
tends to occur in the hospital setting merely as a tran- calyx obstruction
sient phenomenon. Conversely many patients have some
Postsurgical Postoperative repair of PUJ obstruction
degree of chronic post-micturition residual, the clinical
relevance of which is not clear in an asymptomatic patient Following Temporary persistence of dilatation after
57 with normal renal function. The diagnosis of upper tract removal of natural passages of stone of clot
obstruction
obstruction normally relies on deterioration in renal func-
tion and the hallmark of hydronephrosis seen on imag- Causes of obstructed but non-dilated kidney
ing. But of course renal reserve means it is possible to lose Malignant Most commonly in the setting of
up to ~50% of renal function before it becomes apparent encasement transitional cell carcinoma but can occur
biochemically, and imaging the upper tracts may also be with any local tumour
problematic. . Table 57.1 illustrates common examples Obstruction Overt dilatation may not be apparent in
of false positives and negatives, seen on imaging. with AKI the setting of oliguric renal failure
Micro- AKI in the setting of crystal nephropathy eg
obstruction antivirals such as acyclovir (kidney may be
“bright”) and Orlistat (oxalate deposition)
However, UTO often predisposes to renal impairment in
the absence of obstructive uropathy via urosepsis or is Functional High pressure bladder, detrusor instability
obstruction
superimposed on other renal diseases particularly in the
elderly. In practical terms the definition of obstructive
nephropathy is when UTO is the primary or contribut-
ing cause of renal damage. point of view acquired UTO is an important treatable
cause of AKI, CKD, and acute chronic CKD.
57.1 Epidemiology
57.2 Causes
Acquired UTO (aUTO) increases with age, in line with
the prevalence of predominant causes: renal tract calculi, The causes of UTO can be divided into congenital (cov-
bladder outflow obstruction (BOO), and urological/gyn- ered in the chapter on CAKUT) or aUTO. The causes of
aecological malignancies. Globally, conditions such as aUTO are multiple and can be divided up in a variety of
schistosomiasis and tuberculosis also contribute signifi- ways, but in practical terms the most important element
cantly (usually from middle age onwards). Benign pros- in terms of management is where the level of the obstruc-
tatic hyperplasia (BPH) is a common cause of bladder tion is, i.e. upper or lower urinary tract. . Table 57.2
outflow obstruction (BOO) in ageing men; autopsy stud- illustrates the main causes of aUTO and divides upper
ies have demonstrated almost universal benign prostatic and lower into intrinsic and extrinsic causes. Many of the
hyperplasia (90%) beyond 80 years although only a pro- likely causes may be suggested by the history but when
portion of these have symptoms, and it is not clear how this is not obvious, particularly in the setting of lower
many have clinically relevant obstruction. As mentioned aUTO neurological and perineal examinations are very
above, accurate figures for acute or chronic UTO are dif- important (and too often neglected). It is important to
ficult to come by, yet it is clear that with an ageing popula- note that apparent bilateral upper UTO can occur sec-
tion UTO is responsible for a considerable and increasing ondary to lower UTO pathology when there is (a) reflux
healthcare burden. Moreover, from the nephrologist’s to the native ureters or (b) when the bladder wall becomes
Acquired Urinary Tract Obstruction/Obstructive Uropathy
995 57
grossly hypertrophied and occludes the distal ureters. In can result in polyuria (see above). So while urine output is
these circumstances patients can present with upper UTO rarely a critical symptom it does become one in a patient
that does not improve on the catherisation of the bladder. with a single functioning kidney, especially if the other kid-
ney was lost due to obstruction, e.g. stones. Very rarely in
pregnancy or following ligation of a ureter the renal pelvis
57.3 Pathophysiology of Urinary Tract may rupture causing a urinary leak. This is usually associ-
Obstruction ated with intense pain that is constant rather than colicky.
Clinical features may also arise from the underlying
Acute obstruction initially has a largely functional impact pathology: back pain from retroperitoneal fibrosis; fevers
on tubular function and glomerular filtration, but if persis- with tuberculosis; malaise, anorexia, and weight loss with
tent, interstitial inflammation with tubular apoptosis and malignancy. Chronic UTO may also present with the
interstitial fibrosis with nephron loss and tubular dilata- symptoms of advanced CKD mimicking malignancy.
tion follow. Following aUTO there is a drop in the hydrau- Urosepsis is a common presentation of an obstructed or
lic pressure differential across the glomerulus, resulting in partially obstructed system, and partial obstruction must
reduced filtration fraction, a significant drop in renal blood be ruled out in a patient with recurrent urosepsis.
flow within a few hours with further and an abrupt reduc- The examination may reveal a distended palpable or
tion in GFR. Urinary acidification deficits and urinary visible, bladder, depending on the patient’s habitus but
concentration deficits are common, usually only manifest equally may have a grossly hypertrophied wall without
when the obstruction is relieved but explain why it is pos- large capacity (25% of men with lower UTO do not have
sible to be polyuric in the face of partial obstruction. a raised post-micturiction volume). And occasionally an
57 These haemodynamic and tubular changes are initially obstructed kidney can be palpated; however, the exami-
fully reversible, but with ongoing obstruction, macro- nation is not a sensitive tool for diagnosing obstruc-
phage and other leucocytes infiltrate the kidney and pro- tion. It is critical to ensure adequate examination of the
gressive interstitial fibrosis ensues. Tubular dilatation may perineum (excluding causes such as phimosis, urethral
be seen incidentally on renal biopsy and hint at a degree of meatal stenosis, prostatic enlargement, pelvic malig-
obstruction or reflux as an underlying cause. Ultimately nancy, female genital mutilation) as well as a thorough
the renal pelvis dilates further and the surrounding renal neurological examination.
tissue diminishes resulting in a rind of end-stage kidneys
around a grossly dilated pelvis. How rapidly irreversible
damage occurs is not clear, but it seems sensible to relieve 57.5 Diagnostic Tests
obstruction as soon as possible (see Case 4).
Relief of obstruction may result in hyperfiltration of Imaging of the urinary tract with ultrasound or cross-
remaining nephrons with glomerular enlargement and sectional imaging is the definitive diagnostic test in
sclerosis (secondary FSGS). the vast majority (but not all) cases, and rapid access
to imaging in the form of ward or clinic-based bladder
USS as well as upper tract scanning is therefore criti-
57.4 Clinical Features of Urinary Tract cal. Functional studies are also invaluable in a subset of
Obstruction patients with suspected obstruction, compliment imag-
ing in the management of these patients, and also need
The symptoms and signs of UTO depend to some to be readily accessible when appropriate.
extent on the underlying cause, duration, and complete-
ness. The symptoms of acute lower tract obstruction
are usually manifest by intense suprapubic discomfort 57.5.1 Urodynamics
with the patient being clear of the diagnosis; however, it
may present merely as acute confusion or agitation (an Urodynamics is a broad term used for the study of mic-
important diagnosis to make and treat). Chronic lower turition. The term includes:
tract obstruction is often much more insidious with (a) Post-micturition residual volume and uroflowmetry
lower urinary tract symptoms of nocturia, frequency, (study of urinary flow)
poor stream, and incontinence (particularly nocturnal (b) Cystometrography and voiding pressure/flow studies
enuresis); however, urinary tract symptoms of prostatic (c) Video urodynamics
hypertrophy correlate poorly with obstruction [1]. (d) Electromyography
Acute upper tract UTO may manifest as loin pain or (e) Urethral pressure profiling
renal colic if the cause is intraluminal such as stone or (f) Ambulatory urodynamics
clot but is often clinically silent especially if the other kid-
ney is healthy and unaffected. While complete bilaterally Rather confusingly ‘urodynamics’ is often used specifi-
upper or lower UTO results in anuria, partial obstruction cally to describe cystometrography, voiding pressure/
Acquired Urinary Tract Obstruction/Obstructive Uropathy
997 57
flow studies +/− urethral pressure profile which are used or where the result of the test will influence the patient’s
to establish the diagnosis of bladder outflow obstruc- management or provide useful prognostic information.
tion or lower urinary tract dysfunction (such as detrusor Patients are advised to stop anticholinergic, B3 agonists,
overactivity). Whatever the nomenclature, it is impor- and alpha blocker medications approximately 1 week
tant to be clear what the diagnostic question is and beforehand. Fine urethral/bladder and rectal catheters
therefore what test is most appropriate. are placed with a small amount of discomfort. Warn
fluid (either saline or contrast medium) is infused into the
bladder, and pressure studies are recorded. The detrusor
57.5.2 Bladder Ultrasound and Uroflow pressure is calculated from intra-vesical pressure minus
Studies intra-abdominal pressure (rectal catheter, vaginal vault,
or intra-abdominal stoma) and should remain low dur-
Portable ultrasound is cheap, non-invasive, and sensitive for ing filling. The patient is asked to void with the catheters
detecting urine volumes pre- and post-micturiction. A per- in situ to assess the detrusor pressure during micturition.
sistent post-micturition residual (PMR) is really important The procedure usually takes approximately 30–60 minutes
to identify in recurrent urosepsis and may mean obstruction to perform. Cystometrography and pressure/flow studies
or detrusor failure. A residual <100mls is usually accept- are not routinely required to diagnose or institute treat-
able; however, it is dependent upon the expected bladder ment for bladder outflow obstruction in patients present-
capacity. There is no consensus on what is an irrelevant ing with AKI secondary to high-pressure chronic urinary
PMR in the context of recurrent urosepsis, however, and a retention with upper tract dilatation. There may be a role
volume of 50–100mls may be relevant in this setting. Much in some patients presenting with very large residual vol-
of the data on the sensitivity and specificity of PMR and umes who are suspected of having atonic detrusor muscles
flow studies come from men with suspected bladder out- or patients presenting for a re-do TURP. In these patients,
flow obstruction (BOO). As mentioned above, in one study urodynamic studies are sometimes useful in predicting
up to a quarter of men with BOO did not have a PMR and whether outflow tract surgery (e.g. TURP) is likely to be
50% of men with a PMR do not have an obstruction [2]. successful in restoring voiding. The bladder outflow index
Flow studies/uroflowmetry provide a good screening nomogram demonstrates if the patient is obstructed; gen-
test for bladder outflow obstruction. Patients are asked eral indications for urodynamic cystometrography and
to drink until their bladders are comfortably full. Often pressure flow studies are listed in . Table 57.3.
drinking 500mls of water on arrival in the clinic will suf- Bladder compliance is defined as the change in blad-
fice, alternatively patients can be asked to attend the clinic der pressure for a given change in volume, V/P. Under
with a full bladder. A minimum voided volume of 150mls normal circumstances, the bladder is very compliant and
is required to render any flow trace interpretable, there- may be filled with large volumes with very little increase
fore ensuring adequate pre-micturition bladder volume in detrusor pressure. Poorly compliance occurs from
is important to build into the protocol. Both the voided fibrosis and reduced elasticity, e.g. radiation cystitis.
volume and maximum flow rate (Qmax) are recorded as
well as the shape/pattern of the graph and time taken to
void. . Figure 57.1a–e demonstrates different types of 57.5.4 Videourodynamics or VCMGs (Video
flow traces and their corresponding diagnosis. Most men Cystometrography)
with BOO have reduced flow rates, and very low flow rates
are a sensitive test for BOO (90% of men with a Qmax of Cystometrography and pressure/flow studies can be com-
≤10 ml/s have bladder outflow tract obstruction, but above bined with x-ray screening when radiological contrast
this figure, a significant proportion of men with reduced medium is used to fill the bladder. This technique can be
flow rates do not have BOO [2]). Other causes of a low flow useful in demonstrating anatomical aspects of storage
rate include detrusor failure and urethral stricture disease. such as capacity, reflux, diverticula, incomplete emptying,
While they have their limitations, PMR and flow hypermobility of the bladder neck during voiding, and
studies are simple non-invasive and cheap tests and easy intrinsic sphincter deficiency (see . Fig. 57.2). The detru-
to perform in the renal outpatient clinics (avoiding the sor pressure during the voiding phase helps distinguish
need for a second hospital visit) and may have particular between bladder outflow obstruction (high detrusor pres-
merit in following patients for dynamic changes. sure and low flow) and detrusor dysfunction (low detrusor
pressure and low flow). Detrusor overactivity manifests
as spikes of high detrusor pressure during filling. For men
57.5.3 Cystometry and Pressure/Flow there are nomograms to help distinguish between BOO
Studies and detrusor dysfunction [1]. The diagnosis of a poorly
compliant high-pressure bladder is critical as it is likely to
Cystometrography and pressure/flow studies are invasive result in loss of renal function and thus urodynamics can
and should only be used when the diagnosis is in doubt add vital information. Disadvantages include exposure to
998 F. McCaig et al.
a
Flow rate
Maximum
(20 ml/s)
14s flow rate
Average
flow rate
Voided Volume
Flow
Time
Time to maximum void (50s)
57
Super voider. 166 mls voided in
11 seconds, Qmax 31.9mls/s,
average 16.5mls/s
. Fig. 57.1 Typical uroflowmetry traces. (a) Normal flow rate. (b) Flow rate of ‘supervoider’. (c) Abdominal straining. (d) Bladder outflow
obstruction (intermittent, prolonged trace). (e) Urethral stricture (flat box-like shape)
Acquired Urinary Tract Obstruction/Obstructive Uropathy
999 57
c
Flow pa!ern with abdominal straining
d
Pa!ern with bladder ou"low obstruc#on; prolonged with low flows
Clarification of diagnosis before Is the patient obstructed and therefore is bladder outflow obstruction surgery likely to be
invasive treatment successful. Urodynamic diagnosis of bladder outflow obstruction is associated with better
outcomes from TURP and is the gold standard investigation
Lower urinary tract symptoms/ Failed medical therapy. Mixed symptoms, especially if marked storge symptoms. Particularly
suspected bladder outflow useful in young men
obstruction
Urinary incontinence Does the patient have detrusor overactivity/dysfunction or bladder outflow obstruction. Used
when first-line therapy has failed, typically mixed storage and voiding symptoms
Neurological disorders (VCMGs) Mismatch between symptoms and clinical assessment. Is there neurogenic bladder dysfunction,
poor compliance and high storage pressures, with the attendant risk of renal damage. Detrusor
sph
Vesicoureteric reflux (VCMGs) Is reflux causing infection, scarring
57
Blue line shows vesical pressure.
Red line shows abdominal
pressure. Detrusor pressure =
pabdo - pves
Filling phase
Voiding phase
metabolic mayhem such as hyperkalaemia, acidosis, or for failure to drain. Flushing the nephrostomy can usu-
pulmonary oedema, decompression is urgent (the alter- ally rule out blockage, and a displaced catheter is often
native being dialysis followed by decompression) and obvious, but repeat imaging is important to ensure that
the definitive treatment. In noninfected patients the time the nephrostomy catheter has not perforated the urinary
it takes humans with complete obstruction to go from tract.
reversible to irreversible kidney dysfunction is not clear. If possible an antegrade study is done at the time
However, it seems likely given the reduction in blood of the nephrostomy insertion, but often clot or ureteric
flow and early infiltration of macrophages that subtle oedema precludes a descent study, and often a better
progression starts within days. Thus, prolonged delay study is achieved a day or two later. Sepsis is a contra-
in decompressing a healthy obstructed kidney does not indication for antegrade studies or simultaneous inser-
seem prudent for someone likely to need their kidney in tion of ureteric stents. Balloon dilatation of a stricture
the future, and as the speciality involved in managing is not universally successful [10]; strictures of less than
CKD, nephrologists should encourage timely decom- 3-month duration have a higher patency rate (88%) than
pression. The procedure of nephrostomy is very nicely those >3 months (67%) with those over a year having
described by Uppot [9]. . Figure 57.7 shows a nephros- poor rates (15%). Stricture length also appears to be
tomy and nephrostogram demonstrating a tight stenosis important, greater than 2 cm having a poor long-term
of a transplant ureter. In essence, nephrostomy is not patency rate, and malignant strictures do predictably
risk free with a mortality of 0.05–0.03% and transfusion worse than benign ones. Ballooning is usually accom-
requirement of 1–3%. Generally the sicker the patient panied by stenting and stent removal several weeks later,
(and the less experienced the operator), the greater the at which time retrograde studies can be done to assess
57 risk so optimising the patient, operator, and timing are patency and the need for further stents or surgery. Given
important. Acute tubular injury, nephrostomy displace- the significant recurrence rate, patients need a mecha-
ment, blockage, and misplacement are common reasons nism for monitoring either with bloods and repeat USS
or renogram; if the patient has another normal kidney,
then reliance on creatinine and eGFR is probably not
sufficient.
Nephrostomy needle and
nephrostogram of dilated pelvis.
57.8 Post-Obstructive Diuresis
and 70% of these cases are associated with IgG-4 RD. In go unnoticed resulting in permanent loss of renal func-
addition, 50% of IgG-4-related RPF cases have extra- tion. Retrograde studies at the time of stent change may
peritoneal involvement (pancreas, biliary tree, perior- demonstrate free flow, but part of the pathogenesis lies
bital, thyroid, pericardium, skin, salivary glands, breast, in loss of ureteric peristalsis rather than occlusion or
and meninges). The pathology of IgG-4-related RPF dif- stenosis, so free flow may be falsely reassuring. If repeat
fers from that of other causes in that there is dense inflam- imaging shows regression of the retroperitoneal mass
matory infiltrate with a high proportion of plasma cells and retrograde studies show free flow, stent removal
(35–76% vs 0–10% in atheroma related RPF [12]), a sig- may be justified, but a system of monitoring with US or
nificant proportion of which stain for IgG-4. Although diuretic renogram is critical. Where there is no evidence
serum levels of IgG-4 are usually hardly raised, a ratio of of FDG activity, acute phase response or a large bur-
IgG-4/total IgG >0.3 is indicative. den of IS is required to maintain control; then ureter-
Medial deviation of the middle third of the ureters is olysis with lateral or intraperitoneal transposition with
a classic finding but has poor sensitivity, and although an omental wrap is usually definitive but can result in
US is excellent for diagnosing obstruction, it is not sen- devascularisation of the ureter.
sitive for examining the retroperitoneum and determin- The management of these patients requires cross-
ing the underlying cause or extrarenal involvement. disciplinary care, and establishing smooth referral
Therefore, cross-sectional scanning with contrast CT pathways, common guidelines, and an efficient mul-
is the most helpful initial form of imaging. For those tidisciplinary approach is the key to optimal care.
patients with evidence of periaortitis or idiopathic Nephrology departments should ensure that such path-
RPF in whom immunosuppression is planned, then ways and protocols are clearly established with local
57 18F-FDP-PET-CT is both sensitive and extremely useful urologists, radiologists, and other specialists such as
for monitoring response to treatment whether it be renal oncologists.
or extrarenal (see . Figs. 57.9 and 57.10).
The majority of patients with RPF seen by nephrolo-
gists have developed ureteric obstruction usually bilat- 57.11 Malignancy
eral (70%), but renal artery and vein encasement as well
as referral for management of large vessel vasculitis are While obstruction secondary to malignancy is normally
also part of the case mix. The principles of manage- managed between urologists, oncologists, and palliative
ment are similar and involve the decompression of the care teams, a significant proportion of these patients
kidneys (almost exclusively via nephrectomies and ante- cross the paths of nephrologists, and it is worth special
grade stenting) and correction of any critical vascular mention. Ureteric obstruction secondary to malignant
pathology. Excluding any secondary cause, such as infec- invasion is associated with a very poor prognosis, and
tion or malignancy, is critical, and biopsy of the RPF survival is typically between 3 and 7 months neces-
tissue mass is highly desirable where and when possible sitating a thoughtful and holistic approach that is not
(including staining for plasma cells and IgG-4). FDP- always achieved in practice. If appropriate, and follow-
PET scanning and acute phase markers suggestive of ing a discussion of the options with the patient, their
active inflammation, then a trial of immunosuppres- fitness and the stage of the malignancy, the first aim is
sion is usually adopted. There is no consensus on this, to relieve the obstruction to the kidneys. Retrograde
but for ‘idiopathic’ or IgG-4-related RPF, medium-dose stenting is associated with a much higher (×3) rate of
steroids with an antiproliferative such as azathioprine or failure in the setting of external malignancy than with
mycophenolate mofetil are commonly adopted; symp- intrinsic obstruction such as stones, and this seems to
toms, and ESR/CRP and PET scan response are all use- be particularly bad with pelvic malignancies such pros-
ful markers of disease activity. For RPF associated with tate, bladder, and cervical malignancy (success rates
a vasculitic aortitis steroids, methotrexate, azathioprine, of 15–21%) compared to colorectal or breast [14]. For
mycophenolic acid, and cyclosphosphamide are all used. this reason an antegrade approach is often adopted to
More recently anti-TNF monoclonal antibodies (inflix- drainage with percutaneous nephrostomy in the first
imab and adalimumab) have been used with success in instance. Antegrade stenting is either attempted simulta-
inflammatory aortitides such as Takaysu’s aortitis [13]. neously or subsequently when the patient is more stable.
The absence of an acute phase response or activity The decision to decompress both kidneys depends on
on FDP-PET scanning suggests a lack of inflamma- the stability of the patient, their prognosis, whether the
tory involvement, and immunosuppression is less likely renal function needs to be maximised for chemotherapy,
to be helpful. Patients can be managed with retrograde and whether there is felt to be associated sepsis. Both
stent changing, but this is not without complications, stenting and nephrostomy drains are associated with
and blockade of one stent may be asymptomatic and multiple complications and poor patient satisfaction.
Acquired Urinary Tract Obstruction/Obstructive Uropathy
1007 57
. Fig. 57.9 PET-CT scan in a
patient with idiopathic retroperito-
neal fibrosis showing an intense
inflammatory process (showing
yellow) in the pre-lumbar region.
This patient had high inflamma-
tory markers which correlated well
with subsequent PET-CT imaging
following treatment
1008 F. McCaig et al.
57
. Fig. 57.10 PET-CT scan in a patient with idiopathic retroperitoneal fibrosis showing the intense inflammatory process (showing yellow)
in the para-aortic and left renal region. (a) Before treatment. (b) After treatment
Case Study
Case 1 Case 2
Obstetricians performed life-saving surgery on a 28-year- A man aged 19 presented with end-stage renal disease with
old woman following a torrential post-partum bleed, dur- bilateral small kidneys and went on to have a cadaveric
ing which she became markedly hypotensive. She became renal transplant within a year and was transferred to a new
oligo-anuric for a period after the surgery with an AKI transplant unit as he started college. On transfer his creati-
(creatinine of 244 within 48 hours). An ultrasound scan nine was around 200 but progressively rose in the setting of
demonstrated reduced perfusion to the right kidney and variable tacrolimus levels, multiple investigations including,
CT with contrast (. Fig. 57.11a) demonstrated an BKV and HLA antibody screening, and two renal biopsies
acutely enlarged right kidney with retained contrast and over the space of a year were unremarkable, as were dop-
a dilated ureter. A diagnosis of ureteric ligation was pler ultrasounds and a MRA of the renal artery and vein.
made, and a right nephrostomy was performed with an He had initially been unforthcoming about urinary symp-
antegrade study (. Fig. 57.11b) showing a grossly dilated toms, but on direct questioning it became apparent that he
right ureter with an abrupt obstruction. A renogram had enuresis most nights this, the fact that the cause of his
done at this time (. Fig. 57.11c) because of concerns original kidney disease was unknown and his age made a
regarding reduced perfusion demonstrates normal and dysfunctional bladder a distinct possibililty. Video urody-
rapid uptake of tracer in the left kidney but much reduced namics demonstrated a high pressure, poorly compliant
uptake in the right kidney. Over the next 15–20 minutes, bladder with reflux into his transplant (. Fig. 57.12a–c).
the left kidney excretes the tracer whereas the right kid- He was treated with an anticholinergic and clean inter-
ney continues to accumulate and retain tracer. Before mittent self-catheterisation (. Fig. 57.12d arrow) with
definitive surgery, drainage from the nephrostomy almost immediate resolution of his enuresis and a progres-
stopped, and reimaging (. Fig. 57.11d) demonstrated a sive fall in creatinine (. Fig. 57.12d). In retrospect this
dilated renal pelvis and displacement of the nephrostomy diagnosis took too long to make and illustrates the point
tube (no longer draining) and an associated deterioration that it is important to always consider whether a patient
in renal function. A further nephrostomy was performed, may have a high-pressure bladder, especially if features
and she subsequently underwent a ureteric reimplanta- suggestive of CAKUT such as previous posterior urethral
tion and removal of the stitch that inadvertently caught valves or unexplained CKD early in life.
the lower ureter. A renogram done some months later
(. Fig. 57.11e) showed 67% function on the left (arrow) Case 3
and 33% on the right. A man in his late 40s presented with progressive left flank
This case illustrates many points: ureteric obstruction pain, significant weight loss, and retrograde ejaculation, in
must be rapidly excluded in AKI following abdominal or addition to pancreatitis 4 years previously. He was a
pelvic surgery. Acute obstruction cause swelling of the kid- smoker with a strong family history of cardiovascular dis-
ney and significantly reduced perfusion which suggests ease (. Fig. 57.13).
ongoing injury rather than a benign process secondary to This illustrates the importance of establishing not only
obstruction. Nephrostomies are excellent treatments for the cause of the obstruction but the underlying aetiology
acute upper tract obstruction but are best seen as a short- to guide treatment of the cause as there are several causes
term bridge to definitive drainage; in this case the patient of RPF including malignancy infection and autoimmune
had to undergo another nephrostomy and period of disease with very different management options.
obstruction following the displacement of the nephros-
tomy. Finally, periods of obstruction before definitive Case 4
drainage may have a significant impact on the function of A 39-year-old man was admitted following a RTA with
the kidney that is not always appreciated. trauma to his left kidney. He had a major haemorrhage,
1010 F. McCaig et al.
a b
57 c
. Fig. 57.11 (a) A CT with contrast demonstrated and and then progressive uptake of istope in the right kidney. (d) CT
enlarged right kidney with retention of contrast, dilated pelvis scan showing right kidney reobstructed with clearly displaced
and a dilated right ureter. (b) A antegrade study following a nephrostomy. (e) A renogram performed several months after
nephrostomy showing a grossly dilated ureter with an abrupt the original obstruction and subsequent surgical correction
stop at the point of the ligature. (c) Renogram showing delayed
Acquired Urinary Tract Obstruction/Obstructive Uropathy
1011 57
d e
required embolization, and developed bilateral upper of the kidneys at this time was 55% (left) and 45% (right)
tract obstruction attributed to clots, requiring retrograde and demonstrates normal uptake and excretion of the left
stenting. As he recovered, his urinary catheter was kidney (red), but an accumulation continued without
removed, but within a few hours he developed severe right excretion on the right (green) confirming obstruction. The
loin pain. He was recatheterised, and two further non-contrast CT done at the time of presentation
attempted trials of voiding had identical outcomes; there (. Fig. 57.15a(i)) shows marked intra-renal dilatation sec-
was no evidence of neurological deficit. The clues here are ondary to pelvi-ureteric obstruction but with well-pre-
that a 39-year-old failed trial without catheter (3 times) served renal cortex. Unfortunately the patient was lost to
and that he developed severe loin pain on the side of the follow-up, but when seen 6 months later, the CT demon-
stent, implying transmitted bladder pressure and imaging strated almost complete loss of renal parenchymal tissue
focused on the upper tract at the time of obstruction (. Fig. 57.15b(ii)) and a renogram suggesting <5% func-
(. Fig. 57.14) demonstrated a thick-walled bladder (never tion. This unfortunate case emphasizes that there may be a
normal!). He responded to alpha blockers which he significant price in nephrons to pay for ‘elective or routine’
required long term. decompression of obstructed kidneys.
. Figure 57.16 demonstrates the findings in a young
Case 5 man with sickle cell disease who presented with acute loin
. Figure 57.15a shows the renogram of a man who pre- pain. An antegrade stent was placed to the relief the
sented with right loin pain (top). The estimated function obstruction.
1012 F. McCaig et al.
b
57
Voiding
57
Time in years 1 2
a b
. Fig. 57.13 (a) Contrast-enhanced CT abdomen and pelvis ing for ANCA or TB-related disease was negative. (b) Coronal
coronal (a) and axial (b) imaging revealed a circumferential cuff FDG PET-CT imaging. (a) Revealed avid tissue FDG uptake in
of RPF tissue around the abdominal aorta and involving the the RPF peri-aortic cuff and left renal cortex lesion. (b) Follow-
bifurcation into the iliac arteries. In addition a cortical left renal up imaging after 8 months of treatment with a weaning course
lesion was identified and was subsequently biopsied. Histologi- of prednisolone and azathioprine revealed almost complete res-
cal analysis revealed a fibrosing and necrotising granulomatous olution. (Images courtesy of Nemi Ganda and Tara Barwick)
process with some plasma cells amounting to <30 / hpf. Screen-
Acquired Urinary Tract Obstruction/Obstructive Uropathy
1015 57
a b
c d
. Fig. 57.15 (a and b) Renogram. (b) CTKUB (c) at presentation and (d) 6 months later
1016 F. McCaig et al.
a b
. Fig. 57.16 (a) CT Urogram (with contrast) in a patient with because of the tubular back leak and inflammatory cell infil-
HbSS who presented with loin pain and an AKI. It shows a trate. (b) Nephrostomy and antegrade study in a patient with
sloughed papilla with dilatation of the ureter and pelvis. It also HbSS, demonstrating the hydronphrosis and a filling defect
illustrates that in the acute setting an obstructed kidney retains (sloughed papilla)
contrast (i.e. is initially well perfused) but also enlarges possibly
57
Kidney Cancer
David Nicol, Peter Hill, and Ekaterini Boleti
Contents
References – 1037
Kidney Cancer
1021 58
n Learning Objectives
. Table 58.1 Histological subtypes of RCC [1]
1. Kidney cancer is commonly diagnosed as an inci-
dental finding with variable clinical significance. Existing renal cell tumour Additional renal cell tumour
2. Treatments include surveillance, surgery, percuta- subtypes subtypes in WHO 2016 [1]
neous ablation, and systemic therapy based on the
individual patient and tumour features. Malignant
Clear cell RCC
Papillary RCC MiT (microphthalmia transcrip-
58.1 Introduction tion factor) translocation RCC
Chromophobe RCC Tubulocystic RCC
Primary malignancies involving the kidney fall into two Collecting duct Acquired cystic disease-
discrete groups – arising either from the parenchyma or carcinoma associated RCC
the urothelium lining the calyces or renal pelvis. Renal
Renal medullary Clear cell papillary RCC
cell carcinoma (RCC) is the broad descriptor describing carcinoma
malignant parenchymal tumours.
Mucinous tubular and Succinate dehydrogenase-
spindle cell carcinoma deficient RCC
Parenchymal tumours generally arise from the tubular Benign or low malignant
structures of the glomeruli and are described as adeno- potential
carcinomas. A number of discrete pathological sub- Papillary adenoma Multilocular cystic renal
types have been described related to the cell of origin, neoplasm of low malignant
histological appearance (architectural and cellular), and potential
underlying genetic basis. These are outlined in the 2016 Oncocytoma
World Health Organization (WHO) classification [1]. In
this most recent classification system, several new sub-
types have been defined having been in the unclassified from oncocytomas – which are benign and have dif-
group in previous versions. ferent underlying genetic changes. Collecting duct and
The commonest subtypes are clear cell RCC renal medullary carcinomas are both uncommon with
(CCRCC), papillary RCC (PRCC), and chromophobe the latter almost exclusively found in patients with sickle
RCC (ChRCC) with a range of other less common cell trait or anaemia. The remaining tumour types are
subtypes described (. Table 58.1). The vast majority all relatively infrequent. Sarcomatoid changes can affect
of patients with RCC have sporadic disease. CCRCC most forms of RCC and, rather than a discrete entity, is
comprise the majority (65–70%) of tumours and are indicative of an aggressive often locally infiltrative phe-
associated with tumour chromosomal mutations of 3p. notype with poor prognosis.
Sporadic tumours are typically solitary although can be One specific tumour type (acquired cystic disease-
multifocal within the affected kidney in 4% and bilat- associated RCC) is associated with end-stage renal dis-
eral in up to 3% of cases. PRCC are the second largest ease [2]. These tumours arise in kidneys affected by an
group (15–20%) with two recognised subtypes. Type 1, acquired cystic disease which is associated with dialysis.
associated with chromosome 7p, 17p, and 1q mutations, These tumours may exhibit combined features of clear
exhibits small basophilic cells with low nuclear grade and papillary tumours but without the typical chromo-
and may be multifocal. Type 2 tumours, which are gen- somal abnormalities affecting either clear (3p) or papil-
erally more aggressive and associated with 1p, 3p, and lary (7p or 1q) RCC.
5q changes have eosinophilic cells with higher nuclear
grade. Small tumours less the 5 mm in maximum diam-
eter with similar architecture and genetic alterations as 58.3 Staging
type 1 and 2 papillary RCC tumours are regarded as
benign adenomas and occur in over 20% of autopsies This is an important consideration that can dictate
with a close examination of the kidneys. It is uncer- both treatment options and determine prognosis.
tain whether these constitute precursors of the larger The tumour node metastasis (TNM) staging classi-
malignant tumours with the same histological features. fication is the most widely used system based on the
ChRCC (5–7%) typically stain with Hales colloidal iron. size and local extent of the primary tumour as well as
At times these tumours may be difficult to differentiate the involvement of regional lymph nodes and distant
1022 D. Nicol et al.
. Table 58.3 Hereditary renal cancer syndromes. Other hereditary syndromes include Denys-Drash/Frasier and Li-Fraumeni and
Lynch (MSH2) syndromes
on tumour grade, histological subtype, lymphovascular Factors associated with increased survival in patients
invasion, tumour necrosis, as well as capsular and col- with a metastatic disease include a long disease-free
lecting system invasion. Using this system (and other interval between initial nephrectomy and the appear-
scoring systems) patients can be grouped into low, ance of metastases, presence of only pulmonary metas-
intermediate, or high risk of recurrence with 5-year tases, and excellent performance status.
metastasis-free survival of 97%, 74%, and 31%, respec-
tively [7].
58.6.4 RCC with ESRF
a b
c d
. Fig. 58.1 Ultrasound and CT images of an angiomyolipoma showing typical fat density (a) and diffuse hyperechoic appearance (b) com-
pared to RCC (c and d)
with calculi (. Fig. 58.1). The use of Doppler is now lesions but have a substantial or significant component
a routine component of US imaging of renal lesions reflecting the features of adipose tissue (. Fig. 58.1).
demonstrating internal blood flow. The addition of a Other benign lesions including granulomatous pyelone-
microtubule contrast agent is a further recent addition phritis can be more difficult to distinguish on this and
that can be used to detect microvessels (with diameters also other modalities.
as small as 40 μm) and quantitatively assess tumour per-
fusion of solid tumours. This relates to microbubbles
remaining intravascular as they are resistant to extra- 58.7.3 Magnetic Resonance Imaging (MRI)
vascular diffusion.
In the assessment of renal lesions, magnetic resonance
imaging (MRI) is complementary to CT imaging. It has
58.7.2 Computerised Tomography(CT) a role where intravenous contrast is problematic includ-
ing contrast allergy and renal failure. It is also useful
On CT (with pre- and post-contrast and delayed scans), for staging purposes particularly in assessing tumour
renal tumours appear as solid or mixed lesions which thrombus and the level of its proximal extension in
demonstrate variable enhancement with an injection of the vena cava. MRI provides high inherent contrast
iodine-based contrast media. Hyperdense cysts, which between different forms of soft tissue. It has better con-
reflect haemorrhage into a benign cyst, may appear solid trast resolution but less spatial resolution than CT and
on a non-contrast CT but do not enhance with contrast. hence is not as useful for sating of the primary lesion or
Angiomyolipomas may also appear as solid enhancing procedural planning of nephron-sparing interventions.
1026 D. Nicol et al.
Whole-body MRI also has greater sensitivity than lesions where AML is suspected which occasionally
other modalities such as PET and bone scan in the occurs with tumours exhibiting diffuse hyperechoic fea-
detection of bone metastases. It is also more sensitive tures in US but without fat clearly being demonstrated
than CT for cerebral secondary’s but not as useful lung on CT. It may also be considered with small solid renal
lesions. masses if an oncocytoma is suspected. This requires
an experienced Uropathologist as it may be difficult to
distinguish an oncocytoma from a well-differentiated
58.7.4 Positron Emission Tomography(PET) ChRCC.
Core biopsy (18 gauge needles) is preferred to pro-
Imaging with 2-deoxy-2-[18F]-fluoro-D-glucose (FDG) vide an adequate sample for histological evaluation.
and whole-body positron emission tomography scan- Even with this non-diagnostic samples may occur in up
ning has been used in assessing renal tumours but to 20% of small masses. Due to low diagnostic yield, the
lacks sensitivity compared to other imaging modalities. biopsy is also not considered in the evaluation of cystic
Newer radiotracers such as iodine-124-labelled anti- renal masses.
body chimeric G250 (124I-cG250) which reacts with
carbonic anhydrase-IX (‘immuno-PET’) may improve
sensitivity. Whilst sensitivity may be low, its specificity is 58.8 Treatment
high, and a positive scan should be regarded as strongly
suspicious for metastatic disease. It may be useful in the 58.8.1 Localised Disease
assessment of possible local recurrence which can be dif-
ficult with other modalities due to migration of other Surgical excision has been well established as the only
organs into the renal bed, scarring, and artefacts due to potentially curative modality for RCC. The chang-
58 surgical clips. It also provides a mechanism to examine ing spectrum of disease presentation, particularly with
the whole body without risk of renal functional damage respect to small incidentally detected tumours, has
or contrast allergy. resulted in the increasing utilisation of nephron-sparing
surgery including minimally invasive techniques as non-
surgical ablative therapies (. Table 58.4).
58.7.5 Bone Scan
This may be used to diagnose or exclude bone metas- 58.9 Surgical Removal
tasis. These typically produce lytic lesions on plain
x-ray or CT. This reflects the osteolytic activity of RCC Radical nephrectomy (RN) that encompassed removal
metastases with little co-existing osteoblastic response. of the tumour bearing kidney as well as the surround-
In nuclear imaging studies, which reflect bone turnover ing perinephric fat including the adrenal gland has been
and specifically osteoblastic activity, metastatic lesions until recently the standard treatment option for most
may not be highlighted. Hence, a negative scan may not patients with localised tumours. A number of stud-
exclude the possibility of bone metastasis. ies have now shown that removal of the adrenal gland
does not confer any survival advantage – although is
usually recommended with larger upper pole tumours
58.7.6 Biopsy [12]. Lymphadenectomy has also been variously advo-
cated – although confounded by the diverse pattern of
The use of biopsy varies in clinical practice although is lymphatic drainage of the kidney. Published data sug-
increasingly utilised [11]. It has a clear role in metastatic gests that for most renal tumours with clinically nega-
disease in patients in whom treatment is planned with- tive regional nodes, lymphadenectomy does not improve
out or prior to nephrectomy to establish a diagnosis and survival. In those with clinically enlarged nodes and no
histological subtype. In this context biopsy of a meta- evidence of distant metastatic disease, however, resec-
static lesion is preferred to the primary to exclude co- tion of disease confirmed pathologically may confer a
existing disease such as lung carcinoma. It has also been survival advantage. Whilst some centres advocate its use,
advocated in the assessment of equivocal or potentially its primary utility appears as a staging tool which may
benign lesions. HMB-45 (a melanocytic cell-specific be of current significance with the evolution of systemic
monoclonal antibody) immunoreactivity is associated therapies and the definition of their role in the adjuvant
with angiomyelolipomas (AMLs) but not present in setting.
any malignant parenchymal tumours. Thus, it is a very Tumours with renal vein and vena caval extension
specific marker to resolve radiologically indeterminate can also be amenable to surgical excision. In the absence
Kidney Cancer
1027 58
of metastatic disease, the removal of the tumour in tumour size, volume of perinephric fat, previous sur-
conjunction with the tumour thrombus may be cura- gery, and other contraindications to laparoscopy.
tive. This can be undertaken in a multidisciplinary set- Partial nephrectomy (PN) entails excision of the
ting combining standard urological techniques with tumour with preservation of the kidney. Wherever fea-
those employed in liver transplantation for removal of sible this should be undertaken for patients with a soli-
tumours below the diaphragm or with minimal exten- tary or functionally compromised contralateral kidney.
sion above this level. With the availability of veno- Based on the favourable oncological outcomes reported
venous bypass, these tumours can be removed without in this setting for small T1 tumours, partial PN has been
the need for thoracic techniques. Tumours extending increasingly utilised over the past 2 decades in an elec-
into the atrium, however, require a combined approach tive setting with a normal contralateral kidney when this
with cardiac surgery including the use of hypothermic is anatomically favourable. A further factor has been the
arrest. Pre-operative embolization has been advocated dramatic increase in the overall proportion as well as the
as a preliminary to surgical intervention although recent size of T1 tumours related to earlier diagnosis of inci-
publications fail to demonstrate any increase in survival dental masses with the widespread use of cross-sectional
or reduction in complications [4]. imaging for other medical conditions. PN has also been
Laparoscopic techniques were introduced in 1991 facilitated by the dissemination of robotically assisted
for radical nephrectomy for RCC. Its role is now well laparoscopic techniques which has increased the fea-
established with oncological outcomes identical to stan- sibility of a minimally invasive approach – technically
dard open techniques. Laparoscopy may be limited by challenging with standard laparoscopy.
1028 D. Nicol et al.
cellular signalling pathways. There is now an increasing 58.14.2 Mammalian Target of Rapamycin
array of TKI’s entering clinical practice – varying in the Inhibitors (MTORIs)
range and extent of the kinases they inhibit.
Numerous TKI’s, which are oral medications, are now mTOR is a serine/threonine-protein kinase that together
used in metastatic RCC with sunitinib, and pazopanib is with Akt and MAPK regulates cell growth, growth pro-
the most widely used. As their target profiles differ, tumour liferation, and angiogenesis. In RCC, through the syn-
sensitivity can vary between individuals. Side effects can thesis of HIF-1, mTOR regulates the production of
also vary according to their specific targets but the com- proteins involved in angiogenesis such as VEGF thus
monest appear to be fatigue, oral and gut mucositis, dry, rendering mTOR an attractive target for the develop-
skin, palmar-plantar erythrodysaesthesia (hand-foot syn- ment of the relevant inhibitory agents [mTORIs]. The
drome), leucopenia, thrombocytopenia, and altered taste mTORIs have evolved from sirolimus, initially noted for
[24]. Cardiotoxicity, although not common needs to be its immunosuppressive activity and currently employed
considered especially in patients with a previous history in renal and other solid organ transplantation. Two
of cardiac problems. Thyroid dysfunction is also a well- mTORIs have been used in RCC – orally adminis-
recognised consequence and presents usually as hypothy- tered everolimus and temsirolimus that is intravenously
roidism which may affect up to over 50% of patients. In administered on a weekly basis. Pneumonitis is a rare
cases of clinically overt disease, thyroxine supplements but fatal complication of mTOR inhibitors and should
are used. Hypertension and proteinuria are also recog- be avoided in patients with existing lung disease such as
nised side effects of TKIs. TKIs affect the glomerulus in pulmonary fibrosis or severe chronic obstructive pul-
the kidney which leads to proteinuria. Hypertension can monary disease. Proteinuria may develop with mTOR
develop as a result of renal injury and increased vascular inhibitors.
resistance by reducing vasodilatation induced by nitric Temsirolimus is a water-soluble ester of sirolimus
58 oxide and vascular rarefaction [reference]. It is suggested used in the first-line setting in patients with poor prog-
in patients who develop hypertension when being treated nosis metastatic RCC. A large, randomised, phase III,
with TKIs have an improved prognosis [25]. international study which included 626 patients, mostly
Sunitinib malate inhibits c-KIT, FLT-3, PDGFR-b with poor prognosis criteria, was comprised of three
and VEGFR-2, FGFR-1, and IGFR-1 tyrosine kinases. arms. Temsirolimus, IFN-a, or their combination with
It is currently commonly used for the first-line treatment a lower dose of temsirolimus. The primary endpoint of
of patients with advanced/metastatic RCC with good/ the study was overall survival, and temsirolimus demon-
intermediate prognosis criteria. This is based on a mul- strated significantly longer overall compared to IFN-a
ticentre, randomised, study comparing sunitinib, and alone [10.9 months versus 7.3 months], and combina-
IFN-a in previously untreated patients with metastatic tion therapy was significantly better than IFN-a alone
RCC. The objective response rates at the final analysis [8.4 months versus 7.3 months]. Furthermore, temsi-
were 47% and 12% for the sunitinib and IFN-a arms, rolimus demonstrated a better safety profile compared
respectively. Progression-free survival was also signifi- to the other two groups. However, side effects include
cantly longer in the sunitinib group [11 months versus fatigue, stomatitis, rash, hyperglycaemia, and hyperlipi-
5 months]. Overall survival was affected by crossover; daemia.
however, in an exploratory analysis of patients who did Everolimus, an oral second generation mTORI, is
not receive treatment post-study, the median overall a sirolimus derivative, but unlike temsirolimus it does
survival with sunitinib was 28.1 months compared to not convert into sirolimus in vivo. A randomised trial
14.1 months in the IFN-a group. in patients who had failed TKI therapy with sunitinib,
Pazopanib, a newer oral TKI has a selective inhibi- sorafenib, or both demonstrated a statistically improved
tory effect on VEGFR-1, 2, 3, c-kit, as well as PDGFR-- progression-free survival of 4.1 months with everoli-
α/β. Based on a comparative study, it appears equivalent mus compared to 1.9 months with placebo. As with
to sunitinib in terms of survival. It appears to be bet- other studies, survival analysis was affected by crossover
ter tolerated and associated with a better quality of life from placebo to treatment with everolimus. Analysis of
than sunitinib. patients who did not cross over however estimated sur-
Sorafenib, axitinib, and cabozantinib are other TKI’s vival at 14.8 months with everolimus versus 10.0 months
which have also been evaluated in CCRCC. Their effect with placebo alone. Based on this evidence, everolimus
on both overall and progression-free survival appear is now used for the treatment of patients with advanced/
broadly equivalent to both sunitinib and pazopanib. metastatic RCC who fail TKI therapy.
Kidney Cancer
1031 58
58.15 Immunotherapy also have a role in regulating T-cell responses to chronic
infections and tumour antigens. Checkpoint molecules
The occasional dramatic regression reported with meta- including programmed cell death 1 (PD-1) and cytotoxic
static RCC stimulated the use of various immune ther- T-lymphocyte-associated antigen 4 (CTLA4) are expressed
apy approaches to reproduce or accentuate this response on the surface of T cells. Blocking CTLA-4 (ipilimumab),
on the basis that this was an immunological phenom- PD-1 (nivolumab and pembrolizumab), PDL-1, as well as
enon. the PD-1 ligand(atezolizumab), restores tumour-specific
T-cell immunity evoking an anticancer response.
These drugs are administered intravenously at weekly
Immunotherapy treats cancer through stimulation of or greater intervals. These should be delivered at specialist
the patient’s immune responses either via cytokine centres given the significant toxicities which can occur. As a
stimulation of the immune response or inhibition of consequence of checkpoint inhibition, self-tolerance may
regulatory control mechanisms of T lymphocytes. be impaired, and consequently toxicities associated with
these drugs are primarily autoimmune in origin. Almost
any organ can be affected, although the skin, gastrointes-
tinal including hepatotoxicity, pulmonary, and endocrine
58.15.1 Cytokines effects predominate [24]. Most of these side effects can be
managed by treatment interruption or cessation immu-
Interferon-α (IFN-α) and interleukin-2 (IL-2), either nosuppressive therapies when the severity warrants it.
alone or in combination, emerged in the 1980s as the Endocrinopathies including hypophysitis, thyroid abnor-
first systemic treatments for metastatic RCC [26]. malities, and adrenal crises can occur which may require
IL-2, a polypeptide lymphokine, is the principal stim- hormonal treatments. Centres using immune checkpoint
ulator of T-cell growth and may activate antitumour T inhibitors have developed guidelines in collaboration with
cells and NK cells if present. IL-2 is produced by type a number of specialists for the management of toxicities.
1 helper T lymphocytes causing activation and prolif-
eration of the CD4 and CD8 lymphocyte population. A
review of clinical results in 1714 patients with metastatic 58.15.3 Nivolumab
RCC treated with intravenous IL-2 monotherapy indi-
cated an overall objective response rate of 15%. IL-2 can Nivolumab is a human IgG4 antibody against PD1.
give response rates of up to 20% although only 5% of A phase III trial randomized 821 patients with mRCC
them will eventually be complete and long lasting [26]. previously treated by one or two lines of antiangiogenic
IFN-α, a glycoprotein, is a potent immune effector therapy [27]. Patients receiving nivolumab every 2 weeks
agent with antiproliferative and immune-modulatory experienced better clinical outcomes with a median OS
effects that increase the expression of cell surface anti- of 25 months versus 19 months in patients given everoli-
gens. Its effects include a combination of stimulation mus, with a response rate of 25% versus 5%.
of cell-mediated cytotoxicity, a direct antiproliferative
activity, and an effect on tumour circulation. Response
rates are low at 10–15%, and unlike therapy with IL-2, 58.15.4 Ipilimumab
incomplete and lasting remissions are not seen.
Neither IFN-α nor IL-2 are now regarded as a stan- Ipilimumab is a monoclonal anti-CTLA4antibody. The
dard of care. Their role has largely been replaced by a combination of ipilimumab and nivolumab has been
number of drugs with a more specific activity. compared to sunitinib as a first-line treatment of met-
astatic disease in intermediate and poor-risk patients
[28]. After 25.2 months of follow-up, the objective
58.15.2 Immune Checkpoint Inhibition response rate was 41.6% compared to 26.5% for suni-
tinib. Around 10% of patients receiving the combination
Recently therapies stimulating the immune system therapy achieved complete response compared to only
through drugs targeting T-cell checkpoint pathways have 1.2% of patients receiving sunitinib. Median PFS was
been introduced for metastatic RCC and include ipi- 11.6 months for the nivolumab and ipilimumab com-
limumab, nivolumab, pembrolizumab, and atezolizumab. bination versus 8.4 months with sunitinib. Significant
Normally the immune response is tightly regulated to toxicity was observed in 15% of cases including death
prevent autoimmune reactions. A broad class of extracel- in 1.5% of cases. As a result and thus patients who have
lular ‘checkpoint molecules’ has been found to modulate treatment ceased because of toxicity should generally
T-cell responses to self-proteins. Many of these molecules not be rechallenged with these drugs [28].
1032 D. Nicol et al.
58.15.5 General Considerations and plain x-ray of the long bones to identify the need for
on Systemic Therapy urgent to avert a neurological event or pathological frac-
ture. MRI may assist resolve equivocal CT findings of the
for Advanced/Metastatic RCC
axial skeleton. Biopsy should be undertaken and where
feasible, a metastatic site is preferred to establish the his-
Since the millennium considerable changes have
tological subtype and exclude a co-existing malignancy.
occurred in the treatment of metastatic RCC beginning
with the introduction of TKI’s and mTOR inhibitors
and the more recent and evolving entry of new immu-
notherapy agents. Clinical trials have been limited to
58.16.2 Primary Tumour
two agents and largely to CCRCC with little evidence
In patients who are overtly symptomatic with significant
related to non-clear cell RCC. All groups of drugs have
haematuria or pain, nephrectomy should be considered
significant toxicities which can prevent or limit their use
as a palliative intervention, particularly in the patients
in specific patients. The fact that tumour resistance or
with good performance status. In patients with poor
intolerance to one agent in an individual may not be
performance or with extremely large metastatic burdens,
predictive of the effects of another within an individual
this may not be feasible. Embolization of bleeding ves-
patient is another consideration.
sels is an alternative to surgery with bleeding although
These treatments rarely yield complete responses
this may not control bleeding or require infarction of a
and thus are not curative although, based on prelimi-
large mass of tissue that may in itself result in substan-
nary data, may show durable survival in a yet to be
tial ongoing symptoms and morbidity.
defined subset of patients. Healthcare economics are a
Cytoreductive nephrectomy has been previously
further issue that will also influence their role in practice.
widely used based on two randomised controlled trials
All drugs are expensive and frequently exceed the rec-
58 ommended guidelines for funding agencies in terms of
that demonstrated a survival benefit when nephrectomy
is combined with IFN-α compared to IFN-α alone [29].
cost-benefit or cost/quality of life year (QALY). Thus,
In these studies the survival advantage was only evident
access is highly variable based on health care models [4].
in patients with good performance status. This practice
Drug treatment of metastatic disease as well as drug
has continued as TKIs entered clinical practice with
treatment for high-risk localised and locally advanced
cytoreductive nephrectomy being a requirement for
disease is likely to remain highly topical and a con-
some trials evaluating these targeted therapies in view of
stantly evolving process over the next decade. Issues to
their potential effects on wound healing. In intermediate
be resolved include the preferred systemic agents for
or poor prognosis, patients’ cytoreductive nephrectomy
specific tumour types and clinical scenarios, whether
prior to sunitinib does not improve survival compared
combinations of agents in series or parallel are preferred
to treatment with sunitinib alone [30]. As performance
to single-agent therapy as well as the role of surgery
status is a profound influence on prognosis, this study is
together with its timing and combination with drugs in
consistent with the IFN studies in which nephrectomy
neoadjuvant or adjuvant settings.
only improved survival in patients who had good per-
formance status.
The criteria for cytoreductive nephrectomy are shown
58.16 Management of Patient Presenting in . Table 58.7. In patients who do not have cytoreduc-
with Metastatic Disease tive nephrectomy, this can be subsequently reconsidered.
These are good performance status patients exhibiting a
The management of a patient presenting with metastatic substantial response to systemic therapy particularly if
RCC encompasses a number of issues including clini- the primary tumour is large.
cal staging, the primary tumour, localised treatments of
specific metastases, and systemic therapy.
58.16.3 Metastatic Sites
58.16.1 Clinical Staging and Diagnosis Specific intervention may need to be considered for
metastatic deposits. These include intracerebral lesions,
Staging generally comprises CT scans of the chest abdo- vertebral lesions if fracture or neurological compromise
men and pelvis. If any cerebral or skeletal symptoms could occur, as well as femoral and humoral metastases.
exist, then these need to be assessed with CT of the head These can be treated with surgery or radiotherapy often
Kidney Cancer
1033 58
in combination with initial surgical resection or stabili-
sation and subsequent radiotherapy. features including solid elements which increase the
possibility of an underlying or associated RCC. A
risk stratification system, the Bosniak system(see
58.16.4 Systemic Therapy . Table 58.5), is used to direct management. This
system is used in conjunction with clinical parameters
Metastatic RCC can follow an indolent course and in in establishing the likely diagnosis and direct further
view of the toxicity, emergence of tumour resistance and treatment.
non-curative nature of systemic therapy, patients can There are a number solid and complex lesions
benefit from initial active surveillance with subsequent other than RCC that are detected on imaging studies.
introduction of drug treatment when significant degree These may be differentiated on the basis of clinical
progression occurs. With this strategy selected patients history and specific imaging studies or investigations
with initial low volume metastatic disease can defer sys- as outlined in . Table 58.6. If there is clinical suspi-
temic treatment for over 12 months without compromis- cion of these lesions, a tailored investigation may
ing their long-term outcome [31]. Immediate treatment resolve the diagnosis and lead to more appropriate
is advised however where there is an extensive multisite, management. Nevertheless, at times this may not be
progressive, or symptomatic disease. The initial choice possible and the diagnosis only established with surgi-
of therapy will depend on the patient’s prognostic cat- cal removal.
egory, comorbidities, as well as drug availability. Drug Renal Impairment
changes will subsequently be required due to either drug Renal impairment may be an important consider-
toxicity or the emergence of tumour resistance and pro- ation in several aspects of the management of patients
gression. with renal cell carcinoma. This may limit the use of
contrast agents although with the range of imaging
Tips and Tricks modalities alternatives to CT may be employed, often
in combination, to assess end-stage renal lesions.
Small Renal Masses Renal failure may also be a consequence of treatment
The changing epidemiology of renal carcinoma with loss of renal mass – although minimised the use
has resulted in the commonest clinical scenario being of nephron-sparing techniques. At times significant
a small incidentally detected lesion or small renal renal impairment may delay consideration of surgical
mass. This has resulted in a dramatic increase in the or ablative intervention. Where a patient presents
use of surgery and also ablative therapies to treat with creatinine clearance of <30mls/min – a progres-
these lesions. Despite this the overall mortality related sive deterioration in renal function is likely. In this
to RCC has not declined – suggesting that early inter- scenario, particularly with smaller tumours, it may be
vention in these small lesions may represent overtreat- more appropriate to undertake surveillance with a
ment in many cases. Overall the options of radical plan to intervene only if there is significant growth in
nephrectomy, partial nephrectomy, tumour ablation, size or if and when the patient becomes dialysis
and surveillance (with selective use of intervention for dependent. With the latter, patients may have the
rapidly enlarging lesions) all have to be associated opportunity for planned dialysis access and avoiding
with similar cancer-specific survival with incidentally temporary access with tunnelled dialysis lines and
detected tumours <3 cm in size. Each option is associ- other external devices with their inherent complica-
ated with specific implications which may drive the tions. Similarly, patients, even with larger tumours,
choice in individual patient circumstances. may be poor dialysis candidates with poor quality of
Complex Lesions life and potentially limited life expectancy related to
Renal masses may be detected on imaging studies cardiovascular and other comorbidities if end-stage
and need to be distinguished from renal cell carci- renal failure were to occur. In these circumstances
noma. Cysts are the commonest renal mass detected frank discussion with the patient may conclude with a
on imaging studies. The majority of these are benign nonoperative approach.
and require no treatment or follow-up. Simple benign The end-stage renal failure population is also at
cysts are of fluid density, with thin walls and do not higher risk of RCC – and if present may need to be
enhance with the injection of contrast media. considered in their suitability for transplantation.
However, many cystic structures have more complex Historically arbitrary ‘disease-free’ intervals were
1034 D. Nicol et al.
mandated for patients with malignancy with the excep- patients as a consequence of prior nephrectomy and
tion of epithelial-derived skin cancers. Better under- other comorbidities with a small number also on hae-
standing of both the natural history and prognosis of modialysis. The degree of renal dysfunction may dete-
kidney cancer, particularly T1 tumours, means that riorate in approximately 50% of patients with
such an imposition is neither logical or appropriate. pre-existing renal insufficiency who receive a TKI –
Given the high probability of ‘cure’ with surgical although usually resolves with dose modification. The
removal a history of T1 kidney cancer, this should not effects of TKIs can be mitigated with the use of drugs
be a barrier to consideration. In situations where a such as ACE inhibitors, angiotensin receptor block-
patient with declining renal function has a potential ers, and calcium channel antagonists by their effects
donor with a potential T1 tumour, the possibility of of vascular resistance.
pre-emptive transplantation with native nephrectomy Drugs with VEGF-related effects such as the
3–6 months later could be viewed as an option. This is TKIs and bevacizumab appear at higher risk of
highly unlikely to affect the oncological outcome even hypertensive side effects compared to other patients.
with immunosuppression and avoid the morbidity of a Hypothyroidism, a recognised complication of suni-
period on dialysis including that related to access as tinib, also occurs more frequently with renal insuffi-
well as the accelerated cardiovascular complications ciency.
associated with renal disease. With more advanced The toxicities associated with mTOR inhibitors
tumours, a judicious interval would seem appropriate with metastatic RCC in the context of renal impair-
with restaging after an interval of several years before ment reflect those seen in the transplant population
considering transplantation. with similar levels of renal dysfunction. In patients
Successful outcomes have been observed using with RCC, these are associated with higher incidences
58 kidneys from deceased and live donors following exci-
sion of small incidentally detected renal cell carci-
of rash, infections, and dose interruptions than the
patients with normal renal function, with no signifi-
noma. In patients electing radical nephrectomy for cant difference noted in the incidence of other toxici-
small renal masses the kidney, following excision of ties.
the tumour can be used as a novel form of altruistic There is relatively data related to drug toxicity
organ donation [32]. With these donor sources, the for patients who are dialysis dependent. With suni-
risk of tumour recurrence is extremely low with tinib, and presumably other TKis, standard doses
patient survival significantly better than the alterna- and pharmacokinetics appear similar to other
tive of long-term dialysis and graft outcomes similar patients. It does not appear dialyzable, and thus dos-
to other sources of donor organs. Whilst controver- ing can therefore be either before or after dialysis.
sial the presence of a small renal tumour should not Bevacizumab also does not appear affected by dialy-
prevent transplantation of a kidney from either sis with similar pharmacokinetics in this group com-
deceased or potential live donors. In circumstances pared to patients with normal renal function.
where patients elect for radical nephrectomy for small Significant renal toxicity or complications have
tumours, these kidneys should be considered for been reported with TKis and particularly sunitinib –
patients who may not otherwise have the opportunity probably reflecting the greater population exposed to
of renal transplantation. this agent. Thrombotic-microangiopathic haemolytic
Systemic therapies of RCC may have implications anaemia is a recognised toxicity as well as acute inter-
for patients with impaired renal function. Some stitial nephritis and rhabdomyolysis. Toxicity may
degree of renal insufficiency may be present in result in a need for dialysis in severe cases [33].
Kidney Cancer
1035 58
. Table 58.5 Bosniak cyst classification; this was originally described on US criteria although features remain the criteria in
radiological reporting with CT and MRI
I Thin-walled cyst without septae, calcifications, or solid components. It measures as water density and does ±0%
not enhance Virtually nil
II A cyst that may contain a few fine thin septae with possible perceived enhancement. Fine calcification or ±1%
short segments of slightly thickened calcification may be present in the wall or septa. Uniformly high- Extremely
attenuation lesions ≤3 cm that are well marginated and do not enhance (hyperdense cysts) are included in unlikely
this category and do not require further evaluation
IIF Cysts that may contain multiple hairline thin septa or minimal smooth thickening of their wall or septa. 5%
Perceived enhancement of their septa or wall may be present. Their wall or septa may contain calcification Unlikely
that may be thick and nodular, but no measurable contrast enhancement is present. These lesions are
generally well marginated. Totally intrarenal nonenhancing high-attenuation renal lesions ≥3 cm are also
included in this category. These lesions require follow-up surveillance studies to ensure they are benign. ‘F’
in this classification stands for ‘follow-up’
III ‘Indeterminate’ cystic masses that have thickened irregular or smooth walls or septa in which measurable 35%
enhancement is present. Surgery is recommended for these lesions; whilst some will prove to be benign Intermediate
(haemorrhagic cysts, chronic infected cysts and multiloculated cystic nephroma), some will be malignant
(cystic RCC and multiloculated cystic RCC)
IV These are highly complex cystic lesions containing thickened irregular walls and solid components with a 90%
high risk of malignancy High
. Table 58.6 Solid and complex lesions detected on imaging studies which may be difficult to distinguish from RCC
. Table 58.7 Criteria for consideration of cytoreductive nephrectomy for patients presenting with metastatic disease
Case Study
Case 1 Case 2
A 75-year-old man is referred with a creatinine of 190 mmol/l. A 45-year-old man is referred after a chest x-ray reveals mul-
Ultrasound reveals he has a 2 cm solid mass in his left kidney tiple pulmonary lesions consistent with metastases.
when he is investigated. Chest x-ray and liver ultrasound are Investigation of this with a CT reveals a 10 cm tumour in his
normal. An MRI scan confirms the lesion is solid, and the left kidney. Biopsy of a lung lesion confirms metastatic clear
radiologist suggests it may be a small renal cell carcinoma. cell RCC. He is commenced on sunitinib at a dose of 50 mg/
The patient is observed and has a repeat ultrasound 3 months day. His pulmonary metastases demonstrated very signifi-
later which shows no change in the lesion. This is repeated cant reduction in size on CT at 3 months. The primary
12 months later, and the lesion is 3 cm in size. In the interven- tumour shows an only modest reduction in size. He contin-
58 ing period, the patient’s creatinine has deteriorated and is ues with sunitinib with no further reduction in the size of
now 280 mmol/l. Further ultrasound is performed 6 months the pulmonary metastases but develops recurrent episodes
later with only marginal increase to 3.2 cm. At this stage he of macroscopic haematuria associated with intermittent left
has developed symptoms of congestive cardiac failure related flank pain with these episodes. In view of these symptoms,
to coronary artery disease for which he is stented and placed he undergoes a left nephrectomy. The tumour is largely
on antiplatelet therapy. A further ultrasound 12 months later necrotic with only several sites of active disease. This case
shows the renal lesion is 3.5 cm. This remains under observa- illustrates that in the absence of initial symptoms and large
tion with the patient dying 9 months later due to an acute volume metastases, there was no indication for cytoreduc-
coronary event. This case illustrates that surveillance is an tive nephrectomy at presentation as systemic treatment was
appropriate option for an elderly patient with a small renal required. He responded to treatment in a typical fashion
tumour. Biopsy is not undertaken as even if malignancy was with a reduction in the size of metastases and subsequent
confirmed this would not alter treatment. Small tumours stabilisation. Cytoreductive nephrectomy was required for
even with slow growth have little potential for metastases or symptom control but could also have been considered if he
symptoms even if slow growth is observed. remained well in view of his response to drug treatment.
in metastatic renal cell carcinoma: INTORACT trial. J Clin versus sunitinib in advanced renal-cell carcinoma. N Engl J
Oncol. 2014;32(8):752–9. Med. 2018;378(14):1277–90.
24. Pham A, Ye DW, Pal S. Overview and management of toxici- 29. Galazi M, Rodriguez-Vida A, Josephides E, Chau NM,
ties associated with systemic therapies for advanced renal cell Chowdhury S. Cytoreductive nephrectomy: past, present and
carcinoma. Urol Oncol. 2015;33(12):517–27. future. Expert Rev Anticancer Ther. 2014;14(3):271–7.
25. Miyake M, Kuwada M, Hori S, Morizawa Y, Tatsumi Y, Anai 30. Mejean A, Ravaud A, Thezenas S, Colas S, Beauval JB,
S, et al. The best objective response of target lesions and the Bensalah K, et al. Sunitinib alone or after nephrectomy in
incidence of treatment-related hypertension are associated with metastatic renal-cell carcinoma. N Engl J Med. 2018;379(5):
the survival of patients with metastatic renal cell carcinoma 417–27.
treated with sunitinib: a Japanese retrospective study. BMC Res 31. Rini BI, Dorff TB, Elson P, Rodriguez CS, Shepard D, Wood
Notes. 2016;9:79. L, et al. Active surveillance in metastatic renal-cell carcinoma:
26. Coppin C, Porzsolt F, Awa A, Kumpf J, Coldman A, Wilt a prospective, phase 2 trial. Lancet Oncol. 2016;17(9):1317–24.
T. Immunotherapy for advanced renal cell cancer. Cochrane 32. Nicol D, Fujita S. Kidneys from patients with small renal
Database Syst Rev. 2005;(1):CD001425. tumours used for transplantation: outcomes and results. Curr
27. Ochoa CE, Joseph RW. Nivolumab in renal cell carcinoma: Opin Urol. 2011;21(5):380–5.
current trends and future perspectives. J Kidney Cancer VHL. 33. Greef B, Eisen T. Medical treatment of renal cancer: new hori-
2018;5(1):15–8. zons. Br J Cancer. 2016;115(5):505–16.
28. Motzer RJ, Tannir NM, McDermott DF, Aren Frontera O,
Melichar B, Choueiri TK, et al. Nivolumab plus ipilimumab
58
1039 59
Contents
References – 1052
Inherited Renal Tumour Syndromes
1041 59
n Learning Objectives . Table 59.1 illustrates the seven genes that have
1. Inherited cancer syndromes cause disease in a wide been implicated in familial renal carcinoma. These
range of organ systems and are linked by muta- genes are all implicated in two interrelated metabolic
tions in related cellular pathways. pathways. The most common cause of inherited RCC
2. Von Hippel-Lindau (VHL) disease is caused by is von Hippel-Lindau (VHL) disease, which is caused by
mutations in the VHL tumour-suppressor gene, mutations in the VHL tumour-suppressor gene. VHL,
which leads to activation of the intracellular FH, and SDHB all impact on the cellular response to
hypoxia pathway and constitutive growth factor changes in oxygen tension. TSC1 and TSC2, FLCN,
signalling. and MET are all implicated in the activity of the nutri-
3. Genetic testing and family screening can inform ent-sensing pathway, which is centred on the mamma-
reproductive decisions and clarify the role of sur- lian target of rapamycin, mTOR.
veillance imaging.
4. Regular screening has significantly improved mor-
tality and morbidity in affected patients. 59.2 Genetic Diagnosis
5. mTOR inhibitors are now licensed for use in tuber-
ous sclerosis where there have been shown to result A comprehensive family history is an important step in
in multisystem benefits, including shrinkage of the analysis of any disorder, whether or not it is known
large angiomyolipomas. to be genetic. A family history is important because it
can be critical in diagnosis, provide information about
the natural history of a disease and variation in its
59.1 Introduction expression, and clarify the pattern of inheritance.
The following key points are critical in taking a good
Kidney cancer is among the most common adult malig- family history:
nancies [1]. The majority of cases will be detected and 5 Detail all close family and their biological relation to
managed by urologists; however, in 3–5% of all cases the index case.
of RCC, there is a major inherited predisposition. 5 Document consanguinity.
These complex cases may require additional input from 5 Include miscarriages and stillbirths.
nephrologists and clinical geneticists [2]. The presence 5 Document the age of disease onset in each case.
of characteristic tumours or extra-renal signs may 5 Find out the exact histological diagnosis.
point to a diagnosis of a specific RCC susceptibility 5 Detail all other potentially associated conditions in
syndrome. It is important to recognise that renal cancer other systems, such as skin lesions, deafness, or pneu-
is only one aspect of these complex multisystem disor- mothorax.
ders and that optimal patient care requires long-term
follow-up and the close liaison of a broad multispe- A genetic disorder may be inherited from one or both
cialty team. parents’ genes, or it may be caused by new mutations in
Kidney cancer is not a single disease, but comprises the DNA during gametogenesis. Mutations can occur at
a number of histological subtypes. The Heidelberg clas- meiosis and thus be passed on to every cell in the body or
sification system recognises five subtypes of malignant affect just the progeny of one mutant cell (somatic muta-
renal parenchymal neoplasm (. Table 59.1). tion). In kidney cancer, the same gene, commonly the
VHL tumour-suppressor gene, may be affected both by able to collect blood samples for genetic testing in the
heritable mutations and by somatic mutations acquired absence of this support. Our own guidelines recommend
during the lifetime of an individual. referral in the following circumstances:
Excepting translocations of chromosome 3, famil- 5 Familial renal cell carcinoma
ial renal cancer is the result of single mutated genes. – Positive family history, especially first-degree rela-
These conditions are all autosomal dominant; thus, tive (e.g. parent or sibling)
each affected individual may have one affected parent, 5 Young-onset renal tumour
and there is a 50% chance that a child will inherit the – < 45 years
mutated gene. However, autosomal dominant condi- 5 Multiple renal tumours
tions may have reduced or variable penetrance, which – < 55 years
means not all individuals who inherit that mutation go – Clear cell carcinoma
on to develop the disease or express the disease in the – Chromophobe
same way. – Oncocytoma
Most cases of familial kidney cancer are caused by 5 Consider in patients with single tumours but a family
the loss of function of a tumour-suppressor gene. In history of
this situation an affected individual has one abnormal – Renal tract anomaly
copy of the gene present in every cell in their body, but – Renal cysts
the remaining copy of the gene is sufficient for cells to – Other renal disease/renal failure
behave normally. It is only when a cell develops a sec- 5 Recommendations for cancers in other organ sys-
ond, ‘somatic’, mutation in the normal copy that a tems (e.g. phaeochromocytoma, haemangioblas-
tumour begins to develop. toma) are included in the relevant sections below.
Many of these disorders exhibit a correlation between
the position of the mutation within the causative gene
and the clinical signs observed; a genotype-phenotype 59.4 Von Hippel-Lindau Syndrome: VHL
correlation. This is best understood for VHL disease but Disease
59 is also true for less common conditions, such as BHD
or HLRCC. Although genotype-phenotype correlations 59.4.1 Introduction and Epidemiology
can aid clinical decision-making, it is not usual to alter
screening guidelines. VHL disease (Mendelian Inheritance in Man, MIM
193300) is a dominantly inherited familial cancer syn-
drome. It was named after Eugene von Hippel, who
59.3 Referral Criteria described angiomas in the eye in 1904, and Arvid
Lindau, who described angiomas of the cerebellum
These referral criteria are designed to pick up all indi- and spine in 1927 [3]. The incidence of VHL disease
viduals and families who may have a genetic predis- is approximately 1 per 36,000 live births, with similar
position to develop renal tumours or cysts. Ideally all prevalence in both genders and across all ethnic back-
patients with known polycystic syndromes and other grounds [4]. 80% of patients with VHL disease have a
genetic renal cystic diseases with cancer predisposition positive family history, but de novo VHL mutations and
would be managed in a specialist renal genetics clinic. mosaicism are not uncommon.
The following two key principles should guide referral:
1. The most important factor determining whether
screening will be informative is the presence of renal 59.4.2 Aetiology and Pathogenesis
disease in a first-degree relative.
2. Referral should be based on whether establishing a VHL disease is caused by mutations in the VHL gene,
genetic diagnosis would lead either to the productive which is located at 3p25 [5]. Mutation of the VHL gene
screening of the patient or other family members is detected in nearly all VHL families and, importantly,
and/or affect reproductive decisions. the great majority (~90%) of nonfamilial clear cell renal
cell cancer (CCRCC) [6]. VHL functions as a classical
It is important to mention that the budget for genetic tumour-suppressor gene. Thus, tumour tissue in patients
testing is usually held by the medical genetics service. with VHL disease shows inactivation of the remaining
This ensures that patients meeting criteria for a refer- normal VHL allele, either through mutation, deletion,
ral will receive appropriate counselling and that cascade or methylation.
testing of family members can be initiated. Conse- The VHL protein binds to the hypoxia-inducible fac-
quently, patients should generally be referred to medical tor (HIF) and thereby mediates its degradation when
genetics or managed in a joint clinic. It is not advis- intracellular oxygen levels are normal. HIF is a highly
Inherited Renal Tumour Syndromes
1043 59
conserved transcription factor that mediates cellular 59.4.4 Diagnostic Criteria
adaptation to low levels of oxygen [7, 8]. Disruption of
the VHL-HIF interaction results in the activation of The diagnosis of von Hippel-Lindau disease is based
HIF target genes, such as vascular endothelial growth on clinical criteria or genetic testing [2]. Patients with
factor (VEGF), that play a role in the growth and metas- a family history, and a CNS (excluding retinal) hae-
tasis of primary tumours. mangioblastoma, phaeochromocytoma, or CCRCC are
diagnosed with the disease. Those with no relevant fam-
ily history must have either two or more CNS haeman-
59.4.3 Clinical Features gioblastomas or one haemangioblastoma of the CNS or
retina and a visceral tumour. It is important to have a
The most frequent manifestations of VHL disease strong index of suspicion in patients who don’t fulfil all
are retinal and central nervous system haemangio- the criteria and consider either genetic testing or contin-
blastomas, CCRCC, and phaeochromocytomas ued surveillance.
(. Table 59.2 and . Fig. 59.1). These are commonly
multiple and develop at a younger age than similar spo-
radic tumours in the general population. Patients may 59.4.5 Investigations
also develop non-secreting neuroendocrine tumours
of the pancreas, endolymphatic sac tumours (which Mutation analysis is recommended to make a definitive
can result in deafness), epididymal papillary cystad- diagnosis. There are a number of reasons why genetic
enoma (men), and cysts of the uterine broad ligament testing for VHL disease is particularly successful:
(women) [9]. In addition to tumours, patients develop 5 The VHL gene is small and so easier and cheaper to
multiple cysts of the kidney and other organs includ- sequence.
ing the pancreas (. Fig. 59.1) [4]. Mortality is usu- 5 It is possible to identify a mutation in virtually all
ally due to either metastasis of RCC or complications families.
of CNS haemangioblastomas; however, following the 5 Almost all genetic variations in VHL are implicated
introduction of systematic screening for tumour devel- in disease.
opment, life expectancy of VHL patients has greatly 5 Mutations have a high penetrance.
improved. 5 Clinical screening of mutation carriers prevents seri-
There are now more than 350 distinct mutations in ous consequences.
the VHL gene that have been linked to familial VHL dis- 5 Pre-implantation testing is entirely appropriate.
ease, which demonstrates genotype and phenotype cor-
relation [10]. The clinical phenotype is categorised on the Screening for germline VHL mutations should also be
basis of the incidence of haemangioblastoma, CCRCC, considered in individuals with apparently sporadic cere-
and phaeochromocytoma, as shown in . Table 59.3. bral and retinal haemangioblastoma since these are rare
Different types of mutation variably affect VHL’s in the general population [11]. Direct sequencing is the
many cellular functions, resulting in striking genotype- gold standard for detecting germline VHL mutations
phenotype correlation. and can identify the underlying abnormality in 86–100%.
Manifestation Percentage of patients with VHL disease Mean age at Percentage of all cases due to
exhibiting this feature diagnosis mutations in VHL
a b
c d
59
e f
. Fig. 59.1 Clinical manifestations of inherited renal tumour syn- Lightman, UCL). (d) Multiple areas of cystic change in the pancreas
dromes. (a) Nephrectomy specimen demonstrating multiple solid of a 33-year-old with VHL disease, note possible soft tissue enhance-
tumours (arrowhead) and cystic change (arrowed) in a patient with ment arrowed (T1-weighted contrast-enhanced MRI). (e) Multiple
VHL disease. (b) Large cerebellar haemangioblastoma in a 35-year- renal cysts in a 44-year-old patient with Birt-Hogg-Dubé syndrome.
old with VHL disease, arrowed (T1-weighted contrast-enhanced Note cyst with soft tissue component, blunt arrow, as well as a simple
MRI). (c) Retinal photograph demonstrating a large retinal angioma cyst, arrowed (T2-weighted contrast-enhanced MRI). (f) Character-
in a patient with VHL disease. (Image courtesy of Professor Sue istic skin lesions in a patient with Birt-Hogg-Dubé syndrome
Inherited Renal Tumour Syndromes
1045 59
radiofrequency ablation, and should target as many lesions and in those presenting at a young age (<40 years).
smaller lesions as feasible in order to delay the need for Over half of all patients with retinal angiomas have VHL
re-operation. mutations. It is therefore recommended that all patients
Renal replacement therapy may be required if renal with these tumours are referred for genetic testing.
function has been reduced by repeated renal surgery.
Renal transplantation has been undertaken successfully, 59.4.6.4 Phaeochromocytoma
and the subsequent immunosuppression does not appear Approximately 7–18% of VHL patients are afflicted
to affect the course of VHL disease [15]. It has therefore with phaeochromocytomas, with a mean age of onset
been suggested that the usual tumour-free interval until of 30 years [4]. Phaeochromocytomas are neoplastic
an individual is accepted onto the transplantation wait- intra- or extra-adrenal gland lesions that appear histo-
ing list can be shortened to 6 months for VHL patients logically as an expansion of large chromaffin positive
with tumours <3 cm [2]. cells, derived from neural crest cells [16]. Untreated pha-
eochromocytomas can result in severe, episodic hyper-
59.4.6.2 Renal Cysts tension and stroke, malignant hypertension, or death.
Renal cysts are found in 50–75% of patients with VHL Both intra- and extra-adrenal phaeochromocytomas
disease (. Fig. 59.1a). The cysts are usually bilateral and can occur in VHL disease. The mechanism of phaeo-
multiple. Kidney shape usually remains normal, with chromocytoma formation in VHL disease is likely to be
normal renal function and preserved blood pressure. different to that of other tumours in this syndrome and
Renal cysts can be either simple or complex renal cysts, may be due to abnormal apoptosis during sympathetic
which combine cystic and solid components. Complex neural development [16].
cysts are precursors to renal cell carcinoma and require Up to 10% of patients with phaeochromocyto-
close follow-up or surgery, depending on the degree of mas have germline mutations in VHL (. Table 59.2)
suspicion for cancer. In contrast to ADPKD, cyst infec- [2]. This proportion is higher in those with a positive
tion does not occur in VHL disease whereas CCRCC is family history, multifocal disease, and age of onset
common (see above). Likewise, in contrast to ADPKD, <45 years. Given that as many as 20% of apparently
59 pancreatic cysts can be numerous and scattered through non-syndromic, phaeochromocytomas have an identifi-
the pancreas in VHL disease, whereas liver cysts show able genetic cause it is advisable to refer these patients
the opposite pattern in the two conditions. for consideration of genetic testing.
59.4.6.3 Haemangioblastoma
Haemangioblastomas are the commonest manifesta- 59.4.7 Novel Therapies
tions of VHL disease, occurring in up to 80% of patients
(. Fig. 59.1b). They are located most commonly in the While surgery remains the mainstay of treatment for
cerebellum and retina [3, 4, 9]. They are cystic tumours tumours in VHL disease, several new drug therapies
of lipid-filled stromal cells embedded in a capillary net- have been developed. These therapies target the molecu-
work. Patients with cerebellar haemangioblastoma typi- lar consequences of VHL loss of function, in particular
cally present with symptoms of increased intracranial the stabilisation of HIF and consequent overproduction
pressure and limb or truncal ataxia. Hemangioblastomas of secreted growth factors such as VEGF [8]. Current
are rarely malignant, but enlargement or bleeding within therapies have been designed to inhibit growth factor
the CNS can result in neurological damage and death. signalling using monoclonal antibodies and small mol-
The removal of asymptomatic tumours is not recom- ecule inhibitors [17]. These agents have all shown a con-
mended. Complex lesions benefit from surgery in units sistent doubling of progression-free survival over prior
with expertise in VHL disease. standard of care treatments [8]. These drugs are gener-
Retinal angiomas are the most common presenting ally well tolerated, as demonstrated by the quality of life
feature of VHL disease and lead to visual loss in 55% improvement in clinical trials, and result in clinical ben-
of patients with angiomas at 50 years (. Fig. 59.1c). efit for in excess of 70% of patients treated.
Management is directed towards the identification of Immunotherapy with programmed cell death 1
asymptomatic lesions and their treatment by laser pho- (PD-1) pathway inhibitors has also been developed in
tocoagulation or cryotherapy. Optic disc lesions are kept CCRCC [18]. These agents have been shown to be effec-
under surveillance because of the risk of optic nerve tive second-line agents for patients with poor prognosis
damage if they are treated. metastatic CCRCC. Current trials are looking into com-
VHL mutations are found in a third of all patients with bination therapy with agents that block the PD-1 path-
CNS haemangioblastomas (. Table 59.2) [2]. This num- way at multiple levels or in combination with inhibitors
ber is even greater in those with posterior fossa or spinal of growth factor signalling.
Inherited Renal Tumour Syndromes
1047 59
59.4.8 Follow-Up Thus, mutations at the TSC1 and TSC2 loci result in
a loss of inhibition of the mTOR nutrient and energy-
VHL disease is a complex multisystem disorder that sensing pathway that may explain their function as a
requires lifelong follow-up and the close liaison of a tumour suppressor. The tuberous sclerosis proteins are
broad multispecialty team. Patients may have poor mobil- also involved in the formation of the primary cilium that
ity and travel considerable distances therefore scans need is disturbed in many forms of the renal cystic disease.
to be closely coordinated with multidisciplinary appoint-
ments ideally on the same day with MDT discussion of
management. The early diagnosis of most of the compli- 59.5.3 Clinical Features
cations of VHL disease improves prognosis and reduces
morbidity. All VHL patients and at-risk relatives should TSC most often presents with neurological symptoms,
be entered into a comprehensive screening program in and over 90% of affected individuals have subependymal
childhood, except where VHL disease has been excluded nodules and/or cortical tubers on MRI. Approximately
by molecular genetic testing. 90% of patients experience seizures, and virtually all
subtypes of seizure have been reported [21]. About
half of patients show cognitive impairment, autism,
59.5 Tuberous Sclerosis Complex or other behavioural disorders. In approximately 10%
of patients with TSC, the growth of subependymal
59.5.1 Introduction and Epidemiology tumours can cause hydrocephalus due to obstruction of
CSF flow [19].
Tuberous sclerosis (MIM 605284) is an autosomal Renal cystic disease occurs in approximately half of
dominant genetic disorder with a birth incidence of patients with TSC. Renal cystic disease can be microcys-
1:6000. It can affect virtually any organ system, and all tic, and thus undetectable by standard imaging studies.
racial and ethnic groups are affected equally. Males and Renal cysts arise from all parts of the nephron, includ-
females are affected equally. TSC has a highly variable ing the glomerulus. TSC patients may have several risk
phenotype, and two thirds of cases result from sporadic factors for acute kidney injury, including the use of cer-
genetic mutations. TSC most often presents with neuro- tain anticonvulsant and nonsteroidal anti-inflammatory
logic symptoms in childhood [19, 20]. Renal lesions are drugs as well as rhabdomyolysis and hypoxia induced
the second most common finding and include multiple by prolonged seizures [20]. Both renal cystic disease and
angiomyolipomas (80%) and cysts (50%), but early-onset angiomyolipomas may contribute to chronic kidney dis-
RCCs have been reported. Renal failure is the most com- ease (CKD) [22].
mon cause of death for adult patients with TSC [20], Skin lesions are present in 96% of individuals with
and approximately 1% of the TSC population with nor- TSC. The commonest finding is hypo-pigmented mac-
mal intellect requires renal replacement therapy. ules (‘ash leaf spots’), which may require UV light (a
Woods lamp) to visualise in fair-skinned individuals.
Other skin lesions that comprise the diagnostic crite-
59.5.2 Aetiology and Pathogenesis ria include facial angiofibromas (adenoma sebaceum),
periungual fibromas, and shagreen patches. Cardiac
Tuberous sclerosis (MIM 605284) is a dominantly inher- rhabdomyomas were the most frequent finding at rou-
ited familial cancer syndrome. Molecular genetic studies tine antenatal ultrasound testing and are an indication
have identified at least two chromosomal loci for TSC, for testing for TSC [21]. In all, 50–67% of children have
TSC1 on 9q37 and TSC2 on 16p13.3. Mutations in evidence of one or more rhabdomyomas, and these may
TSC1, which encodes the protein hamartin, are respon- be associated with ECG abnormalities, including con-
sible for approximately 20% of cases. Mutations in TSC2 duction defects and arrhythmias, and heart failure in
account for the great majority of cases. TSC2 encodes infancy. Pulmonary involvement, specifically lymphan-
the protein tuberin and is adjacent to the polycystin-1 gioleiomyomatosis (LAM) is the third most common
gene. Deletions of both TSC2 and PKD1 may account cause of TSC-associated morbidity in approximately
for the 2% of individuals with TSC who develop early- 35% of female TSC patients [20]. The female preponder-
onset polycystic kidney disease [19]. ance is not understood. Retinal hamartomas may occur
Hamartin and tuberin form a heterodimer that inter- in 40%. The commonest non-retinal findings on opthal-
acts with Rheb, a Ras-family GTPase, preventing it mological examination include coloboma and papilloe-
from activating mTOR signalling (via mTORC1) [19]. dema due to hydrocephalus.
1048 T. M. F. Connor
59.5.4 Diagnostic Criteria All patients with TSC should be screened for renal
involvement with MRI abdomen [24]. The combina-
The diagnostic criteria for TSC are based on major tion of fat-suppressed and non-fat-suppfressed T2 sig-
and minor diagnostic features, shown in . Table 59.5 nal on MRI is a very effective means of detecting both
[23]. Cases meeting these criteria fulfil a clinical diag- the macroscopic and microscopic adipose components
nosis of TSC; the results of molecular genetic testing of angiomyolipomas, and it is especially successful for
of the TSC1 and TSC2 loci are currently viewed as cor- the detection of those with minimal fat [20]. Renal ultra-
roborative [19]. No single feature of TSC is diagnostic, sound shows good sensitivity for cystic renal disease
and different manifestations of TSC appear at different and most angiomyolipomas, except those which are ‘fat
developmental points from neonatal life to adulthood. poor’. CT is a reasonable alternative where MRI is con-
Secure diagnosis usually requires assessment of all pos- traindicated if concern remains after ultrasound. PET
sible clinical features over a significant time period. scans can be helpful because angiomyolipomas are gen-
erally not PET avid. Imaging should be repeated every
1–2 years when lesions have been identified, and every
59.5.5 Investigations 3–5 years if no lesions are detected [24].
TSC requires lifelong follow-up with regular imaging of Criteria for the diagnosis of BHD have been proposed,
the kidneys. Although renal angiomyolipomas are rare to take into account the clinical variability seen with this
in the general population, only a minority of all cases condition (. Table 59.6; after [26]).
1050 T. M. F. Connor
Hereditary leiomyomatosis and renal cell cancer Fulfilling major criteria indicates HLRCC with a high likeli-
(HLRCC) is an autosomal dominant disorder char- hood
acterised by smooth-muscle tumours of the skin and HLRCC can be suspected when an individual meets ≥2 of the
uterus and/or renal cancer (OMIM 605839). In 2001, minor criteria
an HLRCC-associated gene locus was localised to
Inherited Renal Tumour Syndromes
1051 59
59.7.4 Management Issues in HLRCC is probably low, and such individuals probably do not
require screening.
Screening with annual MRI should begin at age 18.
Given their aggressive nature, all renal tumours will usu-
ally be treated surgically. Preclinical data demonstrating 59.8.2 Hereditary Papillary Renal
that FH loss of function activates pathways that include Carcinoma
HIF and so overlap with those in VHL disease suggests
that there may be value in using similar targeted thera- Hereditary papillary renal carcinoma (HPRC) is a
pies; however, clinical data in this area is still scarce. dominantly inherited familial cancer syndrome char-
acterised by a predisposition to develop multiple, bilat-
eral papillary renal tumours (OMIM 605074). Linkage
59.8 Other Causes of Familial RCC analysis in 1997 showed that this condition was caused
by activating mutations in the c-MET proto-oncogene
A number of other inherited disorders may be associ- on 7q34 [34]. The renal tumours in HPRC have a dis-
ated with renal tumours. In the absence of a genetic tinct histological appearance, characterized as type
diagnosis, individuals with familial non-syndromic 1 papillary, and have a better prognosis than type 2
clear cell renal cancer should be referred to a renal papillary RCC [2]. 95% of sporadic tumours with this
genetics clinic for consideration of karyotype, VHL, appearance show trisomy of chromosome 7, which
and possibly FLCN sequence. If testing is normal, they includes both the MET and hepatocyte growth factor
and their first degree relatives should receive annual (HGF) genes.
ultrasound from 25 to 60 years via their GP (no pub- HPRC is very rare (approximate incidence 1 per 10
lished evidence). million), but identification of germline MET mutations
Individuals with early-onset, non-syndromic clear allows precise diagnosis and targeted surveillance of
cell renal cancer should have Xp11.2 TFE3 transloca- mutation carriers. Moreover, such molecular insights
tion carcinoma is excluded. Affected family members have facilitated the use of targeted oncological thera-
should have karyotype assessed. There is no clear evi- pies [17].
dence to guide whether other family members should
receive screening.
59.8.3 Succinate Dehydrogenase
Case Study
A 42-year-old man moved into the region and was referred education. What specific considerations need to be dis-
for follow-up in the renal transplant clinic. He had a his- cussed?
tory of renal transplantation after bilateral nephrectomy Firstly, general considerations around capacity and
for CCRCC due to VHL disease. He was asking whether consent to treatment relating to her learning difficulties
he still needed follow-up in the VHL clinic. may necessitate a formal best interest meeting. Secondly,
VHL is a multisystem familial cancer syndrome. progressive decline in eGFR and transition to dialysis
Although his native kidneys have been removed, he will affect the clearance of any anticonvulsant medica-
remains at risk of retinal angiomas, CNS haemangioblas- tion she is on. Thirdly, the routine use of anticoagula-
tomas, and phaeochromocytomas. He needs ongoing tion in haemodialysis may impact the specific risk of
screening for these conditions (. Table 59.4). retroperitoneal haemorrhage due to renal angiomyoli-
A 46-year-old woman with learning difficulties due pomas.
to tuberous sclerosis is seen in the pre-dialysis clinic for
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