Edited by

Wooin AHN
JAI RADHAKRISHNAN

COLUMBIA UNIVERSITY
IRVING MEDICAL CENTER

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 CONTRIBUTING AUTHORS
Wooin Ahn, MD, PhD
Assistant Professor of Medicine. Columbia University Vagelos College of Physicians
and Surgeons
Gerald B.Appel, MD
Professor of Medicine. Columbia University Vagelos College of Physicians and
Surgeons
Director, Glomerular Kidney Center New YorkPresbyterian Hospital/Columbia
University Irving Medical Center
Rachel Arakawa, MD
Clinical Fellow. New YorkPresbyterian Hospital/Columbia University Irving Medical
Center
Rupali S.Avasare, MD
Assistant Professor of Medicine. Oregon Health & Science University
Yorg Azzi, M D
Assistant Professor of Medicine, Department of Medicine.Alberc Einstein Medical
Schcoi
Vasanthi Balaraman, MD
Assistant Professor. Department of Surgery. University of Tennessee Health Science
Center
Transplant Nephrologist/Physician. Department of Surgery. Methodist University
Hospital
Andrew Beer ken, MD, PhD
Postdoctoral Clinical Fellow. Columbia University Vagelos College of Physicians and
Surgeons
David Bennett, MD
Attending Nephrologist. Department of Medicine. Bridgeport Hospital
Andrew S. Bomback, MD, MPH
Associate Professor of Medicine. Columbia University Vagelos College of Physicians
andSurgeons
Pietro Canetta, MD, MSc
Assistant Professor of Medicine. Columbia University Vagelos College of Physicians
andSurgeons
jae Hyung Chang, MD
Assistant Professor of Medicine. Columbia University Vagelos College of Physicians
andSurgeons
Efren A. Chavez Morales, MD
Clinical Fellow. New YorkPresbyterian Hospital/Columbia University Irving Medical
Center
JenTse Cheng, MD
Assistant Professor of Clinical Medicine (retired), Columbia University Vagelos
College of Physicians and Surgeons
Chief (retired). Division of Nephrology and Hypertension. Harlem Hospital Center
Russell J. Crew, MD
Assistant Professor of Medicine. Columbia University Vagelos College of Physicians
andSurgeons
Yelena Drexler MD
Assistant Professor University of Miami
 Geoffrey K. Dube, MD
Assistant Professor of Medicine. Columbia UniversityVagelos College of Physicians
and Surgeons
E Hilda Elena Fernandez, MD, MSCE
a Assisrann Professor of Medicine. Columbia University Vagelos College of Physicians
2 and Surgeons
5 Abdallah S. Gears, MD
3, Assistant Professor of Clinical Medicine, University of Pennsylvania

jonathan Hogan, MD
Assistant Professor. University of Pennsylvania
S.Ali Husain, MD, M P H
Assistant Professor of Medicine. Columbia University Vagelos College of Physicians
and Surgeons
Sean D. Kalloo, MD, M B A
Assistant Professor of Medicine (in Radiology). Columbia University Vagelos
College of Physicians and Surgeons
jeanne Kamal, MD
lnscructor in Medicine. Columbia University Vagelos College of Physicians and
Surgeons
Pascale Khairallah, MD
Clinical Fellow, New YorkPresbyterian Hospital/Columbia University Irving Medical
Center
M i nesh K hat ri , M D
Clinical Assistant Professor State University of New York at Stony Brook
K nyszt of K i ryl uk, M D, M S
Associate Professor of Medicine. Columbia University College of Physicians &
Surgeons
MarkV lL K ozicky, MD
Adjunct Assistant Clinical Professor Department of Medical Education/Medicine,
Lake Erie College of Osteopathic Medicine
Assistant Program Directory, Department of Internal Medicine/Nephrology.
SL Johns Riverside Hospital
Wai Lang Lau, M D
Assistant Professor. University of Florida
Hila Milo Rasouly, P hD
Associate Research Scientist. Columbia University Vagelos College of Physicians
and Surgeons
S umit Mohan, MD, MP H
Associate Professor of Medicine and Epidemiology, Columbia University Vagelos
College of Physicians and Surgeons and Mailman School of Public Health
Heat her M orri s, M D
Assistant Professor of Medicine. Columbia University Vagelos College of Physicians
and Surgeons
M ari a B ereni ce Novo, M D
Nephrologist, Department of Medicine. Kaiser Permanente (San Diego. California)
Jordan Gabri el a Nest or, M D
Postdoctoral Clinical Fellow, Columbia UniversityVagelos College of Physicians and
Surgeons
Thomas Nickolas, MD, MS
Associate Professor of Medicine. Columbia University Vageios College of Physicians
and Surgeons
Akshta Pai, MD, MPH
Assistant Professor. Division of Immunology and Organ Transplantation. Division of |
Renal Disease and Hypertension, McGovern Medical SchooIThe University of
Texas Health Sciences Center at Houston
Yonatan Peleg, MD
Clinical Fellow. New YorkPresbyterian Hospital/Columbia University Irving Medical
Center
jail Radhakrishnan, MD, MS
Professor of Medicine, Columbia University Vagelos College of Physicians and
Surgeons
Maya K. Rao, MD
Assistant Professor of Medicine, Columbia UniyersityVagelos College of Physicians
and Surgeons
Renu Regunat hanS henk, M D
Assistant Professor. George Washington University
Dom i ni ck S ant ori el l o, M D
Assistant Professor of Pathology and Cell Biology. Columbia UniversityVagelos
College of Physicians and Surgeons
Shayan Shirazian, MD
Assistant Professor of Medicine. Columbia UniversltyVagelos College of Physicians
and Surgeons
E ric S iddall, MD
Assistant Professor of Medicine. Columbia University Vagelos College of Physicians
and Surgeons
Meghan E. Sise, MD, MS
Assistant Professor of Medicine. Department of Medicine. Harvard Medical School
jacob Sam Stevens, MD
Instructor in Medicine, Columbia University Vagelos College of Physicians and
Surgeons
Zachary H.Taxin, MD
Internal Medicine Resident. New YorkPresbyterian Hospital/Columbia University
Medical Center
DemetraTsapepas, PharmD, BCPS
Assistant Professor of Clinical Surgical Sciences. Columbia University Vagelos
College of Physicians and Surgeons
Director of Quality and Research in Transplantation. Department of Transplantation.
New YorkPresbyterian Hospital/Columbia University Irving Medical Center
Anthony M.Valeri, MD
Professor of Medicine. Columbia UniversityVagelos College of Physicians and
Surgeons
Hector Alvarado Verduzco, MD
Clinical Fellow. NewYorkPresbyterian Hospital/Columbia University Irving Medical
Center
Romina Wahab, MD
Assistant Professor of Medicine. Columbia University Vagelos College of Physicians
and Surgeons
 PREFACE
Pocket Nephrology joins the Pocket Notebook series as a complete
resource for topics related no renal kidney physiology and pathophysiol
ogy designed as a first bedside reference for the busy clinicians.This
book is intended for medical students, internal medicine and nephrology
trainees as well as seasoned clinicians involved in the care of patients
with kidney disease.The book is divided into two sections.The first part
discusses the general approach to disorders of the kidney.The second
part of book will address individual topics under each of the following
categories: Electrolytes and Acid-Base Balance.Tubular, Interstitial and
Cystic Diseases, Extrarenal Diseases, Glomerular and Vascular Diseases,
Hypertension, Renal Replacement Therapy, and Transplantation.
Individual topics are written to make pertinent information readily
available to clinicians in order to facilitate evidencebased patient care.

Wooin AHN AND JAI RADHAKRISHNAN

 CONTENTS
Contributing Authors
Preface

CLINICAL MANIFESTATIONS
Wooin Ahn,jai Radhakrishnan,Abdallah S. Geara,Yonoton Peleg,
Romina Wahab, Eric Siddoll,jonathan Hogan, Minesh Khotri,
Shayon Shirazian, Hilda Elena Fernandez
Proteinuria
Hematuria
Polyuria
Urinary Symptoms
Fluid imbalance
Hypotension
Edema
Nephrotic Syndrome (NS)
Glomerulonephritis (GN)
Thrombotic Microangiopathy
Acute Kidney Injury (AKI)
Chronic Kidney Disease (CKD)
Transition of Care for Young Adults

DIAGNOSIS
S.Afi Husain,Anthony M. Vaferi,Wooin Ahn,jenTse Cheng,
David Bennett, Dominick Santoriello, Hila Milo Rasoufy
R e n a l Fu n cti o n 21
U ri n e Stu d y 22
Imaging 28
Renal Biopsy 210
Renal Pathology 2 12
Ge n e ti cs 217

TREATMENT ANDTOXIN
Minesh Khatri, Hector Alvarado Verduzco, Wooten Ahn, Demetra Tsopepas,
jai Radhakrishnan,jacob Sam Stevens, Geoffrey K Dube,Yorg Azzi,
Anthony M. Valeri
Nutrition 31
Fluid Therapy 32
Pharmacology 36
RAAS inhibitors 39
Nonsteroidal AntiInflammatory Drugs 311
Diuretics 312
Immunosuppressive Therapy 316
Prophylaxis 327
Illicit. Herbal. and Environmental Toxins 330
Plasma Exchange (PLEX) 333
intoxication and Poisoning 334
V ELECTROLYTES AND ACID BASE BALANCE
| Abdallah S. Geara, Zachary H.Taxin,Wooin Ahn
Renal Tubules 41
Evaluation of Acid-Base Balance 43
Metabolic Acidosis 44
Metabolic Alkalosis 412
Respiratory Alkalosis 414
Respiratory Acidosis 415
Potassium 415
Sodium and Water 4-21
Calcium 428
Phosphate 431
Magnesium 433

TUBULAR, INTERSTITIAL,AND CYSTIC DISEASES

Minesh Khatri,jocob Sam Stevens,}ai Radhakrishnan,
Wooin Ahn, Krzysztof Kiryluk
Acute Tubular Necrosis (ATN) 51
Pigment Nephropathy 52
Cryst al Nephropat hy 53
Urinary St one Disease 56
Interstitial Diseases 58
I mmunoglobulin G4Relat ed Disease 510
Sporadic Cystic Diseases s11
Heredit ary Cyst ic Diseases 512
Renal Cell Carcinoma (RCC) 515

EXTRARENAL DISEASES
Hilda Elena Fernandez
Urinary Tract Obstruction (UTO) 61
Reflux Nephropat hy 62
Urinary Tract I nf ect ion (UTI ) 63

GLOMERULAR AND VASCULAR DISEASES

Renu Regunathan-Shenk, Pietro Canetta, Rupali S.Avosare,Wailang Lau,
Gerald B.AppeI,jordan Gabriela Nestor
Minimal Change Disease (MCD) 71
Focal Segmental Glomerulosclerosis 72
M em branous Nephropat hy (M N) 74
P auciI mmune Glomerulonephrit is 77
A nt i GB M Di sease 7 10
I mmunoglobulin A Nephropat hy 711
Lupus Nephrit is 713
InfectionRelated Glomerulonephritis 7 15
I m m une Com pl ex-m edi at ed M P GN 717
C3 Glom erulopat hy (C3G) 7 18
Cryoglobulinemia 720
Amyloidosis 721
Nonamyloid Deposit ion Diseases 724
Heredit ary Glomerular Diseases 725
Antiphospholipid Syndrome (APS)
HUS and TTP
Complementmediated HUS

HYPERTENSION
Yelena Drexler; Andrew S. Bomback
General Hypertension 81 2
Hypertension in ESRD 84
Resistant Hypertension 85
Hypertensive Emergencies 86
Antihypertensives 87
Obstructive Sleep Apnea (OSA) 89
Renal Artery Stenosis (RAS) 8 10
Hyperaldosteronism 812
Pheochromocytoma 8 15

SPECIF IC T OPICS
Russell j. Crew, Geoffrey K. Dube, Shayan Shirazian, Maria Berenice Nava,
Meghan E Sise,jordan Gabriela Nestor Wooten Ahn,Andrew Beer ken,
Maya K. Rao, jai Radhakrishnan,Abdallah S. Geara, S.Ali Husain,
Rachel Arakawa, Thomas Nickofas, Minesh Khatri,Vasanthi Balaramon,
jae Hyung Chang, Mark W Kozicky
Cardiology 91
Pulmonology 96
Extracorporeal Membrane Oxygenation 99
Gastroenterology 910
Hepatology 913
Hepatitis BVirus (HBV) 916
Hepatitis CVirus (HCV) 9 17
Hematology 919
Anticoagulation 924
Monoclonal Gammopathy (MG) 925
Hematopoietic Stem Cell Transplantation 928
Oncology 929
Infectious Diseases 934
Human Immunodeficiency Virus (HIV) 937
Diabetes Mellitus 939
Hyperlipidemia 942
Obesity 9-43
CKDMineral and Bone Disorder 944
Osteoporosis 945
Primary Hyperparathyroidism 948
Uric Acid (UA) 949
Rheumatology 951
Pain Medicine 954
Psychiatry, Sleep Medicine, and Neurology 956
Obstetrics 961
Radiology 966
Dermatology 968
Ophthalmology 970
 Geriatrics 971
Palliative Care 973

RENAL REPLACEMENTTHERAPY
1 Anthony M. Voleri,Wooin Ahn, Efren A, Chavez Morales, Sean D. Kalloo,
Sumit Mohan, Pascale Khairallah
General Concepts of RRT 101
RRT Initiation 103
RRT Modality Decision 10-4
Continuous Renal Replacement Therapy 105
HD Initiation and Prescription 108
HD Adequacy 1011
HD Water Treatment 1013
HD Complication 1014
HD Vascular Access 1019
PD Concepts 1026
PD Prescription 1027
PD Adequacy 1030
PD Complication 1031
PD Catheter 1033
TRANSPLANTATION
Vosanthi Balaraman,jae Hyung Changjeanne Kamal,
Sumit Mahon, Heather Morris,Akshta Pai, Russell j. Crew,
Dominick Santoriello,Yorg Azzi, Geoffrey K Dube,Yelena Drexler;
Andrew S. Bomback, Hilda Elena Fernandez
Recipient Evaluation
Living Donor Evaluation
Immunologic Testing and Monitoring
Kidney Allocation
Allograft Dysfunction
Acute Cellular Rejection (ACR)
Antibodymediated Rejection (AMR)
Infection after KT
Metabolic Complication after KT
Hypertension after KT
Malignancy after KT
Renal Complication in Other Organ Transplantation

PHOTO INSETS
JenTse Cheng, Dominick Santoriello
Urine Sediment Images p11
Renal Pathology Images P21

APPENDIX
Units and Molecular Weights 121
ABBREVIATIONS 13-1

INDEX 11
 PROTEINURIA
Pro:einuria: protein in urine >150 mg/d
t ESRD risk w/ UACR 20-200 mglg in men and 30-300 mglg in women x13.0:
UACR >200 ms/s in men and >300 mg/g in women x471 UASN 20\>9.20:1069)
Albuminuria t ESRD. al l cause and car di ovascul ar mor tal i ty I mmune 2010hJ75;1073)

Urinary Proteins
Protein NlVadueISize Remarks
Tamm-Horsfall 9-35 mg/d Synthesized and secreted in TAL
protein (THP: as kD Defense against UTI: inhibit Ca crystallization
uromodulin) The matrix of various casts, including LC cast
Gene mutation causes ADTKD
Albumin <20 mg/d Predominant serum protein
69 kD Very small propanion is Filtered and reabsorbed
Retinolbinding <163 kg/d Urine level is T in early stage of graft failure
protein (RBP) 21 kD (AIr 2013:13:676)

u1 microglobulin <19 rngld Hemebinding protein with antioxidant activity

27 kD
B2 microglobulin <300 kg/L Synthesized in all nuclear cells
(24hr level not Component of class I MHC
established) Serum level is elevated in MM, lymphoma. and has
12 kD prognostic value: renal dysfunction t
Precursor of ABZM (dialysis related) amyloid
Odler minor proteins (kD): myoglobulin (18). hemoglobin (64). Cystatin C (13), K (22.5)
and 2. (45) light chain.vitamin D-binding protein (58). polypeptides

Low-Mole c ula r We ight (LMW) Pr ote ins

Proteins of a size smaller than albumin: RBR n1, B2 microglobulin and lg light chain
gzip

Freely filtered in the glomerulus

Megalin-cubilin-amnionless complex in PT reabsorbs albumin and LMW proteins
1 urinary LMW protein (tubular proteinuria) suggests proximal tubule dysfunction
Workup
Evaluation of Prvoteinuria
Test Pros Cons
Dipsticlc reaction wl Sensitive to albumin insensitive to LMW proteins
tetrabromophenol Rapid.cheap Semiquantitauve: affected by
blue Possible home monitoring urine concentration
False (+): pH >9 wl urea splitting
organisms. iodinated contrast
Random protein to Convenient Diurnal variation
creatinine ratio Correlates wl 24hr (NUM
(UPCR) 1983:)0&1$43)
Random albumin to Sensitive in detecting Diumal variation
creatinine ratio glomerular lesion More expensive than UPCR
(UACR) Miss nonalbumin proteintina
24hr urine protein Gold standard Cumbersome
Can /CrCl together Over or undercollection: / w/
Not elected by diurnal variation creatinine for adequacy

Initial proteinuria workup: J both UPCR and UACR

Spot urine albumin/protein ratio: < 0.4: tubulointerstidal [nor z01z 27:1s34): <0.2S: light
chain cast nephropathy in monoclonal gammopathy (qAsn 2012:7:1964)
Sulfosalicyiic acid (SSA): semiquantitatively detects all proteins including LC;add 3%
SSA to urine and ./ turbidity;false (+) w/ iodinated contrast. PCN,and ceph.
Assay Sensitivity o¢Various Proteins and Substances
LMW Light Iodinated
Assay Albumin Proteins Chain Lysozyrne Contrast

Dipstick + +I - +I - + +

SSA + + 4 + +

Total protein + + + 4 4

Albumin + _ - _
 Transient proteinuria caused by fever. extreme cold. seizure, and exercise
Orthostatic proleinuriazcommon in child and adolescents;benign condition

GLOMERULAR PROTEINURIA
Loss of glomerular filtration barrier;albuminuria: hallmark of glomerular damage
Infection. exercise can cause transient glomerular proteinuria
Moderately increased (A2.formerly mica) dbuminuria: 30-300 mglg or 3-30 mglmmol
Severely increased (A3.formerly macro) albuminuria:>300 mglg or 30 mg/mmol
Tool to monitor glomerular diseases: J proteinuria wl stable renal function = remission
General Management
Low sodium died more effective than dual RAASi iam;201\=J4J¢a4zes)
ACEr or ARB: nonDHP CCB (xi 2004¢e 5.1~m)
BP goal: 125/75 vs 140/90 in 24hr UPCR >0.22 aM i CKD progression (HR 0.73) (AASK
ne//.1 201036391 $1; in 21 g/d proteinuria a/w L ESRD after 14 yr (HR 0.59) (up 1017,zeevu

TUBULAR PRO TEINURIA

Proximal tubular damage -> inability of absorption of Nkered LMW protein
Can be missed wl dipstick (discordance between UPCR and dipstick)
Acquired Causes
ATN. uibulointerstitial diseases
Light chain proximal tubulopathy: mlc cause of acquired Fanconi syndrome
Heavy metals (I d. cadmium, mercury. copper). ifosfamide. tenofovir
Cystinosis
AR mutations of CTNS gene encoding lysosomal protein cystinosin: cystine accumu.
lotion in proximal tubular cells; mlc cause of inherited Fanconi syndrome
Dent Disease
Type 1:xlinked defect in CLCNS gene encoding Cl'/H exchanger. CLC5,exprased in
the FT aM CD intercalated cells - . cubilin and megalith expression -» LMW proteinuria
Type 2: xlinked defect in OCRL gene encoding 4.5bisphophace 5phosphatase
PT damage (unclear mechanism): aminoaciduria.glycosuria. phosphaturia,and hyper
calciuria: CaO>dCaP nephrolithiasis/nephrocalcinosis; FQGS (qAsn 201J;821979)
Biopsy: FQGS (83%), mild segmental FPE (57%), focal interstitial fibrosis (60%), interstitial
lymphocytic infiltrate (53%), tubular damage (70%) (QASN z01s:11:116a)
Rare Genetic Causes ofTubular Proteinuria
DonnaiBarrow/faciooculoacousticorenal syndromes:AR mutation of LDL receptor
protein 2 (megalith). Hypertelorism. myopia. hearing loss. and proteinuria
Grasbeck-lmerslund disease:AR defect in eider cubilin or amnionless. Megaloblastic
anemia: Biz absorption is mediated by cubilin amnionless complex

O VERFLO W PRO TEINURIA

The amount of filtered protein exceeding reabsorption capacity
Causes: light dlain ast nephropadry. rhabdomyolysis (myoglobulin.l3 on UPEP).helndysis
(hemoglobulin), lysozymeinduced nephropathy
L yso zyme In d u ce d N e p h ro p a th y (AJKD 2009:54;1$9)
Lysozyme (muramidase): small (15 kD) cationic protein produced by monocytes and
macrophages; filtered by glomeruli and reabsorbed in the Fly causing injury
Chronic myelomonocytic leukemia (CMML): neoplasm producing mature monocytes:
chronic monocytic leukemia. multiple myeloma,sarcoidosis who 2011:59::cmiii)
" r region in SPEP w/ (-) SIEE (+) urine dipstick protein: t serum. urine lysozyme
AKI. hypokalemia
LM: eosinophilic protein granules In PT: EM: large prominent lysosomes in PT
Tx treatment of primary disease

PRO T EINUMA AF T ER KIDNEY T NANSrL ANT AT iO N

Albuminuria (>proteinuria) predicts renal outcome after :xp (AJKD 2011;57:73J)
Proteinuria is alw cardiovascular morbidity and mortality (fiumplanmuinn z001.73:134$1
Proteinuria from native kidney rapidly declines after txp (A/T zoom.1660>
Causes: transplant glomerulopathya de fl0lD or recurrent glomemlar disease.acute rejection
Biopsy unexplained proteinuria 23 old Ii(DIGo;Ayr 200949 so: 3:S1)
 HEMATURIA
Hematuria: 23 RBCIHPF on a properly collected specimen (avoid during menstruation)
Dipstick , ,sediment for RBC: not hemauiria: consider myo or hemoglobinuria, semen
Hemoglobinuria: mused by any inuavascular hemolysis (et. HAHA transfusion vacdan.
and PNH) with hemoslderinuria (Prussian blue ; tubular cdls).l hapcoglobin, T LDH
May cause Prussian blue hemosiderin deposit in PT aim 101 0.$6:7S0)
Prevalence of hemacuria: 2.5-1 B% in healthy individuals
Persistent asympzomadc microscopic hemaruria x18.5 risk of ESRD UAMA 2011;zo¢mi

Causes of Hematur ia
Origin Selected Causes
Glomerular lgAnllgAv. thin basement membrane disease.AIpon syndrome
Warfarinrelated nephropathy. Loin pain hematuria syndrome.TMA
Any other glomerular diseases including DN (41%) inwmun Chi Mia
zueaiownisl and MCD (29%) lqAs~ z00u;44s1
Nonglomerular Imerstidal nephritis, papillary necrosis, pyelonephritis. BKV infection
renal Cystic diseases (PKD. acquired cystic kidney disease). Benign mass
Malignancy (RCC. lymphoma. metastatic cancer)
Hypercalciuria. hyperuricosuria
Nonrenal urinary Nephro/uroIid1iasis. trauma (catheterization. instrumentation)
mc: Prostadtis, BPH. endometriosis. malignancy (TCC. SCC. prostate)
Cystitis (infection. chemical. et. CYCassociated). urethritis
Vascular Renal artery thromboembolism. renal vein thrombosis. renal AVM

History
Relevant History for Hematuria Evaluation
Histor y
AKI
CKD
Blood clot
Recent upper respiratory infection
Sensorineural hearing loss. retinopathy.
Ienticonus
Heavy exercise
Recent renal procedure or injury
Unilateral flank pain
Irritative voiding symptoms (frequency.
urgency. dysuria). suprapubic pain
Increased sexual activity,perineal pain.
dysuria, terminal hematuria
Cyclic hematuria aw menstruation
Blunt trauma a/w lower rib fractures
Excessive anticoagulation
Travel/residence in Africa. the Middle East
Sickle cell disease
Sickle cell trait
Potential Causes
RPGN. inr.ratubular RBC casts (eg. Igor)
Acquired cystic kidney disease
Nonglomerular origin
Posunlectious GN. IgA nephropathy
Alport syndrome
Exerciseinduced hematurialhemolysis
Renal aneriovenous malformation (AVM)
Stone. renal infarction. pyelonephritis
Bladder cancer. cystins
Prosutitis
Endometriosis of urinary tract
Traumatic renal injunes
Anticoagulantrelated nephropathy
Schistosoma hematobium <ystit.is
Renal infarction. papillary necrosis
Renal medulla carcinoma

Ancirhromborics e hemacuriarelared complications. bladder ca dx UAMA 2017;31e11160);

should continue hemaruria wlu for underlying causes lAM IM 1994:I54:649)

Gross Hematurla Timing Pattern and Potential Sites

Timing Potential Site of Bleeding
As the beginning Urethra
Ac the end Prosraze gland or the :rigor al area of the bladder
Throughout Bladder. ureter or kidn
Workup
Urine dipstick detects peroxidase activity of Hb; myoglobin has pseudoperoxidase
activity; ascorbic acid can induce false e
Urine sediment: 23 RBC/HPF; RBC casts.dysmorphic RBC glomerular: supernatant
is clear in hematuria; extreme pH (<5 or >8) can cause RBC lysine
Proteinuria >0,5 g/d glomerular. hematuria doesnt cause significant proteinuria
If >10 RBCIHPF + 2 old proteinuria. 93% glomerular. 83% GN (NDT 1018;33<1197)
Urine albumin/protein >0.59. wl urine protein 25 -» glomerular origin lqxn 2008;$22351
Urocrit (hematocrit test of urine) >1% urologic
Urine culture: if . reevaluate 6 wk after treatment
Renal UIS: blood clot can cause hydronephrosis: Doppler study detects AVM
Stone protocol (low radiation) CT wlo contrast only if stone is likely cause
CT orography and cystoscopy if risk factor of urinary malignancy w/o obvious other
causes 4/ Ural Z012;108:24731. Reevaluate after resolution of other causes
Risk Factors of Urinary Tract Malignancy u u»uz012;1eez47J; Ann IM 2o1s;\u1.ea,
Male. >50 lo. past or current smoking, analgesic abuse
Exposure to benzenes or aromatic amines. alkylazing agent, arisrolochic add
Gross hemawria (even if selfIimized). urologic disorder or disease
Irritative voiding symptoms (dysuria. urgency. and frequency)
Pelvic ir dar i n oh . nic UTI. chronic indwelling Foreign body

Cyswscopy: identify bleeding source and ureter laterality: eg. unilateral ureter
bleeding excludes glomerular origin
CT orography CT wlo contrast (stone. calcification. unenhanced baseline): contrast
renal parenchymal phase (enhancing renal mass):excretory phase (collecting system
evaluation)
Cytology very low sensitivity: not recommended for initial workup iA» AM 2016:164:458)
24hour urine study. detect hypercalciuria. hyperuricosuria
Possible Causes of AKI in Hematuria
Gross and glomerular: intratubular RBC cast and ATN, common in IgAN
Microscopic and glomerular: crescentic GN.vascular lesion (vasculitis.TMA)
Gross and nonglomerular: blood clot causing urinary tract obstruction
T r eatment
Glomerular hematuria: consider ACEi or ARB. kidney biopsy
Can serve as marker of activity predicting future relapse (c;As~2018;13:251)
Nonglomerular Origin gross hematuria: generous fluid intake to prevent blood clot
obstruction of the ureter or bladder; bladder irrigation if refractory
If urologic workup is negative, /annual urinalysis.After 2 negative annual urinalyses.
no further urinalyses are necessary U ml 2012;1881247:i1

EXERCISEINDUCED HEMAT URIA

Direct uuuma to :he kidneys +I- bladder in contact sports: renal ischemia dl: T blood
flow to muscles and nutcracker syndrome in noncontact sports
Gross or microscopic hemaruria after strenuous exercise: resolves wu 1 wk w/ rest
Tx: observation, if persists after 1 wk of rest rlo other causes
a Exerciseinduced hemolysis, aka march hemoglobinuria or runners hemolysis:
presents wl intravascular hemolysis. hemoglobinuria (dipstick sediment
Hemosiderinuria (Prussian blue 8 tubular cells), urine iron loss IDA

NUTCRACKER SYNDROME
Left renal vein (LRV) entrapment between SMA and aorta -» LRV HTN rupture of
thin vein into collecting system -» hemaruriaz can be complicated by left RVT
Gross or microscopic hematuria +I- left flank pain in children and Asians
Dx: Doppler UIS, MRA of LRV
Tx: stent: transposition of the SMA or LRV. autotransplantation of left kidney
 LOIN PAIN HEHATURIA SYNDROHE
Glomerular hypertension or GBM instability causing capillary rupture into renal wbules
and tubular obstruction IA/xo zuos;414wl
Recurrent uni or bilateral flank pain. microscopic or gross. w/ nl renal function
Urine sediment dysmorphic RBCs. Kidney bx: RBCs or RBC casts in the tubules
Tax:ACEi/ARB:analgesics, celiac plexus block. kidney autotransplantation. renal dener
Y 3IiOh (n/xo 2017:69:15$). Unilateral nephrectomy not recommended dl: frequent relapses I
in the contralateral kidney

RENAL ARTeRlovEnous MAU=ORt4ATION (AVM)

A communication between :he intrarenal artery and vein
Usually congenital.Acquired forms.calIed AVE caused by trauma or kidney bx (4_18%)
Hematuria. renal colic. hypertension (T renin secretion from hypo perfusion distil to
the AVM)..' renal function decline. CHF
Dx: doppler study, CT angiography. MR angiography.and digital subtraction angiography
Tx: observation. symbolization. total or partial nephrectomy

POLYURIA
UOP >3 Ud; commonly w/ nocturia (inability (O concentrate the urine overnight)
A patient with normal cognition and normal Mint reflex will try to compensate for
polyuria and usually keep serum Na and osmolality within the normal range

Etlologles of Polyuria
Osmotic diuresis Glycosuria. sodium diuresis
Urea diuresis: improving AKI, high pmt diet. tissue catabolism,
parenteral nutrition
1° polydipsia High free water intake do psychiatric illness. hypodialamk lesions
(thirst center)
CDI: defect in ADH idiopathic. trauma. pituitary surgery, ischemk. familial
secretion
NDI: renal resistance Hereditary: mutations d AVPR2 (Xlinked). aquaporin2 (AD or AR)
to ADH Hypeiicalcemia. hypokalemia
Lithium (chronic). cidofovir. loscarnet, vasopressin antagonists.
ifosfamide. demeclocydine
Gestational DI Release of vasopressinase from the placenta during pregnancy
Others Sickle cell diseaseltnit. Sj6grens. bilateral obstructive unopathy.
Bart¢ers. cystinosis
Workup
Na >145 + low umm (<P°,,,,) diabetes insipidus (DI)
Water restriction yes: (WRT) is not necessary and desmopressin challenge an be
done to differentiate between central DI (CDI) and nephrogenic DI (NDI).
WRT differentiates between the different ecologies:
Step 1: restrict water intake and measure UOP and Um Q1h; [Na] and Pm Q2h
Step 2: stop WRT and proceetl to step 3 when U.,,... >600; Um sable for 3 hr: Na
>145 or Pm >300
Step 3: desmopressin challenge: measure Um and UOP every 30 min following des
mopressin 10 mcg IN or 4 mcg SC or IV
J Plasma and urine ADH levels if the response to the WRT is noncondusive
 Polyuria >3 Ud

UM <250 up, >300

Water diuresis Osmotic diuresis/

solute diuresis

'U polydipsia
Up, < Pow

Desmopressln challenge
10 mcg INo r4 m cg SC o rlV

r
TU¢,,\ by TUm by up
No TU,,,.., Tum by >100%
15- 50%, >300 to 45%, <300
Complete NDI Complete CDI
Partial CDI panlal NDI

Copepdn (Coerminal segment of vasopressin pmhermone) level after 3% MCI 250 mL

may differentiate 1 polydipsia from CDI IN£/M z01a4379=41s;.
CopeptinIPn, 20.02 pro/L: 1 polydipsia: <0.02 pmol/L: partial CDI
Basal copeptin <2.6 mol/L complete CDI
1 polydipsia can induce partial NDI (decrease urea accumulation in the medullary
interstilium - defect of the corticomedullary gradient)

CENTRAL DIAae1£s Ir4slru>us (CDI)

Pathogenesis
release of antidiuretic hormone (ADH) (or AVP) from the hypothalamus
idiopathic or autoimmune (30-50%)
Hypothalarnic lesions: tumor. inUltradve disease (eg. Langerhans cell histiocytosis.
sarcoidosis. GPA. and autoimmune lymphocytic hypophysitis). trauma. surgery
Autoimmune disease: IgG4related disease. GPA
 Familla\l:AR or AD mutations In ADH gene
Wblfram syndrome (DlDMOAD):AR muiadcn of WFS 1 encoding wolframln. endaplasmk
reticulum piwatdn. Planillesadons: QI. . gpiic atrophy and deafness: hydronephiosis
Congenital liypopituiurism. septaoptic dysplasia
PostSVT:uansient (Tuft atrhl and systemic pressure -» 1 secretion ofADH)
Clinical Manifestations
Polyuria. polydipsia. nocturia. predilection for iced water: abrupt onset
Na high normal (>142). no to mild increase of Um with WRT. no change to mild
response to desmopressin (U.,... <300)
Low bone mineral density (is not corrected by desmopressin therapy)
During pregnancy. asymptomatic patients with partial CDI start m have symptoms due
to vasopressinases released from the placenta
Surgical or traumatic damage of the hypothalamus has triphasic response: initial poly
uric phase (1-5 d 1 ADH release). antidiuretic phase (6-11 d: release ofADH by
degenerating posterior pituitary) followed by permanent CDI or resolution (most
cases are not permanent)
Treatment
Desmopressin: 0.1 or 0.2mg tablet or 5-10 mcg of the nasal spray preferably at
bedtime (to decrease the nocturia), cilrane up depending on the noczuria. Na should
be measured within 24-48 hours to check for hyponarremia (patient should be edu
cared no decrease free water nuke)
The response to the IN desmopressin is more predictable than the PO
Thiazide diuretics and NMIDs (used mainly in NDI)
Other drugs (less effective, more toxic): chlorpropamide and carbamazepine
(enhances renal response toADH) and dofibrate (T ADH release)
A lowsolute (mosdy lowsodium, lowprotein) diet: for pacienzs with partial and mild DI

NEPHROaNNIC DIAaeTss lnslplous (NDI)

Pathogenesis
Hereditary NDI:V2 receptor (AVPR2) (Xlinked) and aquaporin2 gene (AD.AR)
Chronic lidiium toxicity: dysfunction of the aquaporin2 in the principal cells
Hypercalcemia and hypokalemiaz interference with the countercurrent mechanism:
iaquaporin2 expression
Mild NDI (elderly.AKI, CKD): interference with die countercurrent mechanism
Pos obstructive AKI,sickle cell disease or trait. PCKD. renal amyloidosis, Siogrens
Drugs: vasopressin antagonists, cidofovir, foscarnet. amphoterkin B. demedocycline.
ifosfamide, olloxacin, orlistan and didanosine
Hereditary tubular syndrome Basters. cystinosis. familial hypomagnesemia with
hypercalciuria and nephrocalcinosis
Clinical Manifestations
Polyuria. polydipsia. nocturia; gradual onset
Na >142. no or mild Um with WR12 no or mild response to desmopressin (Um
<300)
Tre a tme n t
A lowsolute (mostly lowsodium <1.3 old. lowprotein 51 glug/d) die: is sufficient in
mos: patients with intact thirst response: medical therapy is only for patient intolew
ant to polyuria/polydipsia
Thiazides diuretics: (1) volume depletion » proximal sodium reabsorption -» 1 UOFW
(2) Inhibition of the urine concentration in the DCT
Amiloride: added thiazide (corrects thiazideinduced potassium wasting) or in lithium
induced NDI (blocks lithium entry through ENaC in the collecting tubule cells
unSAIDs: inhibition of renal PG synthesis. mainly for Bartterlike syndromes
Desmopressin can help in some cases of partial NDI

GESTATIONAL DIAISTES INSIPIDUS U cyan '5w\°!<°l Coll 1010;32:215)

Folyuria can be due to release of vasopressinase from :he placenta
Same lab pattern as central DI
Polyuria response to desmopressin (DDAVP) since in is not inactivated by the vaso
presslnase (arginine vasopressin is degraded by vasopressinase)
Transient condition; treatment is by Increasing access to free water +I- desmopuessin
 URINARY SYMPTOMS
Causes and Assoclamed Conditions of Urine Change
Red. smoky brown. Glomerular hematuria
colacolor If no RBC on sediment.: myoglobinuria. hemoglobinuria
Bright red. pink Nonglomerular hemaruria
Beers. blackberries. rhubarb.food colorir\g.fava beans
Phenazopyridine (iridium). phenytoin. phenolphthalein. rilampin.
doxorubicin. deferoxamine, chloroquine, ibuprofen. methyldopa
Brown Levodopa. merronidazole, nitrofunnwin. iron sorbitol,
chloroquine. rnedwyldopa
Alkapconurix :urns dark brown if left standing/alkalinizacion
Orange Bilirubin from hepatocellular or obstructive jaundice
Green or blue Methylene blue. amitriptyline, indomelhacin, zriamxerene
Propolol (Lama 2u09;m:146zI; UTI of pseudomonas
Pink or reddish orange Uric acid crystal lawn Cur m¢4201139981 al 201zs 1:11s1)
Bright yellow Riboflavin (vit BE)
Porplryria (t porphohilinageu. poiphynn5). UTI with E ii. Kklzdela
Purple
larvruw/¢qz0ollu=n9)
Black Disseminated melanoma l~=lm z0193siz11ul. alkapronuria
(homagendsic acid)
Turbid, milky WBCs. bmeria, fungi; chyluria up 2006:1u 1s1a;
Crystals: uric acid. Ca pin phosphates and indinavir
Foa Hea alburninuria in NS;yellow foam from bilirubin

R e o u c s n U R I N E O U T PU T

Determinants of Urine Output (UOP)

Renal function (glomerular filtration): UOP can be preserved in advanced kidney
injury as in nonoliguric AKI or stagey CKD
Tubular reabsorption: directed by ADHmediated water reabsorpdon
. UW.; 60-1.200 mOsmoI/kg: correlate with ADH activity
Urine solute (mOsmol/d)allected by diet and protein ataholisnm600-900 wide usual did
I( Um is fixed at 150 (et. nephrogenic DI), solute intake should be decreased
Solute load 600: UOP 600/150 : 4 L
Solule load 900: UOP 900/1 SO = 6 l.: may lose more water. increasing [Na]
If Ueun is Fixed at 300 (eg.SlADH). solute intake should be increased
Solute load 600: UOP 600/300 = 2 L: may retain water. decreasing [Na]
Solute load 900: UOP 900/300 = 3 L

O l i guri a
Used to define and stage AKI along with creatinine elevation
Definitions of Oliguria and UOP Criteria i n A K l

Conventional <400 or 500 cold

If solute load Is 600 mOsmolId and kidney can maximally
concentrate urine (1,200 mOsmoIIkg). UOP will be 500 mL
RIFLE (OlU:ulCanlD04£rR204) Risk: <0.5 mUkglhr for 6 hr
Injury <0.5 nUke/hr for 212 hr
Failure: <0.3 nUke/hr for 224 hr or anuria for 212 hr

AKIN (on Care 7.007:11:R]1. Sa ge 1 <0 .5 mUk glhr for 6 -1 2 hr

armco AKI 20121 Sage 2 <0.5 mUkyhr for 212 hr
Stage 3: <0.3 mUkgfhr for 224 hr or anuria for 212 hr

• Consecutive oliguria for a shorter (3-5 hr) period may predkt AKI risk (Cl*9* 2014%1199
Oliguria is alw T mortality (Kr 1011:80:760). T dialysis requirement., >90 d dialysis and
hospital mortality dt nonoliguric AKI lN=p'\~°~ an Flue 101(x11s:¢s9)
Diuretic use for conversion from oliguria to nonoliguric AKI is alw worse outcome
(}AMA ioazzss.1 s4n: consider only in volume overload not requiring RRT odlerwise
In KRT requiring AKI. urine output as initial cessation for CRRT without diuretics is
the best predictor of renal recovery (Cm Car: med 2009;37;1576)
Can J CrCl when UOP >30 mUhr (77.0 mud) (NEjM 1008335%7)
 Anuria
UOP <100 mud; severe AKI. eg. shock RPGN. renal infarct. bilateral urfnary obstruction

URINARY RETENTIO N
Definition: inability to voluntarily pass urine
Normal postvoid residual volume is <50 mL in <65 y0.<100 mL in 265 yo
24% of hospitalized 270 yo patients have urinary netendon >150 mL ww//m4201s;12s¢17l
Acute: predominantly in elderly men alw prostatic enlargement
Chronic: postvoid residual > 300 mL chat persisted for >6 mo and documented on 2
or more separate occasions <AUA1 Ural 2017;I98:153)
Causes
Bladder outlet obstruction BPH (mlc in *), constipation. malignancy (prostate, blad
der), urethral stricture. urolithiasis. phimosis. paraphimosis. blood dots (nonglomeru
lar hematuria, eg. kidney biopsy). urethral diverticulum
9 ; organ prolapse (eg. cystocele or rectocele).Gbroids obstructing the urethra
Underactive bladder:autonomic dysfunction (DM. Parkinson disease). spinal cord
injury: stroke. medications with antimuscarinic property

Diagnosis and Workup

Bladder scan: postyoid >300 cc diagnostic: 150-300 cc possible retention
Bladder and renal U/S to rlo hydronephrosis: EMR urinalysis. urine culture
CKD and hydnonephrosis regarded as high risk -\ furdier work. eg. umdynamic sandy
:Aw Uui 1017;198:1S3)
T reat m en t an d Mo n it o rin g
Urinary catheterization: sometimes also diagnostic; indwelling or intermittent
Bladder decompression may cause transient hypotension
Monitor postobstructive diuresis and hypernatremia
Treat UTI: common complication

NOCTURIA
Nocturia: the need to wake at night 21 for voiding; 2x2/night a/w impaired quality of
life law um:101ms7:4ea)
Nocturnal polyuria: nocturnal UOP >33% of daily UOP in >65 yo (>20% in younger
adults) of daily UOP wlo global polyuria (>3 Ud)
Causes and Pathogenesis
Global polyuria (>3 Ud): osmotic (DM. salt) or water (DI) diuresis. primary polydipsia
Nocturnal polyuria:
Volume overload (CKD. NS. liver cirrhosis.CHF): supine position -» mobilization of
fluid from the LE to trunk _» fluid shift into vascular space T namurel.ic peptide
Aging: blunted diurnal variation of vasopressin: high at night in normal
 Pelvic floor dysfunction: position change may l pelvic floor musculature support
Autonomic dysfunction (et. Parkinson disease): L sympathetic activity
Evening dose diuretics: excessive drinking in the evening
Low bladder capacity: postvoid residual (BPH).bladder irritation (cystitis).bladder
wall fibrosis/surgerylcancer/stone/detrusor overactivity
Sleep apnea (Mom M1242016;s5901): wake up dlt sleep disorder x T natriuretic peptide
Clinical Manifestations
law QoLlal.fra»:u.ue,dea:h u LH¥)\(k1B44I413:lUd1011;1$:S71),dq>l8dON ¢uul=g 2n07:s%91)

Wo rk u p
Frequency volume chart: rlo polyuria
STOPBANG for sleep apnea (sup m¢4 an 2017:36:57)
T reat m en t
Avoid fluid intake (esp. caffeine and alcohol). diuretics in the evening
Furosemide 6 hr before bedtime up url 1m;a1:z1s>
Desmopressin: l hocturia (Coduane umm Syn Rn 1017710CD0120§9)
CPAP in sleep apnea: 1 nocturia. nocturnal UOP (u»=lwzois;as;zaJl

Lower UMNARY Tum SYMPTOMS (LUTS) U uwazonmsmsssl

lopes of LUTS (nays 1012:u1:24an
Obstructive Symptoms Storage Symptoms
Symptoms Incomplete emptying. weak Frequency. nocturia, bladder pain
stream. hesitancy delay in Overactive bladder: urgency 3 urge
initiation. intermiuency. incontinence
involuntary interruption.
straining, terminal dribbling
Causes All causes of bladder outlet BPH. prostatius, epididymitis (6)
obstruction including: Bladder: cystirJs. cancer
BPH, prostate cancer (6 ) Low bladder capacity, ureterovesical
Urethral stricture reflux. urethral and meatal stricture
Spinal cord injury
Symptomatic a1 antagonist (osier) Antimuscarinic: oxybutynin,
treatments doxaz. \:eraz. alfuz*. tolterodine. darilenacin. solifenacin.
tzmsul*. siled fesoterodine. uospium
sle: (orthosutic) hypoten sign; sle: urinarylgastric retention. T HR. dry
a1a selective drugs (*) mouth, blurred vision, dementia and
have less I, BP brain atrophy UAMA nwiul m1473nil

Dysuria
9 >> d;common causes include cyszitis.ured1rids,vaginicis,and prostatids
Common organisms causing urethritis (9): N. gonorrhoeoe. Chlamydia, Mycoplasma
geni tol i um, Tr i char nonos vagi nal i s, HSV
Irrizative symptoms (urgency. urge incontinence,frequency. dysuria. nocturia) + hema
rurix risk factors of bladder cancer; /cystoscopy (ACP Am IM 2016116414488
lnxerscizial cystitis/bladder pain syndrome: bladder pain. pressure. discomfort alw
LUTS of >6 wk. wlo infection or other idemiNable causes (n¢unvna ulv4y»» 1009;zs¢z741

Urinary Incontinence vcr wan Ami :m 2014;1i1:429)

Stress Incontinence Urge Incontinence

Symptom Small amount urine loss wl exertion,
sneezing, coughing or laughing
Daytimelstanding position only
Causes Weakened support structures of the uredlra
Age. obesity. pregnancy. repetitive pelvic
floor stress
Vaginal delivery up 7.01B;l},0;243gl
Radical prosxatecto > TURP
Large amount urine loss wlo
prediction
Day and night urgency and
frequency
Bladder irritation: infection.
inflammation, stone. cancer
Stroke. spinal cord injury
 Workup Urine culture
Cystoscopy. urodynamlc swdy
Tneatrnent Pelvic floor muscle training Bladder training
Weight losslbariarric surgery if overweight Anrimuscarlnk
up IM Z0l5:\7S:1]78) Mirabegron: B3 agonist
Midurerhral sling were2013;36%1124) sle: HTN
Overflow incontinence: incompiere emptying dl: underactive bladder 1 outlet
obstruction

FLUID IMBALANCE
Fluid Intake
Water and food Intake 25-35 mUkgld -» :k climate. habits, level of physical activity
CHO oxidation 200300 mud
Body Fluid Compartment:

Estimation by Percentage of Ideal Body Weight (law)

Young Elderly Male,
Body Fluid Compartment Male Young Female Elderly Female
Total body water (1BW) 60 S0 45
Intracellular fluid (ICF): 2/3 ofT BW 40 33 30
Extracellular fluid (ECF):1l3 ofT BW 20 16.7 15
Interstitial fluid: 3/4 of ECF 15 12.5 11.3
Intravascular fluid: 1/4 of ECF 5 4,2 3.8

Transcellular (1-2 L): synovial. peritoneal. pericardial, inrraoculan and CSF

Measurement of Body Fluid Volumes

Volume Indicators
TBW Deuterium, tritium, antipyrine
Extracellular "Na, 115liodwalamaze. nhiosulfare. insulin
Intracellular Calculate = TBW - extracellular volume
Plasma "Slalbumin. Evans blue dye
Blood volume "Crlabeled RBCs: calculate = plasma volumel(1lkt)
Imersririal fluid Cokulme = extracellular - Plasma volume

Fluid Loss
Insensible: respiratory tract. skin 500-700 mud -o T extensive burns. cold weather:
fever. tachypnea. open wounds. T metabolism (>10fold)
Sweat hypotonic. highly variable -100 mud _.1 exercise. ho: climate (1-2 Uhr)
Feces/GI: ~1S0 mud; T diarrhea. NGT drainage fistula
Urine: main regulator. multiple mechanisms (0.5-20 Ud): also regulates Na, CI. K
0.5 L to excrete 600 mOsm with maximal ADH activity (1,200 mOsmIL)
Sodium and Water Imbalance
Manifestation of Sal! .nd Water Imbalance
Salt Water
Dehcir Volume depletion Dehydration/Hypernalremia
Excess Volume overload He natremia

DEHYDRATION
Effective osmoles cannot cross cell membranes wlo transporter activity
eg, Na. K. glcuose. and mannitol
Ineffective osmoles: freely cross cell membranes. do not affect transmembrane water
flow, eg. urea and alcohol
Osmolality: :he mllllosmoles of solutes per 1 kg of water In is the same through
ICF and ECF since water (via aquaporlns) can freely traverse plasma membrane
Calculated P..,, = 2 x [Na] + [glucose (mg/dL)]/18 + [BUN (mgldL)]I2.B
 Tonicity: :he ratio of plasma effective osmoles (solutes that do not cross membrane
barriers) to plasma water. It dictates :he movement of water across a membrane.
Approximately 2 x [Na] + [glucose (mg/dL)]l1B
Dehydration: a loss ofT BW resulting in hypertonicityn s volume depletion
Hypernatremia: [Na] >145, mainly from water deficit. rarely (rom mul body Na
or K increase with relative TBW deficit
High urea is hyperosmolar but not hypenonit; hypernatremia is hyperosmolar and
hypertonic
Pa t h o p h ysio lo g y
Changes in plasma tonicity >280-289 mOsmlkg are sensed in hypothalamus
-» :him sensation/water intake and ADH go up in a linear manner
-o ADH acts on the V2 receptor on the outer and inner medullary collecting duct
resulting in luminal AQP channel placement in a cAMPdependent manner
-+ water absorption -r tonicity -» hypothalamic stimulus is turned off
Water deficit results from decreased thirst/water intake +I- decreased renal concen
trating capacity (Dl).although the former is the more common mechanism
Increased plasma osmolality-» water shift from the intracellular to the extracellular
space -» cellular shrinkage
In hypematremia/hypenonicity brain cells generate osmolytes to increase Intracellular
osmolality and counter the increase in extracellular osmolality. II hypernatremia
correction Is rapid, iatrogenic cerebral edema can occur due to the delayed
decrease in intracellular osmolality in brain cells.
C lin ica l M a n if e st a t io n s
Thirst. oliguria. anorexia. NN generalized weakness, fatigue, lethargy irritability, confusion
Severity of neurologic symptoms related to rate of rise of [Na] than absolute value
Signs: dry mucous membranemlongiuidinal tongue furrows,seizures. coma.lCH (in infants)
Hypernatremia. T Um. T Urine specific gravity, relative polycythemia
Workup
Determine Me parlen:s overall sodium balance (volume status)
Salt and Water Balance and Mechanisms in Hypematnemia
Volume Status Salt Water Mechanism
Hypovolemic + l Loss of hypotonic fluids
Euvolemic - l Loss of elecrroiyte free water
Hyperwolemic T - Excessive salt intake
Hypovolemic hypematremia (negative sodium balance): loss of hypotonic fluids
Un, >2(k renal loss: diuretics. postATN. postobstructive, osmotic
Un. <2& extrarenal loss: vomiting, diarrhea, enterocutaneous fistula. swearing. burns
Euvolemic hypematremia (normal sodium balance): loss of electrolyte free water
UM <300: renal loss. complete DI
Um 300600: renal loss, partial Dl.ccmpensated diuresis
Um >700800: extrarenal (cutaneous. respiratory) losses. primary hypodipsia. limited
H20 access. post seizures. severe exercise
Causes of Diabetes lnsipidus (DI)
ADHdependent DI ADHindependent DI
Exogenous vasopressin T Uw Exogenous vasopressin does not t Um
CDI: congenital. trauma, neurosurgery. CNS Hereditary NDI: Xlinked recessive,
rumor. inflILrau\re. hypoxia encephalopathy. complete or partial
hemorrhage, CNS infection. aneurysm Acquired NDI: Ca.l K.lithium.
Gestational DI: vasopressinase mediar.ed demeclocydine. amphotericin B. fosamet.
mezhoxyfiurane. vaprans. chronic
imerszizial kidney disease dlt medullary
cystic disease. sickle cell disuse. amyldd.
Sjé s.malnuzriUon
Hypernatremia Not Caused by Total Body Water Deficit
Hypervolemic (positive sodium balance): least common;often iatrogenic after receiv
ing hypertonic fluids. salt poisoning, rarely due co mineralocorticoid excess
Intracellular water shift: electroshockinduced seizures and severe exercise, transient
Treatment
Identify and :rear underlying cause and replete water defick
CDI: desmopressin
 NDI:
Thiazide: (1) mild volume depletion -» * reabsorption <9 l tubular fluid and urine
volume: (2) NCCindependent aquaporin 2 expression (Air Rend 2014;306;F$251
Low Na and protein diets: decreased urine output and water loss
NSAID: PGE; L AQP2 expression: desmopressin if partial
Positive sodium balance: diureticsldialysisa loop diuretics T electrolyte free water loss
as well as natriuresis and thus requires ongoing free water replacement

VOLUME DEPLETION
Definitions
Volume depletion: a deficit in ECF volume, caused by loss or sequestration of
sodium containing fluids
Effective arterial blood volume: required to maintain effective tissue perfusion
In nonedematous states. it is proportion to ECF volume
In edematous states, ECF and effective arterial blood volume are not proportionate
Pathophysiology
Control Mechanisms of Extracellular Fluid
Component Regulation Elle n
Response to ECF volume Deficit
R ¢ninAngiotensin T renin release as JG apparatus Sodium reabsorpUon
Aldoster one System granular cells by: Vasoconstriction
( RAAS) 1. perfusion pressure at affer
ent arteriole by baroreceptor
2.. NaCl delivery to macula
denser in the TALH
3. Badrenefgc receptor acdvradon
SNS Activated by 1 perfusion . HR. BP
pressure/stretch at carotid RAAS activation
sinus and aorta
AD H Nonosmotic release of ADH Water retention
All T release of ADH Vasopressor effect
Response to ECF volume Excess
Natr iur etic Peptides Released by stretch at atria Sodium excretion
and LV l renin release

Etiologies
Glzvomiting. diarrhea.bleeding. external drainage (while on avg only 150 cold. 3-6 Ud
are generated by GI tract. normally all resorbed. if GI pathology lose ability to resorb
and become volume depleted)
Renal: diuretics, osmotic diuresis. salt wasting nephropathies. hypoaldosteronism
In healthy kidney. 120-180 Uday Filtered across glomemlus with >98% resorbed. if
there is even a mild tubulopathy with even a slight L in resorptive capacity, dis will
result in volume depletion (seen in chronic interstitial diseases)
Skin: 1-2 Uhr can octur in hot/dry climate; bum
Hemorrhage: sequestration into a third space: GI catastrophes (pancreatitis, obstruction.
peritonitis), crush 'niuries
C lin ica l M a n if e st a t io n s
Weight loss. orthostatic dininess.oliguria. muscle cramps.agitation. thirst.confusion
Ordiosiztic hypotension. T HR: progress to supine hypotension THR
Diminished skin turgor (less reliable in the elderly), delayed capillary refill
Organ ischemia: nonocclusive mesenteric ischemia
. Hypovolemic shock: cold. clammy extremities, cyanosis. pulsus paradoxus (. SBP 210
during inspiration: DDx: cardiac tamponade. constrictive pericarditis)
Laboratory Flndlngs ofVolume Depletion
False (-): low muscle mass and liver cirrhosis
T urea reabsorption in proximal tubule
False (+): steroid. GIB, tetracycline
LN: l ADH activity: masked by accompanied dehydration
False (): SlADH. HE cirrhosis. NS. CKD. 1 polydipsia
T Hb. albumin Hemoconcentration, masked by accompanied anemia.
hypoalbuminemia
 Na reabsorption in renal tubules
False (-):
Salt wasting from diuretics or underlying renal disease
High rare of water reabsorpcion
Metabolic alkalosis from vomiting HCO; is excreted and pulls
Na with it. /urinary chloride
False (»): HE cirrhosis. NS
Um
T ADH: False (): dehydration

Diagnosis
Fluid responsiveness: improvement of stroke volume and cardiac index by fluid is
diagnostic of volume depletion: prediction prior to fluid administration is challenging
History taking Including weight change
Physical examination: insensitive UAMA 1999:181:1011: I an Care z01J11a1s37,¢1 l
St a t ic Asse ssm e n t s
CVP: did not predict fluid responsiveness (Guest 1oca;n4:1 n: cm Care m¢4 2013;41¢17741
PACIPCWPguided therapy in CHF (sscApz;A~u\ z00s;194=1 szs),ARDS :MMA zoo1:2vo.z71al.
and acute lung injury (n£/M 10D6;3$4:22131 didnt improve outcome
Dynamic Assessments: may be more indicative of volume responsiveness and
potentially improve clinical outcome (on Can M¢42017:4s:1$3a>
Pulse pressure variation (PPV) Incan }00&161:134: Cm Cafe med 2009:37:1642)
Stroke volume variation (SW) (~!A»v==s<1- 2008;101:7612 A»»¢=uiA»»:¢. 1009;10B;$13)
Flassivelegraisinglsetnileornbentposidonwidi4$elevalionofupperpartdhody-»lows
upper body and elevate legat45 xi mirtbrings 300-500cctod\ehar!:TCOand SVV
and PPV predicts fluid responsiveness (Armin-ia*ca»¢z011;1;1; Oucnnenua zolz 101zs1a4au¢
IVC respiratory variation (lntenwe Can Med 2004;30:I8341 Intensive Can Med 2004;l0:I740)
Management
Rapid 1-2 L of isotonic fluid to restore tissue perfusion if there is evidence of shock
Nor possible to precisely predict :he total fluid deficit for a given patient. clinical signs
such as BR MAR UOR MS. peripheral perfusion can guide adequacy of resuscitation

VOLUME OVERLOAD
Background and Clinical implication
Volume overload: sodium excess and expanded ECF volume
a/w longer ICU stay and mortality (on: Care z013:17:msl
In septic shock. alw mortality (vAssT Go Core Med 101 iznssl
In decompensated HE hemoconcentradon (absence of volume overload. measured
by T protein, albumin. Hot by diuresis) is alw 1 eGFR, T survival (aimlamn zoimmz6s)
In acute lung injury, conservative management targeting CVP <4, PCWP <8 was a/w
improved oxygenation index increasing ventilatorfree and ICU free days c/t liberal
management targeting CVP 1o-14 or PCWP 14-18 iFAcn Ne/M z00s;3s4:zss4i.
In AKI a/w T mortality x2,07 lx/ zc0s76:422). 1 renal recovery up 200976¢417s nor z01z.z7.9stn
In CKD a/w rapid progression who 2014263¢681
Volume overload at the RRT initiation is aw morality ion Cae 2012,16=n1971
Hemodilution may lead to underestimation of the severity ofAKl it c0~201m14na2)
Pathophysiology
Appropriate response: stretch at cardiac receptors (atria and ventricle) -» atria
release ANR ventricles release BNP -» natriuriesis.
Heart failure: cardiac output -» i perfusion pressure 4 low effective arterial blood
volume SNS and RAAS activation
Cirrhosis: vasodilatation -» 1 perfusion pressure - low effective arterial blood
volume -» T SNS and RAAS activation
Nephrotlc syndrome: . oncotic pressure - . tissue perfusion .. low effective ans
rial blood volume SNS and RAAS activation (underfill); 1: Na retention (overfill)
Chronic kidney disease: blunted response to rapid sodium intake
Clinical Manifestations
weight. t BRJVD, orthopnea. paroxysmal nocturnal dyspnea. nocturia
Peripheral edema: pretibial and ankle in ambulatoryc sacral in bedridden patients:
periorbital edema in nephrotic syndrome
 Ma ni fe s ta ti ons of Fl ui d O v e rl oa d i n O rga ns
Lungs Pulmonary edema (mies). pleural effusion
CVS filling pressure. 1 cardiac output. conduction disturbances. vasodilation
GI Ascixes. gut edema. malabsorption
Liver Congesti ve hepatopathy
Skin, soft tissue Wound i nfecti on. poor wound heal i ng, pr essur e ulcer
CNS Cer ebr al edema. del i r i um
Ki dn I nter sti ti al edema, T r enal venous congesti on -» . r enal functi on

Hy pona ue mla z 1 tis s ue pe rfus ion in HE c irrhos is -» tADH

Hypcalbuminemix T ulivary loss i\ the NS. L synthesis in cirrhosis. ciludaual;diludonal anemia
T BNR NTproBNP: cleared by kidney; less reliable in CKD
TP CWP >2 2 m m Hg
Thoracic ultrasound: B lines (aka comerrail images) (am: 1005;1z7: 1s90)

Management
Monitor volume status: /daily fluid balance and weight
Address underlying cause and treat appropriately
HF: neurhormonal blockade
Cirrhosis: antivirals/immunosuppression depending of etiology
NS: immunosuppression/RAAS inhibition
Low Sal: diet: restrict dietary Na intake Lo <2 g (87 mEq) per day
Avoid drugs that foster sodium retention as able such as unSAIDs. nonspecific vasodi
Iators. highdose l¥blockers or central uagonists
Diuretics based on underlying conditions
Adjust dose to achieve threshold dose: if weight loss is not achieved, can I24hr
urine urinary Na excretion OR 1-2 hr pos: loop diuretic FEn,
If U's >100 mEqld or FEm >2%ceflective diuledcs:if not losing weighuesuict sak htake
If Un. <100 mEqld or FEn, <2%: ineffective diuretics; t diuretic dose
In severe hypoalbuminemia (eg.cirrhosis with ascites or nephrotic syndrome). albumin
assisted diuresis may be used uAs~ 2001;11:1010: swf/ xfanqoarlumpi 2012:23;J71)
In decompensated HE it is essential to have enough BP to ensure tubular delivery of
furosemide (Nt/M 1011:364:7971. lnotropeassisted diuresis can be considered in low
ouqnut and congestive status in severe LV systolic dysfunction
Dialysis initiation

F L u i l :> I r 4 S A L A N C S i n E S R D

Ba c k gr ound
Volume depletion: alw loss of vascular access and residual renal function (cIA5n
2010;$:1255)C hypotensi on. death UAS~ 2015361720
Volume overload: a/w LVH and death lcmmI4u¢n 2009:11n71: ;ASN 2017:2571491)
Postdialysis weigh: >2 kg above and below are alw monalicy lqAs~ 201s=1 aaae)

Dr y We i ght (DW)
Weight do the patient needs to achieve at the end of dialysis with minimal symptoms
or signs of hypovolemia or hypervolemia
Normal blood pressure s/p HD can be used to assess euvolemia.but d is requires
t he pa t i e nt t o no: be on any other antihypertensive which is rare in HD patients
Needs to be reevaluated periodically (O follow flesh weight change
Overestimated DW: may cause pulmonary edema and HTN
Underestimated DW: weakness,cramps, and hypotension

DW Assessment
Clinical evaluation: edema (peripheral. pulmonary); absence does not r/o overload
Bioimpedance applying electrodes to :he skin and esdmacing volume status by measur
ing resistance encountered by an electrical current passed dmmugh :he bodys tissues.
no: FDA approved in the u.s. war zoesauoe. or 1014.B6.489)
Relative Blood (or Plasma) Volume Monitoring
Blood volume estimation with continuous hematocrit (Htt) measurement
Volume overload: continuous transfer of fluid from interstitial to intravascular com
partment during UF -» stable Hot. flat curve
Volume depletion: refill rate from the interstitium to intervascular space lags behind
the UF rate -» 1 Hct,blood volume" drop
More hospiizlization and mortality than conventional care (JASN 2005:16:2162i
No l intradialytic hypotension (qAs~ 1017:11:1831)
Management WM 1014:64:6B5)
The normalization of the ECF volume is a primary goal of dialysis (volume first")
In HD, fluid removal should be gradual: l interdialytic weight gain. treatment duration
24 hr. UF rate <10-13 mUkg/hr; excessive UF during routine HD associated with
morbidity and mortality (Dons K1 100616942221 HEMO Vu 20119912512 Aixo 201e4se:911>
Avoiding intradialytic sodium loading: sodium profiling T morality (qAsn 1019;14:3asi
Dietary counseling: low sodium diet; fluid restriction
Highdose loop diuretics: if urine output >-200 ccld: Linterdialytic weigh: gain, UF
amount. and intradialytic hypotension (ClASN 201%14:95)

HYPOTENSION
Absolute (SBP <90. MAP <65) or relative (drop in SBP >40 from baseline)
Nor synonymous with shock

H YPO T EN SI O N I N D U C ED AKI
Autoregulacion: hypowision, 1 perfusion pressure - PG.mediated afferent arteriole dila
tion.and angiotensin II (All)-mediated efferent arteriole constriction 4 maintain GPR
unSAIDs and RASi impair autoregulatory mechanisms
If perfusion pressure drops below the autoregulatory range. endogenous vasocon
strictors and endothelial cell injury T afferent arteriolar resistance -» 1 glomerular
capillary pressure -» 1 GFR
If autoregulation is impaired.renal perfusion is dependent on MAP (KI 1994;4623181
Systemic arterial vasodilation from distributive shock (eg. sepsis) and liver cirrhosis 1
renal perfusion and GFR +I- systemic hypotension
Persistent renal hypoperfusion leads to tubular cell injury/ATN

SHOCK

Space of :issue hypoxia due to inadequate oxygen delivery or impaired oxygen udliudon
Most commonly occurs when dvere is reduced tissue perfusion in seeing of hypotension
Multiple zypes of shock often coexist
Types of Shock and Physiologic Charuterisdcs (Parameter)
Preload Pump Afterload Tissue
Types: Causes (PCWP) Function (CO) (SVR) Perfusion (5.01)
Hypovolemic: fluid loss, 4 NL or l i NL or 4
hemorrhage
Distr ibutiveNasodilator y: NLorl NL or T 1 t
septic. anaphylactic. neuwcgenk.
adrenal insuflicienqq thyroid
dysfunction. bums. trauma.
pancneaiitis. postoperative
¢=S°PI¢Si=
1 1
Cardiogenlc: MI, CHE T 1

anrhythmimvaive rupture.VSD.
critical valvular stenosis.
dissection. myncarditis
O bstructive: tension fLora NLorl T variable
pneumothorax. pulmonary
embolism, pulmonary
hypertension crisis. cardiac
umpgnadg
Clinical Manifestations
Hypotension. tachycardia. altered mental status. rachypnea. oliguria, cool clammy. or
warmlvasodilated depending on etiology of shock
Exam: mucous membrane, rashes.JVD. murmurs/rubs. lungs crackles/breath sounds/
hyperinflation. tense or soft abdomen. LE edema. cap refill
Workup
Lactate. cardiac enzymes. renal/liver function. CBC and differential. coagulation
parameters.ABG. natriuretic peptides
ECG. CXR.TTE.infectious cultures. bedside ultrasound.additional imaging as needed
No benefit to the routine use of pulmonary artery catheter monitoring for shock or
ARDS QAMA z003;29m271:i; new z00e;zs4=zz 1zi. highrisk surgical patients requiring ICU
stay (NSW 2003;34e:S): no large studies examining use in tardiogenic shock
G ener al T r eatment
Treat underlying etiology of shock while providing resuscitation: fluid. vasopressors.
inotropes based on hemodynamic assessment
Fluid Resuscitation in Septic Shock
30 mUkg IV crystalloid in the first 3 hr (Intensive Care Med 2017;43:304; JAMA z017;3I7;s47)
Balanced crystalloid is particularly beneficial in sepsis (NEJM 1018;378829)
Early goaldirected therapy (EGDT): fluids. vasopnessors. blood transfusions, and inorro
pes with target MAP 265. CVP B-12. central venous Oz sat 270% within the Nm 6 hr
1 hospital mortality from 46,5-30.5% dt usual care jam pmiuai it/m z001:a4s:13w)
However 3 large multicenter RCTs (process nor/l 2014370168J: Amss new 2014:l71:14%;
promise ~flm 101537213011 and :he prospective patientIe~eI metaanalysis of the RCTs
(PRISM new 2017:37eu23> failed to show lower mortality with EGDT (Likely reflects early
recognition of sepsis and early antibiotics/fluids in most patients since EGDT trial)
Can rend lactate clearance (21084/2 hr) instead of central venous Oz UAMA z01 czz0a139)
No morality difference in targeting MAP 65-70 vs 7085 in septic shock: in pre
specified subgroup of patients with chronic HTN. higher MAP group had less renal
dysfunction and less need for RRT than lower MAP group SE PSISMAM NEJM 2014;3702158J1
Transfuse PRBC only when Hgb <7 in adults,unless active Ml or acute hemorrhage
(TRICC num 1999.34<r409: Truss NE]M 20141371:1381)
Albumin: conside if substantial amounts of aysdloids required (inane Care MM 201791309
Avoid fluid overload a/w T mortality (vAssr GU cm Ms. 1011399591
St e r o id s in Se p t ic Sh o ck
Initially showed benefit UAMA Z002;2SS:a611 but not replicated in subsequent trials
(CORTICUS n9/m 100e:Jsa:111: ADRENAL nz/14l 2018:378909)
Hydrocortisone + fludroconisone 1 90 day mortality (APROCGISS NE]M 2018;378:797)
Small benefits in mortality. length of ICU and hospital stay (cmcmmea2018¢4e14111
Avoid routine use: hydrocortisone 200 mg IV per day if hemodynamic stability not
achieved with fluid resuscitation and vasopressors alone (fntenave Can m¢4 2017;43:304)
Steroids are indicated in patients on chronic steroid therapy or adrenal dysfunction
s/e: neuromuscular weakness. hypernatremia
 VASOPRESSORS AND INOTROPES

Vasopressors generally improve GFR u "wif 19s1;321112 qAs~ zoas¢a:s4e>

Norepinephrine: preferred over dopamine as firstline: no overall mortality difference
bu: more arrhythmias with dopamine (seA»= II new 201(x362=7791
Vasopressin or epinephrine: can be added to norepinephrine to meet MAP target
Epinephrine = norepinephrine for achieving MAP goal (Intensive Care Mm 100e;34;122s)
Phenylephrine vs other vasopressors on clinical outcomes in shock not well studied
Angiotensin II (Giapieza°): in vasodilatory shock. 1 MAR 1 SOFA score <~=1m 20\7;377419);
in AKI requiring RR111 28d mortality and T RRT liberation Lou Cum Med 201&46949)
Lowdose dopamine: does not prevent AKI: may worsen renal perfusion (KI zocwmwal
Vasopressors in Septic Shock
Mortality was lowes: when begun 1-6 hr after onset with IV fluid (cut cm 1¢I¢4101442.21589
Every hour of delayed norepinephrine was ailw t 5.3% mortality (cut Can 201411;532)
Norepinephrine: 1st choice (Intensive can m:4 1017;43:304: /AMA 2017:317:847)
Vasopressin at 0.03 U/min added to lowdose norepinephrine: no difference in mor
tality do highdose norepinephrine; mortality benefit seen in a prespecihed subgroup
of less severe septic shock on 5-14 mcg/min norepinephrine (vAssT no//n 2cas;3s8.e771
Vasopressin (up to 0.06 Ulm in) vs Norepinephrine: no difference in kidney failurefree
days or death. but vasopressin group had less use of RRT ¢VANISH1AMA 20\6;]16;509)
Norepinephrine + dobuamine vs epinephrine: no difference in mortality lime 20071370679
lnotropes
May be added to vasopressors for shock when the etiology is primarily cardiogenic
or significant cardiac contribution in mixed shock states (et, septic/cardiogenic shock,
obstructive/cardiogenic shock in a large acute pulmonary embolus)
Use often prompted by low central venous Oz sat despite vasopressor support
Milrinone dose should be adjusted for reduced kidney function
 RENAL REPLACEMENTTHERAPY IN SHOCK
CRRT: more likely to 1 fluid accumulation than HD (xv 2009;7 s:4z1)
Timing of RRT
In multicenter trial on AKI (KDIGO 3) requiring mechanical ventilation early vs
delayed RRT showed no mortality benefit at 60 d iAKIKI NE/M 2016;375;I 22). Posthoc
analysis in ARDS or septic shock, no benefit of early RRT (A/RCCM 201&198:581
In singlecenter vial on AKI (KDIGO 2-3) and NGAL >150 WmL early RRT was
a/w i 90 day mortality (£LAIN;AMA 201ea1s:21s0), L 1yr mortality and T renal recovery
(up 201Bz1%1011)
In multicenter trial on AKI (RIFLE failure stage) with septic shock. early RRT not alw
mortality reduction. 62% of delayed group dad not require RRT (fig/u 201mz79=14311

ORTHOSTATIC Hyrorsuslon (OH)

Physiologic response to standing: :he pooling of 500-1.000 mL of blood in the lower
extremities and splanchnic circulation -» L venous return to :he heart and cardiac
output and BP -» T sympathetic outflow (baroreceptor reflex) -» t peripheral vascular
resistance. venous return. cardiac output, and BP
OH: postural reduction in SBP 220 or DBP 210 wu 3 min of standing
BP fall w/i 1 mln was alw dizziness. fracture. syncope,and death UAMA IM 101117711319
Delayed OH: OH after 3 min of standing; alw Parkinson disease i--vw z01s:as:136z)
Postural tachycardia syndrome (POTS): T HR 230 beatslmin wu 10 min of standing
or headup tilt in the absence of OH
Postprandial hypotension: BP reduction within 1-2 hr aker a meal
Causes
Volume depletion: fluid loss. overdiuresis. overdialysis: adrenal insufficiency. anemia
Autonomic dysfunction: amyloidosis. DM. Parkinson disease. multiple system atrophy
Drugs:all antihypertensives,111blockers (for BPH or HTN). trazodone. SSRI, MAOi,
TCA. vasodilators (including PDE5 inhibitors)
Clinical Manifestations
Dizziness. weakness. palpicarions. blured vision. fall, syncope. fall
Sometimes asymptomatic due to auroregulacion of the cerebral blood How
Treatment
Volume repletion. dlc of causing drugs; avoid rapid postunl change
Compression stockings. abdominal binder
Fludrocordsonez mineralocorticoid, s/e: supine HTN. hypokalemia.sodlum retention
Midodrine:u1agonist
s/e: supine HTN. urinary brendon. piloerection, scalp prurirus and paresthesia. bn
dycardia. bowel ischemia (On Care mm 1018;46:e628]
Droxidopa: norepinephrine precursor: less supine HTN than midodrine wuinmaimiwnuw
201B:521182)
Familial Dysautonomia
Ashkenazi }ewish.AR. mutation of IKBKAR ormhosradc hypotension. supine HTN,T CKD
19% cl alive pus as age 25 required dialysis l4ll(ozuoe4e7so); KT is an option Ieyasu 201l>.&1s76l
 EDEMA
Edema occurs when :here is sodium retention by the kidney with resultant expansion
of the interstitial space
The sodium retention by the kidney can be 1° (renin and aldosterone are suppressed)
or 2 (renin and aldosterone are increased d/t a hemodynamic stimulus)
In 2° renal sodium retention. the stimulus can be an absolute decrease in the intra
vascular volume (as with disorders of capillary leakage) or due to arterial underfilling.
Disorders of arterial underfilling are characterized by an increase in total blood volume.
but an inadequate arterial perusing volume
Mechanical causes of edema tend to cause edema diet is localized (ie.to an extremity)
in contradistinction to other conditions in which it is more generalized
Causes ('causes that do not respond to diuretics)
Pri ma ry re n a l so d i u m re te n ti o n
. CKDIESRD. nephrotic syndrome (NS, rnaiority) (KI 2012;S2:63S1. thiazolidinediones
Slecondary mud sodium retention
Arterial underfilling (}ASN 2007;1ez0zs)
HF of various etiologies (including constricuve pericarditis). cirrhosis. pregnancy
Severe hypoalbuminemia, usually <2.0. of diverse causes (generally alw relative or
absolute hypotension)
NS (minority) In 2012:82:635)
Protein losing enteropadiy. kwashiorkor, severe chronic illness (particularly infection)
Decreased arteriolar tone causing increased capillary pressure
*Vasodilator antihypertensive medications: minoxidil. hydralazine. dihydropvyridine
Calcium channel blockers (co Cmulal up 2002:4:479)
Increased capillary penneabilicy
*Sepsis. preeclampsia. pancreatitis
*Capillary leak syndromes (xv 1017;9131)
idiopathic systemic capillary leak syndrome (SCLS) aka Clarkson disease
Druginduced (lL2. lL11,IL12.gemcitabine. OKT3, alemtuzumab and rimximab in
hematologic malignancies)
Engraftment syndrome. graftvshost disease following allogeneic BMT
Differentiation syndrome,ovarian hyperstimulacion syndrome
Hemophagocytic lymphohisrjocytosis. viral hemorrhagic fever
Unknown: hypodryroidlmyxedemaexact mechanism is unclean: but it is characterized by
Tplasma volume. l cardiac output. and 1 GFR
Mechanical causes: 'lymphedema."venous obstruction. or insufficiency
Clinical Manifestations
Edema will be unilateral/localized in mechanical causes and symmetric in other causes
In nonmechanical causes. extremity edema may coexist with serous cavity effusions
(pleural. pericardial. peritoneal) or pulmonary edema
Workup
History and physical: relevant new medications: evidence of hear: failure, cirrhosis. NS
NS and CKD: serum creatinine. urine protein: creatinine ratio. serum albumin
Liver disease: coagulation studies and albumin, abdominal ultrasound
Heart failure: Btype natriuretic peptide, cardiac ultrasound
Myxedema:TSH.free T4
Venous insufhciencyz venous LE U/S to evaluate competence of venous valves
Further evaluation for uncommon causes as dictated by the clinical presentation

Treatment of Edema
Cause Treatment
1° renal Na retention.arcerial underfilling Loop diuretics +I- zhiazide diuretics
Severe hypoalbuminemia (<2) with poor IV albumin (to achieve serum albumin >2,0)
response to diuredcslvolume depletion + loop diuretics +I- thiazides
Mechanicalcauses Addras mechanical cause
Others Treat underlying disease
 NEPHROTIC SYNDROME (NS)
D e f in it io n a n d Pa t h o g e n e sis ,
Pnoteinuria: >3.$ old or >3 g/g by urine protein to Cr ratio (UPCR) due to podocyte injury i
Hypoalbuminemia (<3.5 g/dL): urinary losses + tubular metabolism > hepatic synthesis
Edema: 1° Na retention (overfilling) 1 L oncotic pressre (underfilling)lRAAS activation
Hyperlipidemia (cholesterol and/or TG): not required to fulfill the criteria for NS; low
plasma oncotic pressure leads no T LDL T angiopoietinllke 4 - T TG (Not Med 1.1411&371
NS is a phenotype (not a disease): microscopic hematuria.AKI possible (overlapping
f e a t u re s wit h n e p h rit ic syn d ro me )

E t io lo g ie s
Primary podocyte/GBM injury: MCD. FSGS, MN. Some cases of IgAN. MPGN
Glomerular injury dlt systemic diseases: DM (nephrotic range proteinuria > NS).
amyloidosis, lupus nephritis (esp. class V)

E p id e mio lo g y
gzip

518 yo: MCD > MPGN > FSGS ctr 197911159)

1860 yo: FSGS = MN > MCD > LN > DN > IgAN
260 yo: MN > amyloid > MCD > FSGS > DM > loAn (AGID 7.0111961)
2% yo: MCD > MN > amyloid > FSGS > leAn > DM (Acre 1011:19:611

ExtraRenal Clinical Manifestations

Hypercoagulability: unclear mechanism: adults > children:venous > arterial thrombo
ses; MN > other diseases: risk factors:Alb <2.B. heavy proteinuria (qAsn 1012:7:513)
Pleural effusion transdates pattern as in cirrhosis. CHE constrictive pericarditis
Ascites: serum ascites albumin gradient <1.1 as in peritonitis. peritoneal carcinomatosis
Gut edema: NN abdominal discomfort; pericardial effusion
t TSH: thyvoxinebinding globulins loss from proteinuria
Vitamin D deficiency: vitamin D-binding protein loss in urine
In fe ctio n , h yp o g a mma g lo b u lin e mia za n tib o d y lo ss in u rin e

Nephritic SyndromeAssociated Conditions

unSAIDs. penicillamine MCD. MN
Lithium. IFN. pamidronate. HIV MCD. Collapsing FSGS
Riiampin. ampicillin. EBV. syphilis. ehrlichiosis. mycoplasma MCD
Hodgkin lymphoma. dvymoma. ampy/eczema
Slmngyfoides sterroralis (xi re 20183141 MCD.Tip FSGS
Heroin, anabolic steroids. sirolimus. HCV DAA (H4¢ul=¢, 1017:666$8) FSGS
CMV. SV40. parvovirus B19. leishmaniasis. filariasis
HLHlMacrophage acdvauon syndrome. cerebd arredds. aukonset
Still disease. MClD. multiple myeloma. SCD. acute monoblzsdc leukemia.
polycythemia Vera. essential durombocydiania. primary rrrydcibrosis
Gold. mercury. capropril: HBV. syphilis. Malaria. SLE. RA MN
Malignancy (lung. colon. breast. pros re. UKEFUS. gastric)
Chronic osreomyeliris. tuberculosis. RCC. RA. IBD M amyloidosis
Familial Mediterranean fever. hidradenitis suppuraliva

Workup and Diagnosis

Kidney bx required in most cases
Lab: hepatics B and C serologies. HIV.ANA.C3. C4.SPEP with IFE. kappallambda free
light chain assay. UPEP with IFE, Hb Alc. antiPLA2R Ab
In diabetics.consider kidney biopsy if rapidly progressive kidney disease.exu'arenal
symptoms dw systemic disease. (+) serologies.and in patients with short duration of DM
Management of Complications
Volume overload: loop. dmiazdes. MRBs diuretics PO (absorption may be reduced from
gut edema) or IV; IV diuretics + IV albumin if severe/relractory
Hypertension: goal <130/80. use RAAS blockade If persistent protelnurla
Hypercoagulability: prophylactic anticoagulation if bleeding risk is low and serum alb
<2.8 for MN (al 2013;8521412). Role of prophylactic anticoagulation for other NS etiolo
gies uncertain, but could be considered if serum alb <2.0
Hyperlipidemia: statins if persistent due to tHMGCoA reductase activity and risk of
coronary heart disease in NS (Ki 199144638)
Hypothyroidism: treat unless resolves with management of NS
 GLOMERULONEPHRITIS (GN)
Definition and Renal Manifestations
Microscopic or gross hemaouriz dysmorphic RBCslaand1ocytes. RBC asks on sediment
Azoremia, HTN common: proteinuria. usually subnephrotic (<3,5 old). can also have
nephrozic range proteinuria (overlapping presentation with NS)
GN is a phenotype of infiammamory glomerular disease. not a specific disease
Diagnosis
Based on kidney bx and clinical history/labs
Proliferation (mesangial, endocapillary.extracapillarylcrescents) common on bx
Glomerular injury secondary to systemic diseases: et. infections such as endocarditis.
SLE.ANCAassociated vasculitis, Henoch-SchOnlein purpura. Goodpasture syndrome
Lab workup depending on clinical presentation: C3. C4.ANA. hepatitis B and C serolo
gies.ANCA (including anuMPO and ami-PR3 Ab titers). antiGBM Ab. HIV. SPEP/IFE.
serum kappa/lambda free light chain assay, cryoglobulins. RE and blood culture

Common Serum Complement Changes in GN

Low Complement Normal Complement
Immune complex-mediated MPGN. lupus nephritis Pauciimmune GN
In1ecdonrela¢ed GN, cryoglobulinemic GN, C3G AntiGBM dz
PGNMID, MIDD (esp, hea chain). immunoracxoid GN I nephrivJs.libriIIa GN

ExtraRenal Manifestations of Systemic Diseases That Cause GN

Disease Extr aR enal Pr esentation
lA Vasculitis (gAv. aka Skin: uniaria, ecchymoses, maculae. palpable purpura
HSP) Gl:Abd pain, GIB. nausea. vomiting
MSK: arthralgias, arthritis
Systemic lupus Constitutional: fever. malaise. weight loss
erythematosus (SLE) Skin: molar rash. discoid lupus
Lung pleuritis; cardiac: pericardids
Gl:abdominaI pain. GIB
MSK: ardiralgias. arthritis; neuron: confusion, seizure. stroke
ANCAassociated Constitutional: fewer. malaise. weight loss
vasculitis Skin: palpable purpura
Lung cavities. nodules. pulmonary hemoorrhage. cough
Gl: abdominal pain, GIB
MSK: ardiralgias. arthritis: neuro: mononeuritis multiplex
ENT: riiinosinusitis. hearing loss. cartilage destruction
AntiGBM dz Pulmonary hemorrhage
Npon syndrome ENT: sensorineural hearing loss
Eyes lens. retinal and corneal defects
Cryoglobulinemic GN Skin: palpable purpura. ulcers
Neuro: neuropathy
MSK: arthralgias. arthritis. myalgias

RAPIOLY Pnocnessuvs GLOMERULONEPHRMS (RPGN)

Clinical presenlzdon of inflammatory glomerular disease with rapidly worsening kidney
function over days. weeks.or months -» associated with poor prognosis if unrreaced
Causes:ANCAassociated vasculids. antiGBM dz. lupus nephritis. IgAN/IgAV.
infectionrelated GN (especially endocardiris)
Crescents (extracapillary proliferation) often seen on kidney bx in RPGN cases
 Requires rapid diagnosis (kidney bx) and creacmen:
If awaiting biopsy, empiric treatment with pulse IV glucocorticoids (methyiprednisolone
500-1.000 mild X 3 days): will not change biopsy results
PLEX: consider in DAH and severe AKI

THROMBOTIC MICROANGIOPATHY
Endothelial damage -» microangiopathic hemolytic anemia (MAHA). platelet aggregation
and consumption in small vessel -» organ damage
Causes (new 2014:371:654)
infection: enterohemonrhagic E coli (Shiva toxin), Shigella dysenteriae, S. pneumonia.
Influenza AIH 1 N 1. HN EBV. CMV. M. pneumoniae, Bordetella pertussis. Parvovirus B19
TTP: hereditary or autoimmune ADAMTS13 deficiency
Atypical HUS: hereditary or autoimmune disorders of complement regulation
Pregnancy or postpartum: (pre)eclampsia. HELLP syndrome
Transplantation: solid organ. bone marrow or stemcell transplantation
Metabolic: cobalamin C (vitamin Be) def (Lanai 1015;386:1011: am" n¢w--=l z015.10=1z0z>
Autoimmune: SLE.APS.scleroderma renal crisis (SRC, in systemic sclerosis type)
Malignancies: metastatic adenocarcinoma. monoclonal gammopathy (KI Z017;91:691)
Malignant hypertension
Drugs: CNI. gemcicabine. quinine. ticlopidine.antiVEGF therapy (NEW zouauasanml
Genetic: ocxe (Na Gale 2013:45:531; qAs~ N1510.1011). lNF2 we zo\6:4:10s41
Clinical Manifestation and Diagnosis
Hematologic TMA: MAHA (t netic count. T LDH. haptoglobin, t indirect bilirubin.
schistocytes on peripheral blood smear) + thrombocytopenia (<150 or >25% from
baseline) » organ dysfunction
Renal TMA:AKL proteinuria. glomerular hematuria. hematologic TMA. hypertension
Not all renalTMA has all feawres of hematologic TMA
Biopsy: fibrin thrombi (when acute). endotheliosis, mesangiolysis. intimal edema.
"onion skinning" (myocyte proliferation) of vessel wallsaglomeruloid body (organized
thrombus. specific for APLA). capillary loop duplication. subendothelial electrolucent
material on EM (in chronic)
SRC and malignant hypertension: vascular damage predominantly
ExtraRenal Manifestations (Nam nail 2014;1197: x12017;91539)
Neurologic: irritability. mental status change. stroke. focal deficits. seizure. coma
GI: NN bloody diarrhea. pancreatitis. liver injury
Skin: purpura. small vessel vasculopathy. gangrene
Cardiac: cardiomyopathy. Ml. myocarditis. CHE occlusive CAD
Others: pulmonary hemorrhage. rhabdomyolysis

T M A Wo r ku p
Cause, Clues Wo r ku p
All TMA Culture studies. HIV. homocysteine. methylmalonic acid:
cobalamin C deiciency
Paraprotein studies: SPER slFE. serum FLC
HUS: diarrhea (D)+ Stool studies for STEC EHEC
aHUS: no other history or Complement studies: C3. C4. CH50. gene mutations/
family lo TMA autoantibodies: J if KT being considered
TTP ADAMTS13: activity, inhibitor and antigen
SLE ANA. aCL Ab. ll2Gp1 Ab. lupus anticoagulant
Scleroderma RNA polymerase III ab. skin exam
Malignant HTN Retinal exam.TTE. and ECG (for LVH)
Preeclampsia/ HELLP LFls. fetal monitoring. placental ultrasound

T reat m en t
Empiric: PLEX if no obvious etiology identified. CS if low suspicion of scleroderma or
infection; stop potential offending agents
 TMA Treatment When Etiology Known
Cause Tr e a tm e nt
HUS: D+ Supportive care: fluid/electrolyte management. dialysis if needed
aHUS PLEX. eculizumab INE;M 2013.za 2169); CS. rizuximab if auloAb+
TTP CS. plasma infusionlPLEX. Cyclosporine. or rizuximab if refractory.
Spleneczomy rarely needed _
Auloi immune Immunosuppression for SLE,ACEi for SRC. andcoaguladon for APS
Malignant HTN Aggressive blood pressure control
(Pre)eclampsia Deliver baby -» consider alcemative dx ilTMA does not improve

ACUTE KIDNEY IN]URY (AKI)

Ba c k gr ound a nd E pi de m i ol ogy
Overall global incidence 22% in hospitalized patients (qASN 2018:8:1482)
Up to 67% of ICU patients (cm cm z0os:1ixn7:)
Up to 50% in septic shock,associated mortality -707G (KDIGOAlfJ 2012)
Risk factors: volume depletion, age. hypoalbuminemia. female. CKD. DM. 1 EE car
diac surgery. chronic liver disease. malignancy (»(oicoAxl 2011>
De fi n i ti o n
Sudden loss of kidney function. clinically manifested as l creazinine +I- 1 UOP

AKI Staging fKDlGOAKI 1011)

Stage Cre a ti ni ne Ur i ne O utput (UO P )
1 t 0,3 in 48 hr or <0.5 cdkg/hr for >6-12 hr
t to 1.5-1.99x baseline wu 7 d
2 T to 2.0-2.99x baseline wu 7 d <05 cdkg/hr for 212 hr
3 t to 23x baseline wu 7 d: OR increase <03 cdkghr for 224 hr or anuria for
in Cr to 24.0; OR need for RRT 212 hr

More advanced stages associated with worse outcomes an moruliry

CAus E s or AKI
Causes of anuric renal failure: usually due co severe shock. RPGN. bilateral (or
single if one kidney) renal artery or urinary obszruction

Prerenal: L effective arterial volume

Hypovolemia. cirrhosis, early shock of any etiology before progressing to ATN, car
diorenal (CHEAS. RV dysfunction). abdominal comparunem: syndrome. hepatorenal
syndrome. hypercalcemia. capillary leak syndrome

I n tr a r e na l
Glomeruli: GN. look out for RPGN
AnuGBM disease
Immune complex: infectionrelated GN. SLE. cryo. loAn, IgAV/HSR endoardicis
Pauciimmune:ANCAassociated (GPA, MPA)
Thrombotic:TMA (TTP/HUS, DIC. complemenrldrugmediated TMA. anriphospholipid
antibody syndrome. preeclampsia/HELLE malignancy)
Vasculature:TMA (malignant HTN, scleroderma renal crisis). emboli (eg. cholesterol).
renal artery occlusion. renal vein thrombosis. polyaneritis nodosa
Tubules:ATN (sepsis, ischemia, toxins). light chain cast nephropathy.
Crystal induced: urane from tumor lysine. PO. from oral and possibly enema (KI 201680u1
lntersrjtium (AIN):
Drugs (70%) especially antibiotics, unSAIDs, Ppls
Infections (many bacterial incl sizph. suep. syphilis. Legionella; viruses: mycobacteria)
Autoimmune diseases (SLE,SjOgrens, lgG4 vasculitis. sarcoidosis)
Miscellaneous (TINU syndrome. lymphoma)
P os tre na l
Stones. BPH/prosme cancer. retroperkoneal Fibrosis. bladder/pelvic malignancies.
transitional cell carcinomajungus balls. blood clots. papillary necrosis with sloughed
issue causing obstruction
 Wom c ur of A K I
History and Physical Examination
Hypotension: absolute or relative vs baseline
Drugs: unSAIDs. diuredcs.ACEilARB, Pal,andbiotics, herbal remedies/ illicit drug
Volume depletion: diarrhea.poor PO intake
Injection/sepsis, IV contrast
Recent surgery/arterial catheterization: cholesterol emboli
Markers of volume status: BP. skin turgon mucous membranes.JVD, edema. rates
Changes in urine output (oliguria). hematuria
Rashes/joint pain: vasculitis. endocarditis.AlN
Respiratory symptoms: pulmonary renal syndrome. eg.ANCA. andGBM. SLE, cryo
In i ti a l L a b o ra to ry Wo rku p
J on most patients: BME LFTs. Ca, PO4.aIbumin. CPK. UA with microscopy and sedi
ment. spot urine protein/sodium/urea/creadnine.CBC with differential
BUNlCreatinine ratio:normaI roughly 10:1
>20:1 suggests prerenal because hypovolemia causes t reabsorption of sodium and
water in proximal tubule.and urea follows passively
<20:1 suggests intrinsic renal disease
False T BUN: steroids, GI bleeding from increased urea production: creatinine lilith
low muscle mass (eg. elderly. cirrhotics)
False LBUN: low protein intake:
T creatinine release from rhabdomryolysis or impaired tubular creatinine secretion (eg.
trimethoprim. cimetidine)
FEm.: used to distinguish prerenal from other causes
<1X. (prerenal): 1-2% (prerenal or intrarenal); >2% (intrarenal or obstruction)
<1% cutoff for prereial only applies for marked L GFR, prerenal physiology with normal
kidney function can have FE~ <0.1%
Caveats: nonprerenal <1% can occur with contrast nephropathy. rhabdomyolysis, GN.
ATN in background of severe prerenal state (eg. cirrhosis. CHF): prerenal with
>1% can occur with background CKD or diuretic therapy
FF~ accounts for water handling. better than urine sodium alone
FEw,..: likely better than FEm on diuretits (NephiunGnPh:a 201¢z114:¢145)
Laboratory Findings of Prerenal AKI and ATN
Measurement Prerenal ATN
BUN/Cr ratio >20:1 <20:1
Urine sediment Bland or hyaline casts Renal tubular epithelial cells.muddy
brown casts," granular casts
Urine specific gravity >1.020 1.010
Urine osmolaliry >500 <350
Urine sodium <10-20 >20-40
FEn. <1% >2%
FM.. <35% >35%

Urine sediment: uciliry conuoversialc considerable inneroperator variability: polar

ized light to see crystals, lipid droplets in NS (makese crosses)
Urine Sediment Findings and Significance
Finding Significance
RB C Nonglomerularz stones. tumor. exercise. menses. infection. imersrizial
cysuris. transient. AVM. papillary necrosis. PKD. medullary sponge.
hypercakiuria
Glomerular: GN.thin basement membrane nephropa¢hylAlports
Dysmorphic GN, loinpain hemawna syndromeaacanrhocyzes are subtype with 98%
RBC specificity for GN 1xl 1991:4al1sI
RBC casts GN usually. less commonly AlN who zoirsancl
WBC AlN.TB. schiswsomiasis. fungal. stone. rumor. infection. interstitial cysdsis
MM zmsaniw)
WBC casts AIN, GN. pyelonephriris
Only 3% of AIr with WBC casts (A 2014: 54558)
 Medications: acyclovir, indinavin sulfamethoxazole. sulfadiazine.
methotrexate. amoxicillin. Ciprofloxacin
CaOx: ethylene glycol. hypercalciuria.enteric or primary hyperoxaluria.
orlistaf. vitamin C
CaP. phosphate nephropaihycalkaline pH
Unk acid: hyperuricemia. orate nephropathy, tumor lysine: acidic pH
Cystinuria. Struvite: Mgammoniumphosphate."triple phosphate". with
unease splitting bacteria. alkaline pH
Renal tubular ATN
epithelial Any RTEC or granular casts may predict ATN with sensidvlzy 83% and
cell casts specificity 77% (qASN 2008:8:16151
Granular Derived from degenerated epithelial cell casts;"muddy brown casts" are
casts pigmented version (ATN, hyperbilirubinemia)
Hyaline casts Nonspecihcz seen in h Ithy and disease states
Waxy casts Degenerated granular casts: nonspecific. seen in both chronic and acute
disease
Urinalysis
Specific gravity an approx urine osmolality;- 1.010 - 300 mOsms/kg (intrinsic disease,
>1.020 with prerenal disease): discordance with large. heavy molecules (contrast.
glucose) which T sp gravity more than osmolality
(-) blood wlo RBC: myoglobin (rhabdomyolysis, /CK). Hb (/blood smear hemolysis)
() proteinuria only detects albumin (and usually only >300 mg/g crest. previously
known as macroalbuminuria"): if discordante between dipstick proteinuria and
quantified proteinuria. then likely LMW proteins or paraproteins present; sulfosali
tylic acid can be added to detect nonalbumin proteinuria
(~) glucose with serum glucose <180 suggests proximal tubular defect (aminoglyco
sides. paraprotein disease. heavy metals. cisplatin. tenolovir) or SGLT2 inhibitor
Quantilled proteinuria
Spot UPCR or UACR; approximates 24hour urine protein or albumin excretion if
daily creatinine excretion is 1 old (can significantly underestimate or overestimate
daily proteinuria in large/muscular or low muscle masslelderly. respectively)
Spot ratio can also be inaccurate when serum creatinine is fluctuating
Nevertheless 24hour urine collection not usually needed in AKI
Quantify proteinuria even if dipstick protein negative to evaluate for nonalbumin
proteinuria (eg, paraproteins in multiple myeloma)
% urine albumin excretion <25% may predict cast nephropathy in dysproteinemic
kidney disease (c/As~ 2012;71964)
AKI on CKD-proteinuria may be due to the chronic process,and not acute (eg.
ATN in patient with preexisting diabetic nephropathy)
CBC with differential
Eosinophilia may suggest AlN.atheroembolic disease
Significant anemia can suggest CKD.TMA (especially if thrombocytopenia). multiple
myeloma. hemolysis (and pigmentrelated injury)
Thrombocytopenia can suggest TMA (eg.TTR HUS, DIC). SLE. antiphospholipid anti
body syndrome, cirrhosis. / smear for schistocytes if anemic. coags
Leukocytosis can suggest sepsis. myeloproliferative disorder
Calcium
T: can cause AKI (prerenal.ATN); or clue for multiple myeloma. sarcoldosis. malignancy
i CKD. hyperphospharemia: pancreatids, tumor lysine, rhabdomyolysis
Serum albumin
If low. in nephroric range proteinuria, suggests primary NS
Very low levels (<2.8) in NS can increase risk of thrombosis. including renal vein
thrombosis (especially with primary membranous nephropathy)
Large gap between total protein and albumin level suggests paraprotein disease
Radiographic Testing
Renal ultrasound (preferred) or noncontrast CT in mos: patients to rlo obstruction
Small kidneys (<9 cm) suggests chronicity (except with diabetes)
Large kidneys (>11-12 cm) suggests AIN. diabetes. amyloid. PKD. lymphoma. HIVAN.
renal vein thrombosis
Echogenicity not a reliable indicator of CKD IQASN 20142923731
Asymmetric kidneys suggest unilateral renovascular or congenial disease
Additional Tesclng: Dictated by Other Clinlcal Flndlngs
Paraprotein workup - / SPEP/IFE. serum free light chains. UPEP
Ge: if > age 50 wl unexplained AKI; or manifestations of MM.amyloidosis. etc
Serum uric acid: " in any renal disease due to decreased renal clearance:
especially t in tumor lysine. rhabdomyolysis. myeloproliferative disorders. acute
orate nephropathy
If t out of proportion to renal failure (je. >15) then could be cause rather than effect
of kidney disease: urine uric acid:creatinine ratio >1 suggestive of this
If acute orate nephropathy suspected. treatment is IV saline. rasburitase. XOI
If suspecting glomerular disease: serologic workup can include hepatitis B/C.
ANCA.ANA. dsDNA. C3. C4, cryo, andGBm, SPEP/IFE. serum free light chains.
UPER HIV. blood culwres: ultimately need kidney biopsy to confirm
Novel biomarkers for ATN (not yet clinically available)
Urine neutrophil gelatinaseassociated lipocalin (NGAL) (An IM z0ae.14a;s101
Urine kidney injury mdeculel (KIM1) us zcuetnlcus)
Indications for Kidney Biopsy in AKI
Unresolving AKI; suspected GN;AIN for which steroid treatment is being tonsldered
Common Pattems Associated with Acute or Subacute Kidney Diseases
Findings Possible Diagnosis
Acellular unne, Prerenal and ATN most likely.Aln also possible (even
minimal protelnuria without pyuria or proteinuria). obstruction. crystal
(<1 g) disease (oxalate. orate. phosphate nephropathy). cast
nephropathy. atheroemboli
Nephrotic range NS wl ATN (usually minimal change). FSGS (especially
proteinuria, +I- collapsing). amyloid and other paraproteinrelated
microhematuria glomerulopadwya renal vein thrombosis (especially MN)
Pyuria with minimal Infection,AIN, alheroemboli
proteinuria (<1 g)
Subnephrotic Inflammatory glomerulonephritis (immunecomplex such as
proteinuna and SLE/infection relatedllgA. antiGBM.ANCA),TMA. malignant
cellular urine HTN. PAN
Pulmonary-renal ATN from sepsis (pneumonia).ANCA.andGBM. SLE. cryo.
syndromes AIN from pulmonary infection (Legionella.TB,
Streptococcus) or the antibiotics used for treatment.
infectionrelated GN.AKl with volume overload and
pulmonary edema. scleroderma. sarcoidosis. drugs (PTU.
cocaine). lgAv (rare pulmonary hemorrhage). loAn
(hematuria following URI), CJG following URI
Dermatology-renal Vasculius (ANCA. SLE. cryo. PAN. HSP).AIN. endocarditis.
syndromes infectionrelated (cellulitis). scleroderma. atheroemboli. hep
C (porphyry). amyloidosis (purpura). HIV (Kaposi sarcoma.
eosinophilic lollkulitis)
Low complements SLE. infectionnelazed, cryo. C3G. other MPGN, lgG4related
disease. endocarditis, atheroembolism

PREVENTION oF AKI
General preventive measures: minimize nephrotoxins (et. contrast. NSAIDs).volume
depletion, hypotension: renally dose medications
No single medication consistently shown to prevent septic or ischemic ATN
Lowdose dopamine ineffective and potentially even harmful (KA 200s;sm659)
Fenoldopam 1 AKI but not RRT/mortality: needs more data Lon Cane 101s=1*r449)
Auial natriuretic peptide (ANP) with mixed results 1qASN 1009141261)
Remote ischemic preconditioning safe but uncertain efficacy: metaanalysis negative.
do not recommend currently for ischemic ATN icumum Onwiiw So Rev 2017:CDOl0777)
Off pump cardiac surgery did not rates of AKI requiring dialysis (NEW 201I:368:1179)
Withholding ACEi/ARB prior to surgery of uncertain benefit. may prevent periop
hypotension, but need RCT to determine effect on hard outcomes
Aminoglycosides: oncedaily dosing reduces AKI without affecting efficacy (Am/l4¢alui
Syn Mann 1996: 53;1141): gentamicin > tobramycin > amikacin. in decreasing toxicity
Fluld Resuscitatlon
Use crysralloids over colloids;balanced crystalloids reduced kidney evenr,s vs NS in
ICU (new 1018;378:819) and nonICU settings (NEW z01a. annals)

Contrast Nephropathy
Use low/isoosmolar agents. minimal contrast dose. periprocedure normal saline if
pulmonary status ok
Conflicting data on NAC, likely not beneficial we 101&3781603-14), isotonic sodium
bicarbonate not beneficial over NS (new 201s. J7&w3)

MANAGEMENT oF AKI
Mainly supportive; control of underlying process (et. sepsis, volume depletion. RPGN)
No single medication shown IO improve outcomes after septic/ischemic ATN
Loop diuretics can be used no manage volume while awaiting recovery. bu: does nor
hasten renal recovery and should not be used co delay dialysis if indiaced
R e n a l R e p la ce r n e n t T h e r a p y
Indications: acidosislhyperkalemialvolume overload refractory to medications. uremia
(pericardial effusion, AMS). certain ingestions
M o d a lit ie s:
Continuous renal replacement therapy (CRRT). intermittent HD (HD). slow low
efficiency dialysis (SLED); no modality proven to be superior UA/W\ zaoeaswvsl
Hemofiluation may improve clearance of middle molecules but no improvement in
outcomes over hemodialysis (cm Core 1012:16:R145)
CRRT or SLED preferred over HD if patient is hemodynamically unstable. or with
increased intracranial pressure (less dramatic osmotic shifts than HD)
Dose: 3xlwk noninferior to 6xlwk for HD. effluent rate of 20 cc/kglhr noninferior
to 35 cc/kglhr for CRRT (nE/A1 z00s¢3 se1>; aim for modestly higher effluent rate for
CRRT as interruptions will limit actual delivered dose compared to prescribed dose:
weekly Kt/V 23.9 for intermittent or extended daily dialysis (Kolco Ax: 10121
Timing of RRT most evidence does not suggest mortality benefit for early vs delayed
initiation of RRT lAKll(l num 2o16=37s1122. naya 201B;37&143\)i n o sp e cif ic B I JN o r Cr
threshold when to start

Pnocnosls oF AKI
Depends on severity and duration of injury, baseline function. comorbidities
Furosemide stress test; 1-1.5 mglkg of furosemide: increased urine output predicts
more favorable outcome. but does no: alter outcome UAS~ 201§:162023)
Nonoliguric ATN generally w/ better prognosis. possibly dl: less severe injury and better
volume saws; positive fluid balance wlAKI alw worse outcomes (Cn cm mfazoiwri7sai
Full extent of recovery with ATN occurs usually by 6-12 wk
Up to 1/3 of all AKI istransient" (recovery w/i 3 days). but still alw t hospital mor
tality vs no AKl (NDT 201m251833>
T morality in survivors of AKI (rate ratio 2.59) who 1009:s3:961i
Cardiac surgeryAKl T longterm monality.even w/ complete AKI recovery (aodauan
2009;1\91444)
Longterm mortality in survivors of AKI worse if renal function doesnt normalize
(46% vs 83%) cm (one z01z 16n13)
AKI increases risk for CKD (HR 8.8). ESRD (HR 3.1). mortality (HR 2.0) (to zoizei 4421
ICU: hospital mortality t with T severity ofAKl; 8,8-26.3% range (Cm cm 1006;10a73i
35% hospital mortality, 49% 6month mortality in AKl requiring RRT in Finland ICUs
ion co 2012:\6:iuJ1;47% hospital morality. 65% 1 yr mortality in another study in AKI
requiring RRT in ICU
 CHRONIC KIDNEY DISEASE (CKD)
Definition
CKD:prsencedkidneydamageorllddneyfuncdon(eGFR<60)for23mo(4p(Dl9n&3951)
Kidney damage: UACR >30 mg/g. active urine sediment. kidney transplant. or abnor
malities on biopsy or imaging (Lama 2012:37%165)
Staging risk stratifies pts and aids in management we 2002;39:51)

CKD Staging (G: GFR category;A: albuminuria ca gregory)

G GFR (mUminI1.73 m1) A AER (M8/4)
G1 290 - kidney damage A1 <30
G2 60-89 + kidney damage A2 30-300
G3a 45-59 G4 15-29 AA >]00
G3b 30-44 G5 <15
Stages are classified into risk categories (based on rnorxzlicy CV morl:ali:y.and ESRD risk)
All G3b. G4. G5.ar\dA3 prs are consider at high or very high risk (xoico can 2012)
Epidemiology (zoia may annul day wvfll
Prevalence of predialysis CKD (1-5) was -14.8% of the U.S. population in 2013-2016
Stage 3 (6.4%) the most prevalent
Females > males (16.7% vs 12,9%): CKD T w/ age (32.2% of adults >60).
<10% of CKD pts aware of disease 1.4/n z01zas:191).5M awareness in stage 4 CKD

Etiologies of CKD
Category Possible Causes Urinalysis Renal UIS
Prerenal Chronic CHF Minimal protein,
Chronic cirrhosis bland sediment
Vascular HTN (APOLLO) Minimal protein. Small kidneys
Renal vascular disease bland sediment excluding DM
TMA
Glomerular Chronic glomerular (+) protein. HIV. DM: large
disease +I- RBCs kidneys
DM (ml cause of CKD)
Tubulointerstitial inherited disease: cystic (+) protein <2 old, PKD: large cystic
kidney disease eg. +I- WBCs kidneys
PKD, CAKUT DM. infiluative
Infiltrative disease disease: large
Cl\ronicTlN kidneys
Postrenal ObsrrucUve uropazhy Minimal protein () hydronephrosls
RP fibrosis RP fibrosis: +/- hydro
. 36% w/ CKD have DM.31% HTN.and 40% cv disease (1018 USRDSanmIldau ftP°f¢l
C V a n d Al l C a u se Mo rta l i ty o f C KD
CKD a/w traditional CAD risk factors such as HTN. DM.smoking. HLD.older age.
and :he metabolic syndrome UASN 2®S:16§19)
4 eGFR, T UACR = independent risk factors for CV and allcause mortality (Ann IM
1007;167:2490: [ASN 1002.\1745)
CKD is CAD risk equivalent -» risk factor reduction is needed lcnmiiuin z00J;1oa;z1s4l
Nontraditional CAD risk factors: anemia (Ain I cnuiii 20(8:l02:166). inflammation l}ASN
Z004;15:530). <<alciurn balance for 100s;z1=z464). CKDMBD (nor z0os;z1:z4¢4)
Proportion of CV deaths. infections. DM complications T w/ . eGFR UASN 2015:16:1504)
Progression to ESRD
Injury -» Adaptive hyperiiltration initially LCr _> eventually CKD progression
Rate of transition 3 4 CKD - ESRD: 1,5%lyr (AmIM z004:141:9s)
Pts with uncontrolled HTN. DM, and CKD lose -12 mUm in GFRlyr.When treated
4 mUm in GFRlyr In z001:s9:7021
2 and syr kidney failure risk can be predicted with 4 or 8 variables it zoi 1=:0s1ssJ1
WE* 2016;315:164.a~:ilahlu at o»(mD'>
 GENERAL CKD TREATMENT
Evaluate Etiology and Treat Reversible Causes
dlc potential nephrotoxins;prerenaI: hold diuretics. unSAIDs. RASi
Renal UlS to J for obstruction
If Not Reverslble Goals Should Be
Slow progression: adjust medications by eGFR; management of complications
Refer to nephrology when GFR <30. UACR 2300 mglg. glomerular hemawria. or
CKD of unknown eciologyaprepare for RRT

CKD TREATMENT To SLow PROGRESSION

Blood Pressure and Protelnuria Control in Nondiabetic CKD
In nonproteinuric CKD pts. SBP >130 a/w ? CKD progression (A IM 1015:l61:1SB)
L BP in nonproteinuric CKD pus has not slowed CKD progression but l morality
(;ASNz011;28za12>
In proteinuric CKD pos. L BP (SBP 110-129) 1 CKD progression (A/mlm 1003;13911441
In nondiabetic CKD pl.s w/ proteinuria 2500 mglday.ACEi i CKD progression vs
other antihypertensive: (;Asr4 2007;18:19S9).
RASi LCKD progression in proteinuric pts Independent of BP (lnnm I 998:352:1252).
RASi i CKD progression in advanced. proleinuric CKD (N£lM 2006354 131)
Combo ACEi +ARB did not L CKD progression or i mortality T serious adverse events
(ONTARGET Inna( 200&371:547)
Blood Pressure and Protelnuria Control in Dlahetlc CKD
10 mmHg J. SBP J. 12% renal failure. and 1. 5 mmHg 1 cv events we z0003z124121
RASi > other antiHTNsve meds iCKD progression INE;/VI 1001:14s:as11
RASI 1 CKD progression independent of BP effect (~5/m 1991;329114s6; new 20019459611
Combo ACEi and ARB did not LCKD progression or i mortality serious adverse
events (VANEPHI\OND NEW 2G13;369:\091)
Glycemic Control In Diabetic CKD
InT1DM, intensive glucose treatment to nearnormal levels may 4 CKD progression
(DCCTIEDIC NEjM 201156512368
In T2DM. HbA1 c of 7.0% vs 7.9% 1 CKD progression luxros Lancer iweasmsm
SGLT2 inhibitors 1 CKD progression in TZDM (enpA.Rsc ourcoms ~4m 2016:37s8m>
1 kidney failure and CV events (caeosncs NUM 2019138011298
Treat to goal HbA1 c - 7.0% to icxo progression We mizmasol
Other Treatments
Low protein intake -0.8 glkgld may x related deaths lam-nie Canoe" so a¢y 1n09.cnao1a9zl
Smoking cessation: L CKD progression UASN 1004;15:S58)
NaHCO; PO mgT ID (if [HCOa] 16-20) T to target [HCO)] 223 1 CKD progression
and improves nutritional status UASN z009;m107s>
Multifactorial therapy (diet. exercise, smoking cessation.ACEi, and statins) 1 CKD
progression (NE/M 2uoJ;z4e:3a3)

TREATMENT OF CKD COMPLICATIONS

 Hyperkalemia Emergency if K >6.5, symptoms or ECG changes: stabilize ardlac
myocytes (IV Ca) then shift K (insulin 4 glucose. IV bicarbonate. D2
adrenergic agonists) den eliminate from the body (diuretics +I- saline.
sodium polystyrene sulfonate)
Lower K in nonoliguric or planning surgery: low K diet, stop offending
agents (eg,ACEllARB. unSAIDs), NaHCO;. diuretics. cation exchangers
Gl cation exchangers
Paliromer. s/e: l Mg. binds other meds (NE/M 101$;)72:111)
Sodium zirconium cydosilicate: exchanges Na and H for K
sie: edema (HARNONIZE We 2014::i 1};121])
Avoid Kayexalate +I- sorbitol unless lifethreatening hyperkalemia given
risk of colonic necrosis
Plneler T BT dlt uremic toxins. anemia. T platelet NO synthesis
dysfunction Correct it active bleeding or invasive procedure (eg. kidney biopsy)
To DDAVP 0.3 mcg kg IV 1 hr prior to invasive procedure.hepanin4iee HD
or PD. tx anemia to Hb > 10 widi resistant bleeding add cryoprecipitate
Malnutrition Caused by uremiarelated anorexia, decreased intestinal absorption and
digestion. and metabolic acidosis
Maintain die: w/ 30-35 kcal/kgld and 0.8-1.0 glkgld protein
Check dry weights and serum albumin if decreasing -» star: dialysis
Anemia 1 EPO production by the kidneys normocytic normocliromic
Background [Hb] <13.0 in males and <12.0 in females.
T prevalence wl CKD progression: 1% eGFR 60, 9% eGFR 30. 33-67%
eGFR 15 (new it 2002;16z1401l
/RBC indices, relic count. iron.TIBC. ferritin.WBC w/ diff, platelets.and
Biz and folate if MCV >100
If anemia + off ESA, monitor every 3 mo
Anemia - Iron Iron deficiency 4 ifTSat 520% or lenritin $100 fig/mL
Iron may * Hb ifTSa: 530% and ferritin $500 nglmL
Oral iron: 65mg elemental iron QD or QOD (1-3 mo trial)
IV iron (iron dexinn.ferric carboxymaltose. sodium ferric gluconate
complex, ferumoxyiol. iron sucrose. ferric pyrophosphate citrate) it
severe deficiency or no T Hb w/ oral iron
Anemia - ESA Address correctable causes of anemia prior to ESA
Treating anemia no nornormal Hb in predialysis CKD wid\ darbe T smoke
F1NSAT new zuntaaifnm
Consider ESAs if Hb <10 to prevent blood transfusion
Goal Hb 10-11.5
Dont use if malignancy. severe HTN, recent stroke
CKDMBD POW retention, i Ca. 1 calcitriol, T FGF23 and 1 klotho
Background 1st step: PO 4 retention -> 1 PTH who mummy
t PTH. l. calciuiol when eGFR <60 tqasn zuo9,4;\a4. Kl z007:71=3\1
T P04 when eGFR <30 (POW controlled as higher eGFR due to T FGF23
and PTH uAs~ Z09$;16:120S)
CKDMBD /serial POW. Ca, and PTH levels. Imaging, bx not yet used for o<
Treatment Tx Phos to normal w/ diet and phos binders
Non-Cabased phos binders > Cobased u4(\12013;:arma1
If PTH Ting -9 correct T POW. 1 Ca.l vitamin D
Cakiuiol or vitamin D analogs if severe and worsening T PTH
No vitamin D (nutritional or active) if Ca 29.5 or t P04

ENDSTAGE RENAL DlSEASE (ESRD)

Definition (2018 USRDSAnnud Dao Raven)
Defined by CMS as a condition in which regular longterm dialysis or KT is neces
sary to maintain life. ESRD includes chronic HD. PD. or slp kidney transplant
Results from :he progression of CKD or if AKI persists for 23 mo
Epidemiology (20152018 usaos AwmI Do Report)
The USRDS database contains UTD info on epidemiology
726.331 prevalent ESRD cases; 124.675 incident cases in 2016
ESRD prevalence is 9.5x > in American Indians/Alaska Natives. 3.7x > in Blacks.
1.5x > Native Hawaiians/Pa¢:iGc lslanders.and 1,3x >Asians than Whites
Prevalent ESRD with DM 40%:T cognitive impairment in HD (nwwqy 2006:67:1I 6)
 Prevalence of depression in ESRD pts is 3040% (Kl101J>s4=I7v)
35.4% with little or no preESRD nephrology are; mean eGFR at dialysis initiation 9.
Renal Replacement Therapy (1018 urns Aiuunl Dan Know)
87.3% incident ESRD pts iecewe HD,9.7% PD.and 2.8% a preempthie kidney transplant
• 63.1% prevalent ESKD pts receive HD. 7.0% PD. and 29.6% have a kidney transplant
In 2015.home dialysis (HHD or PD) accounted for 8.6% of prevalent dialysis pts
80% use a catheter at HD initiation
62.8% HD pts use an AVE 80% were using an AVF or AVG at 1 yr after initiation
39% ofAvFs fail to mature: median time to first use ofAVF is 108 days
Prognosis of ESRD 4 z017z01s usaosA~»\»l Day m9-=f=1

Survival: transplantation w/o dialysis > transplantation after dialysis

Mortality 265 yr T 7x than general population
ESRD pts are hospitalized . Zxlyr
48% of deaths in dialysis 7J2 CV causes (arrhyd\mias.cardiac arrest. C H E A M L A S H D )
I mortality on Monday orTuesday aker a long weekend <~€Jm 1011:3651099)
Stalins do not J. CV risk 4si4Aru= lame: 1011:377:11B1)
1 K HD bath a/w arrhythmias (Vu 19002171a11l
Medicare spending on ESRD in 2016 was $35.4 billion (72% of overall budget).
$28 billion on HD and $90,971lpt/yn PD costs < HD per pt
Treatment of ESRD
Diet. exercise Sodium, potassium. phosphorus, and liquid restriction
we zouo.as:s17l Protein intake for HD and PD = 1.2-1.3 g/kgld
Energy invoke for HD and PD = 35 k<1II*s if <60 yo and 30-35 kcal/
kg if 2 60 we louaas$n
Exercise is a/w improved health outcomes (Ago 2014;s43BJI
Adequate dialysis Target a deiivened KW of 1.2 per HD session. No T beneNzs
(moon Aero z01 s=seas4= from 1 KrlV... memo NeIM 200z147¢z010I
W)2M1l&$"] Minimum of 3 hr HD with a biocompatible membrane
For PD. target a minimum KtlVurea of 1.7/Wk (residual kidney
function + PD clearance)
No f from T KdVurea lAnv£x M94 z0oru1s0n
Volume Overload Optimize dry weigh!
Chronic fluid overload T mortality (C[A$N 1015.moa1
T ultrafiltration rates (>10 mUhr/kg) T CV mortality (KJ 7.0\1:79:1S0)
HTN SBP <120 and SBP 2150 T mortality uAsr4 zoos;w;sn»
L BP with antihypertensive: 1 CV events wwuie.=»=~ zno9.s:¢as0l
No RCTs of BP targets in ESRD
Tx: 1st step is L dry weight to achieve euvoleni;Target 0.5 kg ,T per
session.Then consider medicadon [iB. RASi. DHP CCB
Bblocker 1 CV event.. hospitalizations in HD prs w/ LVH war
2014;2%672)
In PD. RASi preserves residual renal function WM u104.4J210s0l
Hyperkalemia Emergency if K >6.5.symptoms or ECG changes: stabilize cardiac
my<oytes. shift K, then emergency dialysis
Urgency if K 5.5-6.5:stabilize.shifL then urgent dialysis win 6-12 hr
For dialysis pts with chronic t K, use GI cation exchangers
Avoid low K HD bath:T arrhythmias in \9sixinin
Anemia Evaluate monthly: IV iron ifTSAT <30X and ferrite <500 WmL
txt:>l<;oA»~nn MII) and no active systemic infections
E845 when Hb 9.0-10.0: stop ESAs when Hb >11,5
CKDMBD Evaluate POI. Ca, and PTH levels serially
It(DiGO man zom Treat T POl wl diet and binders: restrict dose of Cabased binders
Non-Cacontaining POl binders: sevdamen landlanum.fenic citrate.
sucroferric oxyhydroxide
Dialysate [alciuml 2.5-3.0 mErelL
Maintain PTH at 2-9 x ULN of assay wl caldmimedcs or vitamin D
analogs; severe T PTH: parathyroidectomy
 90% of adolescents and young adults (AYA) w/ special health care needs survive into
adulthood.Adult services have increasing numbers ofAYA who have either transi
zioned from pediatric care or presented directly to adult services.
Medication adherence worsens posttransfer (Miami nqinmi 1009;24:1055)
17-24 yo :up recipients have higher graft failure rate than older irimqiimuan zoiiazmn
Some childhood onset renal diseases have new clinical manifestations in adulthood.
eg. cystinosis: DM, myopathy. pulmonary, and CNS dysfunction (Non hdau 10I 7i3I191)
Childhood kidney disease even w/ nl renal function is a/w adult ESRD (Ng/4 zomm428)
AYA w/ CKD has impaired sense of selfworth. perceive a precarious future. and feel
limited in their physical and psychosocial capacities We 2013 61975)
Health Care Transition (HCT)
Purposeful. planned efforts to address the biopsychological needs of early adolescents
(11-15 yo). late adolescents (16-18 yo). and emerging adults (18-25 yo)
Goal is co ensure AYA obtain selfmanagement knowledge and skills necessary to
manage their daily treatment needs as independently as possible and become a liter
are health consumer u Alan" NW, Z017:35:160)
Transfer of Care
Dual process of locating & arranging 1°. specialty.& interdisciplinary providers who
provide care to AYA as their eligibility provided by pediatric providers ends
Actual shift from pediatric to adult care
Consensus Statement From lSN and IPNA (KI z011=aw04)
Only transfer AYA following assessment of transition process and AYA preparedness
Health Care Transition Process should:
. Include key supporc parents, family, or significant others
Offer opportunity of informal visit to adult service prior to transfer
Tools to aid in acquisition of disease selfmanagement skills
Transfer from Pediatric to Adult Nephrology
Individualized transition plan, agreed upon jointly by AYA and medical team
Should take place during a period without crisis
Take into account treatment plans by other subspecialties
. Take place with due consideration of financial factors,with adequate preparation

TRANSITION STEPS
Extended HCT Preparation (12-18 yo)
Plan of care with measureable outcome.with derailed timeline
HCT coordinator tocl1ampion"Ilead uansidon,coordinate reie11als.hald1 are coverage
Age of majority (18 yo or on graduation from high school in AK. NV. OH.TN. UT.
VA,WI) needs to be considered.discussion of guardianship. HIPAA
Discuss changing role of parent from 1 caregiver to :hat of coach/consultant.AYA as
CEO of own health
Transfer of Care Period (18-21 yo)
Pediatric providers can provide resources for adult providers
Direct handoff between pediatric and adult providers. with a Transfer Summary
Transfer Summary: comprehensive written and verbal summary of all multidisciplinary
aspects of young persons care: medical. Nursing. Dietary. Social and Educational
Post HCTlTransfer of Care Period (>18 yo)
Documentation that transfer has taken place and AYA connected with adult providers
Assessment ofAYA knowledge & skills; identify and adult 1° care provider and dentist
Review an emergency plan,whom to contact if ill or needs re6lls
Assess ongoing insurance coverage-referral to Financial Coordinators
Discuss future goals with AYA alone and with support system
lnuoducdon ofAYA to key clinic staff: consultation letter to referring pediatric provider
Knowledge and Skllls Assessment Tools
Got Transition/Center for Health Care ht:p:/IwwvLgo:tr:nsizion.org/
Transition Improvement
U. North Carolina STARx Program https:llpediazrics.med.un¢.edu/transition
Transition Readiness Assessment Questionnaire httpsul/ etsu.cdu/com/pediatricsltraq
 RENAL FUNCTION
PURPOSES OF RENAL FUNCTION ASSESSMENT
CKD staging: allows adherence to stagespecific management guidelines
Reduced renal function is one marker of kidney damage along with: albuminuria.
abnormal urine sediment (eg, glomerular hematuria). renal tubular disorders. abnor
mal pathology. abnormal imaging (et, polycystic or dysplastic kidneys or cortical
scarring). and kidney transplantation (KDICO CKD 2011)
Mediation dosing adjusunencs based on renal function
Prognosis: eGFR associated MM renal outcomes (development of ESRD),cardiovascular
outcomes. and allcause death 1~£1m 1013:369932)
Transplantation donor evaluation

MEASUREO GLol4snuLAn FILTNArlON RATE (mGFR)

Administration of exogenous hluadon markers (insulin, iohexol. iothalamate. EDTA)
followed by serial measurements of blood/urine concentrations over time
Most accurate assessment d renal function; imp4acdal for routine use d/t cost, complexity
Does not provide a quantification of tubular function

CREATININE
Organic cation, metabolic byproduct of creatine from muscle and dietary meat
Not reabsorbed or metabolized by kidney
Secreted by organic cation uansporters in PCT
Increased secretion in late sages of CKD
Conditions That Change Serum Cleadnlne
1 Creatinine Creatinine
T GFR 1 GFR
1 Generation: 1 muscle mass T Generation: T muscle mass/bodybuilder. upper extreme
(limb loss. cachexia, cirrhosis. of height
lower extremes of height) T Intake: creatine. high mea: diet
T Secretion: hypoalbuminemia J Secretion: cimezidine. trimethoprim, pyrimethamine,
in NS (nor 200$:20.707) dolutegravir. rilpivirine. cobicistat, ritonavin
amiodarone. dronedarone. ranolazine
Peritoneal reabsorption: uroperitoneum from bladder
rupture (NDI 20069111119). ureter leak
Cross reactivity in alkaline picrate method: atetoaceme
in DKA. celoxitin. ilucytosine

RENAL FUNCTION IN CKD

Creatininebased Estimated GFR (eGFR)
In steady state.creatinine level can estimate GFR by MDRD or CKDEPI equations
Use serum Cr, sex.age. and race to calculate eGFR
Decreased precision at higher levels of GFR (CKDEPI better dun MDRD).and possibly
in advanced age and race other than white/black
Blood Urea Nitrogen (BUN)
Filtered but passively reabsorbed in the proximal tubule
Rises more than creatinine in volume depletion or renal hyperperfusion
Not affected by above conditions affecting creatinine level. but overall a less reliable
indicator of kidney function
GFRindependent e BUN: GI bleed. corticosteroids. high protein intake. catabolic state
(fever. burns)
GFRindependent 1 BUN: low protein intake/malnutrition. liver disease
Cystatin C-based eGFR
Endogenous protease inhibitor produced by most nucleated cells at stable rate
Cysratin C generation displays less interperson variability tl\an Cr
Affected by smoking.thyroid disease,corr.icosteroid use
Alternative CKDEPI equation using both cystadn C and creatinine performs best
(NEW 2012:367:20)
Other Crbased eGFR formulas (CAPA. BIS) not shown to outperform CKDEPI
UAS~2015:19811
Limitation: cystatin C assays not as well standardized as for Cr
Timed Cr Clearance (C,) and Urea Clearance (C.,,,.)
Measurement of serum Cr and urea and umed urine Cn urea and volume
Practical alternative to measure GFR In patients for whom eGFR is inadequate
(e g . kid n e y d o n o rs. p rio r to ch e mo th e ra p y)
C.,,.: underestimates GFR due to passive reabsorption of urea in the PCT
C". overestimates GFR due to secretion of creatinine in the PCT
Mean of C.,.., and Cu: partially adjusts for these limitations
Limited by accuracy of urinary collection: over or undercollection can lead to
e xtre me ly in a ccu ra te e stima te s

Estimated CrCl (Cockcroft-Gault Equation)

CrCI (mUm in ) = [ (1 4 0 age) x weight in kg x 0.85 (if female)]l(72 x SCr)
Less accurate estimation of GFR than eGFR, should not be used in routine clinical
p ra ctice fo r CK D id e n tifica tio n a n d sta g in g
Many drug dosing recommendations are based on CrCI instead of eGFR
N u c l e a r Re p ro g ra m
Can b e u se d to e stima te th e re la rlve co n zrib u rio n of each kidney n o o ve ra ll re n a l
f u n ct io n (e t , p rio r t o n e p h re cmmy)

RENAL FuncTion ON RENAL REPLACEMENT THERAPY

• Residual kidney function for padenzs on HD/PD assessed using timed urine collection
of creatinine and urea
May be able to use serum [Strace protein. [32microglobulin,cyszazin C rather :han
using collection. bu: not common practice (m 1016:89.\099)

R EN A L F u n cT io n IN A K I
Cannot use eGFR in AKI blc Cr not at steady slate (ACr lags behind AGFR)
Changes in UOP may be informative. but cannot be relied upon since UOP an be
preserved even after large decrease in GFR
Kinetic GFR estimate (KeGFR) uses rate of Cr change to estimate GFR when Cr Is
not an steady state (1Asr4 2013:24:577;lvailahll as Q»<mD')

URINE STUDY
URI NE DI P S T I CK

Should wa it for 3 0 s -1 min be fore re a ding

Urine dipstick is semiquantitative assay

Specific Gravity (SG): relative weight (mass) to water

Osmolality is concentration of dissociated solute particle number
Ead\ 0.001 rise from 1 - t 30-35 mOsm/kg when urine solutes are Na. K.NH* url only
SG overestimates osmolality when urine contains hwy sdureszghicose. protein,conuast
SG underestimates osmolality after saline diuresis (Amy mm so 200zm39)

I nte r pr e ta ti on of S G
1.aca-1.012 Isosrhenurla Similar SG of plasma
Possible concenxrarion defect In ATN. CKD
<1.008 Low SG .L ADH: DI. 1 polydipsia; inner diluting capacity.
(hyposrhenuria) impending Na rise w/ water reszricrion
>1.012 High SG T ADH: dehydration, volume depletion

p H (n o rma l: 5 . 5 -6 . 5 )
<5.5 in metabolic alkalosis: nonbicarbonate nonreabsorbable anions. et. cicarciilin,
carbenicillin, piperacillin (CjASN 101*r 14:306)
L: metabolic acidosis.1 protein diet volume depletion (T aldoinduced TH excretion)
T: vegetarian diet. unease (urea -» CO1 + NH;)forming bacteria.ATN
>8: urea splitting organism
>6.5: bicarbonate in urine: high pH suggests NN in hypokalemia uimjme42017;1J0B46)
>5.5 in NAGMA: dRTA, hypokalernia ( ammoniagenesis). toluene
P ro t e in (n o rma l: n e g a t ive )
Trace. 5-20 mgldL; 1+. 30 mg/dL: 2+. 100 mg/dL; B+. 300 mg/dL: 4+, >2.000 mg/dL
<1+ rules out urine albumin creatinine ratio (UACR) 2300 mg/g (Ajxb 201\;58219)
Highly sensitive to albumin. but cannot detect microalbuminuria (<3 mzldL)
 Less sensitive to globulin or light chains. Suspect B]P when a dipstick test shows
trace to 1+ protein yet a turbidity test for urine protein shows 3+ proteinuria
(+) in renal impairment. suggestive of glomerular injury
(-) in renal impairment. suggestive of tubulointerstitial injury
False (+) buffered alkaline urine

Blood (normal: negative)

Detects pseudoperoxidase activity of hemoglobin and myogfobin
Punctate staining: 1-4 RBCIHPF hematuria
Homogeneous staining: free hemoglobin or myoglobin. False (): ascorbic acid
Leukocyte Esterase (normal: negative)
5-15 WBC/HPF will give a positive granulocyte esterase reaction
Lymphocytes in chyluria will not produce a positive test
False (+): contamination with vaginal fluid
Nitrite (normal: negative)
Urine nitrate is converted by nitrate reductase of Enterobacteriaceae
(~) with nonEmerobucterioceae bacteria; False (+): dipsticks exposed to humidity
Glucose (normal: negative)
Glucose oxidase reaction. allowing semiquantitatlon for glycosurla
(+): hyperglycemia >180. proximal tubular dysfunction (Fancohi syndrome).SGLT2
inhibitor or mutation, familial renal glucosuria (qA$N 201&$:133)
False (-): ascorbic acid
Ketones (normal: negative)
Detects acetoacetate and acetone. Does not react with Blvydroxybutyrate
(dominant ketoacid in alcoholic ketoacidosis).
Bilirubin (normal: negative)
Detects conjugated bilirubin; small fraction that is not reabsorbed in die PT
Unconjugated bilinubin binds to albumin and does not pass glomerulus
(*): obstructive or hepatocellular jaundice
False (+): chlorpromazine.phenazopyridine:delta bilirubin (albumin bound bilirubin) in
prolonged cholestasis
False ():ascorbic acid
Urobilinogen (normaI:0.2-1 my dL)
Conlugated bilirubin is metabolized to urobilinogen by bacteria in die colon
Not reliable for detection of porphobilinogen in porphyry
T: hepatocellular jaundice. hemolysis; (): obstructive jaundice

URINE Ssomsm EXAMINATION av Mlcnoscors

Procedure
Spin 12 mL of clean catch urine in a centrifuge tube at 3.000 rpm for 5 min
Completely invert the centrifuge tube. Resuspend the sediment in the urine that
drains back down from :he side of the tube. Flick the bottom of the tube to mix the
sedimemAspirate the sediment with a clean disposable pipette. plate a drop of sedi
ment onto a microscope slide. and cover with a cover slip.
Examine the sediment (wet mount) with subdued light by partially dosing the iris dia
phragm and lowering the condenser of the microscope until optimum contrast is
achieved.The fine adjustment of the microscope should be continuously adjusted up
and down to see die depth of the oblect as well as other structures that maybe on a
different plane.
Scan the entire cover slip under lower magnMcation (x100) and then turn to the
highpower magnification (x400) to identify specific cells and casts. Pay special atten
tion to the edge of the coverslip where many casts tend to accumulate.
Quantify and report casts as numberllowpower field (LPF)
Quantity and report cells as number per highpower field (HPF)
Stains are useful in specific instances.
SedlStain: cellular elements: Gram stain: bacteria or fungi
. Hansel stain (a modified Wright stain): eosinophils and other cellular elements
Sudan Ill stain: oval fat bodies (OFB). fat globules. and fatty casts
 Urine Sediment Findings
Findings Comments and Possible Causes or Associated Conditions
Cells
RBCs Dysmorphic: glomerulan eg, glomerulonephritis. vasculitis
Isomorphic: extraglomerular. kg. interstitial nephritis. UTI. trauma.
stone. or tumor
WBCs UTI. interstitial nephritis. glomerulonephritis
Epithelial cells Desquamated cells from renal tubules. urinary bladder. vaginal
epithelium. urethra. or foreskin
Oval fat bodies Sloughed renal tubular cells containing lipid droplets, typically seen
in nephrotic syndrome but may be seen in polycystic kidney
disease and Fabry disease
Bubble cells Vacuolated renal tubular cells seen in acute tubular injury or tubular
necrosis UASN 199 l:1:999)
Casts: cylindrical structures in the tubule lumen;Tamm-Horsiall protein is matrix
RBC or Hb asks GN.vastulitis
WBC casts lntersuiial nephritis. pyelonephritis or GN
Fatty casts Nephrotic syndrome
Tubular cell casts Renal tubular injury/ATN
Granular casts Dark muddy brown granular cast is alw ATN
Waxy casts Advanced renal disease
Hyaline casts Benign
Crystals: solid particle with a geometric shape men 1016:J745:2465)
Calcium oxalate Envelope or needle shaped
dihydrate or Ethylene glycol poisoning (NEW 2017377314673 And /1444 l98GI4:l45),
monolvydrate hyperoxaluria, hypercalciuria
Caidum dwosphate Asymmetrical rodshaped aggregates; in hypertalciuria, renal stone
dihydrate (bmshke) disease
Uric acid Rhombic plates or lOS¢ll£S. In many forms in acid unine.seen in
healthy individuals: in patients with gout. hyperuricosuria. after
recurrent seizure. after propolol anesthesia. renal stone disease.
and heat stressrelated Mesoamerican nephropathy
Cystine Hexagonal.Cysdnuria: . PT reabsorption x cystinosis
Triple phosphate Coffin lid shaped in infected urine or alkaline urine: infected renal
(struvite) stone disease
Sulfa drug Sheaves of needles on sulfadiazine in volume depletion
lndinavir Starburst form in HIV patients i/~» IM 1997;127:1191
Acyclovir Needleshaped crystals in sediment or inside WBCs;Valacyclovir or
acyclovir toxicity
Bacteria UTI.contaminauon. or overgrowth after prolonged standing
Yeasts or Fungi UTI,contaminations: prolonged indwelling Fol catheter

URINE LABORATORY TesTs lqAsn 201214¢309

Random Spot Urine Collection
Convenient: affected by diurnal variation; both random and timed always need Cr level
Timed Urine Collection
24hr: gold standard for many IESIS. but susceptible to over or undercollection
Creatinine should be checked together to monitor collection adequacy
If nonrenal excretion is negligible and not produced or metabolized in body. reflects
intake in steady state
Can be used for concentration: et. UPEP
Urine Creatinine, Spot (Random)
Should be checked with other quantitative spot urine assays to correct the effect of
urine volume or to consider the amount of glomerular filtration. eg. Fractional
excretion (FE) and random protein/creatinine ratio
Higher than in the serum. Used when suspected urine leak. eg.urinoma dlt post
transplant fluid collection or kidney trauma. urinothorax (pleural effusion from urine)
Urine Creatinine, 24hr
Significant variation in 24hr values suggests over or undercollection
 Estimated 2 4 h r Urine Creatinine Level (mglkg) (n4luun 1976:16:31)
= 2 8 - (0 .2 x a c )

Age 20 30 40 50 60 70
Male 24 22 20 18 16 14
Female (10.85) 20.4 18.7 17 15.3 13.6 11.9

Can be used to calculate CrCl (¢ eGFR due to tubular cieatinine secretion)

Urine Osmolality (Umm. mOsm/kg):ADH Actlvlty
Number of solute particles per unit volume: mainly Na and K salts and urea
Correlates with aquaporin2 activity controlled by ADH
Ranges 60-1.200 to remain plasma osmolality widlin 275-290 and extracellular volume
Aging is aM decreased concentration and diluting capacity: range decreased co 100800
U ri n e Osmo l e s, 2 4 h r
600-900 mOsmolld with normal die: and renal funcuon
Low urine osmoles: low protein, low sodium diet (beer. tea and toast), malnutrition;
CHO and alcohol 1 endogenous protein catabolism; l water excretion (}A$n zaosneiom
High urine osmoles: osmotic diuresis (hypernatremla).sak wasting (hyponatremia)
Urine Protein and Albumin
Random: protein or albumin (rngldL)lCr (mgldL) - 2Mr protein or albumin (g) excretion
24hr: gold standard for prowinuria evaluation
Fractional Excretion (FE)
The percent of filtered solute that is excreted in the urine
Used to evaluate renal handling of the solute excluding the effect of water reabsorption
FE of solute X = Quantity of X excreted in the urine/Quantity of X filtered
(u, )<V)l(S, x CrCl) = (U,JS,)I(U<,IS.)
U . urine concentration of X.S,: serum concentration of X.V: urine volume
Depending on solute.filtered fraction should be considered. eg.0.7 x serum Mg is
filtered dlt protein binding
U rl n e So d i u m (u m)
Sodium avidity (low level): reflects RAAS activation and sodium ieabsorption
24hr: approximate measurement of dietary sodium intake; nonrenal excretion is
unable >10 mEqld; B7 mmol = 2 g: 100 mmol = 2.3 g
UN,/UI< <1 in minenlocorticoid excess (hypovolemia. hyperkalemia)
Fractional Excretion of Sodium (FEm)
In AKI <198 volume depletion. CHF. liver cirrhosislHRS.nephrotic syndrome, severe bum
Vasoconstriction: iodine CIN, rhabdomyolysislhemolysis, sepsis (Cm Can 1013=17=R234).
acute urinary obstruction. acute GN. acute allograft reiecdon
T by diuretics: furosemide can achieve 8% of FEn. (lm um: ~q=»~~=1 z010,41:2731
If <B%.other sire inhibition would be necessary. eg.thlazide
Urine Urea Nitrogen (UUN)
FE.,.,,: 1 in volume depletion (d/t T reabsorption) and adrenal insufficiency: not affected
by diuretic
Urea clearance: used to estimate residual kidney function in dialysis patients
Protein catabolic rate (PCR, protein equivalent of nitrogen appearance) can estimate
protein intake if nitrogen balance is even and protein catabolism is not significant
(steady BUN with steady renal function)
Da i l y Ni troge n Ba l a nc e
Input O u tp u t
Protein invoke Urine urea nitrogen
Endogenous protein catabolism Nonuiea nitrogen excretion (g. nonuio urinary nluugen +
fecal urea excretion) 0.031 x weigh: (kg) in 19952758)
Protein (nitrogen) intake - urine urea nitrogen + nor urea nitrogen excretion
x 6 .2 5 to c onv e rt nitroge n (g) no prote in (g)
et. 60 kg. Up 7 old: weight normalized PCR = [(7 + 0.031 x 60) x 615]/60 0.92 glkgld

F ract io n al Excret io n o f Uric Acid ( F Eu d )

L in volume depletion dlt T reabsorpdomnot affected by diuretic use
>12% in SIADH ucem 2o0a;9a¢1991l.rhiazideinduced hyponarremia UG 2017:127:nsn
Urine Chloride (UCI)
Low Ucl in metabolic alkalosis Cl responsive requiring NaCl
Un, may T due to other anions: bicarbonate. ticarcillin. carbenicillin. piperacillin
High Us in metabolic acidosis due to NHL
In hypokalemia Un.IU¢, >1.6 suggests NN <0.7 suggests Iaxacive (Am m¢4 z017;1ma4e)
Urine Anlon Gap (UAG) and Urine Osmolal Gap (UOG)
Used to estimate NH( renal excretion in NAGMA: NH( <40 mmol/d is dw dRTA
Urlne Anton Gap (mEaL or mmoIIL) = Un. + Un - Us
Negative Positive
Appropriate distal tubule nH.' excretion: Inappropriate nH.* excretion in NAGMA:
GI HCO1 loss (diarrhea) dRTA and type 4 RTA
Ingestion of NH4Cl Appropriate NHi excretion with
pRTA due to T unmeasured action unmeasured anions in NAGMA:
(NHL) wlo significant change of unmea Bicarbonate (alkali dierapy for pRTA)
sured anion -» unmeasured cation Bhydroxybutyrate and acetoacelate
(NHL. Calf r48*) >unmeasured anion Hippurate (toluene)
(HCO; , $04 .PO4,other organic Dlactate (Dlactic acidosis)
anions) INEW 198&J1es941 5cxoproline (acetaminophen)
Typical Western diet (10-90 mEaL) wlo
NAGMA lA»n;m¢asa 19412911981
Respiratory alkalosis: can be used to
differentiate from NAGMA when ABG is
unavailable u 1017;7Q440)
Urine Osmolal Gap (mOsmollkg) = Measured Um - Calculated Uwn
Calculated UW.. = (2 x [U* + Url) + [u.,,, (m8/dL)]/78 + [Uucp~»~ (mgldL)]/18
>Z00-400 <150
Appropriate NHL excision in: GI HCO; Inappropriate NHi excretion w/ NAGMA:
loss (diarrhea), pRTA dRTA and type 4 RTA
Unease-producing bacteria: formation of Healthy individual wlo metabolic acidosis:
NH/ in :he bladder or container 10-100
Osmotically act solutes: mannitol.
methanol. ethylene col

In advanced CKD, UAG is a poor surrogate for nH. excretion ac;Asn z01s:13:z0s)
Solutefree Water Clearance (Cl4,0)
Urine f1 ow (V) = Osmolal clearance (C.,,...) + Free water clearance (Cl41O)
C.; the volume needed to excrete all solul.es as the concentration of plasma csmolality
Caw :V x U 0¢m'P°w
C12o. a theoretical volume of solutefree water that is added to or reabsorbed from
the soosmolal urine to create eidler a dilute (hypoosmolal) or concentrated
(hyperosmolal) urine
Cu,o =V _ Cm-V - (V x U,,,,JP.,,,.,) =V x (1 - U../Paw)
U,,JP.,,,, determines the direction of solutefree water How: excretion vs ieabsorption
U.,,JP.,,,.. <1.0. dilute. (+) C:l,Q.the addition of a soluteNree water to the soosmolal urine
U°,,,JP..,.. >1.0, concentrated. (-) C»4,o reabsorption of solutefree water from the
soosmolal urine
Electrolytefree Water Clearance (C'u1°)
Since the calculation of Cu,o has included ineffective osmoles such as urea. which
plays no role in transmembrane water movement and body fluid tonicity. C»42o may
not be accurate in reflecting renal excretion or reabsorption of electrolytefree water
Instead. evaluation and calculation of C>420 will provide a more accurate assessment
of renal response to change in water metabolism (Am) m¢4 1986;81:1033)
C»i,o =V * [1 ... (Un * UI<)/PN.]
In a patient on high protein feeding who develops polyuria and frypematremla from urea
osmotic diuresis.d\e Cu,o value may remain ().as a result of high urea content musing
Um > Pm., thus suggesting continued reabscrpdon of free water: However. due calculation
d C'14,<0 will give a (_) value and accurately indicates continued renal loss d electrolyte
flee water widi resultant development of hypematremia. requiring free water replacement
(U- + UK)/Pn, for bed side evaluation of patients with hryponatremia or hypematremla
(U* + U»()lPN. 21.0: zero or (-) C'»4,0 no loss of electrolytefree water
(UN, + Ux)/Pro <0.5: (+) C,4,0. renal excretion of significant amount of electrolytefree
water i; Med so 2009t 319:140)
 Urine Laboratory Tests in Appropriate and Inappropriate Renal Handling
Causes of Inappr opr iate Renal
Urine Lab Appr opr iate in a p p r o p r ia t e H a n d lin g
Volume D epletion
Un. <20 >40 Tubular injury. sak wasting. diuretics.
UN,/(Un/Su) <1 >1 adrenal insuNiciency. metabolic
>2 alralosisc Na coupled w/ HCO:
FEn. (Ag) <1
excretion:AGMA: Na coupled wl
orpnic anions
Uo (mEn/L) <15-25 >40 Tubular injury, Sal: wasting,
diuretics. NAGMA: CI coupled
w/ NH( excretion
FEw (96) <35 >50-65 PT injury, acerazolamide. osmotic
Uw../BUN >20 <10 diuresis (mannkol. glucose). sepsis.
elderly
High protein diet and catabolism
FEud (Ag) <12 >20 PT injury
Um... >500 <3S0 Tubular injury. loop diuretic
U"/S" >40 <20 Inefficient water reabsorption from
Um"/Sm >1 .4-2 <1-1 .2 tubular injury
Specific gravity >1 .020 <1 .012
H yponatr emia
u... <100 >100 SIADH. severe renal failure. rhiazides.
volume depletion, Sal: wasting
Hyper natr emia
UM >700800 <700800 DL diuresis (osmotic. loop)
Hypokalemia
U: (mE~/L) <1 S-25 >30-40 Hyperaldosv.¢ronism,Vomidng. NGT.
24hr Up (mEq/d) <20-25 >30 Mg deficiency. dRTA, pRTA. DKA
U 1(/Uv (miqlg) <13-20 >13
TTKG <2-3 >4-7
Hyper kalemia
Un (mEq/L) >20-30 <20 Hypoaldosreronism
24hr Un( (mE/d) >40 <30 1 Na delivery to CD
Un(/U (m£q18) >30-200 <30 Type4 RTA
TTKG >7-11 <3-6 PHAGE,PHAGE
Hyper calcemia
24hr FEW (78) >2 <1 Familial hypocalciuric hypercakemia.
24hr Ca (mud) >200 <100 (Thiazide. milkalkali syndrome)
UcJUc I3/8) >0.01 4.01
Hypophosphatemia
rem. <5% >5% Hyperparazhyroidism.Vi: D def,
24hr Po. (mg/al <100 >100 Oncogenic osteomalacia: T FGF23
pRTA. Heredity hypophospharenic
tickets
Hyper phosphatemia
see. >1S% <15% Hypoparanhyroidism
Hypomagnesemia
F5.4 (use 0.7 x <2% >2% Renal washing
serum Mg)
24hr Mg (mg/d) <10 >10-30
 RENAL ULTRASOUND (UIS) \€1A$~ z0 I4,9.;ez)

Indications
Used to evaluate AKI. CKD.and as a guide for percutaneous renal biopsy
Can detect real cysts, nephrolithiasls. nephrocalcinosis. hydmnephrosis.ADPKD.
postkidney transplantation perinephric liuid collection (urinoma. hematoma. lymphccele)
Can detect nonrenal abnormalities: fluid collection, BPH. bladder retention
Kidney Size
Normal Kidney Length (mm, 10th-90th percentile) WR 1999;1SM3)
All 30s 40s 50s 60s 70s

Left 101-123 104-12s 103-123 102-125 100-122 94-120

Right 9a-122 101-124 100-123 100-122 95-120 91-118

Small (bilateral): CKD. renal scarring

Large (bilateral) hyperfikration (obesity. diabetic nephropathy). interstitial nephritis
(AIN, lgG4related disease). interstitial infiltration (lymphoma, amyloidosis. sarcoidosis).
HIVAN.ADPKD w/ multiple cysts
Asymmetric (>1 cm discrepancy) hypertrophy from contralateral kidney dysfunction.
pyelonephritis. RAS. renal infarction. renal vein thrombosis, congenital abnormality of
the kidney and urologic tract
Echogenicity: normally equal to or less than spleen and liver;sinus is echogenic
Echogenic kidney with combined length <20 cm a/w severe disease (KI 2005;67:1$15)
Increased conical echogenicity (>spleen.Iiver without fatty liver changes)
Alteration/intrinsic histology damage: interstitial inflammation and tubular atrophy
Increased medullary echogenicity with normal cortex: medullary nephrocalcinosis.
Tamm-Horsfall protein In tubules, sickle cell disease. medullary sponge kidney
Decreased cortical echogenicityc acute cortical necrosis, edema
Other Possible Markers of CKD
Kidney volume for 2aon4:1690); Conical tllickness We 1010:19$W146)
Hydronephrosis
Dilation of renal pelvis: high sensitivity for urinary tract obstruction
False (+) diuresis with nephrogenic DI. pregnancy: renal cysts. congenial megacalyces.
calyceal diverticula. parapelvic cyst. transplanted graft (when it is mild)
False (-): volume depletion. early acute obstruction. RP fibrosis, staghom calculi. infil
trative metastasis; can re J after l1 uid; consider retrograde pyelography
If finding is different from clinical suspicion.can J radionuclide scan or CT
Cystic and Solid Mass
Simple cysts: sharply demarcated with thin smooth walls.anechoic content. and strong
posterior wall echo: no further imaging is necessary
Complex cysts: calcifications. septations. mural nodules. internal echoes. majority are
not malignancy: still need contrast CT or MRI to try to exclude malignancy
Solid mass: need contrast CT or MRI
Duplex Doppler Ultrasound
Check flow of renal artery and veins: assessment for RAS and RVT
RAS: main renal artery to aortic peak systolic velocity ratio >3.5
RVT: reversed diastolic flow. absent venous flow, thrombus in venous lumen. t Rl
Ureteral jets. urine flow into the bladder rules out complete ureteral obstruction

Resisd¢e index (Rl)

0.56-0.66 normal
>0.85: nonspezific sign of microvascular compromise. eg. graft reiection.ATN urereral
obstruction. pyeloneph ritis
IndIcatIons
Noncontrast CT: for urinary stone (more sensitive than contrast CT in detecting
small scones). hydronephrosis (attenuation: renal parenchyma > urine > sinus fat),
localization of obstruction. chronicity of renal disease (cortical thinning)
Contrast CT: for complex cyst (for Bosniak criteria). mass. cancer staging, renal/
perinephric abscess, retroperitoneal Fibrosis, RMS, RW papillary or cortical necrosis.
infarction. adrenal masses
CT orography (wlo and w/ contrast): for hematuria with highrisk urothelial cancer
CT Findings
Calcification: stones. nephrocalcinosis. cortex (cortical necrosis,chronic GN). medulla
(tubular pathology. medullary sponge kidney. papillary necrosis)
Perinephric/periureteral siranding nonspecific sign of urinary obstruction. inflammation
Pseudotumor: various conditions can mimic malignancy (A}R 1007;18&13&)
Developmental: prominent columns of Berlin. Dromedary hump, persistent fetal lob
ulation
Infectious: focal pyelonephritis (/DMSA scan). abscess. scarring
Inflammatory: xaruhogranulomatous pyelonephritis, sarcoidosis. malakopkkia. lgG4RD
Vascular: AVM. hematoma. extramedullary hematopoiesis

MR I A N D MR A
For complex cyst. mass (esp. small lesion). RAS. pregnancy widl any indication of CT scan
slezgadoliniuminduced nephrogenic systemic Fibrosis (NSF)
In pa with stage 4-5 CKD, macrocyclic or newer linear (gadobenate dimeglumlne
and gadoxerate disodium) gadoliniumbased contrast agents (GBCA) can be adminis
tered when GBCAenhanced MRI is considered necessary and no alternative test is
available lcfin Assoc m4442018;69136)
MRA without contrast. such as phase contrast MRA is available

RADIONUCLIDE RENAL SCAN

Radiotracers Used for Renal Scan

Radiotracer Function Clinical Use
""TcDTPA Glomerular filtration GFR measurement
Urinary trac: obstruction
""TcMAG3 Tubular secretion: by Split renal function: Urinary tract obstruction
the PCT Evaluate effective renal plasma flow
Used when renal function is reduced
* Tc D MSA Tubular retention: binds Split renal junction
to the SH groups of Conical scarring or infarction:WR
PCT Focal lonephritis vs cancer
""TcDMSA. uchnecium 99mlabeled dimercaplosuccmaze
"TcDTPA. technetium 99mIabckd dielhylenerruminepenuacelk acid

Split radionuclide renal scan: predict posuiephrectomy dialysis requirement

Furosemide renal scan: '*"T¢.oTpA¢"'"T<r1AGa if reduced renal functiomdelayed
renal pelvis clearance in urinary tract obstruction
Capropril renal scan: "'"TcDTPA; use ""TcMAG3 if reduced renal function: can show
peak activity delay or l GFR in the kidney with RAS

OTHER IMAGING TssTs

Angiography
Definitive Les: for and. for some diseases, treatment of vascular abnormalities. RAS.
FMD. large and medium (eg. polyarteritls nodosa) vessel vasculitis
Risk of CIN (in CKD) and cholesterol arheroemboli
Pyelography
For suspicious urereral obstruczion in :he absence of hydronephrosis on UIS or CT
and proper renal contrast excretion is not expected due to AKI
Retrograde: contrast into distal ureter or bladder priNce performed by urologist
along with cystoscopy
 Anterograde contrast injection into collecting system: performed by interventional
radiologist along wid\ therapeutic nephrostomy
Complications: upper urinary tract infection
V oi di ng Cy s tour e thr ogr a phy
To diagnose and evaluate vesicoureteral reflux
Radionuclide cyssogram an be used for followup evalwadon for less radiation exposure

Posit ron Emission Tomography ( PET)

cyst infection in ADPKD l~or 200s;2z:404) and renal graft PTLD (H¢m°l='°s1<v z0139e2m>

P l a i n Abdom i na l Ra di ogr a phy

Can detect radiopaque stone. nephrocalcinosis.and other calcification
I n tr a v e n o u s P y e l o g r a m
evaluation of upper urinary tract in hematuria. flank pain. and stone disease
Replaced by noncontrast CT scan

RENAL BIOPSY
Indications of Renal Biopsy (bx)
RPGN: proreinuria >1 old (with proteinuria >0.S): unexplained renal impairment

Impact of Biopsy on Diagnosis and Management

Diagnosis (AMC Nepiuul ZG09;10:11] Bx Affected Management (nor 199411159
Pr edi cted di agnosi s confi r med 29% Nephr oti c r ange pr otei nur i a 86%
One of di ffer enti al di agnosi s 14% Acute ki dney i nj ur y 71%
Unexpected di agnosi s 15% Chr oni c ki dney di sease 45%
Bx done (0 assess ase sever i ty 29% Hematur i a and pr otei nur i a 32%
Nondi agnosdc 11% Subnephr osi c pr otei nur i a 12%
Technical failure 2% Hemacur i a al one 3%
Over al l 42%

Absolute Contraindications to Percutaneous Renal Biopsy

Uncooperative patient or inability w follow instructions during bx. uncontrolled
severe HTN (>180/120). unconectable bleeding diathesis
Relative Contraindications to Renal Biopsy
Inability to provide informed consent. recent antiplatelet or anticoagulant therapy.
Hb <8.0. platelet <100. INR >1.5. T aPTT. liver cirrhosis
Echogenic small kidneys (<10 cm) (Kl1005;s7:1515).solkary kidney. multiple bilateral
cysts. hydronephrosis. horseshoe kidney, ESRD. UTI. pyelonephritis, or perirenal
abscess/infection. pregnancy after 32 wk gestation
Inability to stop anticoagulation (eg.w/i 3 mo after prosthetic heart valve)
Preparation:Admit HighRisk Patients
Emergent bx is a/w major complications (3.7 vs 0.5% w/ elective) (nor zcoatzsasal
Hold ASA, dipyridamole. clopidogrel. unSAIDs, UFH. LMWH. GP lib/llla inhibitors.
omega 3 fatty acids (nor Plus 2011:4:Z70) it clinically indicated
Prebiopsy Labs: CBC. PI aP7T type and screen. factor X ifAL amyloid is suspected
If Hb <8.0. blood transfusion or hospitalization: BP <140/90:anxiolytic pro
II factor X def. FFR Prothrombin complex concentrate 3factor (II. IX. X. eg. Bebulin.
Profilnine) WH 2014.a91 Isa) or 4factor (II,vll, IX. X. eg. Beriplex. Octaplex, Keenua)
Antiplatelets and unSAIDs
Antiplatelets and unSAIDs (vs d/c 5 d before) T 21.0 Hb drop.no difference in die
need for blood transfusion. surgical or radiological intervention (NDT zuaenaasssl
ASA within 10 d of bx did not increase risk of major bleeding (Ala 20 i0.i94¢7a4)
unSAIDs (esp.one w/ long halflife) T bleeding; Renal impairment 1 clearance
Hal fLi fe of unSAI Ds wav :m 1w1. 1 5121969)
0 - 3 hr fenopr ofen. i bupr ofen, 4 - 5 hr i ndomezhaci n. kewpr ofen
mecl ofenamaxe sodi um, tol medn
6 - 1 5 hr di ¢1uni sal . naproxen. sul i ndac >1 5 hr pi r oxi cam
unSAIDs should be stopped 5 hal(lives for complete elimination
 Hold anriplarelets for 7-10 d before in low CV event risk (Acer Chen 10 1z141=¢3us)
In highrisk pos undergoing noncardiac surgery. perioperative ASA 7 d pre to 3 d
posrprocedure 1 major adverse cardiac events wlo T bleeding 1S¢IAMMI 1010;104:305)
Anticoagulation
Conditions wkh HighRisk Perioperative Thromboembolism (ACCP Gun
2012;14mJus): stop vitamin K anugonists 5 d before die biwfr bridge mM N UFH
(stop 4-6 hr before) or LMWH (stop 24 hr before)
Mechanical HeartValve AFib VTE
Any MV prosthesis CHAD5z >5 VTE li 3 mo
Any cagedball or tilting disc Stroke or TIA wu 3 mo Def of protein C, protein S.
AV prosdiesis Rheumatic valvular heat or anziLhrombin;APLA,
S or TIA w/i 6 mo disuse multiple abnormalities

Uremic Platelets
Renal failure can cause bleeding dl: disturbances in platelet adhesion and aggregation
Unclear if correction of the BT (bleeding time) L clinical bleeding.A low Hot is alw a
t BT: may be corrected by ESA or transfusion (Ann Sur, 1998113311341
ESA wkh Hot t 230% improved platelet function in uremic patients (xi 199r41=ssa1
DDAVP 0.3 uglkg 1 hr prior to bx 1 hematoma (13. 8% vs 30.5%) (A/KO z0\1;578s0)
BT can be shortened by HD ><2 lcs»App4Th»w»=b»4¢»n¢¢ 1012;1B:1B5), estrogen w9/»1
198e31517311. cryoprecipitate 10 bags over 30 min, 1-12 hr WM 19a0x30J=13181

Ultrasoundguided Percutaneous Renal Biopsy

No difference in complications between U/Smarked blind vs realtime UIS guided
procedure and performed by nephrologists vs radiologists (arc nepnui 10\441s9961
Realume U/S guided bx may have better tissue yield (CK:201sx:151;amc ~¢l=~-l z014;1 $961
Spring loaded devkes w/ 14G. 16G, or 18G needles.The larger needle provide more ds
sue and glomeruli (m 2000=$&390). Complication t wl 14G needle WKD 201zw4s2).>5 passes
CTguided Percutaneous Renal Biopsy
When kidney position does no: support U/Sguided bx
In does not allow direct realtime visualization who 200lk36:4\9).
Tra n sju g u la r B io p sy
Performed when bleeding disorders prevent conventional biopsy, for patients on
mechanical ventilation.and if there is a need for bx of both the liver and kidney
The access is via the right internal jugular and an introducer sheather.The right renal
vein is more amenable to bx because of orientation and the shorer length to access.
Contrast (required)induced nephropathy can happen ()\u< linen New 1008;191546)
Slmilar yield (95.8 vs 95.5%) and major complications (1 vs 0.75%) dw percutaneous
bx (naming 1000=21s;aa9l; other series also showed its safety (inncec 1990;33$:1512)

Laparoscopic or Open Biopsy

When percutaneous bx fails. for pos on chronic anticoagulation which unnot be
stopped or w/ coagulopathy religious faith (eg.Jehovahs witness). solitary kidney. multiple
bilateral renal cysts. or body habitus (eg, morbid obesity.cerebral paley) lx/ 199a.s425151

P o st b io p sy C o m p lica t io n s
Automated Biopsy Device and Redtime UIS Guidance 1AprD 101u061i
Postbiopsy Complications Factors on Erythrocyte Transfusion Rate
Macroscopic hemaluria 3.5% Age 240 vs <40 1.0 vs 0.2%
Need for PRBC transfusion 0.9% Cr 22 vs <2 2.1 vs 0.4%
Angiographic intervention 0.6% SBP 2130 vs <130 1.4 vs 0.1%
Nephrectomy 0.01% Hb <12 vs 212 2.6 vs 0.5%
Bladder obstruction 0.3%
D 0.02%

AVF (4-18%): rarely cause hypotension. highoutput HE and hemamria. Diagnosed w/

Doppler U/S or angio. Most spontaneously regress. but some require embolizacion
or surgical ligation depending on size/symptoms UAS~ 1994.5:1J00}
 Hematoma (4%) (}ASN 2D04;15:142). pseudoaneurysm
Page kidney: subcapsular hematoma can cause RAS activation. HTN
Pain: dl: subcapsular hematoma, ureteral obstruction of blood clot
Vasovagal pseudohemcrrhage: i BP & HR during procedure UAMA 1977;237:1159)
AKI T complications: transfusion 8%. intervention 2%. hematoma 7% [qAsn 201&13:1sJJ)

Monitoring and Postbiopsy Care

67% off complications occur wu 8 hn 11% an be seen >24 hr after biopsy UASN 200%1§:141)
Can J U/S 1 hr after percutaneous be: the absence of hematoma has a high NPV for
minor (95%) or major (98%) complications (nor z009:24n4J3)
Bed rest for 4 hi:avoid heavy object lifting,iog.exercise for 1 wk
Vital signs: BP q15rnin x 1 hr. q30min x 2 hr. q60min x 2 hr
./ for gross hematuria; /CBC 4 hr postprocedure: for inpatients, CBC in following AM
Resume antiplatelet and/or anticoagulation in 2-7 d.The exact timing for resumption
o f th e ra p y sh o u ld b e ta ilo re d to e a ch p a tie n t

Management of Bleeding Complications

Bed rest, PRBC. FFP transfusion as needed
Most patients with perinephric hematoma or hematuria will resolve spontaneously
N unremitting gross hemawria especially with clot. a 3way bladder irrigation adweuer
sh o u ld b e in se rt e d a n d irrig a t io n co mme n ce d
If hemodynamic compromise, transfusion requirements or persistent gross hematuria
>72 hr, CT angiogram may show the bleeding vessel or AVF; followed by selective
a n g io e mb o liza tio n o f th e b le e d in g a rte ry
Transarterial symbolization is safe; Rare complications: dissection
Postembolization syndrome: flank pain. fever, NN ileus. rare w/ partial symbolization

RENAL PATHOLOGY
PROCESSING OF TISSUE
Light Microscopy (LM)
Formalinfixed, paraffinembedded tissue; sections cut at 2-3 um
Stain with hematoxylin & eosin (H&E). Periodic acid-Schiff (PAS),Jones methenamine
silver (JMS). and Trichrome
Typical Color after Shining
PAS ]MS Trichrome
Matrix material* Magenta Black Blue
Immune material Glassypink Red Fuchsinophilic
Fibrin Pale Red Bright red
*Basement membrane (BM) and mesangial matrix

» Special stain: Congo red (amyloid).von Koss: (calcium phosphate deposit)

lmmunofluorescence (IF)
Zeus or Michels transport medlum.frozen and cur on cryostat!
Slain with antisera to IgG. IgM, IgA. C3. C1.albumin. Fibrinogen. kappa, lambda. and
C4 d (tra n sp la n t o n ly)
Special techniques protease IF from paraffin block (salvage. masked deposits. LCPT).
loG subtypes (loG 1-lgG4; 1 subtype favors monoclonal), COL4A (112 and a5 chains)
Ele ct r o n M ie r o se o p y ( EM )
2.5% glutaraldehyde;1 pm toluidine bluestained survey section. Pb/Urstained section

COMMON PATTERNS OF GLOMERULAR IN]URY

De6nitions for Commonly Ulod Terms for Glomerular Injury

Focal Involving minority (<50%) of glomeruli
Diffuse Involving maioriry (>50%) of glomeruli
Segmental Part of glomerulus (60%) involved
Global Whole of glomerulus (>50%) involved
 Mesangial Proliferative Glomerulonephritis
LM: diffuse increase mesangial cells (23 per mesangial area)
IF and EM: granular mesangial immune deposits
Ddx : ly \n, LN c la s s II. re s olv ing IRGN.C3 G
Endocapillary Proliferative Glomerulonephritis
LM: occlusion of capillary lumina by infiltrating leukocytes and/or swollen endodvelial cells
IF and EM: subendozhelial 2 mesangial immune deposits
Ddx:
IRGN: endoapillary neuuophils.C3dominant IF w/starrysky" paper. subepi humps
Autoimmune (eg. LN): fullhouse IE strong Clq staining, extraglomerular immune
deposits. endothelial TRls
Cryoglobulinemic: monocytes. immune thrombi
g O the rs : P G NMI D (monoc l ona l I F), I gAN. C3 G

3 Membranoproliferative Glomerulonephritis (MPGN)

LM: hyperlobulated glomeruli owing to increased mesangial cells and matrix. GBM
double contours with cellular interposition. variable endocapillary llypercellularity

Current MPGN Classl6cation Based on IF

Type IF Etiologies
Immune complextype: classical lgzc3 Autoimmune: LN. Siogren
pathway mediated syndrome
Infectious: HCM endovascular
bacteria I
Cryoglobulinemicz HCV.
S}ogrens. LPD
Dysproteinemic or idiopathk
C3 glomerulopa\hy: alternative C3 z 2 x l g C3 G (C3 G N. DDD)
pathway mediated
Mimickers" Negauye (Znonspecific TMA. type III collagen
I and C3) glomerubpa

Historical MPGN Classification Based on EM

Tow E M Fe a ture s
1 Mesangial and subendo
2 Mesangial ring forms and highly electron dense intramembranous
a Mesangial and complex subendo. incramembranous.and su i

Col umbi a Cl a s s i fi c a ti on of FS G S
Va rla nt De fi ni ng Fe a ture s Clinic a l Fe a ture s Associations
Collapsing Implosive retraction of Primary or secondary: Viral infections
capillaries with severe nephroric (esp HIV),
overlying VEC syndrome and AKI; Drugs (pamidronate.
hyperplasia, severe black racial INF),APOL1.
tubular injury. tubular predominance. worst acute vasoocclusion
microcysu. diffuse FPE prognosis
Tip Adhesion of ruff as Usually primary, abrupt Usually steroid
tubular pole w/ foam onset nephrozic responsive.
celIs.di1¥use FPE syndrome favorable prognosis
Ce llula r Expansile lesion with Usually primary
endocapillary
hypercellularity (foam
cells, leukocytes)
Perihilar Hyalinosis and sclerosis Usually secondary: Obesity, HTN, low
centered as vascular adaptation m nephmn number
pole. glomerulomegaly. glomerular sickle cell
focal FPE hyperlilrrarion
NO S Does not meet features mlc variant. primary or
of above variants secondary

Nodular Mesangial Sclerosing Glomerulopathy

Mos: commonly diabetic glomerulosclerosis (DGS):acellular PAS+ nodules i mlcro
aneurysms. capsular drop lesions (BC hyalinosis). PAS+ GBM and TBM thickening, IFITA.
arteriolar hyalinosis. arteriolosclerosis
Idiopathic nodular glomerulosclerosis (ING. aka smokingrelated glomerulopathy):
seen in nondiabetic cigarette smokers ~ endothelial lined channels in expanded
mesangium and at hilus, chronic TMA features common (mesangiolysis wl microaneu
rysms. narrow GBM duplications)

Me mb ra n o u s N e p h ro p a th y (MN )
LM: normal GBM (stage 1) - thickened GBM wick spikes (stage 2) -> chainlike
GBM thickening with intramembrancus Iucencies (stages 3-4)
IF: granular glomerular capillary wall (subepi) staining for IgG. C3. in. A
EM: small subepi immune deposits (stage 1) - intervening GBM spikes (stage 2) »
incorporated into GBM by neomembrane (stage 3) -» undergo resorption and become
more electron lucent (stage 4)
(-80%;antiPl.A2R. 3-5% antiTHSD7A) vs 2 (autoimmune. infection [HBV.
parasites. syphilis]. malignancy. drugs)
Indirect lF staining for PLAZR; positive in 80lS of patients with 1 MN
Th ro mb o ti c Mi cro a n g i o p a th y (TMA)
Early changes
Glomeruli: fibrin thrombi. entrapped schistocytes.endotheliosis. mesangiolysis,
subendothelial fluff," ischemic Loft retraction
. Vessels: endothelial swelling. intraluminal and subendozhelial fibrin. entrapped
schistocytes. mucoid intimal edema. myointimal cellular proliferation
Late changes
. Glomeruli: GBM duplication. mesangial sclerosis. glomerulosclerosis
Vessels: concentric (onionskin") intimal Nbrosis.organization and reanalization
of intraluminal thrombi
Etiologic considerations: dHUS. aHUS. scleroderma.APLS. malignant HTN. preeclampsia.
druginduced (antiVEGE gemcitabine. proteasome inhibitors), HIV -» vascular changes of
TMA predominate in malignant HTN and scleroderma
Glomerular Diseases with Organized Deposits
Glomerular Diseases with Organlzed De posit!
Disease Pathology Cor r elation
Cryoglobulinemic LM: MPGN or DPGN. abundant infiltrating Type I: LPD
GN monocytes. inuacapillary immune thrombi Type II: HCV. S16grens,
lF:monoclonaI In (type I). IgM » x > IgG + 1. LPD (esp.wm).
(type ll).polyclonal IgG v IgM (type III) endovascular
EM:annulartubular substructure (3050 nm). bacterial infections
may be focal Type Ill: autoimmune
Immune deposits may be spare by IF and EM condkions
blc of aggressive phagocytosis by monocytes
(prionase IF useful)
IMMU"0BCEOid LM: MPGN or DPGN +Mspike, Me1l
GN IF: usually monoclonal IgG lymphoprolilerative
94: parallel stacks d microtubule (30-50 nm) disorders.l C
Fihrillary GN LM: MPGN > MesGN > DPGN > MGN; PAS Idiopathic: association
pale silver () deposits:Congo red ( ) with HCV
IF: polyclonal IgG ("smudgy") 2 C3 & C1:
lgGl a lgG4 subtypes
EM: randomly oriented nonbranching fibrils
that infiltrate mes and GBM (16-24 nm)
IHC: DNAjB9

DysproteinemiaRelated Renal Diseases

Can Involve all 3 renal parenchymal cornpartmenu
Useful special rechniqueszcongo red srain.pro\eomics (Alg); IgG subzypec (PGNMID):
protease lF (LCPT. masked monoclonal deposits)
Dysprotelnemiarelated Renal Diseases
Disease Pathology Associations
LCCN LM: hard/fractured casts. PASpalelnegative. MM
cellular reaction
IF: xi), restricted staining
LCPT LM: intracellular crystals in PTC (PASpale, Fanconi syndrome; MM.
Trichromered) smoldering MM. MGRS
IE >90% molten requires protease IF
EM: geometrically shaped or ropey crystals
in PTC
MIDD LM: nodular mesangial sclerosis MM. smoldering MM or
IF: linear staining involving all renal BMS; MGRS: -1/3 occur wl
90% s: (LCDD): can have monoclonal lg LCCN
component (HCDD, HLCDD)
EM: finely granular puncute deposits in BMS
AL amyloidosis LM: amorphous eosinophilic. PASpale. silver MM. smoldering MM or
negative. Congo red+ material MGRS
lF:smudgy" staining. 9. > x
EM: randomly oriented nonbranching fibrils
(8-10 nm)
PGNMID LM: MPGN. endoapillary proliferative GN Paraprotein identified in
lF: 1 IgG subclass + 1 light chain; lgG3x mlc 20-3094; Ddx: type 1
cryo, ITGN
EM: granular electron dense de sits

EndothelialTubuloreticular Inclusion (TRI):"IFN footprint"

Causes: SLE. HIV. CMV log z0\4;7i 114). exogenous IFN01, p, and y (6m5~ zo1o5.son,Ar1R

COMMON PATTERNS OF TUBULOINTERSTITIAL INJURY

Acute Tubular Necrosis (ATN)
Epithelial simplification. loss of PAS+ brush border, coarse clear intracytoplasmic vac
uolization and enlarged nuclei with prominent nucleoli 2 degenerating cellular casts
Ddx = ischemic vs toxic tubular insults
Histology generally nonspecific except in rare instances (it,dysmcrphic mitochon
dria = tenofovir toxicity)
Interstitial Nephritis (Pathologic Clues)
Interstitial inllammauon and edema 4 oubuliris 1 tubulointerstidal scarring
~70% allergic/druginduced (inrerscicial eosinophils)
-20% autoimmunelsysremichnfectious: Siégren syndrome (plasma cellrich). sarcoidosis
(nonaseauhg granulomas; perivascular). IgG4related (lgG4+ plasma cells, storiform
fibrosis.TBM immune deposits by IF & EM). pyelonephrizis (neuuophilic i:ubuli:is.
neutrophil casts)
-10% idiopathic

RENAL TNANSPLANr PATHOLOGY (Bon1yCmena A/r 2018;1B.293)

A¢uteTcell Mediated Reiecdon

Grade Histologic Criteria
Borderline Foci of lubulitis (L > 0) 4 minor interstitial infiarnmnion (i0-1),or
moderatrsevere interstitial inflamrnazion (il-3) + mild tubulitis (t1)
IA Interstitial iniiammation involving >25% of nonscarred cortex (zi2) +
moderate wbulicis (t2)
IB Inrerscizial inflammation involving >25% of nonscarred cortex (QI2) +
severe tubulkis (r3)
IIA Mild [0 moderate intimal arzerizis (vi) 2 any Vi
IIB Severe intimal anerizis (v2) + any it:
III Transmural arzerinis and/or fibrinoid necrosis (v3) 1 any Vt

Chmnlc Active Tic dl Mediated Rejection

Grade Histologist Cnteria
IA lnrersdtial inflammation involving >25% of :oral cortex. mainly in scarred alias
(ti2-3. ilFTA2-3) + moderate tubulitis (:2)
IB Interstitial inflammation involving >25% of :oral cortex. mainly in scarred areas
(:i2-3. iIFTA2-3) + severe tubulitis (8)
II Chronic alto ft arterio ( c03)

Active Antibody Mediated Rejection'

1. Histologist evidence of acute tissue injury (21 )
Microvascukr inflammation: glomerulitis (g > 0) and/or peritubular capillaritis (ptc > 0)
Arteritis (v > 0)
Acute thrombotic microangiopathy without other apparent cause
Acute tubular injury without other apparent cause
2. Evidence of antibody interaction with endothelium (21 )
Linear C4d staining in peritubular capillaries (Cid 2 2 by IE C4d 2 0 by IHC)
» As least moderate microvascular inliammation (g + ptc 22:3 must be 21 ifTCMR)
3. Seroi c evidence of donorspecific antibodies
.

*All 3 criteria must be met for diagnosis.

Chronic Active Antibody Mediated Re)ecdon°

1. Histologist evidence of chronic tissue injury (21)
Transplant glomerulopadiy (cg > 0)
Severe peritubular capillary BM muldlayering (EM)
Arterial intimal fibrosis wlo other apparent cause
2. Evidence of antibody interaction with endothelium (21)
Linear C4d staining in peritubular capillaries (Cid 2 2 by IE C4d 2 0 by IHC)
At least moderate microvascular inflammation (g + ptc 22:3 must be 21 ifTCMR)
3. Seal , . ic evidence of donorspecific antibodies
*All 3 cnceria must be met for diagnosis.
 GENETICS
Background Jun an nepnfa Z018;14:8J: nsi/in 2019:380:142)
Genetic testing has a high diagnostic yield: almost 10% for all cause CKD. >17% for
patients with nephropathy of unknown origin,and >70% for pediatric cases
Genetic diagnosis can:
Confirm a suspected hereditary cause
Discern specific subcategory of condition within broader clinical diagnosis
Reclassify the diagnosis and
Identify a molecular cause for patients with nephropathy of unknown origin
Genetic diagnosis can affect patient management. prognosis.and have familial implications
F eat ur es of G enet ic D iseases
Earlyonset: eg, congenial kidney anomaly or malformation
Extrarenal manifestations: eg. sensory delicit.s.developmental problems. birth defects.
facial dimor phism; Positive family histor y
Absence of clear environmental causes for kidney disease (je. DM. CVD)
Cautionary Note: many patients widl a genetic condition do not have affected family
members and do have other medical problems that can be thought to cause CKD.
like diabetes. heart conditions, or hypertension
Terms Used in Genetics and Genetic Testing
Genetic Counseling: a clinical consultation for individuals and d1 eir families who have
genetic disease or are at risk for a disease.facilitating informed decisionmaldng. Under
current guidelines. the ordering clinician is expected no ensure informed consent.
Informed Consent: required for all Genetic testing. Discussion of benefits, limita
tions (je, sensitivity and specificity of the rest). and risks. so d1 e patient can decide if.
when, and how he/she wants to do genetic testing
Allele: one copy of a gene; each of us has two alleles for all genes on autosomes (and
X chromosome in females).which can be identical or different
Variant: a different allele than the reference allele. aka the allele found in the majority
of the population
Zygosity; how many variant alleles a patient has
Heterozygote: the pauent has one variant allele and one reference allele
Hemizygote: variant allele of a gene on the X chromosome in male; since males
have only one X. they have a single copy of the allele
. Biallelic: 2 variant alleles for the gene
Homozygote = same variant:
Compound Heterozygote n two different variants

TYPES OF GENETIC TESTING

Any :est that can identify changes in chromosomes.genes (DNA sequencing). or
proteins (biochemical rests)
Biochemical cesu are helpful for diagnosing metabolic renal diseases

Genetic Testing Modalities (Na: Revnq=n~1 Zu1a;14¢sJI

A K

SNVs and Gene

small indels panels

Medium and
MLPA
small indels

Large indels CMA

Large genomic
rearrangements

Single Multiple Most Whole

gene gene exons genome

Proponlon of DNA tested In one single test

Odds for Incidental tlndlngs
 SNVs: singlenucleotide variants
Indels: insertions or deletions
Genomic rearrangements: duplications. deletions. uanslocations, and inversions
Karyotype: picture of :he chromosomes; count them and identify large genomic rear
rangements
Chromosomal microarray (CMA): identify genomic ieanangemems such as duplications
and deletions of at least 200 kb
Multiplex ligationdependent probe amplification (MLPA): identify relatively small
deletion and duplications
Sanger sequencing: identify variants (singlenucleotide variants [SNVs] and very small
insertions or deletions) in small. targeted fragments of DNA
Gene panels using targeted nextgeneration sequencing (NGS): identify variants in a
predefined list of genes
Wholeexome sequencing (WES): identify variants in the exons (proteincoding) of most
genes: does not cover certain parts of the genome (eg, noncoding regions)
Wholegenome sequencing (WGS): includes noncoding variants and better detects
genomic rearrangements versus WES

BENEFITS AND RISKS OF GENETIC TESTING

Diagnosis of Renal Genetic Disease
Potential Benefits .nd Risks of Diagnosis
Potential Benefits Potential Risks
Diagnosis: 4 need for further testing I Medical workup additional tests can be
Change care: et. initiate needed subspecialty required to validate the genetic diagnosis
referral. targeted workup. and/or Negative psychological impact genetic
surveillance: guide choice of therapy findings can be uncertain, which can lad
fdentificadon of extrarenal anomalies to T anxiety (nui New Nniosu z013114¢4es)
Family counseling for relatives identified xo Incidental finding: relevant for noncargeted
be at risk of having or transmitting die genetic testing
disorder
Participation in targeted clinical trials
Incidental finding: relevant for nontargeted
genetic testing
Diagnosis of Incidental Findings
Incidental finding any genetic finding unrelated no the primary zest indication (syn
onym: secondary finding). Some genes associated with diseases for which inzerven
tions preventing or lessening the disease complications exist. such that they are med
ically actionable" and have been recommended for broad return (am m¢¢ 2017;1*r249)
Only in the case of nonrargeced genetic resting
Potential Benefits and Risks of Incidental Findings
Potential Benefits Potential Risks
Change care: eg. initiate t Medical workup: the term genetic predisposition" by
needed sulrspecialty definition indicates that there might be no disease YET
referral. targeted workup. but it might develop in the future
and/or surveillanceaguide Incidental findings can require lifelong medical surveillance
choice of dierzpy Discriminadomthe Genetic information NonDiscriminadon
Family counseling: for relatives Act (GINA) protects against discrimination from
identified to be as risk of employers and haldi insurers. but gives exemptions to
having or transmitting the certain employers. and does not include oder types of
disorder insurance. including life and disability coverage
Participation in targeted Predictive genetic information could be used to
clinical trials discriminate individuals in contexts such as housing U
up Med tuna 1016:44:216) and child custody disputes (co
GenetMedRepz01s=49a1
Selffulfilling prophecy: genetic diagnosis an worsen the
clinical symptoms: as in ApoE and Alzheimer (Am 1
lsidvavy 1014;171;10\) and obesity (Hour mf aenuv
20l6;4J:))7]
Negative psychological impact: in the presence of an
incidental genetic Ending. die patient becomes a
patient in waiting" U :mini so new zoiostsaal
 GENETICS RESULTS INTERPRETATION (Genet Med 2015:17405)
Criteria for Pathogenic Variants
De novo variant: variant that is absent in the parents of die index.t odds for
pathogenicity
Reported pathogenic variant variant previously reported in patients as causing a
disease
. t O dds for pathogenicity
The main :we databases cataloguing chose variants are ClinVar and HGMD
Caution: both have a lot of false positive variants.
Minor allele frequency (MAF): frequency at which the allele occurs in a given popula
tion. Current population database:gnomad.broadinstitute.org includes 123.136 exhume
sequences and 15.496 wholegenome sequences used to calculate each alleles MAF.
The rarer the variant the T odds for pathogenicity
Novel variant: variant not previously reported: it odds for pathogenicity
Deleteriousness prediction: there are many insilico scores trying to predict the
impact of a variant on the protein function (lossoffunction.gainoffunction. dominant
negative effect)
II
Benign

Likely pathogenic

Va r ia n t C la ssif ica t io n
Variant classification is based on current knowledge
Thus. all classifications can change with as new knowledge emerges
The patient and his/her family medical histories weigh in the decision whether the
variant should be considered pathogenic or not
Pr o b a b ilist ic D e f in it io n s
Pathogenic (P): the variant is thought to cause a genetic disease.AKA diseasecausing
variants (formerly called "mutations")
Likely Pathogenic (LP): the variant probably causes a genetic disease. but current
knowledge is not suflitient to categorize it as a pathogenic variant
Variant of unknown significance (VUS): current knowledge is NOT sufficient to cate
gorize the variant as either benign or pathogenic
Likely Benign (LB): the variant probably does not cause a genetic disease. but current
knowledge is NOT sufficient to categorize it as a benign variant
Benign (B): the variant is thought to not cause a genetic disease

CLINICAL GENETIC TESTING AND OTHERTYPES OF GENETIC TESTING

Genetic Research (Na: an napiwi 1018:14:83)
• Aim: generate generalizable knowledge useful for future patients
Timeline: while results from clinical resting an be returned relatively fast (res: and
lab dependent). research is usually unpredictable
Results type: most researchsetting are not returning VUS. and P and LP variants usu
ally need to be validated in a clinically certified laboratory by the Clinical Laboratory
Improvement Amendments (CLIA)
DirecttoConsumer (DTC) Genetic Testing
Aim: different DTC companies have different aims. including ancestry.as well as clini
cally actionable diagnosis.They usually do not offer comprehensive genetic diagnosis.
Scope: similarly. different DTC companies are using different genetic nesting modalities
 UseFuL WEsslrss

RENAL GENETIC DISEASES

Inheritance Modes and Associated Family Patterns
Variant Family
Inheritance Zygosicy Examples Family Pattern Counseling
Dominant Hererozygoze or ADPKD, BOR. One of the 50% risk for
(AD and XLD) Hemizygore MODY5, parent has the each of the
disorders variant Renal disorder or par.ienzs kid
coloboma the patient is to have the
syndrome die it (O disorder
have the
disorder in the
family (de novo)
Autosomal Biallelic variants Bardet-Biedl Parents are nor Unafhczed
recessM (AR) Syndrome affected siblings have a
disorders (BBS).Jouber1 tanriers 66% risk to
syndrome, Siblings may be be armers
Barrier affected (25%Risk for the next
syndrome risk [or each) generation
depends on
the spouses
carrier slaws
(higher risk in
case of
consanguinity)
Xlinked H emizygore Xlinked Alporr Females ans not Sisters have a
recessive variants syndrome. af1gcggd Male 50% chance of
disorders Fabry disease. siblings may be being carriers
(XLR) Dem disease affected (50%
risk for mah).
Additional
male family
members may
be aRecced on
the modlers
side of :he
family
Mitochondrial Variants in \he MELAS.MERRF. Variable Maternal
disorders mitochondrial Pearson inheritance: if
(Miro) genome or syndrome. depending on probated is a
(nuclear genes depletion of Keams-Sayre the proportion female. at risk
encoding the syndrome. d af|ected of zransmining
mitochondrial miwchondnial Leigh mitochondria :he disorder
proteins will genome syndrome Siblings may be Sisters of
be in the aM*ecled.aswen aflecred
above as additional individual at
inheritance 'w i n risk of
modes) members on transmitting
:he modlers the disorder
side d the
f=l"i!7
 Extrarend Anomalies Assodetied with Genetic Renal Diseases (laura a01(kJ15:1N1)
Disease G r oup Extr ar enal Anomalies Causal Genes lichen
Polycystic kidney disease Liver cysts. brain PKD 1. PKD2, PKHD1 ADLAR
(PKD) aneurysms
Tubulointerstizial kidney MODY5 diabetes UMOD, REN. mus, AD
disease (ADTKD) (HNF 18). anemia HNF 1B
(REN). Gout
Ciliopathies Retinitis pigmemosa. NPHP 1NPHP9, BBS 1, AR
(nephronophthisis, polydactyl. MR. BBS 12
BBS) hypogenitalism. obesity
Congenital anomalies MODY5 diabetes PAX2. HNF 15. EYA 1. AD:AR
(CAKUT) (HNF 1B), deafness SALL1: FMS 1, FREMZ
(EYA 1). eye anomalies
(PAX2)
Nephrozic syndrome Bone abnormalities. WTLTRPC6: NPHS 12. AD:AR:
immunodeficiency. COQ22 MTTL 1 Miro.
neurologic impairment.
cardiomyopathy (C0Q2)
Alpon syndrome Hearing loss. anterior COl.4A36 AD; AR:
Ienticonus XLR
Tubulopathies Short stature. eye CLCN5, ocxu SLC12A 1, XLR:
anomalies, skeletal SLC 12A3 AR
anomalies
Nephrolithiasis. Retinopathy. peripheral $l.C9A3R 1: SLCJA 1, AD:AR
nephrocalcinosis neu ropazhy, vascular AGXT
anomalies
 NUTRITION
Nutrition consultation for CKD 3-5: rigorous RCT data lacking
Cohort studies associate poor diet with incident or worsening CKD (AJKD 10iJ;s2¢267)
Western diet more acidifying than a fruit/vegetable diet; acidosis may contribute to
CKD progression, which may improve with high fruidvegetable diet (qAsn 201:l:&371)
Higher dietary acid load alw t prevalence of CKD u Fu.. no 2018:4:zs11
Western diet. high animal protein diet. and fructose consumption tunic add levels, linked
to incident CKD i;A94 znoan9;1z04l; UASH diet a/w 1 incident CKD We zoismsasa)
Sodium (Na)
High Na diets antagonize antiproteinurlc effect ofACEllARB
1 Na in t a ke f ro m 1 5 0 100 mEqld .L BP by 2.1/1.3 in preHTNIstage 1 HTN: 1 to
50 mEqld further . BP by 4.6/1 .7 leAsH NUM 2001::44:3)
No RCT has been done in CKD looking at hard endpoints
Low Na diets lower proteinuria and BP Mien added to ARB and diiazide UASN 20ce 19s9s1
Low Na diets had larger proteinuria and SBP L than dual RASi (Bm/2011:34:l:a4zs6)
Protein
Low protein diets (0.8 g/kg/d) in CKD ND may 1 hyperfiltratlon and eGFR decline
Animal protein may lead to more hyperfiltration than vegetable protein, also contains
more phosphorus :han equivalent amount of vegetable protein
Largest protein restriction RCT underpowered. inconclusive (mono new 1994;]30:877)
Higher protein diets (1.2 glkgld) needed in dialysis to prevent proteinenergy wasting
Limited data suggest protein restriction safe in nephrotics ac/ 1997;99:2479)
Potassium (K)
High K diets may 1 BP (3.5/2.0) and stroke (24%) (sm/2013=34e¢n37a)
High K decreases activity of NaCl cotransporter (NCC) in DCT (!*IN 10 u»171981)
Low K die: associated with saltsensitive HTN and worsened eGFR (qAs~ z01s310121 $2)
Recommended Intake in CKDIESRD lktwso cm aim; xnooi W) lll00.3$:s1)
Na <2 ad for CKD: insullitient evidence for <1.5 g/d (Hui of Mia R°v°¢ 20131
K Tailor based on eGFR. K levels. and concomitant medications (eg.ACEllARB):
usually no need for restriction for CKD 1-3
<2 old for HD; 3-4 Yd for PD (more efficient K removal)
Protein Nondialysis CKD 3-5: <0.8 glkgld: HD/PD: 1,2 g/kgld (NDT 200$;20:i3)
Ca <1.500 mud of elemental calcium (combined die: and medications)
P04 800-1.000 mg/d: T bioavailability with animal and processed food sources vs
vegetables: boiling foods L phosphorus lo lowering protein content
Fluids Nondialysis:no restriction unless hyponatremic: HD/PD: 1-1.5 Ud
Fiber No CKD guidelines: 20-35 old for general (us Dietary Guidelines 101s10101
Calories 30-35 kal/kg: 20-30 kcal/kg in AKl up' #fns1n Mimi- 2005:15:63)
Fats <30% tool calories from favs.<10% from sawrar.ed fats

ProteinEnergy Wasting up 200a:73:a91)

Syndrome of muscle wasting, malnutrition. and inflammation in advanced CKD
Associated with increased morality and hospitalizations
No validated criteria bun some characteristics include
BMI <23: unintentional wt loss (5% in 3 mo); body far <10%
Albumin <3.8; prealbumin <30 mg/dL;tot chol <100:muscle:reduced 5% in 3 mo
Protein intake <0.8 g/kg/d (assessed by interview or calculated nPNA)
Treaunent: oral supplements, optimize dialysis prescription, treat comorbidities
lntradialytic parenteral nutrition costly with limited data. consider if not responding
to of supplements alter 2 no;Amino acid solutions in PD (unavailable in US)
hGH improved nutrition. QOL; limited data. experimental l;Asn 2007;i&m1)
Protein Catabolic Rate (PCR. protein equivalent of nitrogen appearance rate)
Estimates protein intake in HD patients using interdialytic BUN change; less often used
in PD: significant caveats limit utility
Formula uses interdialytic BUN change,also urinary urea losses if residual renal func
tion: normalized to weight (nPCR). goal >1.2 g/kg/d
Requires steadystate nitrogen balance.oiten not the case
Overestimates protein intake in catabolic states. underestimates if anabolic
Usually increases with improved dialysis (KtN) due to increased protein intake
No association with mortality in US wu:1004;44:39)
 FLUID THERAPY
INTRAVENOUS FLUID (IVF) FOR VoLur4E DEPLETION

Four Phases of Resusclndon (QA z014m.740)

Rescue Lifethreatening shock; fluid bolus >500 mU1§ mln for a MAP 60-65
Optimization Campensated shock fluid challenge 100200 mU5-10 min with assessment
of tissue perfusion (MAP >65, Cl >2.2 Uminlmz, UDP >0.5 ml./kglhr),
lactate {<2 mmol/L)
Stabilization Steady state. maintenance of fluid losses
Deescalauon Promote negative balance

Crystalloids: solutions capable of passing semipermeable membrane; may be isotonic.

hypersonic. hypotonic; ideal in pt with 1 volume not from bleeding, 1 expensive but
T intersdual edema; can be used for rescue and scabilizadon phase
Colloids: highmolecular weight: draw fluid into intravascular compartment via
T oncotic pressure with low volume of fluid
Blood products: for active bleeding. coagulopathy: improve tissue oxygenation
Composldon of Crystalloids
Electrolytefree
H;OlECF Osmoladt na/cl/K/c=n4g
Fluid Distribution (%) (mOsmIL) (mErelL) pH
D5W 100/33 252 0/0/0/0/0 3.5-6.5
D516 saline 78/50 321 34l34lolol0 3.5-6.5
D595 saline 50/66.6 406 77I77/0lOl0 3.5-6.5
0.9% NS 0/100 308 1541154/ 010/ 0 4.5-7
2% saline 0/100 684 342/ 347JOI 0/ 0 4. 5-7
3% saline 01100 1.025 513151310i0i0 4.5-7
Balanzed crystalloids: buffered solution containing organic a ions. lactate, or acetate
Hannon 12/ 100 278 13111111514 5-7
Lactated Ringers 13/100 273 13011091413 6-7.5
Acerxe Ringers 12I100 276 130/ 112/ 515f 2 6-8

PlasmaL b 0/100 294 1401981510/3

ilnzravascular dissribudonz ii of ECF distribution
'osmolalicy
in intravascular space: 0.93 x osmolariry
PlasmaLy:cA pH 7.4; PlasmaLyte 148 pH 5.5

Compos i ti on of Col l ol ds
Onc otic P re s s ure V ol ume E x pa ns i on (X of
Fluid ( m m H g )30 Adm i ni s te
100-130
r e d V ol um e ) Na CI
5% albumin 20-30 70-100 145 14s
25% albumin 70-100 300-500 145 145
Hydroxyezhyl starch 154 154
(Heostarch) 6%
Dextran40 (1098) 168-191 200 154 154
Dexrran70 (6%) 56-68 120 154 154
Gelatins lofusine. luemaccel): can cause an is. not available in the US

Monitoring: individual ossessmenL clinical (eg, oral dryness, delayed capillary refill.
neurologic symptoms, UOP); technical findings (Passive kg raising, lactate clearance,
dynamic [SW BPM PPV]. vdumeuic [IT BV. GEDV]. echo [IVC. CO])
 Fluid Therapy Consideration forVarious Scenarios
ICU. severe sepsis Balanced crysralloidsz additional albumin . mortality in septic shock
or septic shock subgroup INJEM z01u101411i
Hyperchlorefnic (eg 03% NS) fluid 1 NAGMA,AKlIRRI1 death
W" IM 2014:161347: WM 2012:3001S66. N£}M 201B,378819)
Eadygualdheaeddiaupylmoruilkylargeli1gCW8-12wid\ crysialbid
o rco lo id ,MA P 2 6 5 wide vascacliveagenis.UOP205 rnUI¢glhr;ScvO2
70% widl transfusion we 2001345 u's) but, not reproducible in
subsequent Main iv-new ~ew }!J14J7(!IS83.ARISE new 2.0\4;37l:l4%;
PmMISe ~=/m 1015:)7Z:\J01; msn NEW z017:.7em3)
No n I CU Balanced cryszalloids J. major adverse kidney even's (num zoisaruIs)
Metabolic acidosis Balanced crysulloids
In AKI wl T Cr > x2 or oliguria NaHCO; 4.2% (0.5 mEqlmL) to keep
pH >7.3 I death. RRT uum¢i 20\s.3miI
Lactic acidosis No dear evidence for adding NaHCO; to correct acidemia and
volume deck. but might help to L arrhythmias. t response to
catecholamines. T CO in ' LV conxracriliry 'P
w
Urine alkallnlzarion For removal of weak acids:aspirin, phenobarbital, high dose MTX
(e t . vln s + 5 0 -1 0 0 mE q Na HCO ; )
TCA o ve rd o se NaHCO; 1-2 11188 x1-2: infusion once QRS normalited
Meobolic alkalosis 0.9% NS
with hypovolemia
Hypercalcemia 0.9% NS: metabolic acidosis renal Ca nezbsorption Hsu 2NOs;17¢171
HRS vs volume Albumin 1 glkgld up to 100 g x 2-3 d
depletion Avoid lacraze containing fluid in severe liver dysfunction
Therapeutic Albumin 6-8 g/L of ascizic fluid removal
paracenresis
Poswbstruclive. Hypotonic fluid (et, }'ANS) co replace Yz the UOP (D avoid
p o s: A TN hypematremia
Traumatic brain NS preferred to albumin (t mortality) were 2007:3s7:s741
injury Avoid hypotonic balanced crystalloids to avoid cerebral edema
Hypertonic not beneficial UAMA 2010.J04: l4551
Mannitol T AKI (mea10ne 201$I94:e10!11
Trauma. Packed RBC + platelet + FFP or whole blood
hemorrhagic Permissive hypotension w/ SBP goal 80-90:avoid routine use of
shock crystalloids (new zoimm7ssl
Balanced crystalloids in; sw;201s.10zz41
S"fs=r1
Major abdominal surgery no difference in disabilityfree survival in
restrictive (net zero fluid balance goal) vs liberal (10 mUkg during
induction followed by 8 mUg/hr) fluid resuscitation in the first
24 hr but f AKI in restrictive (8.6 vs 596) (new zoie37ema1

IVF for Sodium and Water Imbalance

IVF Considerations for Sodium and Water imbalance
Hypovolemic hyponatremia
Eu or hypervolemic Hyponatremia
Hypovolemic hypernainemia
Euvolemk hypematremia
Hypertonic if acute or symptomatic
NS otherwise with frequent lab J
Hypertonic if acute or symptomatic; d/c cause of
hyponatremia
No lV fluid initially, otherwise J lab frequently
}§ saline or D;W + NS;after volume deficit connected
can rewm to oral repletion
Enteral water (preferred) or D WWI dextrose can
lead to osmotic diuresis worsening water loss

Rate of Na correction goal: <0.5 mEqIUhr, can correct 1-2 mE/Uhr initially un¢il
symptoms improve if pr with severe neurologic symptoms (confusion. seizures.AMS)
but do not exceed 10- 12 mEq in 24 hr
Correction can be estimated by following equations but they are dynamic processes
and does not consider loss; needs frequent plasma Na monitoring
 Estimated Na Convection by 1 L of IVF (NE/M 1000.34z 15e1)
APn. - (lniusatei + Infusate Pn ,)l(TBW + 1 )
Hyponatremia Hypernatremia
If acute or symptomatic. use hypertonic solution Free water deficit (L) ¢TBW
3% NaCl 100 mL (51 mE) or 8.4% NaHCOx x (P~,l140) - 1]
50 mL (50 mEq) over 10 min x3 as needed et. in 70 kg young male with Pn, 150.
eg. in 70 kg young male with Pn. 110. 3% NaCl (nee water dehcix is 3 L
100 mL will change Pn. by: Initial D§W 1 L will change Pm by:
0.1 x (513 - 110)1[(70 x 0.6) + 1] 0.9 mEqIL 1 x (0 150)1[(70 x 0,6) + 11
-3.5 mErelL
Estlmated ongoing renal water losses: significant in DI (L UM). osmotic diuresis (T Um)
Urine output Electrolyte clearance + Electrolyte free water clearance (€Hx°)
Electrolyte clearance = Urine volume x [(UN, + U,<)IP~.]
C°H,o = Urine volume x [1 - (UN, + UK)/PN.]

Interpretation of Electrolytefree Water Clearance (C'n,o)

C'i4,o Condition Interpretation
(+): free water Hyponatremia Will be corrected if free water intake <Cl4,0
excretion Hypematremia May worsen wlo water input; C'»4,o should be added
to estimated free water deficit
(-): free water Hyponatnemia Fluid restriction only will not correct hyponauemia
retention Consider furosemide to enhance water excretion
Hypernauemia May improve if :here is no signifianz nonrenal loss
C'n,o should be subtracted from free water deficit

Nonrenal insensible losses GI, skin. respiratory uact; 10- 1S cclkgld (Q), 15-20 cclkgld
(d); t during fever. tachypn , burns, open wounds. diarrhea. ecc.
Ma in t e n a n ce I V F Th e ra p y
When pr is NPO. to correct electrolyte imbalances. perioperai:ively.ven¢ilator. cannot
provide basal requirements solely with PO intake
Goal to preserve H;Olelectrolyte balance and nutrition; need monitoring for volume
excess (eg. edema) or depletion (eg, 1 skin turgor. ¢ BP)
The amount of water needed to maintain homeostasis = C'n,o + nonrenal insensible
fre e wa te r lo sse s (ca n n o t b e a ccu ra te ly e stima te d ) 1 . 4 0 0 -1 . 6 0 0 co ld o r 6 0 -6 5 cc/ h r
Water requirement is increased in fever. GI loss
Water requirement is decreased in oliguria. humidified air.water excess (SIADH. liver
cirrh o sis. CHE a n d h yp o t h yro id ism)
Elecuolytes replacement: deficit + loss (renal + nonrenal)
J electrolytes: sodium level reflects water balance: others reflect their balance
Elecerolyn Deficit Repletion
Potassium 20 mEq IV or PO (equivalent wlo vomiting/diarrhea) T 0.1-0,2 mEaL
Magnesium 2 g IV MgSO4 over 3060 min T 0.4 mgldL
Administer 50% calculated dose in impaired renal function
Calcium 1 g IV Ca gluconate over 30-60 min T 0,15 mgldL
Ca chloride if severe hypocalcemir monitor for tissue extravasation
Phosphate 15 mmol sodium phosphate at rate 4-S mmol/hr t 0.4 mg/dL
Administer 50% calculated dose in im ired renal function

Dextrose 100 g (2L of 576) - 340 kcal suppress catabolism

CO MPL ICAT IO NS o F IVF T HERAPY

AKI
AKI from high CI fluid: renal vasoconstriction and l renal blood ilow UCI 19a8;71;7261
AKI from hydroxyedlyl smirch: osmotic PT injury; T RRT requitement. T mortality
(N£IM 2008:3S81251 20111J67:114: /AMA z01330916781

Rap id So d iu m Co rrect io n
Osmotic demyelination syndrome: from rapid correction of hyponatremia
Cerebral edema: from rapid correction of hypernatremia/hypertonicky
O t h er Co m p licat io n s
Volume overload: need careful monitoring in HF. CKD.cirrhosis. and NS
Hyperchloremic NAGMA:from large volume high Cl fluid (eg. 0.9% NS)
 Metabolic alkalosis: large volume balanced crystalloids by metabolism of lactate or
acetate co bicarbonate
Hyperglycemia and hypokalemia: from dextrose conmining fluid
Osmotic diuresis: from large volume saline (sodium diuresis) or dextrose Fluid
Coagulopathyzdilution of clotting factors and platelets: use blood products in hemor
rhage
Anaphylaxis or anaphylactoid reaction: hydroxyethyl starch, gelatin colloids

BLOOD PRODUCTS

Bl ood P roduc ts
Packed RBC 225-350 mL: should be used with platelet and FFP (1:1:1) in trauma
Whole blood 300-400 mL: can be used in trauma
FFP 200-250 mL: used in coagulopathy MM active bleeding. HUS.TTE and
PLEX: needs to be ABOidentical or compatible as in blood
4factor prothrombin :omplex concentrate (PCC) ioinuiw 20ll:128:l234).
3factor PCC are akemadves if bleeding diadiesis. reduced risk of
volume overload and transfusion reactions

Hb <9 is alw death in AKI requiring dialysis flnleMiw Care ma 200$;31:1529). still threshold
for blood tra ns fus ion in AKI a nd CKD is unc le a r
RBC transfusion is nor alw momliry in severe AKI (cn: cm raw 2016:44:a9z1

Studles on Hb Threshold for Blood Transfusion in Nontnuma Conditions

ICU 7 vs 10 lmulciorgan dysfunction. Ml. and pulmonary edema:
1 momliry in less ill and <55 ylo Mme new 19993404091
Symptomatic CAD 10 vs 8: trend for fewer major cardiac events and deaths (Am Ikan I
201l;155:964)
UGIB 7vs 9: T survival me at 6 wk (NEIM 20\J;2ss11)
Septic shock 7 vs 9: no difference mortality and ischemic event (NE/M Z014;371;1JaI)
Cardiac surgery 7.5 vs 9: more deaths. no difference in serious infection or an
ischemic event lNEIM 10IS:372.997)
7.5 vs 9.5 in ICU and 8.5 in nonICU ward not inferior at 28 d
(NEW 2017:]77:1I]3) and 6 mo [NUM zo1aamzzo
Restrictive Hb target <7 in ICU or GIB is alw 1 mortality (inhospital x0.74. wal x0.80).
rebleeding (x0.64).ACS (x0.44), pulmonary edema (x0.48), bacterial infections (x0.86)
w~/m=~120141117:124)
Complications of Blood Transfusion
Infections: bacterial or viral
Acute allergic +/ anaphylactic reactions; delayed hemolytic transfusion reaction
Acute hemoiysis: heme pigment nephropathy
Iron overload from chronic transfusion
HLA alloimmunization in KT candidate (L by leukoreduced blood)
Transfusionrelated acute lung injury (TRALI): acute (during transfusion 6 hr)
hypoxemic respiratory distress with bilateral lung infiltrates on CXR wlo volume
overload/HF/preexisting ARDS
Transfusionassociated circulatory overload: T risk in CKD (x27). CHF (x6.6). and +
fluid balance (x9.4) with T mortality (x3.2) rAm; Mai 2013;1z6..as1.¢19): prevention with
slow infusion (1 mUkg/hr) +I- diuretic use
Hyperkalemia: released from RBC from t storage time, T pRBCs. irradiated: especially
in massive trauma. impaired renal function and infants/newboms
Dialyzer circuit clotting with heparinfree HD
Complications of Massive Blood Transfusion (>I0 units/24 hr)
Metabolic alkalosis: 1 mmol citrate. c,H,o(coo):' -» 3 mmol HCO: in liver
Hypokalemia: d/t metabolic alkalosis; uanscellular exchange of H and K
Hypocalcemia: citrate toxicity in liver failure:1 iCe

ORAL FLUID
Requirement: vary by age. sex. pregnancy. and breast feeding status
Water absorption in GI: NaIH exchanger (NHE). electrochemical gradient. Nacoupled
cotransport with carrier solutes (eg. glucose via SGLT1)
Low Na in oral fluid Turine ourpuc (s»¢/A»1n»,w¢1oae;1o3¢sas)
Oral Rehydration Solution (ORS)
Indications: watery diarrhea wlo severe volume depletion/shock
ORS recommended by WHO: osmolality 245 mOsmIL.glucose 13.5 g/L (75 mmol/L).
Na 75 mEq/L. K 20 mEq/L Cl 65 mErelL. citrate 10 mmolIL equimolar Nalglucose
2 phases: rehydration (correct in 3-4 hr by frequent. small amounts) & maintenance
Advantages: lower cost. easier to administer. less invasive. ambulatory
Commindications: AMS. aspiration. ileus.conditions that limit GI absorption (et.
show bowel), resuscitation, severe volume depletion or vomiting
Water
Benefits: J. recurrence of stones U Url 199e;1 ss=839); l :AMR potential to slow cyst
growdl In ADPKD (c,IAs~ 201D:5:693). 1 recurrent UTI in premenopausal women UAMA
IM 2018:\78:1$09)
No general benefit to support B glasses (2 L) of water UASN 200a:19:10411
Compliadons: hyponauwesnia ap. in competitive mnnes. psychotic poiydipsia,eaa5y use

PHARMACOLOGY
Knowledge of changes in drug disposition from pharmacokinetic and pharmacody
namic alterations in the presence of reduced kidney function among patients with
CKD is important to individualize pharmacotherapy and ensure optimal outcomes

PHARHACOKiNETiCS (AssoapTion, DISTRIBUTION, MsTAaousm, ExcasTlon)

Absorption
Absorption of a medication and subsequently bioavailability (% of medication that
reaches the systemic circulation), may be altered in patients with renal disease
CKD complications that may impact drug absorption. include: changes in GI transit
time from gastroparesis. vomiting and diarrhea. alterations in gastric pH from use of
acid suppressing agents (et. proton pump inhibitors. histamine 2 antagonists)
Phosphate binders form insoluble complexes with some mediations quinolowe amzibioda
Distribution
Distribution of medications into body comparunents: plasma,watei1 fat. red blood cells.
intracellular/extracellular binding sites. and tissue
Volume of distribution (Vd) is a proportionality constant for the amount of drug in
the body to serum concentration and can be used in clinical practice to calculate
medication doses (drug concentration. mg/L* Vd. Ukg) to achieve a desired drug level
Patients with CKD display significant alterations in Vd due to qualitative changes in
tissue binding sites. competitive binding inhibition by accumulation of endogenous or
exogenous substances such as uremic waste. decreased concentrations and confor
mational changes of albumin. and high concentrations of metabolites that accumulate
and may interfere with binding of the parent compound
Vd (Ukg) of Select Medications
Drug Normal ESRD Comments
Increased
Furosemide 0.11 0.18 Decreased plasma protein binding increases free

Phenytoin 0.64 1.4 plasma fraction

Decreased
7.3 4 Uremic toxins are thought to dnsplace drug flam cedar
Digoxin
binding sites; Reduced tissue levels M Na/KATPase
Ezhamburol 3.7 1.6
Metabolism
The breakdown of medications through enzymatic pathways within the liver. gunlungs.
and plasma: oxidation. reduction, acetylation. glucuronidadon. or hydrolysis
CKD may affect hepatic drug metabolism due to accumulation of uremic toxins.
increased oxidative stress from a chronic inflammatory state. and downreguladon of
CYP3A4 and CYPZC9 enzyme expression in the liver and intestine
Pharmacologically active metabolites or metabolites with toxic effects may be formed
Many drugs can stimulate or inhibit the activity of metabolizing enzymes. common
padways. inhlbitors.and inducers are summarized
Excretion
Excretion is the process of removal of a drug from the body
Primary processes hepatobiliary excretion and renal clearance
Hepatobiliary excretion: liver actively secretes drug and/or meraboli¢e(s) into the
bile which then gets excreted in :he feces. Some agents may be reabsorbed through
diffusion by the small intestine and undergo enterohepatic recirculation.
Renal excretion: drug is filtered into the nephron - collecting ducts urine.
Compounds excreted in the urine are water soluble; agents that are lipid soluble
must first be metabolized to increase water solubility.
Renal clearance (CLI\) is a composite of glomerular filtration rate (GPR). tubular
secretion (C ow). and tubular reabsorption (Cl,.,,,,,,,,,,,,) and is dependent on the
fraction of drug that is unbound (f,,); [CL* = (GFR*fu) + CLnAen - CL,,.,...,¢...]
Proxlrnal Tubule Drug Transporters
Transporters Substrates Inhibitors
LuminaJ Membrane
MATE Ritonavir
Cobicisrar
Cimetidine
Pyrimethamine
Dolutegravir
OCTN
 Basolateral Membrane
OAT

OCT Dolucegravir
Rilpivirine
Cimeridine
Quinidine
Rifampicin
Prazosin
HATE. multidrug and :oouc compound extrusion: OCTN.organic carionfcarnirine transporter: MAR multidrug
resistant proceen transporter; PEPI peptide transporters OAT. organic anion cransporrer: OCT. organic
action transporter

CKD may change drug disposition through akeranions in Elzralion, secretion. or reab
sorpnion
Secondary processes excretion through lungs, milk, sweat, nears. skin, hair, or saliva

DRUG DOSING ADIUSTNENTS

Eszimadon of creatinine clearance from clinical data (age. gender. height. weight. serum
creatinine) remains the guiding factor for drugdosage regimen design
Stepwise Approach to Dosimetry in Patients with Renal Insufllciency
Step 1 Obtain history and relevant demographic and clinical information
Step 2 Quantitative estimate of renal function; Creatinine clearance by Cockroft-Gault
Method: estimated glomerular filtration rate (eGFR).or calculated from timed
urine collection
Step 3 Review medications and identify if there is a need for individualized treatment
Step 4 Determine treatment goals.talculate loading and maintenance dose by varying
dose or varying interval or combination method
StepS Monitor parameters of drug response as well as drug levels (total drug vs free
drug and peak/trough levels)
Step 6 Assess clinical res use and adjust men based on tents outcome

HEMODIALYSIS AND DRUG THERAPY

Factors that affect dialyzability of medications include drug characterlsdcs. dialysis
conditions.and patients clinical condition
Hemodialysis units generally administer drugs after the patient has undergone dialysis
to minimize the loss of drug
Drugrelated factors which preclude dialyzabillty Include the molecular weigh: or
size (>1,000 daltons). degree of protein binding (high),and distribution volume (large)
Dialysis prescription: composition and surface area of the dialysis filter and blood
and dialysate flow races. Highflux membranes have a large pore size (allow passage
of drugs with molecular weights of up to 20.000 daltons) and mimic the filtration
characteristics of the human kidney vs conventional hemodialysis.
Drugs extensively cleared by HD: vancomycin, atenolol.and metoprolol. angiotensin
converting enzyme inhibitors (except fosinopril)

CONTINUOUS RENAL REPLACEMENT THERAPY AND DRUG THERAPY

CRRT will remove medications by convection (unbound) and diffusion
Litde is known about drugdosing requirements for patients receiving CRRT; however.
dosing strategies can be between those used for outpatient intermittent hemodialysis
using a GFR <10 up to those used in mild impairment classified as GFR $080
 RAAS INHIBITORS
Renin Angiotensin Aldosterone System (RAAS)
Release Release Act ion C omments and
Component Activator s Inhibitor s Inhibitor s Actions
Renin 1 Afferent Natriuretic DRI PGE2 mediates release
arteriole peptides Convert angiotensincgen
stretch unSAIDs to angiotensin I
1 DCT Na 131 blockers
SNS (un CNI. DN
Angiotensin II ACE ACEr ARB Vasoconstrktion (efferent
(All) Not T K > afferent arteriole):
T Glom capillary
pressure
t BP (NUM 2017:377419)
T Aldosterone.ADH
T NHE3, NCC. ENaC
activity - Na
reabsorption
1 ROMK; T K excretion an
colon or seen
1998227459751
Aldosterone An: K Adrenal MRA. ENaC t ENaC. T ROMK: t Na
(Aldo) insufficiency. inhibitors reabsorption in CD &
ketoconazole CNI TK and H' secretion
ACEr, AR B, DN T Na leahsoqnion by colon
heparin T ROS. inilammationl
fibrosis (nu: Rev nepnm1
201 !:%459)

Angiotensinconverting enzyme (ACE): present at pulmonary and renal endothelium;

Converts angiotensin I to angiotensin II; Kininasezdegrades bradykinin
Natriuretic peptides (ANR BNR CNP): released from atria (ANP) or LV (BNP):
" cGMR inhibition of NHE3. NKCC2. ENaC. vasodilation. L renin release. T GFR
Neprilysin (CD10): neutral endopeptidase. abundant in kidney; degrades natriuretic
peptides. adrenomedullin. bradykinin.VlR and angiotensin II
Potential Changes of RAAS Components by Medicines
Renin Renin Aldo Level/
Type Level Activity All Level Aldo Level Renin Activity
D1 blocker 4 +4 6 +

DRI TT u L l T

ACEr T Tt 1 l 1

ARB T TT T 1 l
MRA T TT t T 1

Nepril in inhibitor 1 T t T
Clinical Use o¢ACEl and ARB
Mild T Cr: could be sign of 1 glomerular hyperfiltration
In CKD,ACEi use is alw 28% . mort. 39% J. kidney failure; 18% l major CV events;
ARB 30% I, kidney failure: 24% L major CV events IA/xo z0161672M1
In T2DMlDN.ARB 16-20% ¢ doubling Cn ESRD and death (RENAAL NE/M 20011345184
lDNTNEW'2001:]45:8$1)
ACEi or ARB is recommended for all diabetic patients with UACR >30 mild and
nondiabetic patients with UACR >300 mg/d lkoioo coo 2012). Proteinuria that would
quickly remit as In MCD can be monitored w/o ACEi or ARB (KDIGO Gn 2011).
In renovascular disease. 1 death. Ml. or stroke and dialysis (A»4/200a:1sss49)
Even in predialysis CKD5.ACEi and ARB aw i dialysis. death (WM IM 1014;174347)
Supramaximal ARB 1 proteinuria wlo lowering BP (nu 200s;6e:1 we }Asr4 2009;z0.s9al
Losartan has less maximal efficacy in BP lowering than other ARBs: losartan 100 mg
<irbesartan 300 mg, valsartan 320 mg. telmisartan 80 mg. candesartan 32 mg
Losartan T uric acid excretion by inhibition of the proximal orate transporter 1 (URAT1).
uric acid reabsorption mechanism WH 2008;2111157)
Use at night: improve BP (ASH 201194 can. L DM incidence l0i4wwf 2016:59:255)
ARBs and fosinoprll are not removed by HD: odmer ACEi are removed by HD
Angioedema from ACEi
Incidence is 0.68% (Ap41004:171103)1 rare with ARB (Ann IM 2011971115823 Am] Caluiui
20124110 ssl): Usually happens wu 1" wk of ACEi. but can happen anytime
bradykinin mediated by LACEmediated degradation
Swelling of lips,tongue. face,and throat (laryngeal edema):abd painzdiarrhea
Absence of urticaria or pruritus An¢¢gyA»uwna can nmmuiur 101117 Suppl 1:s91
Recurrence: 46% after dlc ofACEi 1" recurrence wu 3 mo except 1 case (Ii"59.445
201 1119n731: should not be attributed to alternative drug.such as ARB
Tx: dlc ACEr. airway protection: icatibant (NS/M 2015;]72:41B). ecallantide. C1 inhibitor
concentrate. FFP
Approximate Equivalent ACEi and ARB Dose (mg, Daily Unless Specified)
Drugs Low Moderate High
Lisinopril. Fosinopril 2,5-5 10-20 3040
Enalapril (qdhid) 2.5-10 20 40
Enalaprilar (q6h) 0.625-1.25 q6h 2.5 q6h 5 q6h
Captopril (rid) 6.25-12.5 tid 25-50 did 100-150 rid
Ramipril 1.25-2.5 5-10 20
Benazepril. Quinapril 5-10 2040 80
Moexipril 7.5 15 30
Perindopril 2 4-8 16
Trandolapril 1 2-4 8
Losarun 25-50 100 -
Valsarun 40 80-160 320
Candesartan 4-8 16 32
Olmesanan S 10-20 40
Irbesarran 75 150 300
Eprosarran 400 600800 -
Telmisarun 20 40 80

Side Effects ofACEi and ARB

TCr: in bilateral renal artery stenosis. HF and CKD; /BPIP wu 1 wk after start
Even 1 Cr <30% alw ESRD, ml. HE and death (mu z017:3s6¢i791)
Hyperkalemiaz possible in anuric HD patients (Am}m¢4 2002;1112110); Patiromer may be
used in hyperkalemic pts on RAAS blockade IN£}M 201s::n:211)
ACEi +ARB T AKI and r K in DN IN£;M 1013.J69.1a91)
Teratogenic y: CNS and CVS malformation in 1" trimester (NEW 2006;J54:24431: uro
genital and renal malformation in 2° trimestercavoid MRA and DRI
Anemia: both ACEi and ARB (Q/m 2015;10a;a79).Angiotensin II type 1 receptor enhance
EPOstimulated erythroid proliferation Wm 1ss9;1os; 1s8);ACEi 1 IGF1. erythropoiesis
promoter (fiumplonmuun 1997:64:913). Used for posttxp erythrocytosis or zoonnasol.
Dry cough in ACEr
PLEX reaction in ACEi: Klnin mediated: dlc 24 hr prior to PLEX (rIuvmiman 1994:34;B91)
No T cancer U Hlpenevs 2011;19;623; am;1018:361:k38$1)
Mineralocorticold Receptor Antagonists (MRA)
Addition to ACEr or ARB BR proteinuria ac/is~ Z009;4$41: ac nqmhml 20161111271
Effective addon drug for resistant hypertension (Lancet 2015:J86:2059)
imoriality in NYHA II HF wl EF <35% (new z011:364:11> a postMI low EF(NEJM
1003.34B:1309)
In HD patients. spironolactone 50 mg bid i BP WND 100$146941, S0 mg qd 1 hyperkalemia
w/o changing LV mass (al 101935:973:Z019;9598])
sle: hyperkalemia esp in CKD UASH 201024295), t Cr
Direct Renin Inhibitor (DRI)
Aliskiren » Iosarran L proteinuria dw losartan only (AvolD nsjm Z008;358:2433)
Addition of aliskiren to ACEr or ARB did not improve CV or renal outcome (ALWUDE
NEW 2011;367:2204: 2016:3141S21)
In HF aliskiren +ACEi t Cr;1 K.l BP wlo benefit (NEIM 2014974115211
sle: hyperkalemia. i Cr. angioedema
Angiotensin Receptor Neprilysin Inhibitor (ARNI): Sacubitril
Neprilysin inhibitor T natriuretic peptides, bradykinin. and angiotensin (reason ARB
combination is always required); NTproBNP is not t by neprilysin inhibitor
Indicated for symptomatic HE NYHA It-IV w/ LVEF $40% despite ACEi or ARB
HF w/ NYHA II-III on ACEi or ARB should transition to ARNi (ACCIAHA /Acc 10w270177sl
Do not combine wl ACEi for risk of angioedema icnulaw z002;I06¢920): 36 hr washout
for conversion. conversion from ARB does not require washout
20% J, CV mortality and HF hospitalization (NEW 2014=37w931 and greater 1 NTproBNP
in hospitalized pts dw ACEr (new 201913a95m
sie: more hypotension. less Cr 22.5, K >6 than ACEi (Ne1M 20w371¢993). angioedema
Avoid use prior to PLEX to prevent possible bradykininmediated reaction

NON STEROIDAL ANTIINFLAMMATORY DRUGS

Actions of Progstaglandins (PG) and Effects of unSAIDs

Actions of PG Effects of unSAIDs
Hypotension, 1 perfusion pressure - PGI; and PGE; L Renal blood flow and GFR
mediated vasodilation: mainly afferent arteriole:
maintain renal perfusion when RAAS is activated
High Sal: intake medullary PGE; inhibits NKCC2 0 Sodium retentionlederna
natriuresis Hypertension
T Concentration ability
Volume depletion cortical PGE; renin release from Hyperkalemia
JG cells - RAAS -u K excretion and BP
PGE; . AQP2 expression t Concentration ability
SIADH; used in NDI
Maintenance of medullary interstitial cell blood perfusion Papillary necrosis
TXA}S platelet a2,re son T Bleeding

Kidney express both cyclooxygenase (COX)1 and 2

Pharmacology of unSAIDs
Short Yz life (<6 hr): ibuprofen, indomethadn, ketorolac. diclofenac
Long Y: life (>6 hr): naproxen. piroxicam; phenylburazone (a veterinary NSAID)
Mainly metabolized by liver:Tightly bound to protein
Topical unSAIDs can induce systemic renal effects INDI 1999214 1 B7)
Effects on Renal Function,AKl and CKD
Current NSAID exposure is a/w AKI w/ OR 1.73 (mc nepnfd 101711a,156). ? 20% of AKI
and CKD UAMA Nelw of z019.2:¢1s7s96I: t AKI s. hyperkalemia (nor z019.a4,1 i 451
AKI: from renal vasoconstriction. especially when combined use with diuretics and/or
RAASI i AKI lx:201838396)
Rapid progression of CKD (An»Im¢4 z007=t 2<na0,¢1;
Other Renal Manifestations of unSAIDs
Interstitial nephritis: acute or chronic
T K: unSAIDs used In Bartter (T PG pathogenic) www 20a113431w1 yAsnz017;w1s40) and
Gitelman l;As~2015126:468)
dRTA and 1 K by carbonic anhydrase II inhibition (Cate Rep on Care z013.a7sasn
Potentiate ADH action: can cause SIADH; used in nephrogenic DI (NDI)
MCD, FSGS; MN lA;Kn 20n26z10111
Papillary necrosis: especially with vascular diseases, eg. sickle cell. DM
Sloughed papillae may cause renal colic. urinary obstruction
Contrast CT: irregular papillary tip. loss of papillae IV orography. ring shadow
Increased risk of pyelonephritis when used in lower UTI (Bm)2017:3S914784)
Longterm use may be alw RCC wdilm 2011:171:1487)
Extrarenal Clinical Manifestations
Analgesia, antiinf1ammatory effect
T BP (Lancet zooaarwoI; l antihypertensive effectiveness
r CV events man 1W5:351:1lJ91: BM; lll06:3]2:l30Z)I even in the 1 wk of use lciwiiuvn
2011;113:1126: WJ 2017;]S7:l1909)
T MI: diclofenac. but not w/ naproxen: indication might matter: spondyloarthritis >OA
(Ann Rheum on 201817721137): HF admission iw/ 2016; 3$4: i48$7)
Dyspepsia. peptic ulcer and bleeding
unSAIDs Intoxication and Overdose
Common cause of drug intoxication
Nausea.vomiting,drowsiness,anion gap acidosis (lactic acidosis 4; acidic metabolite).
seizure.aplastic anemia. and granulocytosis (in phenylbutazone intoxication)
AKl:usually reversible
Tx: conservative: HD is ineffective dlt protein binding; may consider PLEX in severe
intoxication (eg, anaphylaxis)
unSAIDs Should be Avoided in the Following Conditions
Any use in GFR <30. prolonged use in GFR <60
w/ lithium and RAASi lxoioo ci<o 1012): HTN (especially poorly controlled) and HF
Poral hypertension and cirrhosis (AGA an Gaauuenmul Hepnuul 10ltl7:59$)

DIURETICS
DIURETICS ACTINC on THE Pnoxinai. CONVOLUTED TuauLe (PCT)
Site of 60-70% of Na reabsorpdon
Drugs: carbonic anhydrase inhibitors (CAI). acerazolamide
L NaIH exchanger (NHE3) and T HCO: excretion by 25-30% and Na is brought
further downstream as the counterion (NKJM 19S4;254759)
Clinical Use: metabolic alkalemia induced by highdose loop diuretics in CHF.
glaucoma. pseudotumor cenebri. highaltitude mountain sickness. posthypercapnea
alkalemia (Run #Mai 1987;1011]6)
W e a k natriuretic when used alone dlt T distal Na reabsorption (N£IM 19s4=2so¢s00)
Effective as a natriuretic when used in combination with more distal inhibitors
(1 CarMawsc Pharmacy 1997:29:367; UM) 1990112318831
PK: usual dose is 250-500 mg daily: Secreted by OAT in PCT (Semen news 2011:31:483)
Electrolyte Effects: metabolic acidosis.profound hypokalemia from distal nephron
Na/K exchange;ensure K replete in considering use (NEW 19$4:250IS9)

DIURETICS ACTING ON THE LOOP OF HENLE

Site of 25% Na reabsorption
Drugs: furosemide. torsemide. bumeranide: ethacrynic acid (nor sulfabased)
Inhibit apical NaK2Cl couansponer (NKCC1) in the TAL of LOH
Clinical Use: greatest natriuretic eliiect among Me diuretics ("high ceiling" diuretic).
Starting diuretic for volume management in advanced CKD.cirrhosis. CHE and nephrosis.
FK: variable PO absorption with furosemide (see table). Highly protein bound, very
little Gltered. Secreted by OATs in PCT (chi HlamThu 19ao:z77a4).
 Pharmacokinetics of Loop Dluretlcs (NEW 1 wmamal= Am]17»er zu09;1w1
Equivalent Dose
Diuretic Oral Bioavailability (76) PO (mg) IV (mg) Tm (it)
Furosemide 10-100 40 20 1.5-2
Torsemide 80-100 20 - 3-4
Bumetanide B0-100 1 1 1
Ethacrynic acid 100% S0 50 2-4
Tar: significantly increases i CKD. CHE and cirrhosis INE}M 199B;339387).

Ceiling Doses of Furosemide (Amjm¢4sa 1u00.3\9¢JU):anlons neulned

in renal failure compete with OAT
Condition IV (ms) PO (mg)
eGFR 20-50 a0 160
eGFR <20 200 400
CHF 4080 80-160

Electrolyte Effects: 1 K (A0.3 mEqIL) and 1 Mg common: 1 Na less common than

in thiazides as NKCC2 inhibition L medullary interstitial osm (s¢mwI n¢w-=l10I1;a1:s42>
Other sle: hypersensitivity (sulfabased. except ethacrynic acid),AIN (uncommon).
ototoxicity (NKCC1 antagonism in inner earzavoid concomitant aminoglycoside
administration. more common MM ethacrynic acid).Vascular smooth muscle relaxation
with improvement in pulmonary congestion in some patients IN£;M t 973¢za&1oen. Can
worsen LC cast nephropathy.

DlunETlcs ACTINC on THE DISTAL CONVOLUTED TubuLe (DCT)

Sire of -5% Na reabsorption
Drugs: hydrochlorothiazide (HCTZ), chlorothiazide. chlorthalidone. metolazone
Inhibit apical NaCI cotransporter (NCC) in the DCT
Clinical Use: antihypertensive in pts with GFR >30; Edema:used in combination w/
loop diuretic for acute decompensated HF (ADHF) UACC 2010t56=1527);Ca nephrolithiasis.
nephrogenic DI (along with low solute intake)
PK: blunted effect when GFR <30
Plnrmacoklnetks of Thiuides yAcc z0I0s&Is2n
Equivalent Duration of
Diuretic Dose (mg) Action (hr) Duration in CKD
H c Tz 25 (PO) 6-12 T
Chlorthalidone 12.5 (PO) 24-72 t
Metolazone 2.5 (PO) 12-24 t
Chlorothiazide 250 (IV) 6-12 T

Electrolyte Effects: 1 K (A~0.5-0.9 mEqIL) and LM; common

Other sle: hypersensitivity (sulfabased).AIN (uncommon), hyperlipidemia,
pancreatitis. i insulin sensiziviry. T Li. T Uric acid. gout. Some thiazide class diuretics
have carbonic anhydrase inhibition (chlorozhiazide. chlorthalidone. and indapamide
are strongest).
Thia zide Induc e d H y pona tr e m ia (TIH )
Risk Factors: old.female. low BW low BMI. highdose thialide, previous h/o TIH
common in 1" 3 mo of thiazide. risk remained high ~10 yr (AmjM¢4 2011:124:1064)

Mechanisms of ThiazJdeInduced Hyponatremi.

lack of effects on medullar interstitial osmolality as in loop diuretic
NCC independent upregulate aquaporin2 (Ayllemllowaosrszsl
Increased water intake (And IM I909.I\a24, lHrw1~~ ZOl5;33:6171
| Water clearance dlt low solute intake: Urine urea <330 mmolld I/»#»v~==~ 201 sa3¢sm
Polymorphisms of gene encoding PG trans . her. EP4 Taqu rin2 zo11:1z7:aas7I

Low uric acid. FEm \4 >12%

Tx: permanently dlc d\Ialide. t solute intake 2 fluid restriction
 DlunETlcs ACTING on THE COLLSCTINC DucT (CD)
Sire of 1-2% Na reabsorption
Mineralocordcoidreceptor blockers (MRB) and ENaC antagonists: Ksparing
Drugs: spironolactone (MRB). eplerenone (MRB). amiloride (ENaC antagonist). trl
amterene (ENaC antagonist);Trimethoprim component ofTMP/SMX inhibits ENaC
MRBs antagonize effects of aldosterone (basolateral NaK ATPase. apical ENaC, apical
ROMK),while ENaC antagonists directly antagonize apical ENaC in principal cells in
the terminal DCI CCIZ CCD limn n°p"wl2011:314a3)
Clinical Use: as mainstay in cirrhosis and nephrosis.and as adjunctive in CHE Can
attenuate the need for K supplementation in combination diuretic regimens.
PK: MRBs enter cytosol via basolateral membrane. ENaC antagonists are secreted
by OCT in PCT
Electrolyte Effects: T K, 4 HCO3 (Semis nepiw 20u;z154z)
Oth e r sie: gynecomasUa (MRBs):Triamterene can result to crystalluria and stone
formation in up to 50% of patients (co. Nephrnl 19B6;16:169)

OTHSN AGENTS WITH DIURETIC EFFECT

Vasopressin Antagonists
Drugs: tolvaptan (PO). conivapran (IV)
Vasopressin2 receptor antagonism blocks effect of ADH. leading to aquaresis
Clinical Use: FDA approved for the treatment for hypervolemic 1 Na and SIADH
PK: dose reductions required with ketoconazole. darithromycin. ritonavir. saquinavin
erythromycin. fluconazole. verapamil
Electrolyte Effects: T K. 1 HCOJ (sm mama 20119115411
Other sle: can cause significant t ALT >AST > bilirubin; Conivaptan also hasV1a
receptor antagonism. can lead to variceal bleeding
Sodium Glucose CotranspowtenZ (SGLT2) Inhibitors
Used in TZDM; 1 mortality. CV events. T wt loss. BR and improved renal outcomes:
we/H zo19;anu9s= JAMA 20188191\5801 GtuiaUun 2016:802277: q/iw 1017111:751: xi 2018;9]231)

Osmotic Agents wa- :m 1981:141:493)

Mannitol is altered by glomerulus. exerts osmotic action throughout nephron
Generally no benefit; should only be used for nondiuresis indications
B N P I A N P Potentiation (run Anna Sachem 1991;14=zoal
Sacubitril: neprilysin inhibitor: T natriuretic peptides: sacubitrlllvalsartan (Entresto°)
4 CV mortality and HF hospitalization lnslm 2014;:719931; in HF with NYHA IIIII on
ACEi or ARB should transition to ARNi (ACC/AHA;ACC 1017:70776)
Nesiritide: recombinant human BNP: no effect on mortality and rehospitalizadon in
ADHF INE;M 101\:36582); not currently recommended therapy

DIURETIC RESISTANCE wxl;2017:69:136)

First assess for dietary adherence (24 hr Un. <100 mmol - 2.3 g) and medication
adherence.Then consider alternative mechanisms for resistance (below).
Diuretic not reaching target: too low dose. poor absorption. organic acids of uremia
competing with OATs in PCT in CKD
 Blunted diureuc response (concomitant use of NSAIDs.activadon of RAAS and Na
retention after diuretics (Ki 1983;24:13J)). disizl nephron adaptation with Na avidity
If 24 hr Un. <100 mmol.then increase PO :oral daily dose (dose or frequency). If no
response.add distal diuretic (DCT or CD). If no response.then transition no IV.

DISEASESPECIFIC MANAGEMENT
Hypertension ISQNI1 Nephrol 2011,31495:Am 1 Hypenenx 2016;29:1110)
Thiazides included in 1"line therapy recommendations by JNC8 kw zo14:a 11=s0n
Furosemide BID vs wmemide QD » similar i BP in CKD2 and 3 (KI 2WJ;64:6321
A cu t e K id n e y I n ju ry
Diuretic use in critically ill wtienu with AKI is a/w adverse ewnu in this group (con
relation, no: clearly causal): may delay initiation of RRT locAno;w 2W2;1W:254"
Diuretic use co achieve a negative fluid balance in paden w/ ARDS and AKI conferred
a 60d mortality benefit (nm qAsn 1011;£9")
Diuretic challenges" in AKI may be trialed to manage volume overload, but requires
frequent reassessment for reWnoriness so as not to delay RRT
No clear role in AKI other than volume management (Grade ZC) (KolGo Axi 20121
Chronic Kidney Disease may may 101ze:1w)
Orpnic acids compete with lobular secretion by OAK rightward shift of doseresponse
cu rve re su ltin g in higher required doses 9ASN 2W1:13n8)
Addition of thiuide to loop diuretic in CKD 3b and 4 results in l weight. plasma
vo lu me . a n d B P in mm 1 %1 ;U:9 2 9 l
In ESRDHD. if still urinates continuing loop diuretic alw lower IDWG. less T K.and
preservation of residual renal function at 1 yr (oomux02w7=4914261 and 1 hospital
iza tio n & in tra d ia lytic h yp o te n sio n (Cl*5 ** z0 \m4 9 5 )
Co n g e stive He a rt Fa ilu re (Se m Ne p n mi z0 1 1 :3 1 =s0 1 )
Diuretic resistance from several mechanisms. but afferent vasoconstriction primarily
responsible for 1 diuretic secretion (both -» and l shift of doswesponse curve)
Torsemide results in fewer ADHF admissions than furosemide (AmI m¢4 z001:1\1;s1s)
For hospitalized patients.similar results in bolus vs continuous IV dosing of loop
diuretics (DOSE new 2011;3s4;n11; however, prior study in resistant patients noted
increased urine output and less ototoxicity with gtt vs bolus dosing (}Acc 1996:7.8:37b)
Combination loop diuretics and thiazide an double FE~, and wt loss, but T risk of 1 K,
1 Mg. L Na.. BP, and worsening renal function (WRF) (;Acc 2010s6¢1s171
Addition of metolazone vs thlorothiazide resulted in similar UOP and adverse events
in d iu re tic re sista n ce in A DHF is-wa rm 1 0 1 s;3 J¢ 4 1 >
In severe. refractory cases. some evidence to support the use of hyperwnic therapy +
highdose loop diuretics (an 1 Heart FM zoaatzwsl

Cirrh o sis(Semn nepml 201 1.311s031

Combination therapy with loop diuretic and spironolactone. usually in a 2:5 mg dose
ratio u Can Gown 19s13a suppl1:73: l4=W4'°l°tY 2W3:38:1S8)
90% will have effective management with Narestriction and this combination
If CKD or OLT. need less MRB and more loop (100;B0 or 100:120) given risk of t K
Loop diuretic monotherapy is Mt recommended. except in cases of 4 K
S p iro n o la cto n e mo n o th e ra p y if K <3 .4
Avoid L K given risk of worsening hyperammonemia (intracellular acid in PCT)
Hold diuretics for worsening encephalopathy or severe LNa <120
No role for IV therapy. even in resistant cases (more WRF with IV)
Amiloride and triamterene less effective than spironolactone (OCTs in PCT)
Ascites: goals of therapy depend on sate of peripheral edema
w/ p e rip h e ra l e d e ma » <2 kg / d
wlo peripheral edema -» <0.3-0.5 kgld (consider paracentesis if symptomatic)
N e p h ro ti c Syn d ro me (N S)
Hypoalbuminemia may reduce diuretic delivery and intrduminal albuminuria may bind
secreted diuretics (not confirmed in humans) l;Asn 1000;11:11W)
Unclear role for coadministration of albumin and furosemide (KJ 1999;$5sz9) routinely.
Consider albumin if signs of intravascular volume depletion (r:,lASN 1uc~x4:907)
Combination with loop diuretics including thiazides, amiloride (filtered plasminogen
_» plasmin activates ENaC) (IASN 1009342991
 IMMUNOSUPPRESSIVE THERAPY
PRINCIPLES OF IMMUNOSUPPRES5IVE THERAPY
Glomerular Diseases
Many glomerular diseases are mediated by immune mechanisms (KI 2014:a6:90$) and
immunomoduladng therapy is a mainstay of treatment
lmmunosuppression (IS) therapy is divided into 2 phases in some glomerular disease
:her relapse frequently (et, lupus nephritis and ANCAassociated vasculitis)
Induction therapy: intensive IS to induce remission in proliferative glomerulone
phritis (eg. pulse methylprednisolone followed by cyclophosphamide)
Maintenance therapy: after remission is induced. reduced IS is given co prevent
relapse avoiding severe toxicity of IS (eg.AZA. moderate dose MMF)
Renal dysfunction, hypogammaglobulinemia. and complement loss from proteinuria all
susceptibility to infection (Aim 19941414271
Gut mucosal edema d/t NS can l PO absorption of medications
Hypoalbuminemia and proteinuria affect drug metabolism and clearance
Regimens are tailored to the clinical syndrome being treated. patient compliance
(IV or qd instead of multiple dosing if nonadherent). and comorbidides
Comorbldides and Selection of lmmunomodulators in Glomerular Diseases
Comorbidity Avoid if Possible Hay Consider
Advanced CKD CNI . CS.MMF
DM CS.Tac CsA, HMF
Gou: AZA if on xanthippe oxidase inhibitor MMF
Pregnant MME CYC (contraindicated) CS.AZA. or CNI
Kidney Transplantation
IS can be achieved by depleting lymphocytes Cr blocking lymphocyte response

gzip
Fcell activation postTx dependent on 3 responses:
Signal 1: antigen-Tcell receptor interaction (via CD3 signal)
Signal 2: costimulation with dendrite cells (via CD80l86:CD28 interaction)
Signal 3: activation ofTeR pathway -» cellular proliferation (new 1004051:2719
Induction therapy: intense IS in 1H wk postTx; can be either lymphocyte depleting
(thymoglobulin, alemtuzumab) or nondepleting (basiliximab); CS typically also given
Risk factors for acute rejection: number of HLA mismatches: younger recipient age:
older donor age;AfrlcanAmerican race: PRA >0%; presence of DM; blood group
incompatibility; DGF; cold ischemia time >24 hr or zooms supplJ:S8)
Choice of Induction Based on Immunolodc Risk Factors for Acute Rejection
H ig h r isk Lowrisk
Use lymphocytedepleting agen: (ATG more Use either lymphocytedeple¢ing aden: or
common than alemcuzumab) IL2RA
ATG more effective :han IL2RA as 1 and Dm are mixed whedler ATG more
5 yr II preventing acute rejection. though effective as preventing rejection dw
no difference In patient/graft survival basiliximab. though adverse events with
(NEW 20083551967: 200e335921 vi ATG (r.....¢ii»i¢u~\ iwxsvnan u~=¢
Early rejection equal between ATG and 2016;388:3006)
alemzuzumab, T lame rejection with
alemtuzumab [NgI4101 mummy

Maintenance therapy: ongoing IS to prevent acute reiection.Typically 2 or o n .

Most regimens consist of a CNI (in US -90% Tac and -10% CsA) and andmeabolite
(in US >91>% MMF). +I- CS (in US. 67%) WT zola;1s $uppl1:1 B).
If unable [D tolerate CNI d/¢ severe s/e. can convert to mTORi or belatzcept
Nonadherence occurs in 20% of KTR and is a/w T late acute neiection and graft sur
vinlal; more common in adolescent: (QASN 2010.sn10s: re,ww 1W5;18:l12I)
In pts as T risk of ncnadherence, consider simplified dosing regimen of daily medkadons
(TacER. prednisone, sirolimus. and/or AZA) and/or use of monthly IV belanacepv:
Infection Screening Prior to IS ¢c}As~ 101a;131z641
J HBsAg. antiHB: Ab. HCV Ab, HIV Ab. strongyloides Ab
• ./ PPD and/or IFNgamma release assay (IG RA)
IS can cause false (-) in many Ahdetecting and cytokinebased methods. Nuclek acid
testing and both o( PPD and [GRA should be considered [O T sensitivity
 C o a T l c o s T ER o 1 o s ( C S)

Mechanisms ofAction
CS refers to a class of steroid hormone and the synthetic analogues that bind to
glucocorticoid and mineralocorticoid receptors
Glucocorticoids bind to the inuacellular glucocorticoid receptor -» binds to
glucocorticoidresponsive element -i gene expression regulation -» t antiinflammatory
protein, i proinflammatory protein
Neutrophil migration to inflammation site: T neutrophil secretion of bone marrow
Inhibition of the function ofAPC; inhibition of the vasodilation: 1 vascular permeability
Inhibition of the swithesis of arachidonic acid -» L PG and LT
F o r m u l a ti o n s
Relative Activity and Action Duration of CSs (Alqynavna an lnmuwl 1MBMB)
Drugs Gluc oc ortic oid Mi ne ra l oc orti c oi d Ac ti on Dur a ti on
Hydrocortisone 1 1 Short (8-12 hr)
Cortisone 0.8 0.8
Prednisone 4 0.8 Incermediaze (12-36 hr)
Prednisolone 4 0.8
Merhylpredraisolone 5 0
Dexamenhasone 30 0 Long (36-72 hr)
Beramedwasone 30 0

Prednisone/prednisolone 5 mg = methylprednisolone 4 mg - hydrocortisone 20 mg

Physiologic cortisol: peak as 6 AM; equivalent. to prednisone 5-7.5 mild
Clinical Use and Dose
Dose early in AM; mult iple dose may T sle union Diabet es End¢1<llnaI 201B: 6: 173)
Tapering: unnecessary if CS used <3 wk. Rapid tapering may T relapse and withdrawal.
No consensus on tapering method I; Rheumalal 2013;40:1646).
RPGN: methylpnednisolone 500-1.000 mg or 7-15 mglkg IV qd x3 d followed by
highdose PO CS.eg. prednisone 1 mglkg qd
Proliferative GN (eg. lupus nephritis. pauciimmune GN): highdose CS
Glucocorticaid responsive MCD and FSGS. 1g/\N: prednisone 2 mg/kg god or 1 mg/kg qd
Adult MCD may require high dose for 4 mo (qAsr4 2no7:2:44s1;Avoid use >6 mo
A cu t e i n t e r st i t i a l n e p h r i t i s
Induction and maintenance iS aker KT: CS withdrawal is center dependent: 71.8% on
cs 1 yr after KT in 2016 (ovrwsurni/r201m1s :ii 118)
No consensus on the optimal maintenance dose after KT 1K1:>IGo As 2009.9 suppl 3.si)
Early steroid withdrawal alter transplant performed to avoid longterm sle of CS
Early dlc alw T risk of recurrent GN but no T in graft failure (riuiapiiiniiaan 2011191113861
In lowrisk. early dl: a/w similar patiendgraft survival & rejection rates (qAsn
20 lZ:7:494)
In highrisk, similar Gndings with early steroid withdrawal (fmiisplalimuan 2004;78=1397)
Lace steroid withdrawal after transplant a/w T risk of acute rejection and graft failure
In pts who have 1st acute rejection after steroid withdrawal, maintenance CS may l
risk of 2nd acute rejection and graft failure or z007;7:194a)
Acute cellular and antibodymediated rejection
Pharmacology
Metabolized by cytochrome P450 (CYP) 3A4
Infection
Pneumonia x5.42. candidiasis x4.93. sepsis x3.96, zoster >(2.37 (runs mu 101Q1J¢¢i002024)
Risk is a/w dose Inner of an re Am 1016:42:1$7)

Adrenal Insufficiency
3 adrenal insufficiency from withdrawal of chronic CS use; rare with <3wk use
Weakness. fatigue. anorexia. NM hyponatremia, hypotension
TX: T dose to physiologic dose (prednisone 5-7.5 mg/d) and retry tapering stllss dose
CS for surgery and shock
Osteoporosis and Fracture INEJM zo1a:anzs47l
.L eGFR and T albuminuria are alw fracture (Ach IM 2007;167:1!1l: A/xo 2016;67:21B)
Vitamin D deficiency is common in proteinuria from vitamin D binding protein loss
CS .. bone formation of osteoblasts. T bone resorption of osteoclasts. T RANKL
Prevention for all raking prednisone 22.5 mg/d for 23 mo lAcitAiu»n» Nienmuiai z017;¢<z1s11l
 GlucocorticddInduced Fracture Risla (Act wins luununi 1011421511i
Risk Aduks 240 lo Adults <40 ylo Management
Low FRAX <10%Is1% None below Ca.Vir D. lifestyle
Moderate-High Prior oszeopororic Prior osteoporotic Ca.vit D. lifestyle
fracture fracture PO bisphosphonate
FRAX >10%l>1% Ol1 prednisone 7.5 mg
Hip or spine BHDT for >6 mo AND
score S-2.5 in cl hip or spine BMD
250 lo and Z score <-3 or
postmenopausal 9 rapid bone loss
>10%lyr
. If 240 lo /FRAX (hnps:llwww.sheffield.ac.uk/FRAXI) for 10yr risk of major osteo
porolic and hip fracture
If prednisone S-7.5 mg/d. / glucocorticoids use and use reported risks
If prednisone >7.5 mg/d. J glucocorzicoids use and x1,15 for major osteoporotic. x1.2
for hip fracture risks
If <40 lo and has h/o osleopororlc fracture or has risk factors (malnutrition, signifi
an: weight loss or low body weight, hypogonadism, 2 HPI thyroid disease. FHx of
hip fracture. ha of alcohol use [23 units/d] or smoking). /BMD wu 6 mo of the star!
of CS
All require optimal Ca (1,000-1.200 mold) and vitamin D (600-800 lUld) invoke
All require lifestyle modifications: balanced diem. maintaining weigh: in the recommended
range.smoking cessation. regular weightbearing or resistance training exercise. limiting
alcohol intake to 1-2 alcoholic beveragesld
PO bisphosphonates (aler. iban. risedronaze) are prelerned and safer than IV
O t her Slde Ef f endi
HBV reacdvarion: prophylaxis (et, enlecavir 0.5 mg qd) if andHBcAb (+) and predni
sone dose 210 mg/d for 24 wk or andHBcAb (+). HBsAg (+).and any dose prednisone
for 24 wk (AGA Guideline auuuneimulig z01s¢ 14ez1sl
Hypertension. fluid retention, weight gain. DM, hyperlipidemia, avascular necrosis
Psychosis, mood change, insomnia
Atrophic striae.acne vulgaris. myoparhy. dermal thinning. cauracrs.glaucoma
GI ulcerauon/bleeding unclear association when used wlo unSAIDs IAMAM 1991;114.73s)

AnnEnocoRTlcoTnoplc Hon rous (ACTH)

Mechanisms of Action
cs release; melanocortin 1 receptor activation J proteinuria UASN 20II:21:1290)
Formulat ions an d Do se
ACTH=r° gel: porcine pituitary preparation: 80 IU/mL SC or IM x2-llwk
Synacd1en°: synthetic tetracosactide: 1 mg IM x2/wk: available in Europe
Clinical Use and Side E¢yects
MN (Ajxb 1006:47:23J). other resistant NS (Amjuephm12011136;58; C/ASN zmamonl
Cortisol level may remain low due no consolbinding globulin loss through proteinuria
Similar side effects to CS

C A L C IN £U N iN IN H iSiT O R S ( C N I)
Mech an ism s o f Act io n
Calcineurin dephosphorylates NFAT -» nuclear translocation of NFAT -Transcription
of IL2 and other cytokines and T cell signaling
Calcineurin dephosphorylates synaptopodin -» synaptopodin degradation -» module
cytoskeleton of podocytes (nm m¢4 2coe;149J1l
Cyclosporine A (CsA) binds to cyclophilinnzcrolimus (Tac) binds to FKBP12: these
complexes inhibit phosphatase activity of calcineurin
Clinical Use
Maintenance immunosuppression after transplantation.Tac is superior to CsA: less
acute rejection, better allograft survival (NEW 2007;357:1561>
MCD. FSGS. MN. dassv LN (ASr zc09.z0=901)
In naive kidney disease. consider avoiding use In advanced CKD. esp severe interstitial
fibrosis and tubular atrophy
Formulations and Dose
CsA modified: neoralz capsule. solution; initial dose 9-12 mglkg/<1 in 2 divided doses
CsA nonmodified: sandimmune°°: capsule. solution. IV
Conversion from PO [O IV: 1/3 of the PO dose
Tac immediate release (IR): prograf: Starr w/ 0.2 mglkg/d in 2 divided doses
Conversion from PO IR to SI.: 1/2 of the PO dose in divided doses q12h ITnueplnm nu
1010.4243]1i Fl'¢'"'°<°0*'°P/1013:33:31)
Conversion from PO IR to IV: 1/3 1/5 of die PO dose as a continuous infusion over
24 hr. Its correlation with AUC is less known; SL form is preferred.
Tac extended release (ER):Astagraf XL°,Envarsus XI: no generic formulation
Not interchangeable with IR and each other: time peak level and daily AUC differ
among formulations. Starting conversion dose from PO IR to PO ER: total daily
dose of IR = daily dose of Astagraf; dose of Envarsus XR = 7 0 8 0 % tota l da i l y dos e |
of IR or 201721714321
Tac ER has similar efficacy to TacIR and may have fewer side effects: Envarsus XR
may be alw fewer neurologic sle than other formulations [Clin Tiuniylnnl zo1 s.293m1
No difference in allograft survival.acute rejection rates.or renal function among Tac
formulations or z010:10z632; AjKD2016:67:648)
Unclear whether ER formations improve adherence (Arr 2014:14:2796;1010.10L1632)
Pharmacology and Drug Interaction
Nanow therapeutic window needs therapeutic drug monitoring trough level is preened
Target Trough Levels (fig/mL) in KT: should be individualized according to rejection
risk. ieiul Iunczion, other immunosuppressive agents. and infection risks
0 -3 m o 3 -6 m o >6 mo

CsA 250-350 150-250 50-150

Tac 8 -1 2 6 -1 0 5 -8

Unclear above level should be achieved in glomerular diseases

Mainly metabolized by CYP 3A4 and S: CsA inhibits CYP. avoid or use with low dose of
simvasratin. Iovastadn > acorvastaUn: rosuvastz:in.piravasmdn.and pravastacin are safer
Due to CYPIPglycoprotein inhibition. CsA markedly increases colchicine exposure.
Use reduced dose of colchicine for prophylaxis and uearmenc of acute gou: racks
in patients on CsA innnua Rheum 2011;63:2226)
CsA binds IO Iipoprozeinsnac binds to albumin.u1 acid glycoproteimand RBC: RBC
exchange :ransfuse used for coxiciry (Fen ail mann:2011:26:2145)
Fa c tors Affe c ti ng Drug Le v e l s of CNI
Increasing Decreasing
CYP inhibitors: grapefruit juice. pomegranate CYP inducers: rifampin. rifabutin. SL John
iuite. diltiazem. verapamil. azoles. won. antiepilepdcs (phenytoin.
darithromycin. erythromycin. protease barbiturates). nakillin. ciro. imipenem.
inhibitors ticlopidine. ocrreotide
Diarrhea: intestinal CYP and pglycoprotein Cinacalcet for 209&1311049
inhibition (Pedatr Tranwinnl zuosnisi
Henadc im torment

Rifampin. phenobarbiral. & phenytoin (Case Rep hunapbm 2013:2013:375163): used for toxicity
S i de E ffe c ts

S ide E ffe c ts of CNIS

Com m on S i de E ffe c ts
Nephropathyz afferent vasoconstriction, tubular isometric vacuolization. arteriolar
vacuolization. arteriolar hyalinosis. FSG$.TI*1A, striped interstitial fibrosis
Hypertension: . NCC acziviry (no #442011:17:130q. hyperkalemia
Infections: CMV. PML.]C. BK. parvo B19. fungal
Malignancy: skin. lymphoproliferarive
Neuroloxicizy tremor. headache, PRES (headache. seilure. posterior MRI lesion). CNI pain
syndrome: LEx pain (as 1 Plum z0ms1ss4»1
 More Common in CsA
Hirsuzism. hyperuricemia. hyperlipidemia.
hypenriglyceridemia
Gingival hyperplasia: metronidazole (lunar
1994;J43sesl or azizhromycin (flwViwwfivvl
199B;6$:\611)mayhelp

roTOR INHIBITORS (Smounus AND EveRoLlr4us)

Mechanism ofAction
Blnds to FKBP12.an intracellular protein -v inhibition of mammalian (or mechanistic)
target of rapamycin (roTOR). serine/direonine kinase -» inhibition ofT cell response
to cytokines G1 cell cycle arrest - Inhibition of lymphocyte proliferation
roTOR signaling is important in pathogenesis of tuberous sclerosis. various cancers.
and antiphospholipid Abmediated endothelial cell injury WM 20141371=a031
Clinical Use
Maintenance IS following KT in combination with CNI 1 CS: less commonly CNI
avoidance protocols. Used in <5% of recipients in the US Wt 201s;\s Sippi1¢1Bi
Often avoided in early postoperative period due to delayed wound healing
Conversion from CNI to mTORi used as CNIsparing strategy to preserve renal
function alter KT and nonrenal solid organ transplantation (NRSOT)
May be slight improvement in GFR over time but no difference on allograft survival
lffiiwlillwififivfl 2017;1irI57). KT pts with l GFR or proteinuria at time of conversion
less likely to benefit (Twnpbmadan 2009.8722331.
Baseline proceinuria also reduces chance of renal benefit with roTOR conversion
after hear: u »4¢¢n Um Transplant 2011;315651 and lung Txp (an Transplant 201421s1u6213 Renal
function improves with conversion after liver Txp but there is an increased rate of
acute rejection lTuuplalun zowiasziy.
Switching from CNI to sirolimus Kaposis sarcoma (NE/M 200S;3521317) i new squa
MolJ$ cell carcinoma 1~£/m 201z=w.3291 L 56% risk NMSC vs CNI in 2014:349¢:°579)
after K[ Sirolimus but alw higher mortality (qASN 2016;11:1845).
x angiomyolipoma size In tuberous sclerosis or sporadic lymphangioleiomyomatosis
(l.¢nl 2018;381:l17)2 adjunctive therapy for breast cancer, RCC; 1 seizure in tuberous
sclerosis (lima 1015389111531
Sirolimus L endothelial hyperplasia graft failure in APS (NUM 10142371;3031
Contraindicated in pregnancy
Formulation and Dose
Sirolimus (rapamycin): Rapamune°: sir: 1-5 mg qd: Loading dose can be given:
trough level goal: 5-15 fig/mL
Everolimus: Zortress°;0.75 mg q12h:trough level goal: 3-8 nglmL

Side Effects
Proteinuria, edema. hypertension.AKI: FSGS and TMA (KI Rep zola 2017;3;ZB1)
Bone marrow suppression: rhrombocynopenia. anemia. Ieukopenia. neuuopenia
Delayed wound healing/wound dehiscence
Angioedema when used with ACEr (c;A5~ zo1ms:10:>
DM. hyperlipidemia, hypertrigiyceridemia. Iymphoprcliferative disorder
Mucositis/stomatids. ILD (T"=v~=a4¢wvr PM zumsam)

MVCOrHENOLATe MOFETiL (MMF), MYCOPHENOLATE Soolum (MPA)

Mechanisms ofAction
MMF metabolized to MPA: inhibits racelimiting enzyme, cosine monophosphate
dehydrogenase in the de novo pathway of purine synthesis; ' Iympho¢yl.e proliferation
Clinical Use
Maintenance IS following KT: superior co AZA for graft survival and prevention of
acute rejection (Cndnune Daiaaae Syn Rev 2015;11:CD007746)
Lupus nephritis (LN) III and IV induction & maintenance; ANCA vasculitis induction
[Ann Rum. o; 2019;78399) & maintenance; Inierszitial nephritis IQASN 1IJ06;1;71B)
Contraindicated in pregnancy
Formulations and Dose
MMF: CellCept°:; PO. IV; 1,000 mg q 12h for KT
African American requires higher dose. 1.500 mg q12h (Tmiuplmmuan 1997;64:1277)
Oral and IV are equivalent
• Entericcoated (EC) MPA Myfortic°;720 mg MMF 1,000 mg
Pharmacology and Drug Interaction
Highly (97%) protein bound. Unbound form is active. Primarily liver clearance.
Factors Affecting Drug Levels of MMFIMPA
Increasing Decreasing
Tacrolimus 1 Absorption: sevelamer. Ca. Mg. iron. Hz anugonlst. PPI
HypoalbuminemialNS (1h¢wnq10l¢¢y N1Q49:2%1 : A;r 200949:1650)
Uremia CsA: by inhlbidon of enrerohepazic circulation
CSto200116z10eo)

Therapeutic drug monitoring is no: routinely performed

Side Effects
Nausea.abdominal pain.diarrhea: splitting (low frequent dose) and delayed lower GI
absorption of EC MPA may lower GI intolerance: can cause colitis with similar
appearance to IBD. not related to dose (lisxapaunaligy 1013:63:649)
Neutropenia.anemia. pure red cell aplasia.temtogenicity. pregnancy loss
Lymphoma, hypertension, hyperglycemia. hypercholesterolemia
Infection: esp.. herpes virus: no P.jiiuvecii infection from ? protective effect (an mm on
zoozassal. Lower risk of serious infection Chan CYC or CS In LN (ac mm z01s8141m.

AZATH»OPRINe (AZA)
Mechanism ofAction
Metabolized no 6mercaptopurine (6MP) -2 inhibi: de novo and salvage pathways for
purine synthesis -» inhibit DNA replication -r inhibit lymphocyte proliferation
Clinical Use
Maintenance for ANCA vasculitis: superior co MMF wl more relapse (x1.69) (mAMA
zoIma04=ns1); maintenance therapy for lupus nephritis
Maintenance immunosuppression following KT
Relaciveiy safer for pregnancy than MMF and cyclophosphamide
Formulations and Dose
Imuran° (50 mg).Azasan° (7S. 100 mg): 1-3 mglkg (usually 50-150 mg/d) qd: adjust
forWBC
Pharmacology and Drug Interactions
Metabolized by xanthippe oxidase or thiopurine methyltransferase (TPMT)
TPMT deNciencyr T toxicity; enzyme activity. and genotype are /ed when initiating
AZA in IBD IAGA Gauiueuaulqy 2017.153:827). Not routinely /ed for KT or glomerular
disease.
Xanthine oxidase inhibitors (allopurinol, febuxosrat) T toxicity: avoid coadministration
or iAZA dose by 75% and monitor CBC closely
Side Effects
Myelosuppression, hepatitis. chclesusis. pancreaxiris
Infection: bacterial, fungal. prorozoal: lymphoma. PTLD

LEFLUNOMIDE
Mechanism ofAction
Metabolized to teriflunomide -» noncompetitive inhibition of dihydroorome dehy
drogenase - inhibit pyrimidine synthesis in lymphocytes
Clinical Use
Refractory BK nephropathy after KT (rmniplnmnlmn 2006:11904: qAs~201);7:1093)
BK hemorrhagic cystitis after HSCT (Aan Haemaw zoIJ:I:o.s2): resistant CMV infection
(co Rep mpnrd Dial 20!5:S:96)
RA: contraindicated in pregnancy
Formulations and Dose
Arava° (10 mg, 20 mg): Dose 2040 mg daily: Can give loading dose 100 mg qd x 3 d
Monitoring of drug levels not routinely performed
Monitor CBC and LFTs: do not use if ALT >2x ULN
Pharmacology and Drug Interactions
Active metabolite (teriflunomide) has long terminal halflife as undergoes enterohe
padc recirculation; detectable levels may persist in plasma for 2 yr after discontinua
r.ion.To eliminate drug rapidly if toxicity develops.give cholestyramine B g :id x 11 d
o r a ctiva te d ch a rco a l 5 0 g b id x 1 1 d .
May 1 or L warfarin level through interaction with CYP metabolism; monitor INR
Due to effect on CYPZC9 may alter levels of glipizide, Celecoxib, and fluvasratiri
S i d e E f f e ct s
Nausea and diarrhea (may be more severe if loading dose given). rash, alopecia
Leukopenia.anemia, thrombocytopenia: cytopenias more common if concurrent use
of other marrow toxic medications. May T INR in pts on warfarin.
Hepatotoxicity (31 f in ASTIALT) in up to 13%. reversible with dlc. severe liver inlury
and fatal liver failure are rare. More common in concunent use of unSAIDs. MTX, or
EtOH. II ALT T to >2x ULN. dlc and sun cholestyramine wash out (FDA am sally
Corrvnunltauan htqas1lwwvmldago»Dm1slDru¢Saietylu¢m2186791.
Hypertension: more common with concurrent NSAID use 4Af¢i IM 19'i9.159:1542)
.. ILD, avoid use it h/o ILD or MTX lung toxicity (Anhnus Rheum 2ooe;s4 1435)
Peripheral neuropathy: develops after mean 6 mo on Rx. may be reversible if discon
tinued early after symptoms develop (cu. Iliaymocolfher 2004;7sse01

CVCLOPHOSPHAr4IOE (CYC)
Mechanism ofAction
Alkylate DNA -» J. DNA replication, transcription -o cell death of proliferating cells
Clinical Use and Dose
Indications: induction therapy of lupus nephritis (LN) Ill. IV. and ANCA GN
LN NIH IV dose is used for other aggressive forms of proliferative GN. eg.ANCA
GN (1A$n 1996:7:33). crescentic loAn (nor 1003;18:1321)
Contraindication: pregnancy. untreated infection/malignancy. urinary retention
Cy c lo p h o s p h a mid e Do s e s

Regimen I n i t i a l Do se Do se A d j u st me n t

LN NI H (Una: 1~m534a7411 I v 0 . s- 1 u m* mo n zh i y X I St an an 0. 5 glmza adiusz f or

WB C

L N E u r o L u p u s mvl ml s n m- i m I V 5 0 0 mg q 2 wk x6 No : r e q u i r e d
10014411211
LN icuw 200s. 4. 11s4) PO 1-1. 5 m d (max Required
150 mild) for 2-4 mo
A NCA G N ( A we iv 15 mg/kg (max 1.2 s) Cr >3 . 4 : l b y 2 . 5 mg / kg
1c09.1 saalol q 2 - 3 wk u n t i l 3 mo a f t e r 60-70 lo: . by 2.5 mg/kg
remission >70 ylo: L hry S mglkg
WBC <3K: I 2076: <2K; 140%

A NCA G N ( i n : m PO 2 mglkgld (max 200 mg/ d) 6 0 - 7 0 ylo: 1 by 25%

m0ms0; s70) unt il remission. 1. 5 mg/ >70 lo: l by 50%
kg l d x3 mc WB C <4 K : h o l d a n d r e st a r t
wh e n >4 K wl L 2 5 mo l d

A mi G B M d i se a se l A M i n P O 2 - 3 mg / kg l d >5 5 yl o
2001.1!o1033I
MNP ' l o d i f i e d P o n ci ce l l i P O 2 . 5 mg l kg l d i n mo 2 . 4 . 6 Required
regimen" IIASN 199u,4441 wit h CS in mo 1. 3. 5
MN (nor 2004;19 1147; AMC PO 1. 5-2. 5 mg/ kg/ d f or Required
N=F1"°l 2017:1Bz44) 2 - 1 2 mo 1 p r e d n i so n e 2
K TX

Dose adiusrmen: for renal funcuionc et. 30% for CrCl <40. 50% for CrCI <20
Do se adjustment of age: eg, 50% for > 60 loa HD removes CYC: dose alter HD
Highdose regimens require dose adjusunent to keep WBC >3-4K
Mesna (2mercap:oerhane sulfonate) 60-100% of CYC dose with IV CYC to rever:
hemorrhagic cystitis. no evidence of bladder cancer prevention (Ardvmx Rheum 2010.s2:91
Pharmacology
Prodrug: CYP metabolized to phosphoramide mustard (active mecaboliu) and acrolein
All mecabolires are excreted by urine; adjust dose for low renal function
Malignancy

NHSC. nonmelanoma skin cancer

No established safe cutoff dose

Prevention: lowest possible dose, lifestyle modification (eg. smoking cessation)
Screening: at least USPSTF recommended level, urinamis. CBC. skin exam
Other Side Effects
Lymphopenia, agranulocytosis:Tx with GCSF or GMCSF
Hemorrhagic cystitis dl: acroleinz correlate w/ cumulative dose and duration: PO > IV
plw hematuria (microscopic or gross). bladder irritation. blood clot
prevention:AM PO dosing: Mesna
Female infertility ovarian failure T w/ age and cumulative dose (0% in <30 ylo <10 g;
100% in >40 lo >30g) (Amino Rheum 199e44118311
Prevention: GnasH agonists (leuprolide depot 3.75 mg lM.goserelin) 14 d prior to
monthly CYC; amenorrhea (xO. 12) in SLE (aim ewe us Tree: 2010.msoaI
Ovarian tissue cryopreservation is an option
Male infertility: azoospermic or severely oligospermicz 72% recover after cumulative
dose <7.5 x/m1 and 11% recover after >7.5 g/m2 (caiar 1992;7027031
Sperm cryopreservation, testosterone can be used (Am IM \997;1z6;292. A;KD zaaeszaan
SIADH: common with high dose of hypotonic fluid (NDT 2010;25:I520>

ANTIBODY AGENTS
Polyclonal Ab: MG. thymoglobulin

Monoclonal Ab Agents
Chimera Humanized Human
(75% human. ximab) (95% human. zumab) (10056 human. una)
Basiliximab Alemruzumab. Daclizumab, Belimumab
Riruximab Eculizumab Ofarumumab
All Ab agents can be removed by PLEX: If PLEX is required, info$eAb regimen after PLD(
Infusion (Related) Reactions
Common with rituximab, alemtuzumab.antithymo»:yte globulin (ATG). MG
Mechanisms:Ag-Ab interaction cytokine release
Fever, rigors, pruritus. flushing. dyspnea. chest discomfort NN/D
Preventiomacetaminophen. diphenhydramine, and methylprednisolone pretreatment
and slow infusion lower incidence
Tx: hydrocortisone. diphenhydramine. aceunminophen: slow infusion rate
Anaphylaxis
Rare, but fanalz reported with riruximab,ATG (All¢llyAld$ma Um lmniuna 2011113131
IgEmediated type I hypersensitivity reaction
Urticaria. cough, wheeze. angioedema. throat lightness (laryngeal edema). shock in
addition to other symptoms of infusion related reactions
Lab: T nrypcase.DIC
T>c dlc infusion,ep6nephrine 0.2-0.5 mg (1:1.000.0.2-0.5 mL) IM.O2 2 inzubazion. IV fluid
Do not rechallenge w/o proper desensitization AAA¢fgy an Nwnual 2a0a;12z:s7l
 INTRAVENOUS Immune GLoauun (MG)
Mechanism of Action 1qAsn 1l)16:11:331)
Prepared from plasma pooled from healthy donors
Binding to natural Ab. cytokines. inhibition of complement fixation; inhibition of FcR
mediated recycling of native IgG -v antiinflammatory effects, immunomodulation
Clinical Use
Desensitization for (») crossmatch living donor donation.ABO and HLA incompatible
living donor KT with rituximab (NE/M 10085512421
AMR: 100 mgNq after PLEX. followed by rituximab WT 20awx1099>
Less common: refractory KT rejection: 2 glkg (Tmnsplanmuan 1001;72:419): BK nephritis
lrfumpmmn 2006:5:117)
Parvovirus B19 prevention and tx WTz0\1;11.19s) rdiaetory CMV infection or 201113931
Premedications: diphenhydramine. acetaminophen
Side Effects
AKI from osmotic proximal tubular damage with sucrose containing MG lqAs~
2006:1:844;Ajxn 2000lSl.49l), hemolytic anemia: pigment nephropathy (A}KfJ 201lkS§148)
Hyponatremia dlt water retention (on be new# 1006:10124). pseudohyponatremia d/t
protein load (NE/M 199s;aJ<rs32); / asm to differentiate
Thrombosis. MI. aseptic meningitis

ANTITHYMOCYTE GLoauun (ATG)

Mechanism ofAction
Polyclonal Ab against humanT cellsztargets multipleT cell markers; lymphocyte depletion
Clinical Use, Formulation,and Dose
1st choice induction immunosuppiession in KT in high risk for acute rejection or DGF
L Acute relection. similar DGF dt basiliximab (~fi~1 znae:ass:19s7)
Thymoglobulin (rabbit origin) preferred in KT: 1.5 mg/kg for 4-10 d for induction
(centerdependent): x7 d for acute cellular relection (IB, ZA. 2B, 3). Giving total dose
as continuous infusion for induction alw similar outcomes dw divided daily dosing.
Starting infusion intraoperatively a/w 1 DGF compared with starting postoperatively
(nunspiantauan z00&es1u91;1003;76i798)
Atgarn° (equine origin): 10-20 mg/kg x 8-14 d for aplastic anemia, Inferior to thymo
giobulin when used for induction or treatment of acute rejection after KT lrlulqiiiiniauan
1999;67:1011: 1998:66:29)
Premedications: methylprednisolone. diphenhydramine. acetaminophen
Dose adiustmenrs to keep lymphocytes <5%. absolute count 5100; Can follow CD3. CD4
Keep WBC 23, plt >7$K; 150% for WBC 2-3. pit 50-75K: hold for WBC <2. pit <50K
Serum Sickness (App: Z010:55:141)
7-27% in KTR, with prior rabbit exposure
Immune complex-mediated type Ill hypersensitivity reaction
Clinical manifestations: arthialgia (jaw. temporomandibular joint), even rash. malaise
7-14 d after ATG initiation: clinical diagnosis
Tx Corticosteroids (CS) +I- PLEX
Other Side Effects
Leukopenia. thrombocytopenia. anemia
Infusion reactions/cytokine release: fever/chills. L BR pulmonary edema: anaphylaxis
PTLD: more than with other induction agents or 1001¢71z619)

ALEMTUZUMAB
Mechanism ofAction
Recombinant DNAderived humanized monoclonal Ab against CD52
CD52 is expressed OnT cells. B cells. monocytes. macrophages, NK cells
Lymphocyte depleting agent
Clinical Use
Induction IS in KT (offlabel): L early acute rejection in low risk for rejection or
basiliximab or thymoglobulin. Similar efficacy in high risk KT m5;/A z0 n.3s419091
Lacute rejection (x0.42) dt basiliximab induction (Lin 1014.za41\s041
ACR (offlabel): may be alw Trisk of infectionrelated death lT1v~p'°mm"1009=87.1092i
Multiple sclerosis. CLL. Sectary syndrome
Formulation and Dose
Campathsz 30 mg IV x 1-2 d for induction and acute cellular reiecdon
Premedicadons: merhylprednlsolone. diphenhydramine. acetaminophen
Side Effects

BASILIXIMAB/DACLIZUHAB
Mechanism ofAction
Interleukin2 receptor antagonists (lL2RAs): Humanized monoclonaIAb against IL2
receptor G chain (CD25) on T cells -» inhibits IL2 mediated actions
Nonlymphocyte depleting agent
Clinical Use, Formulation, and Dose
Basiliximab (Simulect°): 20 mg IV on d 0 and on d 3 or 4: daclizumab: withdrawn
Induction IS in KT with low immunologic risk (eg. 2 haplotype match living donor):
l acute rejection rate and graft loss dt placebo. No difference in graft loss or clinical
acute rejection. biopsyproven acute rejection at 1 yr. l s/e and malignancy dt
antithymocyte globulin (eww¢ Drhaee so Rev 201D:CD00389l)
History or expected thymoglobulin intolerance (et, cardiopulmonary disease)
Side Effects
Infections. lymphoproliferarive disorders

BELATACEPT
Mechanism ofAction
Humanized fusion protein monoclonal Ab. CTLA4Ig: Fc fragment of human lgGl +
extracellular domain of CTLA4 (CD152): competitively Inhibit CD28 on T cell
CD28 OnT cells binding to B71 (CD80) or B72 (CD86) on APCs -» T T cell activity
CTLA4 OnT cells binding to B71 or B72 -» IT cell activity
CTLA4 is constitutively expressed on regulatory T cells
Clinical Use, Formulation, and Dose
Nulo]ix®
De novo IS after KT: used in combination with MMF and prednisone as CNIsparing
regimen. Higher 1yr acute rejection rate than CsA. but higher eGFR and patient/
graft survival than CsA (NEW 2016:374=3331
10 mg/kg on d 1. 5.at the end ofwk 2.4.8. & 12. then 5 mgA<g quo wk beginning at
wk 16
Conversion from CNIbased regimen following KT: T acute rejection in 1" yr. slight
T eGFR at 3 yr. no difference in patiendallugraft survival (qASN 20\1:6:430. Ayxo 1017:69:557)
5 mg/kg on d 1. 15. 29, 43. 57.then S mg/kg every 4 wk. Reduce CNI dose by 50%
on d 15, discontinue d 29. Slower taper of CNI may be a/w .L risk of rejection.
CNI should be reduced slowly every 2 wk (no reduction on d 1. 50% reduction on d
15, 80% reduction on d 23, discontinue d 29)
/ EBV IgG: must be (+) due to risk of PTLD in IgG (-) pts
Side Effects
PTLD (predominant involving the CNS). anemia. and Ieukopenia
Diarrhea. increased risk of infection: CMV. HSV. fungal, protozoa!

BELIMUMAB
Mechanism ofAction
Human monoclonal Ab against the soluble form of a B cell survival factor. B cell
activating factor (BAFE aka B lymphocyte stimulator. BLy$)
Clinical Use and Side Effects
Approved for active autoantibodypositive SLE (lance: 101 I;177;72\)
iSerum BLyS level but did not reduce naive B cell number in KTR (Lana: 2018439196191
May lower proteinuria in lupus nephritis (Auzaunmun Rev 20I7;l6:187)
Side Effects: infusion reactions
 R l1 ux lm A s ( R TX )
Me ch a n ism o f Act io n
Chimeric murine monoclonal Ab against CD20 on B lymphocytes
Prevent SMPDL3b downregulation in podocytopathy Isa r»u»¢Im¢42011¢Jxsr=4e)
Inhibit of B cell derived IL4 mediated proteinuria u6H»=»1»~ z01ns1 s:el
C lin ica l U se
AN C A vasculitis: induction luv: nz/1»1 z01Qu3¢221: ruruxvAs new 1010.n3¢1111 and main
tenance (NEW 2014;371:1771)2 refractory LN: cryoglobulinemia (Animas Rheum 2012:64:843),
MCD. FSGS (NEMCHASN zo 1412s=aso>. MN (MENTOR new 101%]813¢:]ASN 2017L28:34B1
Induction IS for (+) crossmatch living donor donadon.ABO and HLA incompatible
living donor KT with lymphocyte depleting agents. MG l~£1m 200a:3s9141) and PLEX
Antibodymediated rejection (ABMR):with CS. IVIG.and PLEX
F o r m u la t io n a n d D o se
Rituxan 1.000 mg ><2, 2 wk apart: 375 mglmz x4, weekly; 375 mg/m7 xi eg, for ABMR
Can redose if CD19(+) cell is not depleted (>5-10 cellslmm') or lymphocytes >1%
J HBsAg. HBsAb. HBcAb prior to administration
HBV Sefulogy Interpreatlon and Rituxlmab Administration (H¢¢nli!y N\u1:1M)
HBsAg HBsAb HBcAb Management
- - Administer rizuximab
Vaccination prior no rinncimab or 6-12 mo after
+ Administer riruximabz HBV immunized
+ + Administer rizuxirnab wish prophylaxis
4 /r/O window period (HBc IgM ~)
Administer rkuximab widl prophylaxis
Vaccination if no: from and co inuermediaxe or higi endemicity

0 + Hold rixuximab: /ALT. HBeAg. HBV DNA

Refer co h solo 3

Premeditations: acetaminophen. diphenhydramine. methylprednisolone 100 mg umm

Rheum 1006;54:1390)
Slow infusion (first dose83 mo since previous dose or poorly tolerated previous infusion):
Start at 50 mg/hr;T by 50 mg/hr q30min; max 400 mg/hr
Sundard infusion (previously well tolerated infusion <3 mc):
Stan at 100 myhr: t by 100 mg/hr q30min; max 400 mglhr
HBV Reactivation impairing 2018:67:1560: Caaraunemiqy 2017:1$2:1297)
Reappearance or t of HBV DNA or reverse seroconversion of HBsAg
p/w impaired synthetic junction (TBII >3, INR >1.5). ascites,encephalopatlry,and deadi
RM factors: HBsAg (12.3% vs 1.7% w/o HBsAg). high baseline HBV DNA level. HBeAg.
chronic hepB; HBsAb () (14% vs 5% w/ HBsAb) (»4=n<=¢d°¢v z017:66.379y
Rituximab T risk of reactivation:24% w/o HBsAb. 5.6% wl HBsAb (H¢p¢i¢iqy zor 7:se.a79l
Prophylaxis: see prophylaxis chapter:Tx: HBV treaunent
Progressive Multifocal Leukoencephalopathy (PML)
Subacute demyelinating CNS infection caused by JC virus reactivation
Multiple cases reported in HIV. hematologic malignancy SLE and RA; Incidence 4/100.000
in rituximabuated RA vs 0.4/100.000 in untreated RA (in-naw so zonnzsrl
Many cases in SLE were found w/ minimal IS wlo RTX or alkylating agent (Auraimmun
Rev 20ce1s;144); Rarely in GPA treated with CYC and CS (JAMA rsszzselsool
No report in MCD. FSG S.and MN
Cognitive impairment, motor weakness (hemiparesls. ataxia).vislon or speech problems
Median survival in PML wlo HIV is 3 mo (An new z006;so¢1 $2)
MRI: unifocal or muluTocal white matter lesion:]C virus DNA in brain biopsy or CSF
Tx: reduction of IS: allogenic BK virus specific T cells Ive;/m z01e¢a79:144:l
O t h e r Sid e Ef f e ct s
Infusion reactions: fever.chills. rash. itching, mild wheezlng:28% in MN (/ASN
2012;23114161; common with 1st dose; prevented by slow infusion and premedicazions
Tx slow me or hold infusion and resume if symptoms resolve
Anaphylaxis: urticaria. hypotension. angioedema. hypoxia. bronchospasm. strider
Tx: dlc RTX. epinephrine 0.2-0.5 mg (1:1,000.0.2-0.5 mL) IM. O21 incubation. lV Huid
Ofatumumab: human monoclonal CD20 Ab: successfully used after anaphylaxis asso
dared with ricuxlmab (n5/m 2018:37B:92)
Rarely pulmonary infil:rates.ARDS. MI.VF. cardiogenic shock. or death
 Ser um si ckness (s¢»wl Anhmn Rheum zo1 s;4s:n4): fever . r ash. ar r hr al gi az type I I I hyper sensl
:ivicy reaction 7-21 d after infusion; low complemencTx: CS
Blumed immune response no vaccination UACJ 2011;1z&129s)
Hypogammaglobulinernia: esp low IgM; T with repeated cycle U Rnwmmal 20102375558)
Leukopenia (even 3-6 mo after adminiszra¢ion).anemia
Not al w T mal i gnancy (Ann Rheum Du 2017:76:1064)

E CULI ZUMAB

Mechanism ofAction
Monoclonal Ab against CS: inhibition of C5 cleavage to C5a (neutrophil chemoatuac
tant) and CSb (component of membrane attack complex)
1n
Clinical Use and Dose
Monitoring (goal): CH50 (<10% of nl), alternative pathway hemolytic activity/AH50
(M 10% of nl). eculizumab trough level (50-100 mcg/mL); sC5b9 may remain detect
able. not recommended for monitoring (KJ 2017;91:S39)
aHUS: IV eculizumab 900 mg weekly x4, 1,200 mg 1 wk later,then every 2 wk: sup
plemental 600 mg wu 60 min after each TPE
PNH: IV eculizumab 600 mg weekly x4, 900 mg 1 wk later. then every 2 wk
OHlabel use: C3G (qAs~ z01zm74a). ref ract ory APS I A/ unt s Rheum 2012: 64: 1719; Case nap
Hmtol 20i4;704371); recurrence prevention ofAPS after KT <~£1m z01¢xss1=\744;
Offlabel use: prevention and treatment of acute AMR (fmnsplnnintion zovxmlo; 30801549).
chronic AMR or 2017:17:681) and desensitization or 2011;1 122405)
Prophylaxis (co op" u»f¢¢i of 201923191
Meningococcal vaccination: both polysaccharide quadriwalent and serogroup B vaccines
(can be oWn simultaneously at different sites) >2 wk prior to the 1st dose; if <2 wk.give
penicillin VK 250-500 mg bid or ciproiloxacin $00 mg qd until 4 wk after last vaccine
Meningococcal polysaccharide quadrivalent conjugate vaccine (MenACWY): MCV4D
(Menactra°) or MCV4CRM (Menveo°l),2 doses, 8 wk apart: boost every 5 yr
Meningococcal serogroup B vaccine (MenB): MenE4C (Bexserow. 2 doses 1 mo apart)
or MenBFHbp (Trumenba°. 0, 2. and 6 mo) (MMWR 2015;64:600)
Pneumococcal vaccine: PCV13 and PPSV23; Haemophilus inffuenzae vaccine
Side Effects
Infection: encapsulated bacteria esp. meningococcus (MMWR 20\6:6S:696)
lgG2 and IgG4 x staining of eculizumab: not pathogenic (MSN 2011;2311229)

PROPHYLAXIS
VACCI NATI ONS

CKD who 2012¢s<»\:s61. NS we 1994;z4447l.and immunosuppresslon (IS) • risk of InfeWon

I S decr eases effi cacy of the vacci ne: eg. i t takes 1 y r no r e ga i n i m m une r e s pons e a f t e r
riruximab ilAlknlv aw. Imnrnnol 2011;\188:1195)I in may take longer depending on disease: et.
ANCA (Amni Rzsfher 1017;19:101)
More vaccines are recommended than nonCKD population: vaccination should be
s ta rre d prior to IS a nd progre s s ion to a dv a nc e d CKD

Recommendation Based on Vaccine Type Ann an willem. Air zoner: no 45111

inactivated Vaccines Live Vaccines
Vaccine FCV13. PPSV23.Tdap/Td MMR.Varicella. ZVL
Inactivated influenza, RN HW
Prior to ISIKT Ideally 22 wk prior to the Ideally 24 wk prior to the
mIuaum imuauon
During IS Recommended if indicated Contraindicated
After KT Recommended if indicated Contraindicated
Usually 2-6 mo after KT
If influenza outbreak. 1 mo after
KT or 2011;\\:10201
Household and close Recommended if indicated Recommended if indicated
contacts If rash develops after ZVL or
varicella. avoid contact and
consider antiviral prophylaxis
 Vaccination Indication (R: Recommended; X: Contraindicated)
hupallwww.cdc.govlvaccines, (xntco CKD 1012; IDSA oo zo14;sa:Jot A11201393 sqapl 41311)

Vaccine CKD O n I S I KTR

lnlluenza. inactive R: annually
TdapfTd R:Tdap x1,Td q10y
MMR R if born in 1957 or later X
Varicella R if born in 1980 or late X
RZV R i( 250 lo Insufficient data
HPV R i f 9 Q UO l o 6 $ 2 1 l o
Pneumococcal R
no
~. H BV R For eGFR <30
M
Z o s te r V a c ¢ i n e
Recombinant lester vaccine (RZY Shingrix°) is recommended for nonimmunosup
pressed 250 y/o regardless of past foster infection or zoster vaccine live (ZVL)
vaccination history
RZV: contains adjuvant suspension r.ha\: boosts Tcell function.TheoreticaI graft rejection
and glomerular disease flare up were not well studied.
ZVI.: is contraindicated in pts on IS and KTR. Disseminated zoster on low level IS
(MUM 2017;66:763) and a fatal case in Can re 2016:PMlD 271476291 reported.
P ne um oc oc c a l V a c c i ne
Recommended for all adult CKD including <65 lo. pts on IS and KTR
PneumococcalVa¢¢ine in CKD (eGFR do) and Immunocompmmised States
Prior Vaccine Indicated Vaccine
None FCV13 - PPSV23 28 wk Iver then 2" FFSV23 25 yr Iazer
1 dose d PPSV23 PCV13 21 yr after :he PPSV23 :hen PPSV23 28 wk aker
PCV13 and 25 yr after the 1st PPSV23
2 doses of PPSV23 PCV13 21 yr after :he most recent dose of PPSV23
PCV13 PFSV23 28 wk after PCV13 den 2"' PFSV23 25 yr after
dte 1 PPSV23
PCV13 and 1 dose of PPSV23 2' PPSV23 28 wk after PCV13 and 25 yr after :he 1"
PPSV23

If the most recent dose of PPSV23 was at age <65 yr, as age 265 yr. administer a dose
of PPSV23 28 wk after PCV13 and 25 yr after the las: dose o( PPSV23
PCV13 to PPSV23 interval should be 21 yr for chose indicated only by age 265
H e p a t it is B Va ccin e
CKD patients have reduced immune response to vaccination 50-60% vs 90% in non
CKD W/(0 1<19&31:10411; require higher dose
J AntiHBsAb 1-2 mo after series in (pre)dialysis and immunocompromised patients
If antiHBsAb <10 mlU/mL r epeat another ser ies
If annual antiHBs Ab falls m <10 mIUImL Recombivax HE or EngerixB' 40 mcg xi
Surveillance in HD: monthly HbsAg if antiHBs Ab <10 mIUlmL
HBsAg could be (+) after vaccinatiomdo not / w/i 3-4 wk (ISSN 19964711228)
(+) HBsAg: use dedicated machine at isolated room
Unknown HBsAg: bleach disinfection of diamis machine
Recommended HBV Vacdnadon Dose (mcg) and Schedule (mo)
Condi ti ons Re c o m b i v a x HB' E nge ri x B' He pl i s a v B'
NonCKD 10: 0, 1,6 20: o. 1. 6 20: 0. 1
Immunocompromised 40: 0. 1. 6 40: 0. 1. 6 lnsufhcienz day
(Pre)dia is 41k 0. 1. 6 40: 0. 1.2. 6 Insufficient data
 ANTIMICROBIAL PROPHYLAXIS

Antlmlcroblal Prophylaxis for Patients on Immunomodulators

CMV or :mans Sufi 491) Alter KT,Valgancklovir (adjusted for CrCI) for as least 6 mo
in high risk (D+/R) and 3 mo in intermediate risk (R+):
Pneumocystis iraieai
Candida or zuuss so>pI 3:62)
Lav.enl:TB (A/1 romans Suppl 1:66)
consider 3 mo in low risk (D-/R)
Also prevent HSV1, HSV2, EBV.VZV. HHV6,7.8
Alter KT.TMP/SMZ SS (801400 mg) qd x 1 yr (prevent
also UTI. Ilsteria. and nocardia infection)
If sulfa allergy, dapsone 100 mg qd (/G6PD before; sie:
melhemoglobinemia) (Cami 10II;117:3454] or atovaquone
1,500 ms qd Wr z01an a Swv! 41272)
No consensus in IS use for nontransplanulion setting. One
reeommendazion is TMP/SMZ DS (160/800 mg) x3Iwk in
pi: receiving an equivalent of prednisone >16 mg qd x
28 wk 1NE/M 20041Jsaz4s71 Umm Ds avi NAM z01s:42: 1st
After KT. fluconazole or dozrlmazole (may T CNI and
mTORi level; monitor Ievel).or nysuzin 4-6 mL bid.
Total prophylaxis for 1-3 mo.
If positive PPD or IGRA (Quan:iFERON gold°)
Isoniazid 300 mg qd x 9 mo widi pyridoxine 25-50 mg qd or
Rifampin 10 mglkg (max 600) x 4 mo (no 1018;J79440): may
i CNI level: monitor level of CNI

HBV PROPHYLAXIS (ca==»»<~==m1»=v 2015:148:215: A)T 20\5;l5:1162l

*If HBsAg (+). consider obWning hepaxology consuk: HBV DNA 22.000 UImL and ALT elevation:
Chunk Mpuixis B requiring :naunenr
'Morison /HBsAg. ALT. HBV DNA q3mo

Regimen:
Entecavir 0.5 mg qd (if CrCI 30-50 q48h; if CrCl 10-30 q72h: if CrCI <10 qwk)
Tenofovir alafenamide (TAF): 25 mg qd (avoid if CrCI <15); better renal function than
TDF (lance: Gasziuenierd Hw.al 2016.1.185; 1 Hepalal 2018;68:672)
Tenofovir disoproxil fumarate (TDF): avoid for proximal zubulopathy
Lamivudine: avoid for resistance
Sian: 2-4 wk before initiation of IS
End: 212 mo of last dose of B celldepleting aden: (eg. rituximab) or 26 mo others:
reactivation beyond 12 mo has been reported in malignancy (nun Re 201615046)
Prophylaxis is alw 87% and 83% reducion of reactivation and hepatitis Rares. respecmrely
ic.1==»==~»=~=lw zo1s;14&zzn: reactivation rarer with HBsAg (-) pa up 2013331127651
 ILLICIT, HERBAL, AND ENVIRONMENTAL TOXINS
The kidneys are vulnerable to injury from exogenous toxins dl: to their filtration,
concentration.and metabolism. i clearance in CKD may cause T toxicity
Older adults use OTC (42%).dietary supplements (49%) frequently QAMA tooasoozssn
1/12 US adults is raking Z1 harmful supplement with kidney disease (AlKD 2018;6117391
Herbal supplements are not regulated by FDA for content or purity; Side effects may
rise from contaminants. such as heavy metals
Purpose of the medicine may give clues: pain control (analgesic nephropadiya salicylate
intoxication). diuretic (salt wasting. hypokalemia. volume depletion)
Renal toxicity could be from other organ injury: hepatorenal syndrome from hepato
toxic substance. rhabdomyolysis from seizure evoking component
Lists of herbal supplements to avoid in CKD. hyperkalemia.and hyperphosphatemia:
https:/lwww.kidney.org/atozlcontentlherbalsupp

HERBAL AND DIETARY SUPPLEr4SNTARY AGENTS

Aristolochic Acid
Sourcezariswlochia plan: containing slimming Chinese herbs;flour in Balkan endemic
nephropadly (BEN): endemic in Bosnia, Croatia, Bulgaria. and Romania
pRTA. tubular proteinuria, concenrraning capacity impairment. expensive inzersririal
fibrosislrubular atrophy. cellular atypia
Renal insufficiency is a/w cumulative dose, may plugress after dlc
TCC T lifelong risk: the renal pelvis. ureter > bladder: cysroscopy not sufficient (num
zuaaJ4z1¢sal; 52.9% after °<p during 27 mo flu (un in zc09xz=z0ol
Tx: GC may be tried in early nephropathy (AjKD 19*Js;27:2091
Cancer surveillance: yearly CT + urereroscopy
Bilateral nephrourecerecromy prior so LDKT or DDKT Iisring um :m 2013:15s:469)
Herbal, Supplementary, or Nonprescription Agents and Renal Toxicity
Substance Used for Renal Toxicity
Bee pollen Appetite. stamina AIN
Cats claw Antiinflammatory AIN
Chromium picolinate Glc. lipid. we control ATN.AIN
Cranberry UTI Oxalate nephnopadvylnephrolidiiasis
Creatine Muscle performance AIN
Dienkol Bean Meal in Southeast Asia AKI. needlelike crystals
Ephedra [MaHuang) Allergy, weight loss HTN. urinary stone
Flavonoid Vascular disease ATN
G¢11y\;l\iull\ Immunity ATN
Glucosamine joint pain AIN
Glycyrrhiza (Licorice) Antiinflammatory. AME (HTN. hypokalemia. metabolic
sweet taste alkalosis)
lanes tridentaia (Chaparral) Joint pain, weight loss RCC
Mg trisilkate Antacids Silicate calculi
Quinine Drink (Tonic water), TMA (~f:m 2017.375:74): 33% of drug
tramp induced TMA um 7012125 may
Rough Bark (guaiienesin) Chest congestion. cough Urinary stone
Star fruit (carambola) Oxalate nephropathy who 20013741s1
Delirium. hiccups. vomiting. paresis
in CKD; dialyzable (nor z003:1a=1 10)
Sugar sweetened beverages CKD(a»s~1019;14¢491
Triptolide (Thunder God Antiinflammatory Hypotension.ATN
Vine)
Vitamin C Cold Oxalate nephropathy/nephrolithiasis
Vitamin D Milk alkali syndrome/hypercalcemia
Willow Bark (Salix Pain Papillary necrosis
daphnoides)
Wormwood Digestion AKI, rhabdomyolysis
Yohimbine Erectile dysfunction AKI. drug induced lupus
 DRUGS OF ABUSE
IVDU is alw inrersMial inllammazion and renal parenchymal alciiiacion WKD 101443545)
Tobacco
Current smoking 1 risk of CKD (34%) and ESRD (51%) INN z017;n:47s)
alw nodular glomerulosclerosis (Hm tuna zoozzmezel. glomerular hypedikradon &
prcceinuria (qAsn 2011:612462)l passive smoking 1 CKD lqAsn Z019:14:515)

Heroin
Heroinassociated nephropathy: FSGS.AA amyloidosis (95% used heroin in the Pacific
Northwest) (qAsn 1018413110101 from recurrent infection and inflammation. Declined with
highpur ity her oin.
Possibly alw ApoL1 nephropathy. HIV. HCVmediated renal lesions _
Rhabdomyolysis: heroin crystal nephropathy (clq z01 s;eaz9l. CKD in ~29n~l 2016:44:447) E
A
O xymor phone :
Injection of reformulated Opana ER°TMA lmmwn 101J:62:1: up 20ll;63:1022). HIV. HCV
PLEX was tried. but unnecessary (AJH 1014824951
C o ca in e
Rhabdomyolysis. malignant hypertension; hypertensive and ischemic damage (Aalto
1014;63:945). renal infarction Is" ~¢n~l 2009=722341,AlN (Ago 100B:S2:79Z)
ANCA GN (very high MPO or MPO and PR3) wl skin ulcer: contaminated levamisole
lqA$n z011:6:2799)I hyponauemia (Can Nepal 2011;7511)
Methylenedioxymethamphetamine (Ecstasy) lqAs~100e:3¢1ssz: nor 2013:18:2277)
Amphetamine derivative: release serotonin. dopamine, norepinephrine
Hyponatremia: T ADH secretion polydipsia (thirst. hyperpyrexia, ready availability of
fluids and iGl motility - water absorption); common in single.first use in young 9
AKI: nonuaumatic rhabdomyolysis. liver failure. and vasculitis
Cerebral edema. pulmonary edema. hypertension, arrhythmia
Anabolic Steroid [MSN 2010;21:163)
Used by bodybuilder s with highpr otein die:
Rl. proteinuria (1.3-26.3 old). NS (3/10); Can improve w/ dlc and recur with reuse
Biopsy, FSGS. collapsing or perihilar, 15-95% too: process effacement
C a n n a b is ( M a r iju a n a )
Cannabinoid hyperemesis syndrome is associated with heavy daily use of marijuana:
AKI (mainly prerenal azozemia) has rarely been reported in such pts
Synthetic ("designer") drugs that do not appear on urine toxicology screen have also
been associated with AKI l.vlmwR 20 1316z9932 qasrv 2013:8:5131
BiopsyATN,AlN 1c/Asn zowmvsel; AKI resolved w/o RRT
Brodifacoum associated T lnR.gross hemaruria and abdominal pain: renal imaging
abnormalizies: perinephric stranding. dilacarion of collecting system (NEW zo 1a;379:121s)
alw DKA in T1 DM (x1.98) up IM 2019:119415)
Synthetic Cathinone (Bath Salts)
Nor detected on toxicology screen
AKI. rhabdomyolysis. hyperuricemia WM 2012:$<k2731
DIC. liver failure.muluorgan failure,coagulopathy (some contains vitamin K antagonism)

METALS
Alumlnum lKDOQI nun 2003; KolGo Mao 2009)
Source:aluminumcontaining phosphate binder and antacid. dialysate contamination
Dementia. osteomalacia. bone and muscle pain, ironresistant microcytic anemia.
hypercalcemia. and neurologic abnormalities
Rare dlt less use of aluminum hydroxide. improved water purification. high flux dialyzers
Dx: /Serum level: if 20-200 ugIL, /deferoxamine stimulation test (+ if increase in
serum aluminum of >50 kg/L 2 d after infusion)
Prevention: avoid aluminumcontaining drug and citrate ( GI aluminum absorption)
TX: daily HD w/ high flux dialyzer if baseline >200 kg/I; deferoxamine if stimulation tests
C admium
Source: battery. metal alloy plants. g1ass.ct>ntaminated rice. cigarette smoke
Itaiitai disease:osteoporosis, osteomalacia.and kidney damage
Tubular proteinuria (eg. 132micoglobulin). pRTAIFanconi syndrome. hypercalciuria.
stone, chronic TIN.gfomerular ischemia. HTN
Occupational exposure is alw ESRD (x2.3) (AjKD 200123&1001)
Lead
Source: foundry. paint (pre1978 building). gasoline (removed in 1980s), diet. drinking
water. smoking, dust. soil
Organic cation transport system at PCT reabsorbs lead: mitochondrial damage
Stored in bones: halflife is decades
Acute toxicity: pRTA (inclusion body in PT cells)lFanconi syndrome. hemolytic anemia.
peripheral neuropathy, encephalopathy
Chronic toxicityc triad of gout. HTN and CKD (chronic TIN); nephrdithiasis. CKD
progression (n5/m 100];348:177), CVD (Lanai Mk »4:w1 201B:3:0177)
High level is a/w lower kidney function (MMA IM 2010. 17a7s; Ayxo 1018;72:381)
Chelation (WM z013a09:12411 controversial; Highdose EDTA is alw AKI

Other Metals and Renal Toxicity

Metal Source Manifestation
Chromium Contaminated food and water CKD esp with lead and cadmium (XJ 2017927201
Mercury Bakery. alloy. mirror plants Chronic TlN,ATN. pRTA. MN
Arsenic Food, water. mining, pesticide, TIN.ATN; CKD. proteimria quo 20 17:7a7an
woodpreservaniyes CVD (Am IM 201195%6491
Seafood concaining organic Kidney. bladder. lung izncer (/4402018;11m411
form is less :oxk
Gold Medical use (RA) MN
Platinum Medical use (cancer) ATN ( pr.osis and necrosis)

ENVIRONMENTAL SUBSTANCE
Pardculare matter air pollution is alw T CKD and ESRD (;ASN 201sIz9:21e) and t MN:
PLA2R was (-) in 83% uAsr4 201697137391
Pathogenesis: inflammation. oxidation stress. coagulabiliry (Na: Rev n9p»».ui 201&14313)
Silica exposure i s a / w ANCA vasculit is (qAsn 2M7: 2: 290) and CKD (Run an 2011=345401
Renal Effects of Environmental Chemicals (nm an nqm m i z01s;1 1:6101
Phthalates TAlbuminuria, BFW used in IV tubing: level may Tx9 after HD
BisphenolA TAlbuminuria. BE used in IV tubing; levels high in HD. PD pts
Dioxins t Albuminurla. BP. uric acid.. eGFR
Polychlorinated biphenyls T Albuminuria. BR uric acid.. eGFR
Perfluorinated chemicals r BR uric acid, . eGFR lqAs~ 1019:13:14199
Melamine Radiolucent stone. l eGFR

EXERCISE AND HEAT

Swear is hypotonic t Na (28%) > i Na (5%) (Am Icinriuml 2oo 13z:3a6)
Heat stroke:AKl, Mabdomyolysis
Exerciseassociated Hyponatremia (EAH) (Clip j Span mm 201522533031
Occurs often in endurance events in 6% (PNAS 2005;\07;185$0)
Risk factors: high fluid intake w/ weigh: gain. unSAIDs use. low BMI
Pathogenesis: excessive water intake with hypotonic fluid >water loss;ADH secretion
Manifestation: asymptomadc.weakness. headache. NN seizure. coma. cerebral edema
TX: if mild. oral hypertonic saline; if severe 100 mL 3% (51 mEq) NaCl or 50 mL 8.4%
(50 mEq) NaHCO; over 10 min;can repeat x2; avoid hypo or isotonic fluid
Prevention:"drink to thirst"
Mesoamerican Nephropathy (CKD of Unknown Etiology, CKDu)
Endemic in Central America (El Salvador. Nicaragua. Costa Rica) (A1KO 20 1z1s9s31).
Sri Lanka (qAsn 1019: 14: 224). Uddanam in I ndia (A/ xo 20161683z441
Potential pathogenesis: recurrent dehydration (hyperosmolarity)induced aldose
reductase (polyp pathway) leading to glucose to sorbitol and fructose, hyperthermia,
volume depletion -> " Heat suess nephropathy" (QASN 2016.11:14n)
Risk factors of rapid GFR decline: outdoor work. agricultural work. lack of shade
availability during work break UAW 10189942001
Manifestations 1 Na, K. Mg. T uric acid. lowgrade proteinuria
Bx: glomerular ischemic injury. inr.ersutial fibrosis. and tubular atrophy who 10174916261
 PLASMA EXCHANGE (PLEX)
Apheresis
Extracorporeal treatment that removes blood components
Therapeutic plasma exdiange (FLEX) is a type of apheresis do removes plasma and
replaces with allogenic plasma.colIoid.or crystalloid. PLEX can be performed using highly
permeable fiber widl standard HD equipment or a centriibgation device.
Membrane used for apheresis has pore size of 0.2 pm with MW cutoff 2.000 kDa
Substances Removed by Apheresis
PLEX: proteins (cryoglobulin, Ig including Ab form drugs). complement components.
Immune complex. cytokines. drugs w/Vd <0.2 Ukg and protein binding >80% (Pllasma
ltuelTn:vls1\ls fzdinal l 984:$:305)
Rituximab can be given 24-36 hr before PLEX (Ami an :we 100a=1u1s9z1

Cyvapheresis (hemapheresis): leukocytes (hyperleukemlc leukosusis). platelets

(severe thrombocyzosis). abnormal red cells (sickle cell disease),and parasites
LDL apheresis: Ilpcproreins
Indications in Renal Diseases (Amman Saauyfamuele; ah4nuz01s=J1=149)
Should be Considered Can be Considered
ANCA RPGN wl Cr >6. dialysis dependence or DAH Catastrophic APLS
AntiGBM disease w/ DAH or dialysis independence Symptomatic/severe
Atypical HUS with factor H amibodies.TTP cryoglobulinemia
Recurrent FSGS after o<p.AMR Myeloma cast nephropathy
Desensizizazion in LDKT.ABO incompatible in LDKT Severe SLE

Co n sid erat io n s Prio r t o St art F L EX

Ideally. diagnostic lab specimen should be drawn prior (D start PLEX:ANCA, andGBM
Ab.ADAMTS 1 3 . CFH Ab. C3 ne phritic fa c tor
Timing of antibodybased medicine: dose eculizumab, riruximab after PLEX session
PLEX Regimen
Volume: 1-1.5 plasma volume will maximize efficiency
1 plasma volume = 50 mUkg of weigh: or 70 mUkg of weight x [1Hct]
Single 1 plasma volume . plasma macromolecule by 6094; 1.4 plasma vol l 75%
Replacement fluid (RF): 5% albumin +I- NS +I- FFP
FFP is given at the end of session to prevent coagulation factor removal
FFP if (1) repletion of any plasma component is desiredTTR some forms of aHUS or
(2) coagulation factor should be repleted: DAH, recent surgery. kidney bx. T PT
Cryoprecipitates: for low fibrinogen
Schedule: daily if life threatening (eg.active DAH) then god
Number: not standardized;7 in ANCA vasculitis lMEFEX}ASN 1017.1e=21sol;can continue
until disappearance of target (eg. antiGBM Ab)
Access: dialysis catheter,AVF or AVG: anticoagulation: citrate. heparin
Complications and Monitoring
Albumin RF is alw less adverse reaction than FFP (1.4 vs 20%) WKD 1994933171
ACEiassociated reaction:flushing. hypotension. abdominal cramping; Kin in mediated:
alw albumin RF lrlwnw 1994;34:s91);Witl\hoId ACEr for 24 hr prior
Coagulation factor def: /PT. fibrinogen; replace w/ FFR cryoprecipitates, respectively
Immunoglobulin depletion. injection (including catheter related)
Metabolic alkalosis: from FFP containing citrate conversion to bicarbonate and
reduced renal excretion:Tx: switch to albumin replacement: can be corrected by HD
Metabolic acidosis: acidic profile of albumin replacement
Tx: can be partially corrected by 40 mEq NaHCO; PO or IV (fulufuslun 1015;55:1653)
Hypokalemia: common with nonplasma RE dilutional: Hypomagnesemia
Hypocalcemiazl iCe by citrate chelation:Albumin RF also an fuse (I ample 199%14:114)
Can be prevented by 10% calcium gluconate 10-20 mL (1-2 g)
Potentially rebound antibody production; use as supplementary to antiproliferative
Kau E- unihulu -adinn rnnliinn
 INTOXICATION AND POISONING
General Management of Drug Intoxication
. Airway. breading, circulation.volume repletion: prevent AKI. increase toxin elimination
Dextrose: correct hypoglycemia in AMS. Hemoperfusion can cause hypoglycemia. In
aspirin intoxication seizure can happen from low CNS glucose wl nl serum glucose
Poison Control 8002221222; http://www.extripworkgroup,org
Activated Charcoal

Urine Alkalinization (Goal: Urine pH z7.5)

Facilitate renal excretion of weak acids: aspirin. barbi:umtes.mechotrexace
NaHCO; IV 1-2 mEqlkg bolus followed by 150 mErelL NaHCO; in 1 L of D5W
Complication: hypokalemia. hypocalcemia, volume overload. CaP precipitation

EXTRACORPOREAL THERAPY OF INTOXICATION

Characteristics of Drug and Toxin Removed by Hemodialysis (HD)
SmallVd (<1 Ukg):any noncontinuous extracorporeal methods
Large Vd need for continuous therapy: rebound after therapy
Small solute (MW <500 D) can be removed by HD with diffusive clearance
5-20 kD: high flux membrane with high Qb and Qdzconvective clearance helps
45-100 kD: only high cutoff membrane (unavailable in USA) can remove
Lower (<80%) protein bound: high protein bound drug can be removed by PLEX
Water soluble: less rebound (movement from storage cornpanments into circulation)
Considerations for HD
May need high flux (efficiency) dialyzer and long session for maximal clearance
Dialysate designed for reduced renal function can cause 1 K, l PO 4. 1 Mg. and
metabolic alkalosis in normal kidney function
Maximal clearance may cause dialysis disequilibrium in CKD patients
If significant rebound is expected (lithium, methotrexate,dabigatran. metformin)
repeat HD early or initiate CRRT
Hemoperfusion
The passage of blood through a circuit containing an adsorbent (charcoal. carbon. or
polystyrene resin)
Remove theophylline. disopynmide. phenytoin. phenobarbital, procainamide. carbam
azepine. valproic acid. dapsone. methotrexate,Amanita mushrooms
Can remove large MW proteinbound.and lipophilic toxins and drugs
Blood How (Qb) 250-400 mUm in: can cause hypotension
Circuit similar (0 HD;wlo dialysate: no electrolyte/lluid overload correction
Anticoagulation required
sle: charcoal symbolization. 1 Ca, 1 gk, l BP: leucopenia. thrombocytopenia
Other Extracorporeal Therapies
CRRT: lower clearance than HD; consider for hefnodynamically unsuble pts: molecule
with rebound;when dialysis disequilibrium risk exceeds benefit of rapid removal
PD ineflectjve. not recommended
Plasma exchange (PLEX): an remove lipid or proteinbound substances with smalIVd
(<0.2 Ukg) regardless of size; rarely used for Amanita mushroom poisoning. snake
envenomation. paraquat. dioxin (digoxinfab complex removal), cisplatin. amitriptyline.
nanalizumab (Semin on: 2012;25:201)
 Drugs Removed by HD (MW,Vd, Protein Binding)
Drugs Clin ic a l Fin d in g s I n d ic a t io n o f HD O t h e rTn e a t me n t s
Aspirin AGMA, respiratory >100 mgldL Aczivared charcoal
(138. 0.2 Ukg, alkalosis >8 0 mg /d L w/ CKD Keep blood pH 7.5-
8 0 -9 0 %. lo we r wl Acid e mia t CNS Meubolic acidosis 7.59: avoid
toxic level) toxicity w/ pH s7.2 acetazolamide
Seizures dlt low Pulmonary edema Keep glucose >80:
brain glucose wl Seizures. coma, urine alkalinincicn
NL serum glucose cerebral edema
level AKI
Da b lg a t ra n Bleeding lqAs~2013: Lifethreatening Idarucizumab:
(628, 50-70 L 35%) 8:1533) bleeding nemralizing Ab
(Lacer 2015:JB6:6W)
Me d o rmin lactic acidosis (Lype B) Lactate >20 mmollL Activated charcoal
(165. 1-5 Ukg, No) NN abd pain pH 57.0 (acute overdose)
Death 23-30% (lm Shock Na HCO ; :
£/vu!ma z009;s4a1& Failure of supportive controversial
Cm Cue zuoa 1z¢a14sl measures
Decreased level of
consciousness
L it h iu m L A G (L i is ca tio n ) >$ mEq/L IV fluid: T urinary Li
(7.0.6-1.0 ukg, 0%) NN/D. leukocytosis >4 mEq/L w/ AKI. excretion
AMS. ataxia. seizure. CK D Bowel irrigation
irritability. tremor. >2 .5 mE /L with widl SR nab
myoclonus. symptoms Sodium polystyrene
fasciculations sulfate
FlatT wave. T QT.
bradycardia
Th e o p h y llin e Ventricular 60 up/mL Aczivared charcoal
(180.0.5 Ukz. arrhythmias. l BR >50 kg/mL in infants Hemoperfusion
5 0 6 0 %) tremor. seizure, abd < 6 mo o r > 6 0 lo
pain, NN ¢ K. PO 4. Seizures, shock.
Ca, gk. lactic acidosis arrhythmias
Me t h o t re x a t e Renal intruubular No consensus IV fluid. urine
(454.0.4-0.8 !Jl<8. precipitation Marked rebound alkalinization
50%) L ive r to xicity. NN le u co vo rin
Gluca dase

TOXIC ALCOHOLS
For an AGMA of uncertain cause or clinically suspected toxic ingestion. /osmolality
alcohol (methanol. ethanol, ethylene glycol. isopropanol and acetone) level
Isopropanol ingestion manifests w/o anion gap

Causes of Osmolal Gap (OG) >10 mOsmlkg

(+) Anion Gap Metabolic Acidosis
Merlunol. ethylene glycol, diechylene glycol.
propylene glycol
Formaldehyde, paraldehyde
Advanced CKD wlo regular dialysis
Keloacidosis (diabetic and alcoholic)
Lactic acidosis
(-) Metabolic Acldosls
Edlanol. isopropanol, diethyl ether
Glycine. sorbkol.or mannirol solutions
Pseudohyponatremia: severe
hyperproceinemia or hyperlipidemia
 Early stage: typically OG >10
Late stage: metabolites are not active osmoles, but are anions with sodium as the
accompanying cation; L OG, AG were 201887831701 qAsn 2008:3:208)
AS... (mOsmlL) per 10 mgldL Serum Alcohol (qASN 2008.17.08)
Methanol
3.09 Isopropyl alcohol 1.66 Propylene glycol 1.31

Ethanol 2.12 Ethylene glycol 1.60 Diethylene glycol 0.9

Clinical Manifestations of Toxic Alcohol Ingestion

. Manliest dons of Toxic Alcohols (AGIOG)
Alcohol Source Metabolism (391115) Manifestation
Methanol Windshield wiper Formaldehyde Hemonrhagidischemic
(/11) fluid, industrial - formic acid/formate injury to basal
produns lnrrir =rill Kemnes ganglia. Blurred
vision. central
scoromara.
blindness. coma.
death
Ethylene glycol Antifreeze Glycolaldehyde CaOx deposition in
(l ) (fluorescence of -» Glycolic acid (tubular kidney (AKI.
urine under UV toxicity) hematuria. oliguria,
light). adhesives. -» Qxalit acidloxaiue blank pain). hear
pesticides, inks (crysta can be seen (myocardial
on urine sediment) dysfunction), lung
and brain (CN
palsies)
.l Ca (tuscany. low BP)
lsopropanol Rubbing alcohol. Acetone CV collapse. coma in
(n u 1 ) hand sanitizers massive ingestion
(levels >500 mg/dL
and osmolal gap
>100)
Dietliylene glycol Automotive brake 2hydroxyethoxy AKI: could be
(tlt or NL) fluid, industrial aceuldehyde inwersible
products 4 1hydroxvedmxyagetic Hepatitis. pancreadtis
194 AMS. peripheral
facial diplegia,
flaccid tetraparesis
Propylene glycol lV lorazepam . Lactaldehyde Minimal clinical
(NL or WT) diazepam, -a D and l:liSiiie abnormality
phenobarbital. RareAKl
etomidate

General Management olToxic Alcohol Ingestion

Acidemia " uncharged toxic metabolite.formic acid that can enter endorgan tissue
IV NaHCO; to correct metabolic acidosis (1-2 mEq/kg for pH <7.3 followed by a
continuous infusion no maintain systemic pH >7.35)
No role for GI decontamination. eg.acdvated charcoal
Fomepizole (4Methylpyrazole)
Inhibit: alcohol dehydrogenase and aldehyde dehydrogenase:has . need for HD
Initiate if alcohol level >20 mg/dL
Preferred over ethanol that requires level moniwring (>100 mg/dL) and sedative effect
To . more toxic metabolites: methanol. ethylene glycol. diethylene glycol
Do not use when metabolites are less toxic: isopropanol (acetone less toxic)
Dose: IV 15 mg/kg loading followed by 10 mg/kg q12h x4.then 15 mg/kg q12h
(increased dose for alcohol dehydrogenase induction by fomepizole)
Until alcohol level <20 mgldL (methanol <6.2 mmole/L or ethylene glycol <31 mmoleIL)
Removed by HD: 1-1.5 mg/kg/hr during HD or redose immediately after HD
HD in Toxic Alcohol Ingestion
All of the alcohols are dialyzable: low MW little or absent protein binding. lowVd
General indication:AKl,anion gap metabolic acidosis with pH <7.3
 Treatment of Toxic Alcohol (MW,Vd) Ingestion
Indication of H D O ther T r eatment
Alcohols
Methanol >50 mgldL Fornepizole
Blurred vision or blindness. seizures Folic acid SO mg N q6h or
(32,0.6-0.7 Ukg)
leucovorin 50 mg IV q6I\
to replete tetrahydrofolate:
T Formate metabolism

Ethylene glycol >50 (300 K lcmepizole given) mg/aL Fomepizole

Altered sensorium, coma, seizures Thiamine 100 mg IV qd and
(62, 0.5-0.8 Ultg)
pyridoxine 100 mg IV qd:
T Glyoxylate metabolism

lsoproprandol >500 mgldL Supportive

(60. 0.6 UP Hypotension. lactic acidosis Do not use fomepizole
Diethylene glycol Fomepizde
( 106.12,0.5 up
lacto acidosis Stop infusion containing
Propylene glycol
(75 11 propylene glycol it able

HD duration (h): V In (SIA)/0.06k we 100$:46:509)

V: Watson estimate of :oral body water (L).A: the initial alcohol level (mmolIL)
For mg/dL - mmolIL. x03121 (methanol), 0.1611(ezhylene glycol), 0.1644
(isopropanol)
k: 80% of the dialyzer urea clearance (mUm in) at the observed Qb
Avoid heparin if methanol ingestion suspected (risk of basal ganglia hemorrhage)
 RENAL TUBULES
PROXN4ALTUBULE (PT)

Physiology of the Pmxlmal Tubule

NaCl. water: 60-70% of isownk Peritubular capillaries pressures . All and
reabsorpzion Norepinephrine
Glucose: lull reabsorpdon Luminal SGLT1, SGLT2
AA: full reabsorption Luminal NaM conranspon
HCOJI reabsorpcion Luminal NHE3
P043 rvabsorprion Luminal NaPi
Reabsorpnion of K. POI. Ca, Mg. urea. orate: ammonia production
Complete neabsorprion and metabolism of LMW pnueins
Secretion of orate. cationic drugs
Transporters + paracellular transport allow 70% of ulua6I:rate reabsorpdon

Cystinosis
AR mutation of CTNS gene encoding cystinosin, protein that transports cysteine
across the lysosomal membrane -» accumulation of cystine in lysosome - Cystine
1 glutathione -» T oxidative stress - apoptosis: cystine forms crystals in DT - stone
3 clinical presentations depending on the underlying genetic mutation: the infantile
(nephropathic) form. the lateonset (juvenile) form, and the adult (benign) form
Nephropathic cystinosis -> PT dysfunction: polyurialpoiydipsia, tubular proteinuria.gly
cosuria. phosphaturia. hypounicemia.and aminoaciduria (symptoms of volume depletion
and electrolytes imbalance starting at 3-6 mo). Usually progress to ESRD by mid.teens.
Extrareml symptoms: rid<ets.growth retardation. corneal cysteine deposiWpliotophobia.
hepatomegalyq portal hypertension. hypothyroidism.T1 DM. myopathy. hypogonadism.
azoospermia,and excessive bone fracture. Patients have normal cognitive function.
Dx: T cystine content of WBC. cystine corneal crystals. or genetic testing
Tx (1) symptomatic treatment for the volume and die electrolyte imbalances:
(2) nutrition supplement (some pt require Gtube feeding): (3) cysteamine
Cysteamine (metabolizes cysteine): preserves kidney function and delays most extra
renal manifestation except for the cornel deposits (treated w/ cysteamine eye
drops). it does not reverse the preexisting organ dysfunction immediate release quo.
enteric release form q12h. / WBC cystine level for efficacy. sle GI intolerance.
unpleasant breath. sweat odor,and bruiselike skin lesions at the elbow and knee.
Renal exp. successful w/ excellent longterm outcome wlo recurrence in the graft
Continue cysteamine to avoid progression of the extrarenal manifestations.

LOOP OF HENLE
Urine dilution and sodium reabsorption (15-25%) via NKCC2
Countercurient multiplier creates the medullary osmotic gradienc responsible for
concentrating the urine in collecting duct
Basolateral NaKATPase 4 l intracellular Na - reabsorption of Na.K. Cl via luminal
NKCC2 -» K secretion via luminal ROMK - electropositive lumen
Paracellular reabsorption of Ca. Mg via claudin 16. 19, driven by luminal + charge
CaSR inhibits ROMK and NKCC2 to decrease calcium uptake in hypercalcemia
Tubuloglomerular feedbadc 1 NaCl delivery to macula denser of ascending limb of Henle
- t PGE2 production -» t renin release from juxtaglomerular (]G) cells and ladenosine
mediated afferent arteriole vasoconstriction; SGLl12 inhibitor may inhibit renin release
Bartter Syndrome
Heterogeneous presencarionzchildhood onset. MR.growth defects. polyurialpolydipsia

Types of Bartter Syndrome

Type Mutated Protein Clinical Manifestations
I Luminal NKCC2 Severe, nephrocalcinosis. ESRD. early onset
II Luminal ROMK
III Basolazeral ClCKb Classic, less severe. later onset: some mutations
have hypocakiuria: CKD. nephrocakinosis
IV Bartin,l3 subunit of CICKb Sensorineural deafness. less nephroalcinosis. CKD
v GOF mumion of basolateral AD. Milder, laser onset. 4 Ca. 1 Mg. No . PGE2
CaSR
 DISTALTUBULE
Reabsorption of NaCl via NCC. las: diluting segment of the tubule
Reabsorption of Ca (TRPV5) and Mg (TRPM6)
Connecting tubule glomerular feedback: T NaCl transport in the connecting tubule
(sensed by ENaC -o afferent arteriole vasodilatation)
Gitelman Syndrome: Loss of Function of NCC
AR. late childhood and adulthood presentation. more severe phenotype in Q
Polyuria. nocturia, cramping. fatigue. chondrocalcinosis. CPPD disease x
Tx: NaCl ad ibiwm. K/Mg supplements. Ksparing diuretics (an worsen sodium depletion). Q
unSAIDs UAS~ zoisaessal, avoid QT prolonging meds
Bartter Syndrome Gitelman Syndrome
AR.. K. meubolic alkalosis, 2° t renin (hyperplasia of d 1e IG apparatus) and 1 Aldo
Volume contraction. 1 BR loss of maximal diluting capacity
Mimics/bunted response so loop diuretics Mimicslblunted response to rhiazide
Pluuvions in NKCC in the TAL Mutations in NCC in the dismal tubule
Loss of concentrating capacity Preservation of the concentrating apaciry
Hypercalciuria +I hypomagnesemia Hypocalciuria + hypomagnesemia
PGE2 - Vasodiladon Nomlal PG secretion

EASTlSeSAME Syndrome
Muradons of the basolateral K channel (KCNJ10; Kir4.1) -» i NaK ATPase activity
- L Na gradient for NCC -v renal Sal: wasting, T renin. hypoK. met alk. and lownl BP
Epilepsy. anoxia. sensorineural deafness, and tubulopathy/seizures. sensorineural deaf
ness, aizxia. mental retardation. and electrolyte imbalance)
Pseudohypoaldosteronism Type 2 (Gordon Syndrome)
WNK1.4,Cullin3. or Kelch3 muxadon -» T NCC. mirror image of Gitelmanlzhiazides
Familial hyperkalemic HTN. metabolic acidosis. L renin. l aldoscerone, low BMD.
hypercalciuria dl: l Na and Ca absorption in PCT
To: low sak diet. chiazides

COLLECTING DucT
K secretion via ROMK and BK: T by aldo (ROMK. BK).r.ubular How (BK). 1 Mg
Sodium reabsorption via ENaC: T by aldo
Urine concentration via aquaporin: . by ADH
Urea absorption is both passive and UT1: by ADH
Acid (H) secretion at typeA intercalated cell via H ATPase
Base (HCO,) secretion at type B incercalated cell via pendrin. CIIHCO: exchanger
Liddle Syndrome
AD. GOF mutation of ENaC (inability to bind wl a ubiquity protein ligase. Nedd4)
HTN at young age. L K. metabolic alkalosis. l PRA. PAC
Tx: amiloride. triarnterene: spironolactone is NOT effective
Pseudohypoaldosteronism Type 1
AR form: ENaC mutation. militia crystcallina popular rash dl: high Na in sweat, chest
congestion d/t airway expression of EnaC man 199<ra41.1s61
AD form: mutation of MR milder salt wasting. improves with age
Volume depletion. FTT,T PRA. T PAC (aldosterone resistance)
. Tx: high salt diet. highdose fludroconisone (1-2 mold). carbenoxolone (1 metabolism
of cortisol. as wl licorice activate the mineralocorticoid receptor)
Pendred Syndrome
AR mutation of pendrin; no electrolytes imbalance under normal conditions
Metabolic alkalosis and hypovolemia with thiazide therapy
Associated phenotype: sensorineural hearing loss and hypothyroidism with goiter
 EVALUATION OF ACID-BASE BALANCE
Background
Acid-base balance is maintained by renal excretion of noninducible titrauble acid
(HPO4Z/H;PO¢) and inducible buffers (mainly NH: + H -4 NH4).and pulmonary
excretion of CO1 (CQ, + H 10 H H1CO; H HCO; + Ir)
Henderson-Hasselbalch equation: pH = 6.10 + log ([HCO;]/[0.03 x ?Co,])
On the ABGs. HCO; is calculated: usually 2 mE/L less than the measured blood CO1
Normal Values of Blood Gas Analysis
pH Hco; pCOz
ABGs 7.3s-7.44 21 -27 3644
Peripheral VBGs L 0.02-0.04 i 1-2 1 3-8
Central VBGs 10.03-0.05 H 14-5

Step 1:ArteriaI pH Defines the Primary Disorder

Acidosis (pH <7.36) or alkalosis (pH >7.44)
VBGs has a good diagnostic accuracy for mos: acid-base imbalances
Step 2: Metabolic vs Respiratory Disorder
Acidosis + low HCO3 -\ Metabolic acidosis
Acidosis + high pCO; -> Respiratory acidosis
Alkalcsis + high HCO;' -» Metabolic alkalosis
Alkalosis + low pCO; -» Respiratory alkalosis
Step 3: Compensation Assessment
In a simple disorder. the compensatory changes in the same direction of 1° disorder
The respiratory compensation of metabolic disorder starts within 30 min and is
complete in 12-24 hr
The metabolic (renal) compensation of respiratory disorder takes 3-5 d to complete.
thus the difference in expected compensation for acute (<3 d) and chronic respiratory
disorders (>5 d)
Compensation Assessment
Primary Compensation Expected Compensation
Metabolic 1 Hco, lPaCOz 1 mE/L 4» 1.25 mmHg
acidosis (hypervendlanion) PaCOz = 1.5 x HCO: + 8 : 2
paco, = Hco, + 15
Paco) = decimal number of the pH
Down to 8-12 mmHg
Metabolic T HCO: . PaCOz 1 mEaL ¢ 0.7 mmHg
alkalosis (hypoventiiadon) Up co SS mmHg
Respiratory . pCO; . HCO1 10 mmHg <-» 1 mEq/L (acute)
acidosis 10 mmHg H 3.5-5 malL (chunk)
Respiratory PCO: 1 Hco, 10 mmHg 44 2 mEaL (acute)
alkalosis 10 mmHg H 4-S mErelL (dwronk)

Step 4:Assess for Mixed Disorders

Mixed acid-base is present when:
1. Greater or lesser than expected respiratory or metabolic compensation
2. PaCO; and HCO; change in opposite directions
3. TAG in other forms of imbalance:additionaIAG metabolic acidosis
In metabolic disorder
PaCOz is higher than expected:additional respiratory acidosis
pCO; is lower than expected: additional respiratory alkalosis
In respiratory disorder
HCO; is higher than expected: additional metabolic alkalosis
HCO; is lower than expected: additional metabolic acidosis
 METABOLIC ACIDOSIS
Background
Daily acid ingestion (50-100 mEq of H*) is balanced by reabsorpdon of HCO; at PCL
excretion of H by the distal part of tubule;most of the renal excretion is in the form
of Utrarable acids H;PO{ and NH(
Renal ammoniagenesis excretes hydrogen ions. NH; + H -r NH4`

or hypokalemia due no exit of intracellular K in exchange with extracellular H

Wo rku p
In pure metabolic acidosls.pH is decreased,serum HCO; is reduced and PaCO1 is
reduced as a compensatory mechanism
Winners formula: PaCO1 = 1.5 x serum HCO; + 8 i 2
To diagnose mixed acid-base disorders, the degree of PaCO; compensation needs to
be assessed: Mixed disorder. arterial pH may not be decreased:
1. If PaCO; is higher than expected: metabolic acidosis + respiratory acidosis
2. If PaCO; is lower than expected: metabolic acidosis 4 respiratory alkalosis
3. These assumptions are valid as long as HCO; is >7 (PaCO; can be lowered only
to the range of 8-12)
Serum Anion Gap (AG, mEgIL) = Na - (CI 4 HCOs) = unmeasured anions (albumin.
PO». orate, sulfate, IgA) - unmeasured actions (K. Ca. Mg, IgG)
Normal AG 3-9 (Variation can occur dependent on the lab)
High AG (>9) Organic metabolic acidosis (ker.oacidosis; lactic acidosis: ingestions:
pyroglutamic acid)
Hyperalbuminemia. metabolic alkalosis: t in albumin negative charge
Hyperphosphatemiaanionic monoclonal IgA
Low AG (<3 J Hypodbuminemia: expected AG:2.5 x [albumin]
Severe NAGMA: 1 albumin negative charge
.. K. t Ca. T mg. lithium intoxication. cationic monoclonal IgG. bromide
(pseudohyperchloremia)
Negative AG Na underestimation (severe hypernatremia)
Cl overestimation (hyperlipidemia: salicylate intoxication: Bromide)

mpH iuco,

Metabolic acidosis Serum AG calculation

Calculation of expected
PBCO2 with Normal AG: TAG:
Winters ¢ofmula or NAGMA AGMA
decimal digits of the pH

/Urine AG /AAG/AHCOU

PaCO, PaCO2
Measured > Measured < 1

calculated calculated

Additional Additional RTA type 1 Super

Super
respiratory respiratory hypcaldo imposed
imposed
acidosis alkalosis steronism metabouc
NAGMA
(RTA WIG 4) alkalosis

Approach to metabolic acidosis.

 In NAGMA. appropriate (>200) vs inappropriate (<75) urinary NHL' can be estimated
by urine anion gap (UAG) and urine osmolal gap (UOG)
Urine anion gap (UAG, Un, + Un - Uci) is used as indirect measurement of the urine
NHL concentration, this relation is disrupted in some disorders: (1) urinary excretion
of unmeasured anions (DKA-43hydroxybutyrate. ketoaceute; toluene inhalation -v
hippurate; proximal RTA -» bicarbonate: Dlactateaacetaminophen - 5oxoproline);
(2) Neonates; (3) CKD
In the presence of unmeasured anlon.¢he calculated UAG will have a positive value
which falsely suggest a low level of NHL excretion. In these disorders UOG is used
to estimate NH. excretion

ANION GAP MsTAsouc Acloosls (AGMA)

I fAG is elevated. /AAG/AHCO; ratio;
AAG - calculated AG - expo<ted AG: AHCO3 = 24 - measured HCO3
AAG/AHCOs 1-1.6: anion gap metabolic acidosis (AGMA)
In lactic acidosis, due to Intracellular H buffering :he fall of bicarbonate is not
equal to the increase in the AG and the expected AAG/AHCO; can be up to 1.6
AAG/AHCO; <1: AGMA + hyperchloremic acidosis (NAGMA)
AAG/AHCO; >1.6: AGMA + metabolic alkalosis
Etiologies
Edologles of AGMA
Increased Acid Generation
Ketoacidosis" Diabetes mellitus. starvation. alcohol
Ingestion Methanol. Ethylene glycol.Aspirin.Toluene (early phase)
Diethylene glycol. Propylene glycol
Pyroglutamic acid (5oxoproline) dlt chronic acetaminophen
ingestion (usually malnourished women)
LLactic acidosis Hypoperfusion. aerobic glycolysis
DLactic acidosis Metabolism of carbohydrate by intestinal bacteria in patients with
show bowel syndrome
Metabolism of propylene glycol (solvent for IV lorazepam.
automotive antifreeze)
Decreased Renal Acid Excretion: CKD
'High acetone level (>100 mg/dL) can falsely elevate sCr (T sCr with normal BUN).
Tre a tme n t
Address and :rat the underlying process
Use of IV HCO; for the treatment of AGMA is controversial; the common practice
is to use IV bicarbonate only when pH <7.1
Potential benefits of treating chronic metabolic acidosis with alkali (bicarbonate or
citrate) are: 1 dyspnea. improve skeletal grovnnh. i kidney stone and nephrocalcinosis
in RTA type 1, slow progression of CKD
Potential concerns with bicarbonate therapy includes: T CO: and worsening inna
cellular acidosis. T lactate generation though T phosphofructokinase activity. decrease
of ionized Ca, hypernatremia. and hypervolemia
Bicarbonate Is available in 8.4% 1 mEq/mL 50 mL vials of hypertonic NaHCO;
Calculation of the HCO; deficlc
The volume of distribution (Vd) of HCOJ Is 50-55% (T up to 70% in severe meta
bolic acidosis due to high buffering capacity).
HCO; deficit = 0.7 x Lean body weight x (desired HCO; - measured HCO:)
 LACTIC Acloosls [Ne/M 2014;371:2309)
Pathogenesis
Lactic acidosis occurs when generation of lactate exceeds consumption
Anaerobic glycolysis generates Pyruvaze which is metabolized by Iacune dehydrogenase
(LDH) no lactate
Pyruvate + NADH + H H lactate + NAD
Lactate is consumed for gluconeogenesis and oxidative phosphorylation
Hyperlactatemia can occur due to systemic or local tissue hypoxia (type A), the
resulting acidemia is autoexacerbated by l of lactate removal by the liver in cases of
severe hypoxia and acidemia
Hyperlactatemia results from aerobic glycolysis (type B) in hyperdynamic states (et.
sepsis. severe asthma. shock, pheochromocytoma)
Metabolic alkalosis stimulates 6phosphofructokinase leading to hyperlaccatemia from
aerobic glycolysis
Lactic acidosis contributes to cellular dysfunction: T cardiac arrhythmias. 1 myocardial
contractility.and responsiveness to catecholamines
Hyperkalemia is very common when the etiology is 1 Oz delivery: with hyperlactate
mia d/t epinephrine stimulation. hypokalemia occurs dlt l32adrenergic stimulation
Etiologies of Lactic Acidosis
Decrease Local or Systemic O1 Delivery (Type A)
Shock Cardiogenic. hypovolemic. septic. severe trauma
Severe hypoxemia Lung disorders. CO poisoning
Others Severe anemia. vigorous exercise. seizure. shivering. cocaine
Aerobic Glycolysis (Type B)
Epinephrine stimulation Cardiogenic. hypovolemic. sepzit shock
Sepsis. Pheochromocytoma, Cocaine. Ii;agonists
Cancer Warburg effecc usually in the setUng of concomitant liver
metastases limiting the lactate clearance by the liver
Others NRTIs. toxic alcohols (methanol, ethylene glycol). salicylates.
cyanide. pmpofol, thiamine deficiency
Other Mechanisms
DM Unknown mechanism
Liver disease 1 lactate Clarance
Medormin Suppression of hepatic gluconeogenesis
Propylene glycol Metabolized to Dlactate and Llactate
Treatment
Restore tissue perfusion with volume expansion using crystalloids;albumin can be
used as alternative for volume expansion. avoid other colloids
Balanced salt solutions (less chloride content) could prevent dilutional acidosis
IV bicarbonate is potentially helpful for severe acidemia (pH <7.2). Use with caution
(nuacellular acidification.. iCe leading to cardiac contracniliry)
DLactic Acidosis
Etiologies: short bowel syndrome (carbohydrate metabolism by colonic bacteria).
ingestion of propylene glycol (solvent for IV medications notably lorazepam and
diazepam) and DKA
Episodic metabolic acidosis with neurologic symptoms (confusion.ataxia. slurred speech)
Diagnosis: special enzymatic assay for Dlactate (the commonly used lactic acid assay
does nor detect Dlactic acid): It cause a combined AGMA and NAGMA (NAGMA is
due to excretion of Dlactate with Na and retention of the H)
Treatmenc oral antimicrobials. NaHCO: and addressing the underlying fuse

KETOACIDOSIS
Background
Metabolic acidosis secondary to ketone (acetozcetic acid. Bhydroxybutyric acid. ace
tone) accumulation: diabetic. alcoholic or fasting ketoacidosis
Urine dipstick detects acetoaceute and acetone. no: [5hydroxybutyric acid (can be
measured in the blood)
Correction of ketoacidosis leads frequently to NAGMA secondary co renal loss of
ketone bodies which are considered potential bicarbonate"
 Fasting Ketoacidosis
13hydroxybutyrate is the main ketone
Neonates and pregnant lactating women are at risk dl: T metabolic requirements
Alcoholic Ketoacidosis
Malnourlshed alcoholic patients. the severe acidosis occurs after :he patient stops
alcohol ingestion (alcohol ingestion limits fatty acid lipoiysis and decrease generation
of acetylCoA): plasma levels may be low or undetectable
Manifestations hypo or hyperglycemia, hypokalemia (GI and renal loss). L PO¢
(i intake and I renal Ioss).i Mg. l OG
Diabetic Ketoacidosis
Ketone bodies are both Bhydroxybutyric and acetoacetic acids
DKA is the result of insulin deficiency, glucagon excess leading to glucose utilization.
increased gluconeogenesis, increased glycogenolysis. and Iipolysis
Treatment:
Correction of the hypovolemia with isotonic solution: Insulin administration
Correction of the hypokalemiaz early and aggressive correction is needed in antici
pation of worsening of the l K following insulin therapy and volume expansion

MSTI4ANOL AND ETHYLENE GLYCOL

o
<9 Background
Methanol and ethylene glycol can be ingested as ethanol substitute. accidently (illicit
distillation) or to inflict selfharm. It is Found in: antifreeze and deicing solutions.
windshield wiper fluid. solvents. cleaners. fuels

Ethanol
Fomepizole

MethanoI° Ethylene glycol'

Alcohol .|
dehydrogenase r

Fomlaldehyde Glycoaldehyde

Formic acid° Glycolate"

Tetrahydrofolate

r 1

Less toxic Oxalate"

metabolites

Metabolism of Methanol and Ethylene glycol (Nontoxic alcohol;"Toxic meobolkes).

Pathogenesis
Formate causes retinal injury (hyperemia and blindness). basal ganglia hemorrhage
Glycolate causes tubular injury; oxalateCa crystals causes tubular obstruction
The toxic metabolite causes the T AG: the parent alcohol contributes to the osmotic
gap (as the alcohol is metabolized the osmolar gap decrease and the AG increase)
Folic acid accelerates the metabolism of formic acid
Ingestion of 1 g/kg is lethal: toxicity can occur with as little as tsp of methanol
C lin ica l M a n if e st a t io n s
CNS sedation and inebriation similar to ethanol intoxication than an progress to coma.
seizure. and hypotension
Methanol poisoning visual blurring, central scotcrnata. and blindness. On eye exam.
mydriasis, retinal edema. hyperemia of the optic disc and loss of afferent pupillary reflex
Ethylene glycol: oliguria. hematuria.flank pain. tetany (hypocalcemla)
When ethanol is colngested. the clinical manifestation is delayed dlt alcohol dehydro
genase inhibition
Diagnosis
Advanced degree ofAGMA (frequently HCO1 <8) w/o T lactic acid
Alcoholic ketoacidosis causes AGMA bu! with a lesser degree of acidosis
t Osmolal gap (OG) >10 can be seen during the early phase d the intoxication (before
the alcohol is metabolized)
OG = Measured Posm - Calculated Posm
Calculated Posm = (2 x plasma [Na]) + [glucose]/18 + [BUN]/2,8
Limitation of OG measurement:
(1) Cannot differentiate among the different alcohols (ethanol, methanol, ethylene
glycol, or isopropyl alcohol); (2) a decrease of OG is a sign of metabolism of the
alcohol to d1e toxic metabolkes and it is not a correlate of recovery (3) OG increases
in critically ill patients due to idiogenic osmoles
Solvent screen" does not measure for ethylene glycol
Lactate can T in ethylene glycol intoxication (glycolate has similar structure as
lactate)
Oxalate crystal and fluorescence of the urine with UV light in ethylene glycol intoxi
cation >
Q
Tre a tme n t o
GI decontamination has a limited role since these alcohols are rapidly absorbed
NaHCO; no correct systemic acidosis (in an acidic milieu, tl\e toxic metabolic are in
their uncharged form and thus easier to penetrate and cause organ damage), goal to
keep arterial pH >7.3
Inhibition of alcohol dehydrogenase: early treatment is important before the fonrnation
of the toxic metabolites
Fomepizole 15 mg/kg loading then 10 mg /kg q 12h;adiust after 2 dzadjust for HD:
Continue therapy until pH is normal and serum alcohol concentration <20 mgldL
. Ethanol if fomepizole is unavailableztarget ethanol level 1/3 of the other alcohol:
Loading 10 mUkg of 10% ethanol with maintenance of 1 mUkg
HD remove both the alcohol and the toxic metabolites. it is indicated in any patient
with (1) AGMA regardless of the alcohol level or (2) evidence of organ damage or
(3) large methanol ingestions
If a toxic alcohol ingestion is suspected but not yet confirm: the threshold to start
HD is pH <7.1 (it is unlikely for alcoholic ketoacidosis to cause such an advanced
acidosis);a concomitant fomepizole therapy can be started until :he diagnosis is con
firmed or ruled our: treating with ethanol for nonconhrmed intoxication is debatable
due to SE profile of the therapy
./ toxic alcohol levels every 2 hr of end of HD to determine the need for additional
HD; fomepizole is dialyzable and an additional should be given at the sur: of HD
PD and CRRT are inefficient at clearing alcohols
Treating with cofactors (folic acid. thiamine.and pyridoxine) to optimize nontoxic mez
abolic pathways: for methanol intoxication folic acid S0 mg IV q6h; thiamine 100 mg IV
or pyridoxine 50 mg IV in ethylene glycol
Isopropyl Alcohol
isopropyl alcohol is used as disinfectant (rubbing alcohol).antifreeze. and solvent
Causes CNS inebriation and depression.a fruity breath odor
It does NOT cause an elevated anion gap acidosis; it is metabolized by alcohol dehy
drogenase to a ketone
Diagnosis: T isopropyl alcohol levels and T OG: isopropyl alcohol does NOT cause
tAGMA nor . ;ihydroxybutyrate: ketone in the urine are expected after 2 hr of
ingestion (the urine ketone detection can be delayed if the patient receives fomepi
zole or ethanol)
Treatment; hydration and supportive are.no role for GI decontamination. no Indication
for alcohol dehydrogenase inhibitors. HD can help in massive ingestion
Toluene Inhalation (Glue SnifTing)
Toluene is metabolized to hippuric acid and benzoate leading to AGMA
With normal renal function these anions will be excreted with Na. NH4, and K. and
the AG is progressively corrected and the patient start developing NAGMA
Despite an increase in urinary NHL, UCI does not increase due to the presence
of hippurate leading to a positive UAG. NAGMA + * urine pH + T UAG can be
misdiagnosed as type 1 RTA: in this disorder UOG is used to estimate NH4
excretion
Hypokalemla is frequently present; (1) volume contraction leading to 2 hyperaldo.
(2) high distal Na delivery (Nahippurate and Nabenzoate)
 NONANiON GAP (HYPSNCHLONEMIC) MeTAsouc AclDosis
Causes and Pathogenesis
Normal anion gap metabolic acidosis is due to NaHCO; deficit
Mechanisms of NAGMA
Renal Reduction of acid excreting capacity CKD.distal RTA. type 4 RTA
Bicarbonate loss: proximal RTA
GI Bicarbonate loss: diarrhea, pancreatic fistula, ureteric diversion (ile el loop)
Other Loss of organic anions: recovery phase ofAGMA (DKA. toluene ingestion, and
Dlactic acidosis): Na and K Sal: excnedon w/ impaired acid excretion
Dilutional acidosis: volume expansion with a nonalkali containing fluid: rare
unless extraordinarily large volume is given
Addition of HCl:TPN
Diarrhea
Diarrheainduced NAGMA is frequendy associated with hypokalemia.hypokalemia
induced intracellular acidosis.and T NHL excretion and elevate urine pH
The more chronic is the diarrhea and the more profound is the hypokalernia. :he higher
is the urine pH (can be falsely diagnosed as dRTA or toluene inhalation)
Resolution Phase of an AGMA
In patients with AGMA and normal kidney function. the renal excretion of ketoacid
anions reduces the AG.a NAGMA is generated by loss of the ketoacid anions (potential
bicarbonate) with retention of H
Ureteral Diversion (lleal Loop)
Ureterosigmoidostomy: (1) urine is exposed to colonic mucosa. the Us is exchanged
for bicarbonate by anion exchanger (SLC26A3) » bicarbonate loss and NAGMA3
(2) urea in the colon is metabolized to NHL that is reabsorbed in exchange of Na
leading to NAGMA
lleal conduit: unlikely to cause NAGMA since the urine is not In contact with the
epithelium for long before it is drained to an external bag. if NAGMA develops it is
sign of malfunctioning of the loop
Treatment; NaHCOi administration

DISTAL RENAL TUBULAr Acii:>osls (dRTA,TYPE 1 RTA)

Causes and Pathogenesis
Impaired dismal acid secretion/urine acidification in the presence of NAGMA
L Activity of HATPase or increase luminal membrane permeability (leading to move
ment of the H from :he urine lumen back to the blood)
Hypokalemiaz due to . K excretion which offsets impaired H secretion needed to
maintain elecuoneuuality from sodium absorption
Etiologies of Distal (Type 1) RTA
Autoimmune Sjégren s. rheumatoid ardlri\is. SLE
Autoimmune hepatitis. primary biliary cirrhosis
Medications Arnphotericin B: reversible dRTA: less wl liposomal formulation
Lithium: incomplete RTA (mild to no metabolic acidosis)
ifosfamide. ibuprofen/codeine
Hypercalciuria Hyperparadlyloidism,\hc D intoxication. samoidosis. idiopathic hypeiulciuria
Hereditary SLC4A 1 encoding Cl/HCO; exchanger (AE1 or band3):AD. milder
acidosis than AR. presents later in life (young adults). Hypercakiuria.
nephrolithiasis. nephrocalcinosis. osteomalacia. and erythrocytosis
ATP6V181 encoding apical HATPase: AR: Sensonineural hearing
impairment. nephrocalcinosis
ATP6VOA4 encoding apical HATPase:AR: No early haring loss
Other Obstructive unopathy:l. Na entry in the principal cells 4 . H excretion
Medullary sponge kidney. transplant rejection.Wilson disease
ldiopathk
Diagnosis
Urine pH >5.5. Un. >25; positive UAG; L UOG
Other causes of persistently elevated urine pH >5.5: diarrhea with hypokalemia.
toluene inhalation
 Urine osmolal gap <150: dRTA
Urine osmolal gap >400: chronic dlaMea. toluene
Clinical Manifestations
Recurrent calcium phosphate kidney stones and nephrocalclnosis.from associated
hypercalciuria and hypociuaturia
Tre a tme n t
Correction of :he acidosis Is indicated in children zo restore normal growth. in adults
with K wasting, nephrocalcinosis, osteoporosis. and CaP stones
Goal [HCo,] 22-24
NBHCOJ or Na citrate (bicitra) 1-2 mEqlkg/d: K citrate 4 Na citrate (Polycitra)
K citrate: for recurrent kidney stones (increases urinary citrate and K moves inm
cellularly H exit the cell - . intracellular acidosis)
Avoid Na citrate: may increase stone formation
Correcting the systemic acidosis will T urinary citrate (acidosis T proximal citrate
reabsorption)
Incomplete dRTA
Impaired urinary acidification and inability to reduce urine pH to less than 5.3 but
the net acid excretion is maintained at a rate equal to acid generation by overforma
tion of NHL. In chronic condition. patients are not acidotlc. Some patients progress
to complete dRTA
Urinary citrate -» calcium phosphate stones. osteoporosis
Pathogenesis: not well understood. it is related to low intracellular pH in the proximal
tubule leading to increase formation of NHL. the acidosis episodes are intermittent
Diagnosis with acid load (NH4CI 0.1 g/kg or 3 d of modified diet) -> 1 serum HCO;
by at least 3 and urine pH is >5.3
Voltagedependent RTA
Dejects in distal sodium reabsorption leading to loss of the electronegativity of the
lumen leading to . K and H secretion
Etiology: severe hypovolemia. obstructive uropathy (1 NaKATPase pump). lupus
nephritis. sickle cell disease. amiloride. lithium
• Hyperkalemic RTA

PROXIMAL RENAL TUaULAR Acloosls (pRTA,TVPe 2 RTA)

Isolated pRTA: defect in proximal bicarbonate reabsorprion
Fanconi syndrome: a generalized proximal tubular dysfunction with impaired reab
sorpdon of phosphate. glucose. uric acid, and amino acids
Patients are in chronic acidbase balance and can reduce the urine pH no less than 5.3
Pathogenesis

Edologles of Proxima! (Type 1) RTA

Paraprotein Light chain proximal tubulopathy
Drugs, heavy Ifosfamide, tenofovin aminoglycosides. cisplatin. valproic acid. delerasirox
metals Carbonic anhydrase inhibitors: acetazolamide. donolamide. wpiramate
Lead, cadmium. mercury. copper
Hereditary Dent disease. cystinosis. tymsinemia. galactosemia.Wilson disease. Lowe
disease, hereditary fructose inizolerance, mitochondrial rnyopathies.
glycogai storage disease (type 1)
Mutations Off
$LC4A4 encoding NaHCO; cotransporter (NBCe1):AR, isolated
pRTA. Eyes. teeth. and cognitive disorders
SLC9A3 encoding NHE3:AD pRTA
CA2 encoding carbonic anhydrase II (CA II)
Other Renal transplantation.Vit D deficiency. paroxysmal nocturnal
hemogiobinuria, Siégren syndrome

Variable K excretion dependent on d 1e alkali intake:

In chronic stable alkali/acid intake. K level Is normal
After alkali therapy - dismal tubule Na delivery - t K excretion -» hypokalemia
T r eatment
pRTA requires a higher load of alkali therapy (10-15 mEqlkg/d)
Alkali therapy increases bicarbonawria and T K loss;thiazide can help by inducing
volume depletion :had stimulates proximal Na and bicarbonate reabsorption
Carbonlc Anhydrase (CA) Inhibitors
Acetazolamide. medmazolamide. dorzolamide. topiramate
Inhibits intracellular CA II and intraluminal CA IV in proximal and distal tubules
pRTA (w/o Fanconi syndrome) + dRTA. L K. nephrocalcinosis. Ca? nephrolithiasis
Mixed Renal Tubular Acidosis (Type 3 RTA)
Mainly in the Middle East and North Africa,Arabic descent
AR. carbons anhydrase 2 deficiency. Guibaud-Vainsel syndrome or marble brain disuse
Both pRTA and dRTA, osteoporosis. cerebral calcification. mental retardation, facial
dysmorphism with conductive hearing loss and blindness

HypoALoosTsnonlsl4 (Tvrs 4 RTA)

Pathogenesis
Either decreased aldosterone secretion or aldosterone resistance
l ENaC activity o L electronegative lumen -» 1 K excretion -» hyperkalemia
NAGMA through multiple mechanisms mainly mediated by hyperkalemia
1. K enter the proximal tubular cells -» H exit the cells - intracellular alkalosis -»
1 NHL production from decreased gluuminase
2, Hyperkalemia 1 NHL medullary reabsorption in the thick ascending limb of Henle
3. In the collecting duct. K competes with NHL at the level of the NaK ATPase which
leads to decrease the amount of intracellular H available for excretion
In summary,the tubule has the opacity to secrete H.but the lack of the luminal buffer
prevents excretion of higher load of acid
Etiologies of H ypoaldostemnism

Hypoaldosteronism. Diabetic nephropathy. chronic interstitial nephritis. acute GN

hyporeninemic unSAIDs . Renin + Allinduced aldosterone release
Calcineurin inhibitors (75% of transplant patients)
Pseudohypoaldosteronism type 2
Hypoaldosteronism. ACEi/ARBs. Direct rein inhibitor
hyperreninemic Heparin and LMWH: direct adrenal toxicity
1 adrenal insufficiency autoimmune. infection. HIV
Congenital isolated hypoaldostemnismzdelect in aldosterone syndiase
Resistance co Mineraloconicdd receptor blocker spironohctone. ederesione
aldosterone Epithelial Na channel (ENaC) blocker:amiloride. triamterene.
trimeihoprim. pentamidine
lMineralocori:icoid receptor expression: calcineurin inhibitors
Pseudohypoaldosteronism type 1

Pseudohypoaldosteronism type 1: mutation of mineraloconicoid receptor (AD form)

or ENaC (AR form); resistance to aldosterone
Pseudohypoaldosteronism type 2.Gordon syndrome, familial hyperkalemic hypertension

Diagnosis
Mild metabolic acidosis (HCO1 >17). hyperkalemia
J Plasma renin aczivicy (PRA). plasma aldosterone concentration (PAC).and serum
cortisol after the adminiscranion of a loop diuretic or 3 hr in :he upright position
Treatment
d/c offending drugs if possible
Hypertensive: loop or thiazide diuretics
Hypotensive: fludroconisone + high Sal: diet or isotonic fluid
 METABOLIC ALKALOSIS
T pH caused by T [HCOJ]i frequently associated with hypokalemia

P a t hoge ne s i s
Normally :he kidney has a high capacity to excrete alkali load in de PT
Metabolic alkalosis develops as a result of excessive alkali load and/or impaired renal
excretion of HCOJ (et, effective hypovolemia)

Vol ume depl eti on/ CHF/ ci r r hosi s

* Sympatheti c l G FR

TAI do

Proximal tubule: Type A imeroelated Frindpal cells:

TNa/ H exchange cells: T Na r eahsor pl i on (ENaC]
V 1 y pe HATP a s e Tv t y ps HATP a S 8 -» Elaclronegative lumen
T N8/HCO3 cotransporl

TReabsor pl l on of HCO3 TH secr eti on LFIIlgI8¢1 HCA:

Mechanism of hypovolemiamediated maintenance of metabolic alkalosis.

Hypokalemia is common occurrence due no several reasons:

1. Same pathogenic mechanisms contribute to both disturbances: primary or sec
ondary hyperaldosteronism + high distal Na and water delivery
2. Metabolic alkalosis - T NaHCO; distal delivery (nonCl anion + high load of Na)
-1 T K se cre tio n
3. Hypokalemia -» K exit and H enter the cell -» intracellular acidosis -»T NH;
renal production, ¢ H secretion (T H/KATPase In type A intercalated) and
T re a b so rp t io n o f HCO :
1 hyperaldosteronism T distal Na and water delivery + high Aldo -» T K and T H'
secretion (distal tubule H/KATPase and HATPase in the typeA intercalated cells)
Type B intercalated cells express increased luminal pendrin (HCO;/CI exchanger)
with the net effects being secretion of HCO; and reabsorption of Cl
The compensatory hypoventilation contributes co the maintenance of the metabolic
alkalosis: hypoventilation -» T Pco, -» T intracellular acidosis -» T renal H excretion
E t io lo g ie s
Mos: of :he etiologies combine a process :hat directly or indirectly generated HCO;
with a process of . renal HCO3 excretion to maintain the alkalosis
E t io lo g le s o f Me t a b o lic A lka lo sls
Etiologles That Help Maintain Metabolic Alkalosis
Hypovolemia... arterial blood volume (heat failure or cirrhosis)
Hypochloremia hypokalemia:T and ammoniagenesis
AKI o r CKD. Hyp e ra ld o ste ro n ism
Etiologies that Generate (Directly or Indirectly) HCO1
I n t ra c e l l u l a r H ' s h i f t Hypokalemia
G I H lo ss NN NG T su ct io n
Gastric H secretion is neutralized by die HCOi secreted
by die pancreas. liver, and intesdilea the loss of H leads
to HCC: a b so rp tio n
Exogenous alkali
Renal H' loss:
I distil Na and water delivery +
T mineralocorticoid activity
Other
Contraction alkalosis
Antacids in advanced renal failure
Mg hydroxide. Ca carbonate (when combined widl SPS)
Without SPS.the Mg and Ca vecombine with HCO; in do
distal intestine and does not cause acidbase dismrlaance
Vlhth SPS. Mg and Ca are chelated by SPS and the her
outcome is absorption of HCO;
Hypercalcemia. milk or Caalkali syndrome
Bicarbonate therapy. citrate after blood transfusion.
freebase or crack cocaine
1 hr./peraldosteronism: aldosr.eronesecnting adenoma:
Bilateral/unilateral adrenal hyperplasia;familial hyperaldo
(type I/glucocordcddremediable aldostercnism. type II
and lll).adreno<ord¢al carcinoma
2 hyperaldosteronism: CHE cirrhosis + diuneucs
Banter and Gittelman syndrome
Pendred syndrome (CIIHCOJ exchanger mutation:AR)
Posthyper¢apnic alkalosis
Some diarrhea: villous adenoma. laxative abuse. congenial
chloridorrhea (mutation of the CIIHCO; exchanger
-» high CI dionhea)
Excessive chloriderich sweat in CF
1 Extracellular volume with a constant total amount of
HCO, -» 1 [HCOx]. egearly phase of diuretics

Clinical Manifestations
Since HCO; moves slowly across the different body compartments. specifically :he
brain. symptoms are uncommon in Me: alkalosis
Muscular spasms. tetany. and paresthesia (due to 1 ice, L Mg)
Etiologyrelated symptoms and signs (hypovolemia. CHE cirrhosis)
Compensatory hypoventilation -» TpCOz
Wo rku p
J U61: help to assess volume ams
UN.: nosy increase d/t biaarbonaturia
Tre a tme n t
Both :he generation and maintenance of HCO; should be corrected
For vomiting and NGT suction, H;blockers and PPI L HCI loss
Correct hypokalemia: K repletion may connect metabolic alkalosis. volume expansion
w/o hypokalemia correction would not correct the metabolic alkalosis
Correct hypovolemia. restoring the blood volume with a Clcontaining solution will
correct the alkalosis and allows the kidney to excrete the excessive bicarbonate:
type B intercalated tells express luminal CIIHCOJ exchanger allowing excretion of
HCO3 after restoring euvolemia
T Us is marker of resolution of the hypovolemiaz urine pH T to >7 dl: bicarbonaturia
CHEF/cirrhosis (edema + low intraarterial blood volume): mineralocordcoid blockers
(spironolactone and eplerenone) helps with d1 e metabolic alkalosis and comes :he
hypervolemia; acetaxolamide (carbonic anhydrase inhibitor) can be added no :he diuretic
regimen (inhibits proximal Na/HCO: reabsorption)
Posthypercapnic metabolic alkalosis if nonedematous. volume expansion with
Clcontaining solutions (0.9% NS) will correct the alkalosis; If edematous (requires
additional diuresis). acetazolamide treats acidosis and corrects the hypervolemia
Dialysis will correct :he alkalosis in ESRD or severe AKI
HCI (only given through a central line) or NH4Cl is only used in patient with severe
alkalosis (pH >7.55) in whom dialysis cannot be done
Calculation of the HCO; excess
HCO; excess = 0.6 x LBW x ([HCO)] - 24) for men
HCO; excess = 0.5 x LBW x ([HCO1] - 24) for women
When infusing acid frequent assessment of pH and BMP should be done
 /Urine CI

1 r
1

<20 mEq/L >20 mEq/L

Recent diuretic therapy HTN

Vomiting, NGT suclion
Posthypercapnea
CI depletion (Villous
adenoma, laxative.
sweating in CF,
chloridorrhea)

Ongoing diuretics
/Serum renin
Barter
Gitelman
hypukalemia (<2) 1

Hypomagnesemia

/Serum aldo Ongoing diuretic

RAS
Fleninsecreting
tumor
Mal ig rant HTN

Cushing syndrome
EXQQGFIOUS Adrenal adenoma
oorlicosleroid Adrenal hyperplasia
17hydroxylase Adrenal carcinoma
detidency GRA
Liddle syndrome Familial hyperaldo
Chronic licorice

Diagnostic approach for me: alkalosis.

RESPIRATORY ALKALOSIS
Ba c k gr ound
Hypervenmilazion (T minute ventilation on vent) -» 1 CO ; - t pH
The renal compensation for acute respiratory alkalosis (1-2 d) is 1 HCO3 by 2 mEq/L
for every l pCO; by 10 mmHg.for chronic respiratory alkalosis (>3-5 d) is l HCO;
by 4 -5 mE q/ L for L pCO z by 1 0 mmHg

P a thoge ne s i s
t Minute ventilation is sec to T depth and/or race of ventilation
Some of the symptoms (et. tuscany. muscle cramps) are due to changes in the binding
of Ca to alb: resp alkalosis Te a a l b bi ndi ng 1 ionized Ca
Within 10 min, H is released from body boilers (intracellular protein. Hb.and phosphate).
In addition. T lactate levels possible from hypoxia from peripheral vasoconsuicticn.
Renal compensation takes 2-3 d and includes 1 NHL and T HCO; excretion
E ti ol ogi e s
Hypoxemia (, pOz -> T minute ventilation): pneumonia. interstitial lung disease.
pulmonary emboli. CHE hypotension, severe anemia, high altitude
Simulation of the resp centers: psychogenic (eg.anxiety). liver cirrhosis. salicylate
intoxication. postcorrection of mer acidosis. pregnancy. stroke. CNS tumor
Mechanical ventilation
 Clinical Manifestations
Paresthesias.headache. lightheadedness. due to local and cerebral vasoconstriction
(1 PCO: -» lceiebral blood flow):Tetany and carpopedal spasm due to lionized zzlcium
Pts are only intermittently aware of hyperventilation (SOB. air hunger), SOB is as
rest with frequent sigh (normal 0-3/15 min) exacerbated by anxiety
L P04 through Intracellular consumption (intracellular alkalosis -» T giycolysis -> T for
mation of phosphorylated compounds), [Phos] as low as 0.5 mg/dL have been
reported. severe hypoPhos causes muscle weakness and respiratory muscle weakness
Treatment
Treat the underlying pulmonary or excrapulmonary etiology (PE.AMI, etc.)
For anxiety pos: reassurance. benzodiazepine, and breathing into a paper bag leads to
improvement of pCO; levels and pH

RESPIRATORY ACIDOSIS
2
4 Background
g ; pH and t pcoz: CON is formed through endogenous metabolism and accumulated
§ when alveolar ventilation is 1 (hypoventilation); CO; + H;O 14 H;CO; H H + HCO;
5 CON is eliminated by alveolar ventilatiomstimuli are 1 P02 and t pCO;
o
n.
Pathogenesis
In physiologic conditions, t CON is the major stimulus of the respiratory center
In chronic hypercapnia. 1 Oz becomes the major respiratory stimulus;Treat.ment of
the hypoxemia in chronic hypercapnic pts can lead to T CO; and 1 pH
Renal compensation: T H excretion and retention of HCO; and takes 3-5 d
Etiologies
Inhibition of the CNS respiratory center: medications (opiates, benzodiazepine. seda
tives. anesthesia): obesity hypoventilatiori syndrome: CNS lesion oxygen therapy for
chronic hypercapnia; metabolic alkalosis
Chest wall and respiratory muscle defect: myasthenia gravis. Guillain-Barré. severe
1 K. severe 1 PO.. spinal cord iniury.ALS. MS. myxedema, kyphoscoliosis,obesity
Upper airway obstruction: OSA. foreign body aspiration. laryngospasm
Lower airways disease: COPD. asthma. pneumonia.ARDS. pneumothorax
T CO; production (associated with impaired alveolar ventilation): fever. thyrotoxicosis.
sepsis.steroid.overfeeding. exercise and metabolic acidosis
Clinical Manifestations
Depeiding on the baseline CO1 (symptomatic at higher PC02 for chronic hypaupnic pts)
CNS: level d consciousness (at advanced stages it 1 respiratory drive -> CO; retention).
T cerebral blood flow and ICP
Cardiac 1 myocardial and diaphragmatic contractility, cardiac instability, and arrhythmia
• Hyperkalemia due to respiratory acidosis is mild
Treatment
Treat the underlying etiology: Mechanical venrilacion if indicated

POTASSIUM
PoTAssium REGULATION
Transcellular Shift
98% of K is intracellular
Balance of K between intracellular and extracellular fluid depend on:
1. NaKATPase pumps 3Na out and 2K into the cell: t acUvity by catecholamines.
insulin. thyroid hormone;1 by digitalis
2. Catecholamine: B;receptors T :areceptors 1 K cellular entry
3. Insulin: T K entry into the liver and skeletal muscle
4. K load passive K entry into the cell air high K load
5. Extracellular pH: metabolic acidosis T K exit (uncommon with organic acidemia)
6. Hyperosmolarityf plasma [K] T by 0.0.8 for every t 10 of P... (hyperglycemia,
hypernatremia. mannitol): solvent drag
7. Exercise: through skeletal muscle ATPdependent K channels
Ncrmokalemix exercise -».l, ATP -u Open K channels » lnal T K -»Vasodilation
Determinants of Renal Potassium Excretion
Aldosterone: T secretion in the principal cells by T de number of ENaC allowing Na
absorption creating an electronegative lumen favorable for K secretion through
ROMK and BK channels (stimulus for T aldosterone includes K and hypovolemia)
Plasma [K]: T K secretion (independent from aldosterone)
Dismal Gow T distal flow -» t K secretion; GFR
Tubular Potassium Handling
Proximal Tubule Bothaccount for >90% dtime Passive reabsorption paracellular
Loop of Henle lllnered K is iuhsorbed NKCC
Distal convoluted K secretion Basolaceral NaIKATPase - 1
tubule intracellular Na Na entry via
NCC -» Electroneuual K into
tubular lumen via ROMK
Initial and outer Principal cells: K secretion Basolareral NaIKATPase -» T
medullary CD nintercalated cells: K Intracellular K -» K secretion
reabsorption via ROMK
HIK ATPase (H secretion and K
reabsorption)
Inner medullary CD K secretion 2Passive

K secretion in the distal tubules is dependent on Na' reabsorption from the lumen
into the peritubular capillary creating a negative charged lumen that potentiates K
secretion; this potential is continuously dissipated by :he paracellular absorption of
Cl.T his mechanism explains the hypokalemia in pathologic conditions where Na is
reaching the distal tubule with an anion other than CI (eg. RTA type 2, carbenicillin
induced or tolueneinduced hypokalemia)

IENaC activity in the

lAldosterone LK secretion
principal cell

Hypokalemia
K depletion coneclion

ilntraoellular K in TAe1ivity of Hn<+ TK raahsorption

the intercalated cell ATpase e

tna/KATpase and TK secretion

TAldos1erone ENaC aclivi\y

Hyperkalemia
K load TK cellular entry correction

TColonic secretion

HYPERKALEHIA
Pathogenesis
Potassium adaptation: the efficiency in handling a K load is enhanced if preadapred by
a previous K load (the initial smaller load t NaKATPase activity and the density of
luminal K channels making the kidney more adapt no handle a higher load)
Chronic high K intake is unlikely m cause hyperkalemia unless associated with another
K balance defect (impaired secretion or cellular entry)
 Etlologles of Hypedralemla
Increased Cell Release
Pseudohyperkzlemia Blood draw technique (hard venipunccure. repeated fast clenching,
Light tourniquet)
Long specimen storage
Thrombocytosis (T by 0.15l 100K pks): /K in a heparinized
plasma; nonclotted specimen
Leukocytosis (WBC >120K) in CLL; 9 K in plasma and serum:
/K in the serum of cloned specimen before centrifugation
Hereditary RBC fragility (et. stomatocytosis)
Red cell breakdown Transfusion of old PRBC; Intravascular hemolysis
NAGMA H enter :he cell and K exit
0.acti< and kexoacid enter the cell widi H md do not fuse t K)
Hyperosmolaricy Solvent drag (eg. hyperglycemia, sucrose after lVIG.
radiocontrast)
Insulin deficiency et, Fasting in ESRD patients
Respiratory acidosis Mild effect
Tissue catabolism TLS. Rhabdomyolysis
Exercise Level of t K depends on the intensity and physical conditioning
Medications 82blockers; not wick selective B1 blockers
Digitalis overdose (inhibition of NaKATPase)
Succinylcholine.aminocaproic acid (K exit the cell)
CNI. diazoxide. minoxidil ( ATPdep K channels)
Decreased Renal Excretion
l Aldosterone secretion Hyporeninemic hypoaldosteronism (DN: CNI)
ACEIs.ARBs.and direct renin inhibitors
Impaired aldosterone synthesis: chrunk heparii therapy. Primary
adruW insufficiency. Severe illness, Inherited disorders
(21 hydroucylase deficiency and isolated hypcaldostewnism)
i Response to Minealocordcdd receptor antagonists spiionolacwne,eplaencne
aldosl.erone ENaC blockers: amiloride. triamterene. trimethoprim.
pentamidine
Pseudohypoaldosteronism type 1 (AR mutation of the ENaC
or AD mutation of the mineralocorticoid receptor)
Acquired or congenital defects in Na reabsorpzion by the
distal tubule principal cells (voltage RTA): obstructive
uropalhy.SLE. renal amyloidosis. and sickle cell disease
Progesterone antagonize aldosterone. Pregnancy improves l K.
HTN. and metabolic alkalosis in primary aldoszeronism.
Drospinenone 3 mg spironolaccone 25 mg
1 Dismal Na and water Volume depletion
delivery CHE cirrhosis
Urererojeiunoslomy Urinary K absorption in die jejunum
CKD and AKI
aka Gordon syndrome Pseudohypoaldosnercnism type 2: muracions causing T NCC
» Metabolic acidosis. HTN, . K excretion

Workup
rlo pseudohyperkalemia; review of die history. med: volume status and renal function
Transtubular K gradient (TTKG). (UKIPK) + (U°,,../Pm.) is used to evaluate renal K
excretion corrected for the movement of water.The presence of urea recycling in
the inner medullary segments of the collecting tubules affects U..." and TTKG is not
a valid formula to assess renal K excretion (fun of nepal Hwewens z011=201s4n
Urinary potassium has limited diagnostic value since it correlates with K Intake
24hr urine K >40 mEqld. spot KlCr ratio >200 mEqlg.TTKG >11 -o e cell release
24hr urine K <30 mEq/d. spot KlCr ratio <20 mEqlg.7TKG <7 -» renal excretion
ECG abnormalitieszarrhythmias with K >7 or very rapid rise (sinus bradycardia.sinus
arrest. slow idioventricular rhythms,V1zVE and asystole)
Tall peaked T wave with a shortened QT interval - t PR interval and QRS duration
-» QRS widens to a sine wave
Treatment
Assess for emergency: (1) muscle weaknesslparaiysis; (2) cardiac arrhythmialconduccion
abnormalities; (3) K >5.S with ongoing TLSlrhabdomyolysis: (4) K >6.5
In emergent case. treat with IV Ca. IV insulin + glucose and SBA K removal (diuretics.
cation exchangers +I- dialysis if refractory); EKG monitoring: K check Q 1-2 hr
Treat the underlying etiology of hyperkalemia
Avoid long fasting period for ESRD pos (oral intake t insulin which i K)

Therapy of Hyperkalemia
Stabilization of the Membrane
IV calcium Works within miruaction lasts up to 1 hr
Ca gluconate 3 amp (3 g. 10% 30 mL. 14 mEq Ca) via peripheral line or
CaCl; 1 amp (1 g. 10% 10 mL 13.6 mEq Ca) via central line over 2-3 min
Avoid In digitalis toxicity
Drive Extracellular Potassium into the Cells
Insulin Bolus 5-10 units of insulin R + 50 mL of 50% dextrose
glucose Effect smrrs in 10-20 min. peaks at 3060 min. lasts for 4-6 hr
K drops 0.5-1.2 mEq/L
Albuterol Lowers the serum potassium concentration by 0.5-1.5 mEq/L
10-20 mg nebulizerz peak effect in 90 min
Used as adjuvant to insulin + glucose
Sodium Beneficial mainly in metabolic acidosis in acute Kzand in chronic . K
bicarbonate in CKD
150 mEq in 1 L of 5% dextrose in water
Removal of Potassium from the Body
Diuretics Can be used for MM acute and chronic hyperkalemia
Dosage depends on the renal function
GI cations Patiromer (NEW201§.]72.211)
exchangers 8,4-25.2 g qd: give 3-6 hr after or before other po meds
Exchanges K for Ca in :he colon
sle: constipation. Mg
Sodium zirconium cyclosillcaze lns}m zo1s=m:ml
Sodium polystyrene sulfonate (SPS)
15-60 g single dose po (4I- sorbitol):50 g enema (without sorbitol)
Avoid in postop, ileus or bowel obstruction (s/ez intestinal necrosis)
Dialysis HD is more efficacious in K removal than PD
CRRT can be used subsequently in patients widl ongoing K release
Dialysaie K <2 a/w sudden cardiac arrest (KA 1011591181
Rebound K: K shift to serum after HD. More pronounced after
albuterol. insulin and high Na dialysate I/ASN za00:11:znn. postHD .K
should not be corrected unless clinically indicated

HYPOKALEMIA
Pathogenesis
Decreased intake Is rarely a cause of hypokalania since renal excretion can be lowered
to S mEq/d; Main hypokalemia etiologies are cell entry and renal excretion
If lab processing is delayed. pseudohypokalemia occurs in AML (WBC consume K)

Etiologies of Hypokalemia
Increased Cell Entry
Insulin mediated Exogenous insulin in DKA zherapyz refeeding syndrome
l32adrenegic mediated Endogenous carecholaminesc alcohol withdrawal. acute myocardial
infarction. head injury and xheophylline imoxicazion
Exogenous agonists: albuzeroI. zerbuzaline. doburamine.
pseudoephedrine.and ephedrine
Metabolic or K by <0.4 for every T pH by 0.1
respiratory alkalosis Hypokalemia maintains :he metabolic alkalosis (T HCO1
reabsorpuion)
Hypokalemic periodic inherited AD or acquired in hyperthyroidism
paralysis Sudden entry of K into :he cell leading to paralysis and resp failure
J, K (1.5-2.5 mEqIL) precipitated by exercise,high CHO mal
Risk of rebound hyperkalemia after therapy
T Blood cell pmducdon Viz B 17 or folic acid therapy in meplobWdc anemia
GMCSF treatment of neutropenia
O Men Hypothermia. antipsychotic drugs intoxication: chloroquine.
Barium (blocks K channels). Cesium
Incr eased G astr ointestinal Loss
Dianrhea.villous Lower intestinal losses are high in K
adenoma Acute colonic pseudoobstruction (Ogilvie syndrome) have high
K in the colon lumen due no activation of colonic K secretion
Geophagia White clay binds K in the GI mc: (red clay is high in K and tK)
Incr eased Ur inar y Loss
Vomiting, NGT Gastric secretions are low in K
drainage Metabolic alkalosis .i HCO3 Eltmion -» T distal i1 ow -r
urinary K loss
T Mineralocorticoid Diuretics. 1 hyperaldo. renin secreting tumor. RMS
activity Chronic licorice ingestion: inhibition of the 11Bhydroxysteroid
dehydrogenase2 (11BHSD2)
Apparent mineraloconicoid excess (ruction of 11[3HSD2)
T Dial delivery of Na 1 polydipsia. diuretics therapy primary hyperaldo. Loss of gastric
and water secretions
Nonreabsorbable RTA type 2 (bicarbonate). DKA (B hydroxybutyrate). toluene use
anions (hippurate) and penicillin derivative
Lowcalories diet (ketogenesis induces * urinary K loss)
Others Polyunia. RTA type 1
Hypomagnesemia: K renal loss with open ROMK channels of the
DCT
Amphotericin B: T K membrane permeability
Saltwasting nephropathies: Bartter, Gittelman, reflux nephropathy.
SiOgren
Liddle: gain of function mutation of ENaC
Sweat losses (cystic fibrosis)
Dialysis, plasmapheresis

11l\HSD2

Conisol Cortisone

Agonist O1 Chronic licorice ingestion No mineralocon\oold

mineraloconieoid receptor Apparent mineralocomooid excess acclivity

HTN, L K. metabolic
alkalosis
l renin,
1 aldo

Mechanism of AME and chronic licorice ingestion.

Wor k up
Assessment of acid-base status. Mg level
Urine K >30 mEqld. spot K/Cr >13 mEq/g.TTKG >7 -v renal loss
Urine K <25 mEq/d. spot KlCr <13 mEq/g.TTKG <3 -» extrarenal loss or cellular entry
Cl i ni c a l Ma ni fe s ta ti ons
De pe nde nt on the de gre e a nd dura tion of hy pok a le mia
Severe weakness. muscle cramps. and rhabdomyolysis (K <2.5): Resp failure. illus
Cardiac arrhythmia: PACS, PVCs. sinus bradycardia. paroxysmal atrial or junctional
uchycardia.AVB,VI1VF.Torsade de poinne if l K is alw J, Mg
Depression of ST segment. L amplitude of theT wave. and T amplitude of U waves
 Risk for ardvythmia T in elderly pts. organic heart disease. or concomitant digoxin
Can precipitate hepatic encephalopathy in cirrhotic patients
Effects of Hypokalemia on Kidney
Nephrogenic DI: impaired urinary concentrating ability dlt (1) the resistance to ADH is
due to L expression of aquaporin2 In the collecting tubules: (2) AWvit y o f N a KZ C I
cotransporter of the thick ascending loop of Henle leading to defect of the interstitial
corticomedullary gradient the driving force for free water reabsorpdon
Electrolytes imbalances: T HCOJ reabsorption (maintenance of metabolic alkalosis).
t Na reabsorptiorl (hypertension)
Hypokalemic nephropathy: reversible proximal lobule vacuolar lesions develop
after 1 mo of hypokalemia. more prolonged hypokalemia (et, eating disorders, laxa
tive or diuretics abuse) leads to chronic irreversible interstitial changes with tubular
atrophy (more pronounced in the medulla)
The patient can still maintain the ability to conserve K

Hypokalemia

Cellular exchange:
exit of K/entry of H

Intracellular acidosis Cyst formation

Complement activation Tubular damage

tNH3 production

T T G F B, MCP1. IG BP1 Interstitial fibrosis

Mechanism of hypokalemic nephropathy.

T r eatment
Repletion of K should be cautious in hypokalemia dl: entry of K into the cell: risk of
rebound hyperkalemia in hypokalemic periodic paralysis and drymtoxic periods paralysis
Hypomagnesemia should be corrected to avoid continuous renal wasting
Bblockers (nonselective) is helpful in hypokalemic thyrotoxic periodic paralysis
Estimation of K deficit: 200400 mEq total K deficit l [K] by 1 mErelL
The total deficit of K needs to be adjusted widi the associated metabolic disorder in
DKA. correction of the hyperosmolarity and the insulin deficiency will drive additional
K inside the cell. K supplementation should occur for K <4.5;in diarrhea associated
NAGMA. the total K requirement need to be adjusted up since the correction of
the acidosis will drive K intracellularly
Krich food is less effective since it is under the form of K citrate and K phos which
have only a 40% retention
For chronic hypokalemia from loop diuretic therapy. Ksparing diuretics could be
considered as chronic therapy
Rarely or citrate (RTA, diarrhea). K acetate. K phos (Fanconi Sd) are used

Potassium Supplement
KCI IV Should be given in dextrosefree solution to avoid K entry inside the cell
Rare 10-20 mEq/hr (max 40 mEq/hr); max IV concentration is 60 mEqIL
High concentration is a/w pain and phlebitis
KCI PO Solid formulation is preferred; good bioavailability
Extended release formulations may result in a ghost tablet in the stool
sle: pillinduced esophagitis from osmotic injury
Liquid form: 15 mL 10% (1.5 E) 20 mEq KCI
K citrate In nephrolithiasis, dRTA with hypocitraturia
KHCO:
K phosphate Used in Fanconi syndrome
Salt substitutes 1 s(= 1/6 teaspoon) contains 10-13 mEq KCI (JAMA 1977;23e;ws)
 SODIUM AND WATER
Determinants of Serum Sodium Concentration (Sn-)
Plasma sodium concentration (PN.): a measure of total body solute concentration.
does not conflate with extracellular volume: it does reflect the total body sodium
to water min. a surrogate for osmolality of the extracellular compartment
Pn, = (total body exdungeable Na + :cial body exchangeable K)/total body water (TBW)
Serum sodium concentration (S~.):a reflection of water balance
Conversely. alteration of sodium balance (high or low intake of salt) leads to changes
In extracellular volume
Urine sodium (U~.): correlates with the extracellular volume (hypovolemia -» .L UN,)
Dehydration (water loss -» T [Na]) at volume depletion
P.,,,.and by consequence PN.. is regulated by ADH secretion and thirst

Waler loss:
Water load sensible (sweat)
(drinking water) insensible (thermoregulation)

TPm s. TSn.

Hypothalamic Hypothalamic
osmoregulaiors osmoregulalors

lADH secretion iThirsl TThirsl TADH secretion

nu.,,,,. Correction nU»sm

gzip
Diluted urine of PM & SNs Ccncamrated urine

Feedback mechanism to maintain P... and [Na].

HY P O NATRE MI A

Ba ckg r o u n d
Definition: [Na] <136
Usually due zo 1 water excretion and rarely solely from t free water intake
Classification
Mild (130-135); moderate (125-130): severe/profound (<125)
Acute ( <24 hi) ;chr onic ( >48 hr )
Symptomatic: asymptomatic
Hypotonic: pseudohyponacremia (or isotonic): hypertonic
Hypovolemic: euvolemic: hypervolemic

C lin ica l M a n if e st a t io n s
Water movement into the brain leading to brain edema acutely
Related to the degree and the rapidity of establishment of the hyponatremia
Symptoms in acute hyponatremia can be nonspecific like malaise. nausea progressing
to headache. lethargy. gait imbalance and In extreme cases seizures and coma
Chronic hyponatremia <130 is associated with subtle neurologic symptoms leading
to fall. general malaise. and decrease attention span
Severe acute hyponatremia can rarely lead to brain edema-induced brain herniation
especially in premenopausal women and young children
 Wonxur OF HYPONATREMIA (;ASN 2017;28:13401
Stepl: Differentiate Hypotonic from Nonhypotonic Hyponatremia
Measure P.,,m to rule out nonhypotonic hyponatremia
Calculated Pm = 2 x [Na] + [Glucose]/18 + BUN/2.8 (normal: 275-290 mOsmoI/Kg)
Measured Pm (done in the lab) reflects the total of all osmolytes in plasma
Hypertonic hyponauemia: osmotically active compounds (eg, glucose, mannitol.
alcohols) drawing water our of cells
Isotonic hyponatremia: waterinsoluble substances (eg. protein and lipid) may
interfere with the measurement of sodium.The osmolar gap (MeasuredCalculate
Pm) is helpful in these circumstances: a difference of more than 10 is in favor of
an additional osmolar substance
Treatment of nonhypotonic hyponatremia is centered around the underlying etiology,
et. hyperglycemia where indicated
Step Z: U.,,m and GFR to Assess the Role of the Kidney
Um is expected to decrease in response to hyponatremia. If lvypotonic hyponatremia
coexist with low U°.,,. (<100). this can be explained by:
1. 1 polydipsia (usually >12 L): overwhelming the excretion of dilute urine
2. Low dietary solute nuke (eg. malnutrition, alcoholism) :he low total solute
excretion limits :he amount of maximal daily urinary water excretion due to
reduce delivery of fluid in the diluting segment and creates an environment where
even a mild increase of hypotonic intake leads to hyponatremia
Step 3:Volume Status Assessment for Patient with High Up" (>100) and Un,
U.... >100 in a hyponatremia (elevated ADH levels): true hypovolemia.effective hypo
volemia. SIADH, hypothyroidism. and Addison disease
lt is sometimes difficult w differentiate clinically hypovolemic hyponatremla from
euvolemic hyponatremia (sensitivity and specificity = 50%) (Ami M 44 1995;99:34si
Una <30 can be used as a supplement to assess volemia (using a cutoff of 30)
Un, diagnostic value is limited in CKD. recent diuretics use.dietary Na restriction
. [Na] with isotonic saline infusion trial is favor of hypovolemic hyponatremia (in
SIADH with U°,,,. <500. [Na] improves with isotonic saline infusion)
Since ADH is a uricosuric hormone.fraction of excretion of uric acid (FE) is a
helpful diagnostic tool: FEud >12% is sensitive and specific for SIADH

Hypsnonlc
I P I 3 $ M3 Hyperglycemia
osmolality Mannitol
Malloselsucrose MG

J u.....
u,l,,, <1 0 0 : Low ADH
Primary polydipsia
umzlm Low dietary solute intake
Advanced renal failure
Beer potomania

/volume assessment and

UN.: it recent diuretic or U* 2 3 0 4
Un: <30 + CKD, Una is unreliable and hypovolemla
hypovolemia consider etiology based on Vomiting
Diarrhea vomiting volume status only I adrenal insufficiency
3° spacing Renal salt wasting
Remote diuretics Cerebral salt wasting

Una <30 + Una 230 * euvolsmia

hy pe wole mia SIADH
CHF 2 adrenal insufficiency
Liver cirrhosis Hypothyroidism
NS

Diagnostic approach for hyponamemia based on Pm. Um. Un.. and volume situs.
 TREATMENT OF HYFONATREMIA noT Z014;Z9i1: Am; mia Z01J; 126:S1)
When hypokalemia is concomitant with hyponatremla. the correction of hypokalemia
may contribute to the correction of the hyponatremia (the replecion of K helps restore
plasma osmolarity by t coral body osmoles)
• For acute or severely symptomatic hyponatremia, a bolus of hypertonic saline 3%
(100 mL over 10 min x3 as needed to relieve symptoms or the [Na] increases by 6)
In hypovolemic hyponatremia, patients will start autocorrecting as soon and the vol
ume Is expanded, to avoid rapid correction, it is recommended to combine volume
expansion with desmopressin
a The limit for correction is 8 mmollUd; Hypotonic fluids and/or DDAVP can be used
to relower [Na] if overcorrection occurs
Restrict fluid intake (both PO and Iv) to 500 mud below the 24hr urine volume in
low Um. hypervolemic hyponatremia and Syndrome of Inappropriate Anddluresis
(SIAD)
If Um >300-500, consider lurosemide to lower U.,,,,.
Urea: induces osmotic diuresis free water excretion. used as second line co fluid
restriction; safe and effective (qASN 101B;13:lb17); Even if overcorrection occurs with
urea, the risk of ODS and demyelinauon lesions is less
Salt tablets increase urine solute load: Usual doses for NaCl tablets are 6-9 g daily
ADH Antagonist (Vaptans) (NEW 2015:3711107)
Block V2receptors in collecting duct principal cells aquaresis
Tolvaptzn (PO): start with 15 mg qd; up to 60 mg. 30 days
Conivapan (N): sun with 20 mg over 30 min dlai 20 mgf24 hr: up to 40 rng/24 hl;4 phys
NOT indicated in the treaunent of acute or severely symptomatic hyponatremia
s/e: overcorrection. liver toxicity
On initiation. fluid restriction should be stopped and patient should be allowed
access to free water intake to avoid overcorrection; if the target Na is no: achieved
after 24 hr of vaptan initiation.fluid restriction will be resumed

Treat:lnent of Hyponatremla
Conrecdon limit 8-10 mEqlU24 hr
Correction rate 46 mEdU24 hr
Overcorrection Hypotonic solution Only if baseline <120 mErelL
DDAVP 2-4 us IV
Treatment of ODS Hypotonic solution Lower [no] by 16 sEq/L
DDAVP 2-4 pg IV
Severe symptomatic NaCl 3% (100 mL over 10 min) Symptoms improve or Na
hyponatremia x3 as needed by 6 mErelL
SIAD 1" line address :he stimulus of Fluid restriction calculation
ADH secretion + Fluid (Un. + Ui()1Sn.
restriction >1 - <S00 mud
2" line: urea. salt tablets =1 - 500-700 mud
3' line: lithium. demeclocycline <1 -» <1 Ud
Hypoyolemic Isotonic volume expansion DDAVP concomitant in
hyponatremla patients with high risk of
ODS (hypokalemic.
alcoholic. malnurridon)
4-8 ug N q6sh
Hypervolemic 1" line:f1uid restriction High risk of overcorrection
hyponatremla 2' line: vaptan" or hypertonic with Vapzan
saline loop diuretics
'Ri sk of nonnspcnder s Ur l 2130 mmol / L: Um 2500 mOsml l g: UOP <1. S00 mud
'AvoidVapnn in patients widl liver disease

Hy pona tr e m i a For m ul a s
Effective Pa, = 2 X [Na] + [glucose]/18; (normal value: 270-285 mOsmol/kg)
Since Na and K is the main extracellular and intracellular solutes. respectively:

P la s ma [Na ] = (r.ota I body Na 4 tota l body K)/TBW

This formula explain why correcting hypokalemia could improve hyponatremia

Plasma volume: 93% aqueous (water). 7% nonaqueous (fat and protein)
Physlologic [Na] = reported [Na]l0.93 (eg. 143/0,93 = 154 [Na] in 0.9% isotonic saline
fluid)
Brain Ad ap t at io n t o Hyp o n at rem la
Hyponatremia and l Pm -a water flow across the blood-brain barrier -» T ICP -> loss
of Na and water into the CSF -» improving ICP within min (acute adaptation)
Chronic adaptation srarcs within hours through intracellular K loss (cell swelling
sensitive cationic channels) followed by loss of brain organic osmolytes (glutamine.
glutamate. Maurine, and myoinositol) that needs up to 72 hr to be complete

Loss of Na and water

Min
into me CSF

Water "OW T ICP and

aaoss the BBB Brain edema

First few hr
Loss of intracellular K

Within 24 hr and upto 48-72 hr

Depletion of brain organic
osmoles

Brain adapmrion to hyponatremia.

The rate of correction of hyponauemia is important whenever the brain has adapted |
to hypomonicity (after 48-72 hr of established hyponarremia)

Osmotic Demyelination Syndrome (ODS)

alw rapid convection of hyponalremia (>8 mEq/L in 24 hr: >16 mEaL in 48 hr)
The hourly rare is not a risk factor of ODS unless the daily rate threshold is exceeded
Prevention: target a rate of correction of 4-6 mEqlUd in chronic"asymp:omaLk"
hyponauemia

Ris k Fa c tors for ODS

Admission plasma ¢ [Na] $120 mEq/L (mainly for $105 mErelL)

Na . [Na] >120 posdiver uansplanz or CDI alter doAvp discontinuation
Therapy Hypersonic saline
Vasopressin anngoniss
AucocorrecUon . Hypovolemic hyponanremia :razed with volume expansion
following therapy Adrenal insufficiency creamed with glucocorticoids
(rapid renal free Holding DDAVP in overtreated Central Dl:Holding diiazide diuretics
water loss) ESRD on HD
Patient related » Alcoholism: malnutrition; liver disease: pregnancy
. Hypokalemia

In hyponatremic ESRD. during dialysis,the rapid T Pm induced by the correction of

hyponatremia is counterbalanced by HDinduced L of potassium. uremic toxins
including urea (urea does not cross the BBB as fast as water and act as an effective
os mole re la tiv e to the bra in c ompa rtme nt)

Chrome hyponalremia
Rapid hyponatremia
correction

Normal size Drain depleted lB ra ln vo lu me

from organic osmolytes ODS

Mechanism of osmotic demyelination syndrome (ODS),

Clinical manifestation are delayed (2-6 d), irreversible. or partially reversible: dysarxhria.
dysphagia.paraparesis. quadriparesis.and locked in Sd: behavioral disturbances. tremors.
araronia and seizures, led1argy.confusion.disorieruaLion.obmndadon.and coma
MRI could show Me demyelinacion lesions (delayed finding up w 4 wk) which can allen
a n y p a r: o f :h e b ra in a n d sp in a l co rd
S o me p ro p o se d p re ve n tive me a su re s:
In pus likely to overcorrec: (hypovolemic hyponauemia): DDAVP (1-2 pg IV or SC
q6-8h) is given at the sur: of onset volume expansion (NS or hypertonic saline)
In pts on therapy where the goal is likely no be exceeded or overcorrected -» sup
t h e ra p y + DS W (6 n Uk e ) o r d DA V P
 Relowefing [Na] to die daily correction limit of 8 mEq/L an l the severity of ODS and
even air the onset of neurologic, it is recommended to reiower [Na] by 16 mErelL
For patient with baseline [Na] 2120. it is probably unnecessary to relower Na in case
of overcorrection. slowing the correction rate is enough in these cases

SPECIFIC ETIOLOGIES OF HYPONATREHIA

Diureticsinduced Hyponatremia
More common with thiazides than loop diuretics because loop diuretics plevent the
generation of a conicomedullary interstitial osmotic gradient which limits :he ability of
the collecting tubule to reabsorb flee water even it ADH is elevated
Thiazideinduced hyponatremia is due to several mechanisms: (1) reduction in diluting
function of the distal tubule: (2) an underlying tendency to increased water intake
(polydipsia): (3) impaired ureamediated water excretion
Hypervolemic Hyponatremia
Hyponatremia is an important prognostic factor in CHF and cirrhosis
Syndrome of Inappropriate Antidiuresis (SIAD) (NUM 29074$52064)
Desalination: since volume expansion does not affect Umm in SIAD. an expansion with
isotonic solution results in a net electrolytefree water gain in patients with SIAD
(especially if Up, >500) leading to worsening of the hyponatremia
Etidogies: drugs. cancer (small cell lung cancer). pulmonary disorders. CNS disorders.
hereditary nephrogaiic SIAD (GOF rotation dv2 ieceptontreated with urea; vaptan are
ineffective therapy), idiopathic and transient (nausea, pain.anesthesia)
Copeptin is produced during the cleavage of die vasopressin prohormone, it can be
used as an indirect measurement tool for vasopressin levels
Um is an indirect measurement for the ADH concentration. using copeptln in hypo
nauemia is o( limited utility (beyond distinguishing primary polydipsia from d1 e other
etiologies of hyponauemia) (Endocrine 201a:w.aa4)
SIAD has 5 subtypes
Type A: vasopressinlcopeptin secretion Is no: related to So: erratic ADH secretion
Type B: relationship between So. and Vasopressinlcopeptin is intact but lower threshold
(reset osmosis)
Type C:vasopressin/copeptin secretion is not related to So.: COHSGUI ADH secretion
Type D undetectable vasopressin/copeptin (nephrogenic SIAD)
Type E: reverse relationship between So and copeptinlvasopressin (barostat reset)
due to increased sensitivity of baroreceptors to increased vasopressin release
Cerebral (or Renal) Salt Wasting
The same lab profile as SlAD (hyporuuemia. concentmed urine, high Un.. hypouricemia.
and t FEud >1176). The FEud does not decrease after coneciion of the hypomuemia:
stays >11%;in SLAD the FE,iAde4:iases to less than 11%with the correction of the hypo
natieinia (An I Med so 10168528851
Adrenal insufficiency
Cortisol deficiency disrupts die negative feedback loop that inhibits ADH release.The
increase of conicotropinreleasing hormone production in response to consol defi
ciency promotes hypothalamic ADH release leading to hyponatremia (PNAS z000s7.4e 11
Acute Hyponatremia
Etiologies always involve a high free water make with additional pathogenesis: postop.
exercise. the use of 3.4merhylenedioxymethampheramine (P1DPlA.Ecstasy"). haloper
idol. thiazide diuretics, desmopressin. oxytocin.TURPlhysterectomy irritants (glycine.
sorbitol, mannitol. and IV cyclophosphamide)
Glycine and sorbitol cause cerebral edema: mannitol does not cause cerebral edema
(hypertonic hyponatremia)
MDMA T ADH release and free water intake in an effort to prevent hyperthermia
Hypertonic saline 3% is an effective and lifesaving for hyponatremiainduced cerebral
edema
Mild Chronic Hyponatremia (qA§N zoisnmzzssi
Asymptomatic, >72 hr and [Na] between 125 and 135 mErelL
Hyponatremia is alw higher mortality and morbidities in outpatient. inpatient. and
ICU settings (neurocognitive deficits, gait disturbances. falls. bone fractures. osteopo
rosis)
It is not clear if correction of hyponatremia improves outcomes
 HY P E RNATRE MI A

P a thoge ne s i s
Thirst reflex tend to correct hypernauemia/hypertonicity for patients with access to
free water. For hypernatremia to occur. in addition to the free water loss, the patient
has to lose access to free water (eg.AMS. infants, loss of thirst)

Etiologies
For the etiologies of hypernatremia. :he pathogenesis is a combination of electrolyte
free water loss combined with impaired thirst or limited access to free water
Nor all fluid loss will induce hypematremia.the Na + K content in the fluid should
be lower than the plasma [Na] to induced a net fluid loss and T plasma [Na]
Secretory diarrhea: Na + K loss in the stools = plasma [Na] -» no effect on [Na]
Osmotk diarrhea. lactulosenomidng, osmotic diuresis. sweating: Na + K loss < plasma
[Na] -» T plasma [Na]
Hyperglycemia and mannitol therapy initially lead to hyponatremia from to.,. and
T water exit from the cells -» Osmotic diuresis -» free water loss and hypernatremia
Etiologies of Hypematremia
Unreplaced Water Loss
Skin Insensible (cransepidermal loss)
Sensible: swear (swear is hypotonic to plasma)
GI Vomiting. NGT suction
Nonsecnetory diarrhea
Urinary Central and nephrogenic DI
Osmotic diuresis
Decreased Water Intake
1° hypodipsia Defect in thirst; patten: should be encouraged to t water intake
Adipsic DI Congenital and acquired CNS lesions
Mild volume expansion -» suppression ofADH
Treatment by adjusting water nuke based on body weigh:
Reset Primary mineralocorticoid excess
Osmostat Mild hypernatnemia (high 140s)
Water Loss into Cells
Severe exercise, seizure (uansienr hyperNa for 5-15 min)
Na Overload
Intake or administration of hypertonic sodium solutions
eg. infusion of hypertonic Na bicarbonate solution. hypertonic saline for traumatic brain
injury. hypertonic saline during procedures (hydaiic cyst irrigation. abortion). sak
poisoning (child abuse, accidental)
Cl i n i c a l Ma n i fe s ta ti o n s
Acute hypernatremia (<24 hr) can cause irreversible brain damage (osmotic demye
libration and cerebral hemonrlrage); since die brain did not have :me so adapt to
hypematremia. [Na] should be acutely corrected to normal level by giving die entire
water deficit volume within 24 hr
The clinical symptoms are mainly neurologic
Acute hypematremia: lethargy.weakness. irritability: sei1ures.and coma
Chronic hypernacremia (>48 hr): it is difficult to attribute the symptoms to hyperNa
itself or to the underlying etiology causing the impaired mental status

Water exit across

tlnaVtp,,,,,, Brain volume
the BBB

1
Water moves from the Cellular uptake of Cellular accumulation
CSF to interslilium Na and K of osmolyles

Brain adaptation to hypematremia.

 TREATMENT OF HYPERNATREMIA
General Approach
Administration of dilute fluid no correct the free water deficit and the ongoing loss
In DI. desmopressin is :he main therapy (review polyuria)
Free water deficit + electrolytefree water clearance as
Free Water Deficit =TBW x ([Na]I140 - 1)
Total Body Water (TBW) = Lean Body Weight (LBW)* x 0.6 (young male), 0.5 (young
female.elderly male). or 0.45 (elderly female)
Another way to estimate: 1 mErelL of T [Na] =Water deficit of 3 mUkg
eg.To correct [Na] by 10 point in a 50kg female patient with a sodium of 150
Using the formula: water deficit = 50 x 0.5 (150/140 _ 1) = 1.700 mL
Using the estimation: water deficit = 3 x 10 x 50 = 1.500 mL
Calculation does not estimate the ongoing free water loss
*Fat has lower water content than muscleTBW is lower in obese and elderly
Free Water Clearance (Cwo) =V..i¢ x (1 - U.,,..JP,,,..)
If (+): the amount of free water that is lost in the urine;ADH absent or ineffective
(NDI or CDI)
If (-): the amount of free water retained by the kidney;ADH present and effecdye
(osmotic diuresis)
The cell membrane is permeable to urea: urea does no: contribute to the eH*ecti~»e PM
Since the medullary collecting tubules are not permeable to urea and NH3. urea does
contribute co the effective U.,,...
This discrepancy in the handling of urea between die kidney and the other organs limits
the value of Cup in predicting the effect of urine output on serum [Na] especially if
solute diuresis is suspected (postobsuuctive. hyperalimentation, high catabolic state)
and C4»<=,.=»v-4~»H»° is used in solute diuresis to measure che ongoing renal water loss
Electrolytefree Water Clearance (C»4,0) =V,.¢,* x [1 - (UN. + UI()lPN~]
The absolute value of free water volume needed to avoid worsening of the hyperna
Estimates the contribution of the urinary loss on Pow and plasma [Na]
If (.); the amount of electrolytefree water that is loss in the urine: should be added
to total volume of (ree water deficit calculation
If (-): die amount of electrolytefree water retained by the kidney (kidneys are cor
recting the hypernatremia); this amount should be subtracted from the total volume
of free water deficit
Repletion Solution
Oral or NG or PEG mbe free water tube boluses are the preferable repletion access
DSW: preferred IV solution. Can cause hyperglycemia especially in DM, leading to
osmotic diuresis worsening hypernatremia.Tx: D2.5W or insulin therapy
Na (for hypovolemia) or K (for hypokalemia) added .l free water amount in IVF
1 L of 0.45% saline (-154 mOsm): 500 mL of Me water
1 L of 0.45% saline + 40 mEq of KCI (-234 mOsm) 250 mL of free water
The Rate of Correction
Chronic hypernatremia (>48 hr): lower Na by 10 in 24 hr; max is 12Id
Acute hypernatremia (<48 hr): lower [Na] by 1-2 mEqIUhr until [Na] of 140
(Initial rate of DSW is 3-6 mUkg/hr until [Na] reaches 145 and then 1 mUkglhr
until [Na] 140)
Rapid correction of the of chronic hypernatremia may fuse brain edema. but evidence
is not strong (QASN 201m4=s561
Chronic hypematremia causes accumulation of intracellular osmoles as chronic adap
tation to avoid of brain volume: rapid correction of hypernatremia creates a hypo
osmolar serum compared to the brain and leads to brain swelling mainly in children
Slow correction rate (<6 mEqlUd) are associated with higher mortality
J [Na] q2-4 hr initially,then adjust depending on cowction rate
 CALCIUM REGULATION
Role: bone structure. muscle contraction. coagulation; cell signaling. secretion. and adhesion
Daily intake 1.000 mg. net intestinal absorption -200 mg
Bone contains 1.000-1.300 g Ca (>99%) by weight as hydroxyapatite: C210(P04)s(0H)z
ECF Ca content is <0.1% of total body stores

CaSR in parathyroid gland senses ionized Ca (iCe) and controls PTH secretion
Vitamin Do (cholecalciferol, from UV lightmediaxed skin productiomanimal) and vita I
min DO (ergocalcilerol, from fish. plants) are convened to 25(OH)D2 (calcidiol) in
liver; converted to 1.25(OH);D! (calcirriol) by 1a hydroxylase in kidneyzactivated
by PTH: inhibited by FGF23
Serum Calcium Regulating Mechanisms (qA91 w1s;10.12s1)
Site Increasing Serum Ca Decreasing Serum Ca

Inratine Caki!riol: calbindin.TRPV6 mediated Excreted in the bile

Bone
PTH: RANKL -r osteoclastmediated
resorption - TCa. POW release
Metabolic acidosis: Ca. PO. released
from bone I~qM 1971 aomsasl
Kidney PTH: reabsurprion in TAL DCT;
t calciumiol synthesis
Volume depletion, :hiazide
Metabolic alkalosis T TRPV5 - renal
reabsorprion uAs~ z0\oJ1:144m
Calcitonin: . osteoclast activity -»
Lbone resorption umjmwiul
199sa71:Fz1s1
Cakitonin: l robsovption
TQ: CaSR -»i reabsorprion
Volume expansion, loop diuretics
Metabolic acidosis: lTRPV5 -> J, renal
reabsorpdon UASN m0s:17=6m

Serum Acidosis: i albumin binding (t iCe) Alkalosis: T albumin binding (L iCe)

Kidney filters -10 old; reabsorbs 97-99%;excretes 100-300 mg/d; 24hr FEw. 1-3%
Renal Reabsorpdon of Filtered Calcium (qAsr4 misiiaiun
PCT (60-70%) Passive solvent drag by sodium uanspori; T by volume depletion.
zhiazide; x by aceuzolamide. osmotic diuretics
Minor active zransporz regulated by PTH and calcitonin
TAL (20-25%) Paracellular via claudin16/19, driven by (+) lumen from ROMKI
NKCC2: inhibited by loop diuretics
Basolazeral CaSR inhibits claudin16/19 via claudin14: . reabsorpnion
PTH inhibits claudin14: f reabsorprion was zo17;ii4:en44)
DCT (10%) and CD Apical TRPV5, intracellular calbindinD2BK: T by PTH
( 594) Basolazeral NCX moves Ca w blood: T by ihiazides

Calcium Measurement
ionized Ca (iCe): preferred measurement. unbound. physiologically active form
ApH by 0.1 0.08 mmolIL Aica in opposite direction (dlt .\H albumin binding)
Serum protein (albumin and lg) level changes serum coral Ca level so maintain iCe level
Adjusted Ca = Ca » {0.8 x (4 - albumin in g/dL)}
If 1 GFR, unadiusred value may be more accurate (WI as... 201B.8:e017703)
Pseudohypocalcemiaz gadodiamide, gadoversetamide interfere wl :oral Ca assay
Calcium Balance in CKD
KDOQI urge:8,4-9.5:boch below and above Inge are alw t mcmllry (nor 20112e194e>
Hypercalcemiaz alw exrraskelecal calcification and cardiovascular morbidity
Hypocalcemia: common in CKD;alw t PTH secretion
 HY P E RCALCE MI A

Pathogenesis and Causes of Hypercakemia

PTH 1 hyperparadlyroidism (HPT). 3 HPT slp kidney transplantation
Parathyroid cancer; MEN 1I2A (pituitaryldiyroid cancer FHx). lithium
PTHrelated SCC. RCC. breast. ovarian, bladder cancer > leukemia. lymphoma
peptide (PTHYP) Pregnancy.tends co be mild r€»1a»a;zaus=ss;9s1
Caldtriol Vi: D excess.granuloma (TB, sarcoidosis.ANCA, Crohns). lymphoma
Sarcoidosis + vit D (><2) or renal dysfunction ()<4.1) or,Im=¢ so zowasuszI
ldiopazhk lAM wi 1997;1§7:2141)
Osseolysis, Multiple myeloma. metastasis. hypervitaminosis A
Bone turnover Pager disease. hyperthyroidism Imam ma zooamswl
Renal retention Thiazide. milk (or CaCO;)alkali syndrome: vomiting or volume
depletion worsen metabolic alkalosis - renal Ca reabsorpdon
Familial hypocalciuric hypercalcemia (FHH):AD CaSR inactivating
mutation -r t Mg. Ca reabsorption: T PTH
Acquired form:Ab against CaSR Hsu# zo04:as1ss2l
immobilization Usually <11. possibly resorpdve mechanism (NEW iveuosiuel

Clin ical Man if est at io n s an d Wo rku p

AKI (vasoconsnictlon). constipation. weakness. fatigue. memory loss. confusion
NDI: 1 aquaporin2 & t medullary Ca deposition -» osmotic gradient impairment
Chronic hypercalciuwia (1 HP12 sarcoidosis) _» nephrolithiasis. nephroukinosis - CKD
EKG: Short QT interval, prolonged QRS,bradycardia. U waves
Hypomagnesemia d/t CaSR activation -) J, renal nabsorpdon

Typical Calcium Level (g/dL) by Causes

>12 Mal i gnancy. cal ci tr i ol pr oducti on. i ngesti on
<12 1 HPl 2 i mmobi l i mi on. FHH. mhi ui de. l i thi um

If PTH inappropriately normal (no: suppressed) in hypercalcemia, 1 HPT possible

P TH a nd P 0 4 Cha nge s I n Hy pe r c a l c e m l a
PTH Po. P os s i bl e Ca us e s PTH P04 P os s i bl e Ca us e s
4 Thi azi de. mi l kal kal i syndr ome | + 1 HP I FHH
l T T Ca l c i t r i oL bone l um ov e r 7 T a HP T
1 Var. Mal i gnancy: J P THr E 1, 25V i t D.
SIFE/UIFE, FLC

Renal retention:24hr FE<;, <1%. Ca <100-200 mud: random CaICr <0.01 (less reliable)
Tr eatment
Fluid: PO: I V i f sympzomar i c or Ca >13;g°al U O P 1- 2 mU g/ hr : NS to avoi d alkalosis
Loop diumics: : f ue l volume repletion Iiude eflecr solely (Am IM 2ao&149:2s9l;may alkalosis
RescricrVixamin D and dietary Ca (<400 mg/d) in calcitriol mediated
Supplement if 1 HPT deficiency may T PTH
Bisphosphonames inhibit osteoclast activity; onse: of action is 2-4 d after administration

Bisphosphonate Un in Hypercalcemla (KJ 1008;74:13B5; Na a- no ~¢~-I zuue.r4ssl

Dr ug S i de E f f e c t s Cr CI < 3 0 Cr CI > 3 0
Pami dr onate Rare collapsing FSGS 60-90 mg over 4-6 hr 90 mg over
uAsn 100I:1z:11s4l HD: 3 0 m g qd x 3 d 2 - 3 hr
Zoledronic acid Dose and i nfusi on Avoi d >60: 4 mg
superior in r ar e dependent $060: 3, 5 mg
maligvuncy ATN In 2001441141) 4049: 3. 3 mg
u an of z00l ;\ 9sss) 30-39: 3 mg
over 15 mi n
 DenosumabzantiRANKL monoclonal Ab: inhibits osteoclasts and bone resorption
s/e: prolonged . Ca: common in CKD. Low dose. eg.0.3 mg/kg w/ vitamin D may
be safe (Un lymphamu Mjduma Leuk 1014;14:1207)
Gallium nitrate L osteoclast activist:y;AKI reported. Not recommended if Cr >2.5
Cinacalce:: start at 30 mg bid. ticrate up to 90 mg bid: in 1 and 2 HPT
HDICRRT: in volume overloaded CKD or severe symptoms: low Ca bath: <25 mErelL
bash alw arrest (KA 2011;791118)
Pararhyroidectomy In 1 HPT with Ca >1.0 or more above the ULN ucem 2014:99,314»1)

HYPOCALCAEMIA
Pathogenesis and Causes of Hypocadcemia
PTHRe\ated Mechanisms
Hypoparathyroidism UCEM Neck surgery (7596). neck radiation. DiGeorge syndrome
z01s;101 ;2273JcEm z0\e10us00) CaSRacr.ivaringAb and mutation (AD). IdiopathIc
lnfikrative: Wilsons. hemochromatosis. meususis
Pseudohypoparadmymidismz T PTH (resistance), L Ca,T POW
Hungry bone syndrome (Am j Abrupt . PTH after parathyroideczomy -a T bone upuke
Medl98BlB4:b$4) of Ca. POW. and Mg, ¢ renal reabsorpnion of Ca.
iintesdnal rabsorpdon of Ca. POW
Nadir Ca typically 2-4 d posmop; 1 Ca may last mo
Hypomagnesemia PTH deficiency and receptor resistance (up 1999:101616)
CaSRRelated Mechanisms
Hypermagnesemia CaSRmediated PTH suppression
AD hypocalcemial CaSR acUvaring mutation we/m 19wazsn11sl -» . PTH
hypoparadiyroidism secretion: inhibition of ROMKINKCCZ -» typev
Bartter syndrome wl 1 K. metabolic alkalosis;4 Ca. Mg
Calcimimerics (cinaczket. TCaSR sensitivity no Ca -a ¢ PTH
etelcalcetide) Ca in 69% and 60%. respectively UAMA z0\7517:1ss)
Yitamin D Related Mechanisms
W: D deficiency . Sun exposure. diet. aging. posunenopause. malabsorpdon
CKD t FGF23 inhibits alcirriol synthesis
Nephrodc syndrome Loss of calcidiol bound to vitamin Dbinding protein
CYP inducers Phenyroin, phenohaibiial. rifampin. INH: metabolize caldiol
Other Mechanisms
Sequesrradon Pancrealitis. foscarnel. acute respiratory alkalosis
Citrate: used in blood transfusion and CRRI;a/W liver
dysfunction: . conversion (O HCOxC nl wal Ca. i ice
POW: CKD,AKI. rhabdomyolysis,TLS
Osteoblastic metastases: breast. pros re cancer
Bone resorption Bisphosphonazes. denosumab
Spurious irypocalcemia Assay interference of gadodiamidegadovenexamide

Clinical Manifestations and Workup

L BR irritability. spasms. oral/distal paresnhesia -» papilledema, seizure. remny
Chvostek sign: facial nerve rapping facial muscle contraction; low specificity
Trousseau sign: BP curl inflation 3-5 min ) carpal spasm: high specihciry ln5,lm 2011;367)
EKG: \QT length A Ca level from baseline: narrow T. heart block TdP
PTH and P04 Changes In Hyponlcemia
PTH Po. Common Causes PTH P04 Common Causes
1 1 . Mg t 1 Vi: D deficiency
1 T Hypoparathyroidism T T CKD
Pseudohypopararhyroidism

Treatment
Correc: low Mg: IV or PO Mg depending on severity. PO access
Correct high WE t CaP04 product may cause AKI; still need IV Ca if symptoms
 Correct respiratory alkalosis
Vitamin D: if deficient: 4 Ca requirement by T intestinal absorption
Ergocalciferol 50.000 IU weekly x8 wk (mu 100S;3U=129a) or active vitamin D if ESRD
In postsurgical lvypoparathyroidism. maintain Ca 8-8.5. 24hr urine Ca <300 mg Lo
prevent hypercalciuria induced nephrocalcinosis and nephrolithiasis dlt absence of
PATHmediated Ca reabsorption 1ziiaw PM 2011217 suppI1:18)

C alcium Supplementation
IV: if symptomatic. EKG A. iCe <1.0 mmoUL or total Ca <7.5
Ca gluconate 1-2 g over 10-20 min: if ice in 30 min <1.0 mmollL drip + PO calcium
J Ionized Ca. BME Mg, P04 q6h
Do NOT mix w/ HCO; or P04 to avoid insoluble Ca salts, IV Ca an worsen dioxin toxicity
Ca gluconate 1 g (1 ampule. 10%10 mL) 93 mg (4.65 mEq) elemental Ca
Sur: drip with 0.5-1 m hr of elemental Ca (5.4-10.8 mg/kglhr Ca
gluconate) and adjust to maintain zonal Ca 9. iCe 1.2 mmollL
1 mg/mL elemental Ca solution: 11 g (1.023 mg elemental Ca) + 890 mL
or 12 g ( 1.116 mg elemental Ca) 1.000 mL of NS or DSW
Ca chloride 1 g (1 ampule. 10% 10 mL) = 272 mg (13.6 mEq) elemental Ca
Use only in unstable patients: sle: infusion site reactions
PO if mild, asymptomatic: between mais if P04 is normal or low: with meals if P04 is high
s/ezconstipation.. PO (») Ca balance: kidney stone (NEW 200s;354¢669i
Ca carbonate Elemental Ca 40% by weight, give tid up to 2-4 old
Ca citrate Elemental Ca 21% by weight: avoid in CKD ( Aluminum abso son)

PHOSPHATE
PHOSPHATE REGULATION (CW of, nehru I.#memes 2013:22MB1)

Phosphorus (P): chemical element. always in combo w/ other elements

Organic phosphate (POW"): phosphoric ester; component orATE DNA. RNA: intracellular
Inorganic phosphate (Pi):fraction measured in ECF; Hpo.*/H,po. u 4:1 as pH 7.4
Typical American diet contains 1.000-1,500 mg/d; recommended minimum 700 mgjd
GI absorption: nonsaturable. constant. 60-80% of dietary load: by calcitrioldependent
type Ilb Na POW cotransporter (Npdb) + alcitriolindependent paracellular uanspon
Total body stores ~900 g: 85% in bone. 45% in soft tissues. -0.01% in ECF
ECF is reservoir for all pa exchange. tightly regulated (qAs~ 101s= \05\zs71

Serum Phosphate Regulating Mechanisms um Rn no z01317s:s3s: Aaaa zounmm

Site Increasing P04 Decreasing POA
lntesdne Calcitriol. » P04 FGF23 via lcalcitriolz nicotinamide
Bone Calcizriol, PTH
Kidney Calciuiol. J. PO., PTH. FGF23. T POW -» 1 rabsorption
Thyroid hormone, IGF1. FGF23 also lcalcitriol synthesis
Eddronate. Steroids, estrogens (KI znaann 141)
Alkalosis Acidosis (c/Asu z014m1 s27l

ACUTE PHO SFHATE NEPHRO PATHY

Acute P04 load from tumor lyses syndrome (TLS). sodium phosplure po we zuusneasaz
x0 1l](J9:76:1021) or enema we, AM 201Z;172z163) -a AKI
Kidney biopsy: CaP deposition in lobular lumen and Lobular cells with (+) von Kossa min
Prevention: avoid sodium phosphate agent in high risk paUenrs (CKD. volume depletion):
POW binder in established or high risk TLS
 HYPERPHOSPHATEMIA
Causes of Hyperphosphatemla
Nonrenal Origin (FEm, >15%) Renal Retention (FE90, <15%)
Acute load: N3P04 bowel prep ()A$n Renal dysfunction: inadequate renal excretion :
2005:16:3389). high dose fosphenytoin 2 HPT Tbone release in CKD
Transcellular shift: rhabdo,TLS. (rarely) Hypoparathyroidism
hemolysis Pseudohypoparachyroidism: PTH resistance
ECF shift: severe metabolic acidosis. Vi: D toxicity: T Ca -. PTH
hyperglycemia Familial auroral calcinosis: mutations .LFGF23
or anion. soft :issue calcified masses
Ac . ly. etidronare
Clinical Implication in CKD
Hyperphosphazemia is alw T PTH. * FGF23. i calcitriol (directly and indirecdy from
t FGF23). Tvascular injury oxidative stress and calcification
Sequence in CKD: t FGF23 -» 1 Calcitriol > T PTH -» T P04 UASN 2u 10;21\4z7)
I n H D pts, POW >5.5 a/w T mortality by 20% do 3.5-4.5 (nam 2uce;3 s9¢$a4)
In nondialysis CKD pts. Po. 3.5-4.0 a/w T mortality by 32% dt 2.5_3 (MSN 100s.16:s20i
FGF23: alw morality in HD (new/in z00s13s91se4), ESRD and mortality in CKD UAMA
2011:l05:24]2)
Clinical Manifestations and Workup
Hypocalcemia: skeletal and extraskeletal CaP precipitation
Rarely symptomatic from accompanied hypocalcemia: could be life threatening
Pseudohyperphosphatemia lab erior dlt high level of Ig, lipids. bilirubin, liposomal
a mp h o t e r i ci n B

Tre a tme n t o f Acu te H yp e rp h o sp h a te mi a

IV fluid in volume depleted AKI and nondialysisdependent CKD
HD:AKVTLS wide symptomatic hypoakenia or Ca x P04 270 mg'ldL' or advanced CKD
Tre a tme n t o f C h ro n i c H yp e rp h o sp h a te mi a
Diet restrict <1 old (MMA 2009;301:629). then use PO4 binders
Goal in CKD: 3.5-5.5 0(¢>001A!»(0200:i;42=s1>:"normal range" (xoico man KI z017.9z26)
Phosphate binders: 29941 allcause mortality 22941 CV mortality In CKD5 (al 2oIa.s4.mi
P h o sp h a t e B i n d e r s
Dr u g s Comment s
C a l c i u mb a s e d b i n d e rs Affordable; help control of metabolic atidosis and . Ca
sle: FQ and Ca x PO¢. constipation. meohdic allalods
Ca acet at e. Ca carbonat e
Ca cit rat e t GI a lu min u m a b so rp tio n (xi ivsa we a n ~ to xicity
N o n c a l c i u mb a s e d b i n d e rs 1 Mortality in CKD (RR 0.54) (qAsi4 zoieu:zazI
J Mort alit y overall (Lancet z0 u. Ja211s81
Sevelamer carbonat e (Renvela° ). l Morality. hypertalcemia. LDL dw Cobased binders
S e ve l a me r h yd r o ch l o r i d e ( Re n a g e l ° ) in 2o1zue7; up zoixszm; qAs~2016411.232)
s/e: metabolic acidosis (sevelamer hydrochloride)
Lant hanum carbonat e l Ml burden lq4wzuoe1i4m; s/ ecdiarrhea; T hone
uumcven in rars, accumulates ii the liver W zlussalwy
Ni t o t i n a mi d e THDL iqAsn 1n0e:a:11a1)
Ferric cit rat e t TsaL Hb (up 1015: 161493)
S u cr o f e r r i c o xyh yd r o xl d e 1 pill burden (nor a01s:3a10m 1 Tsar. Hb (nor zoirazmol
A l u mi n u m h yd r o xi d e Pat ent POW kiwedng eilecc slealuminum
deme\ ch. ost eomalacia; should be limit ed t o a f ew

HD: removes 800-900 mg/session: significant rebound after HD (mobilization of FO;

occurs more slowly than K, Ca. BUN); can be used in nonCKD (A/xo z01 a11z;4sn
Cinacalcei: in 2 HPT/CKD. more pus achieve <5.S lqASN z00a23.m1
i PTHmediated bone resorption. L requirement d active vitamin D may l GI ahsorpdon
Parathyroidecromyzl bone resorption: consider if refractory
Aceuzolamide in familial :unmoral calcinosis: T renal excretion of PO 4
 HYPOPHOSPHATE IA (Am .I Med 1006:1181W4)

Causes of Hypophosphatemla
Nonrenal Origin
FEI0, <5%. 24hr urine POW <100 mg
Transcellular shifts: insulin. glucose. refeeding
syndrome, hungry bone. respiratory
alkalosis (head injury)
l Absorption: GI resections. diarrhea, POW
binders. aluminum. Mg
CRRT. immediately after HD
Renal Wasting
Firm, >5%, 24hr urine POW >100 mg
Fanconi syndrome
1 or 2 HPTlVi: D deficiency
t FGF23: genetic hypophosphamemic
rickets. oncogene osteomalacia
Hepazectomy (jA$N l0\4:1S:761)
Chronic alcohol use 1~£1m 1011:37l:1368)

Vtamin D deNciencyz L intestine absorption and T renal wasting l Ca -» 2 HPT -» T Ffvo.

Nutritional phosphate deficiency: low FEpo, low/normal PTH. calcitriol
Fanconi syndrome: PCT damage-» renal wasting of gk. UA.AA. POW; from light chain
(LCPT). heavy metals. NRTls. tenofovir. ifosfamide. cystinosis.Wilson disease
Genetic hypophosphatemic rickets: xlinked (PHD().AD (FGF23).AR (DMP1, ENPP1)
I Oncogenic Osteomalacia (Tumorinduced Osteomalacia)
Mesenchymal tumor secreting FGF23: rarely osteosancuma. SCLC, colon a umm zouwiaaan
Labs: Ffvo.. T FGF23, J, or inappropriately nl caidtriol.nl or t (by calcitriol) PTH. nl Ca.T AA
Imaging: skeletal survey (fractures. osteomalacia). "GoDOTATATE PEI/CT
Manifestations: weakness,bone pain. recurrent fractures.Tx: tumor resection
Clin ica l Ma n if e st a t io n s
Symptomatic if <1: myopathyz seizure, confusion. 1 myocardial contractility (NEW 1977297901)
; diaphragmatic contractility (NEar 1985;313:420). rhabdomyolysis
Treat ment
Correct any existing vitamin D deficiency: T intestinal absorption. 1 renal wasting
PO if asymptomatic: 1-1.3 mmollkgld divided >d:an add skim milk (15 mind POJ48) mL)
PhosnaK powder: 250 mg elemental P (8 mmol). Na 6.9 mEq. K 7.1 mEq/packet
PhosNaK tablec 250 mg elemental P (B mmol), Na 13 mEq, K 1.1 mEq/tablet
IV if symptomatic Na or KP043 max B0 mmol within 12 hr
. if P04 <1.5,0.64-1 mmol/kg: if POW 1.6-21.0.32-0.64 mmollkg
s/e: precipitation of Ca x PO¢ can muse hypocalcemia w/ tetany
Dip yrid a mo le : l re n a l re a b so rp t io n

MAGNESIUM
MAGNESIUM REGULATION (KI 1997;51:11B0: in 19941417371

Inuke ~350 mg/dzabsorption in small bowel via sarurable TRPM6, passive diffusion
Total body stores: 26 g: 60% in bone. 4D% in soft tissues, <1% in ECF
70% of :oral plasma Mg is not proteinboundzfikered in kidney:95% reabsorbed
Renal Magnesium Reabsorptlon lqAsn 201s:1a17.sn
PCT (20-30%) Passive
TA L (5070%) Paracellular via claudin16I19.dniven by (») lumen from ROMK/NKCC2.
Inhibited by basolateral CaSR via claudin14 UAS~ z01s26;111.
DCT (5-10%) Apical TRPH6: mediated by epidermal growth factor receptor (EGFR)

HYPERMAGNESEMIA
 Clinical Manifestation
Symptomatic if >5. progressive neurologic silencing effect; loss of DTR. nausea. lethargy.
confusion, paralysis;AV block, arrest
1 Co by CaSRmediated suppression of PTH
Treatment
d/c administration: if J, renal function IV fluid and/or loop diuretic; HD if severe
If symp\:omaxic.Ca gluconate IV 2 g over 10-20 min to stabilize membrane: dialysis

HYPOMAGNESEMIW

Causes of Hypomagnesemia
Nonrenal Origin Renal Wasting
re <2%. 24hr urine <10 mg/d FE >2%. 24hr urine >10-30 mud
. GI absorption: PPI luqm zaus;ass¢1a34). Metabolic acidosis: lilzerable Mg
pauromen large bowel resecuon. Loop and zhiazide diuretics, Bartxer. Gitelman
chronic diarrhea PostATN. poszobsrrucnion. uncontrolled DM
t Bone uptake: hungry bone Cisplatin. amphotericin. foscarnet
Alcohol. poor nutrition Basolaleral CaSR activation: Ca, aminoglycosides
Complexalion: pancreaxids. transfusion (polycadon) - inhibits ROMK and claudin
lnuacellular shift: insulin, refeeding 16/19 . Mg, Ca reabsorpzion
ibiauiniinpa I9S&29;644): Bagonist. acute Familial hypomagnesemia w/ hypercakiuria and
alkalosis. severe burns nephnocalcinosis:AR claudin19 muzanion
. TRPM6: m (1Asr42004;lS:$49). CsA. EGFR Abs
cetuximab, panitumurnab. maruzumab.AR
muzadon we Genes 200L31=1711
Chronic alcohol abuse: poor nutrition 4 renal tubular wasting (N5IM 1993:329:19271
If unclear w/ history J FEw I [(UH¢ x P<;,)/(0.7 x P) x Up.] x 100%
Clinical Manifestation
Terany and seizure (similar [0 i Ca). nysugmus. apathy, depression, azhetosis
QRS widening. peakedT waves. prolonged PR (similar to T K). :orsade de pointes
. K: t ROMKmediated K secretion in DCT from 1 nuacellular Mg (;ASN 1007;I&2s49)
1 Ca: PTH deficiency and resistance
t NODAT UAS~ 2016;27:1793). t rnorraliry in HD we 2ois:ss:1047l

Treatment
PO if asymptomatic use sustainedrelease or small frequent doses to T absorption
Elemental Mg content: oxide (60%6 > OH (41%) > SON (10%) > gluconate (5%): least
diarrhea:
sle: diarrhea. GI discomfort. Mg: Half dose for eGFR <30
N if symptomatic or <1 mg/dl; 2 g MgSO4 (192 mg, 16 mEq elemental Mg) over 15 min:
in symptoms persist infuse up to 8 g over 24 hr; monitor telemetry DTRs
For patients with arrhythmias (esp. ventricular). maintain Mg >2 mg/dL
Amiloride. triamterene, and spironolactone: for renal wasting or medical conditions
requiring diuresis despite hypomagnesemia
 ACUTE TUBULAR NECROSIS (ATN)
Background
ATN and prerenal azotemia are the leading causes of acute kidney injury (AKi)
• ATN causes 38% ofAKl in hospitalized pts. 76% of AKI in ICU (Ann IM 2007137:744)
Causes
Main causes of ATN: ischemia.sepsis,and nephrotoxins
Ischemia includes any cause of renal hypoperfusion and prolonged prerenal state
Hemorrhagic, cardiogenic. hypovolemic. anaphylactic shock
Renal artery occlusion (eg, embolic. renal artery dissection)
Surgery (especially cardiac. intraabdominal)
Nephrotoxins: numerous medicaUons. iodinated contrast media. pigment (hemoglobin
myoglobin from hemolysis/rhabdomyolysis), ethylene glycol. synthetic cannabindds
Less frequent causes: nephrotic syndrome (especially MCD), hyperbilirubinemia.
hypercaltemia
Pathogenesis of Ischemic ATN (man R n¢w/vi 2011.71B9l
Decreased effective arterial volume in prerenal azotemla leads to activation of neuro
hormonal cascade including l sympathetics. RAAS. and vasopressin
t Angiotensin II during hypovolemia leads to preferential efferent arteriolar vasocon
striction. which attempts to preserve GFR despite J, renal blood flow. eventually
afferent arteriole vasoconstricts and overall renal blood flow and GFR drop
To prevent excessive vasoconstriction. kidney produces vasodilatory NO and prosta
glandins. but this counterregulatory system has its limits
Ischemia -o tubular cell apoptosis/necrosis. esp in PT blc high metabolic demands
and susceptible micracirculadon: leakage/dysfunction of PT cells - t afferent arteriole
vasoconstriction. inflammation. endothelial damage
ischemia also injures endothelium causing deranged coagulation and permeability -»
ischemic microcirculal.ion.extending AKI damage
ATN may cause dysfunction in other organsaanimal models show increase in pulmo
nary vascular permeability and cardiac inflammation
Pathogenesis of Septic ATN (cin of on Cave 101412ssa1
Occurs even in setting of preserved or increased renal blood flow
Sepsis triggers dysfunction in renal microcirculation involving endothelium. vascular
tone, abnormal coagulation. oxidative stress, and inflammation
Clinical Manifestations and Workup
As wide other causes of AKI. praents widl rising creatinine +J- diguria (see AKl definition)
Nonoliguric ATN with better prognosis than oliguric
FEn. >1%. FEw., >3$%. Urine sodium >20-40. BUN:Cr ratio <20:1
FEn. can be <1% ifATN occurs in cirrhosis or CHF
. Urinalysis: usually acellular with <1 g proteinuria. sediment can have muddy brown"
casts and renal tubular epithelial casts
Kidney Bx: PT slmplificationlflattening. loss d PAS+ brush border. vacuolization
Management
Correct ischemia and sepsis: discontinue nephrotoxins

ATN FOLLOWING CARDIAC SURGERY

18% incidence of AKI. 2-6% requiring HD (qAsn 2o1s ;111s001
Similar pathogenesis as for odier ischemic ATN:alsc mechanical trauma. embolizacion
Risk factors: usual ATN risk factors: also: multiple cardiac surgeries in one operation.
prolonged bypass time cardiogenic shock (qAs~ zoisnosooi
Off pump surgery did not improve rates of AKI requiring dialysis lngpvi 2013;368:1179)
Cleveland score may predict need for RRT after cardiac surgery 1;As~ 2005;16:161)
5 points for preop Cr > = 2.1; 2 points for preop Cr 1.2-2.09
2 points for preop balloon pump, emergency surgery, CABG +valve
1 point for female, CHF, EF <35%. COPD. IDDM, prior cardiac surgery
1 point for valve only surgery. 2 points if other cardiac surgery
Risk ofAKl requiring RRT: (0-2 ps 0.4%: 3-S pts 1.8%:6-8 pts 7.8%: 9-13 pos 21.5%)
 PIGMENT NEPHROPATHY

RHABDOMYOLYSIS
Causes lnqm 1c09:361;62) and Pathogenesis (NEW 2609961162: re 1996;49:314)
Category Examples
Trauma Crush injuries. exercise. seizures. elecutucution. thermal (hypothermia.
hyperthermia. NMS). limb compression from LOC. compartment
syndrome. iaimgenic occlusion in OR. thrombosis. embolism
Infections Bacterial (Strep. Staph. Clostridium. Legionella.Tularemia).
Viral (Influenza A & B, EBb HIV. Coxsackie). Malaria
Electrolyte t [Na], 1 [Na],l [K].l [Ca].l [Pow]. lfyperosmolar states
Endocrine Hyperaldosteronism. hypothyroidism. ketoatidosis
Drugs and Toxins Stalins. librates. antipsychotics. antidepressants. antihistamines
Recreational: alcohol. heroin. cocaine. amphemmines. LSD. toluene
Environmental: he/y metals. insect venom. snake venom. CO
Genetic and Disorders of: glycolysis.glycogenoiysis. lipid metabolism. mitochondria.
Meiabdic pentose phosphate pathway. purine nucleotide cycle
Autoimmune Polymyositis. dermatomyositis

imbalance of cellular ATP causes K/NaATPase and CaATPase dysfunction -» t [Calm

Myocyte breakdown releases Myoglobin.CPK. K. POW. purines
Massive fluid sequestration in damaged muscles. CaP precipitation and deposition
Myoglobin is rapidly filtered (MW 17.8 kDa and not protein bound)
Endocytosed by PCT and causes cytotoxicity via hyargxyi radical
Piedpitates w/Tamm-Horsfall protein (promoted by acidic urine) forming obstnxdvie ass
Vasoconstriction from sequsuadon -> RAAS acdvanion and local inflammatory mediators
Clinical Manifestations and Diagnosis
May be asymptomatic, Myalgias. red or brown urine. +I- oligoanuria
Labs: U/A widi +Heme but no RBCs (Sens,809lS), +I- pigmented granular asts.+l- AKl
(FENa often <1%). T CPK (mostly MM isoform. >$-10K to cause AKl.rises within 12 hr
of injury and Tm of 1.5 d). T uric acid, T AST/ALT. T LDH. T [K]. t [p]. 1 [Ca]. lacer can see
T [Ca] (leaches from muscle). Do not / serum or urinary myoglobin (insensitive).
Treatment of Pigment Nephropathy (Intensive Care Med 20011z7803; new 1009;361:62)
Address the underlying cause of rhabdomyolysis and hemolysis
Aggressive IVF: (1) volume resuscitate in rhabdomyolysis d/t sequestration (1-2 Uhr
initially); (2) T urinary tubular flow rate to prevent pigment asts (target UOP >300 mUhr).
Continue until CPK <5K or hemolysis improved & able to take PO.
Consider urinary alkadinization (pH >6.5) but no clear benefit. Monitor ice and pH
If oliguric or volume overload. loop diuretics. No clear benefit from mannitol,and
potential for harm (if used. restrict <200 old and OG <55).
Medically manage electrolyte complications: avoid repleting Ca unless severe
or symptomatic.Allopurinol if uric acid >8 mg/dL
HD or CRRT 9nj! for renal failure indications. No role for pievenzive myoglobin
clearance wid\ CWHDF An¢A»¢¢uieiaI swi41005;49:a59) or plasmapheresis
Risks of poorer prognosis (AKI. need for RRI mortality) include age >50. female. Cr
 CRYSTAL NEPHROPATHY
Crystal nephropathy: acute or chronic kidney injury caused by crystal precipitation;
Uric acid nephropathy is Mc
Nephrocalclnosisz generalized calcium deposition In the kidney parenchyma and tubules
Nephrolithiasis/Urolithiasiss condition a/w renal intratubularlurinary stones.formed
from crystals precipitating from the urine
Pathogenesis
Crysnllizadon is determined by supersaturation (SS) of consdluent molecules
SS: depends on the product of the free ion activities d components. promo.er. inhibitor
(citrate, Mg. pyrophosphate). and urine pH
Urine pH Favoring CrystaII$tone Formation
Acidic Urine Uric acid, cysteine, MTX. rriamrerene. sulfadiazine, djenkolic acid
Alkalinizadon (citrate. HCO:) might be prevenzive and rherapeuzic
Alkaline Urine CaP, indinavir. auunavir. Ciprofloxacin
pH if de ndent CaOx

AKI. hemamria. auria. renal colic (Hank pain, NN), precipitation an cause morbid urine

OXALATE NEPHROPATHY
Source of oxalate: dietary (30-6096). liver; Excretion: >90% into the urine. 10-40 mg/d
Intestinal Oxafobacter formigenes breaks down oxalate
Intestinal oxalate secretion via SLC26A6 and CFTR uA=~2017;242421
Obesity associated inflammation L intestinal secretion (xv z01s.93:109s)
Kidney bx; CaOx deposits wl birefringence under polarized Iighc interstitial inflammation
Primary Hyperoxaluria
t oxalate production of liver caused by mutations of genes encoding hepatic alanine
glyoxylate aminotransferase (AGT. type 1). glyoxylate reductaselhydroxypymvate
reductase (type 2). 4hydroxy2oxoglutarate aldolase (type 3)
Severe hyperoxaluria (usually >80 mg/d)
Manifest during childhood or adolescence; ESRD at median 33 y/o Iam/n¢pnw11005251901
Systems deposition -» flecked retina. a mm.mMiomoww. ardiropadiy. fracture
Tx: pyridoxine (vit Ba: cofactor ofAGT) and P04 is;/n 1994;331=1ssJ).combin¢d liver
and kidney txp in type 1:very high recurrence rate wlo liver up
Enteric Hyperoxaluria
Causes: pancreatic insufficiency, CE IBD (CD > UC). small bowel resection, ieiunoileal
or gastric bypass. orlisnt (lipase inhibitor) lAM :m 2011:171:703)
Mechanism:
1. Fat malabsorption -» Ca binds to fatty acids -» 1 free Ca - T free oxalate -» T
oxalate absorption -r T CaOx crystal formation in kidney
2. Diarrhea -» metabolic acidosis -» hypocitraturia -o T CaOx crystal formation
Impairment of SLC26A6mediated intestinal secretion may contribute WK0 2011;W.s621
Mean urine oxalate 85.4 mild; >50% require RRT up up 7.018:3:136J)
T>c lowoxalate diet, T fluid image. K citrate for metabolic acidosis or hypocitramria, PO
Ca: reversal of gastric bypass may impnwe renal function (cum Nap rupnu M 1016:61114)
Oxalate Loading
Causes: ethylene glycol.Vi: C (in) nww201II20I 1:146927l, Iaxadve conralnlng ascorbic
acid In 20\7;9l:9B9), methoxyflurane, rhubarb leaves. sur fruit (ummbola). nuts. cocoa.
parsley. potato, spinach (KI z01629¢x711). beetroot, almond. chocolate. yellow dock. sorrel.
cranberry concentrate rablecs (u,wwf 200l;57:26]
Tac d/c oxalate: HD for ethylene glycol. large amount of ascorbic acid (lnuaullau 2016:44za9)

ACUTE PHOSPHATE NEPHROPATHY

Causes: hyperphosphaturia/hyperphosphatemia from sodium phosphate PO (Hum 11d1u1
20o4;3s;s1s).TLS. enema alw 1 eGFR (Ajxo zo 1s;s7<sor»
CaxP >60 mg'/dL* T risk of precipitation in :he renal tubule
Kidney bx: inrraluminal tubular and tubular intracellular CaP deposition
Tx: dlc offending drug. IVE avoid urine alkalinizacionz RRT if CaxP 270 mg'/dL2

CALCIUM PHOSPHATE STONE AND NEPHROCALCINOSIS

Aparke (crystal) >brushize (calcium hydrogen phosphate CaHPO4 2HzO)
Causes of Calcium Phosphate Crystals we z01s;71(4)A12)
Hypercalciuria M hypercalcemia Hypercalciuria y/9 hypercalcemia
Syszemic excess 2 renal handling Dysregularion of renal handling of calcium
1 HPI sarcoidosis.viomin D overdose. dRTA. medullar sponge kidney. Den: disease.
Milkalkali syndrome Bauer syndrome. chronic hypokalemia
Primary Hyperparathyroidism (1 HPT)
24% of hypercalcemia on thiazide has 1 HPT (}COM 2016; 101: 11ss)
If normal serum Ca. hypercalciuria and high PTH. J thiazide challenge (HCTZ 25 mg
p o b id x 2 wk); P TH re ma in in g h ig h ma y su g g e st 1 HPT U uawra 1009: 23: 191)
Dist a l RTA (d RTA )
Causes: CAI (acetazolamide. topiramate.zonisamide).Sj6gren syndrome
. Pazhcgweis: (1) Chronic metabolic acidosis - t Ca. P release from bone: (2) intracellular
acidosis -> t miiiochondrial citrine uptake -> t duate realzeorpdon in FCT i u r i n a r y ci u a u e
Ma n ife sta tio n : Ca P sto n e /n e p h ro ca lcin o sis. o ste o ma la cia
Hypol<alemic NAGMA. severe hypocitraturia. (+) urine AG.constant urine pH >5.8
Incomplete dRTM w/o systemic NAGMA;could be difficult to diagnose
K >3.8 + second morning fasting urinary pH <5.3 excludes dRTA (cusp 2017:12:1 son
Urinary addificadon :ec NH¢CI 100 mg/kg xi or PO funosemide 40 mg f lludmcordsone
1 mg (xl2007:71:1 :1ol and ./ urine pH hourly x s hi:failure to 1 urine pH <5.3 is diagnostic
Me d u lla ry S p o n g e K id n e y
Congenital malformation of pericalyceal terminal collecting duct
Asymptomatic. dRTA, CaP 2 mixed CaOx stone and nephrocalcinosis. UTI. rare ESRD
IVP: paintbrush appearance: CT: calcium stones at calyceal area
Tx K citrate to v urine citrate >450 mg/d provided urine pH <7.5 l stone despite
p H T f r o m 6 . 4 - 6 . 9 (qAsn z010.s:1663>

Diagnosis
Swne analysis: kidney bx: tubular, imersnizial. and inuacellular basophilic calcifucarion

Characterization of Crystals
Blrefringence Under
Crystals von Kossa Stain Polarized Light
CaP +
CaOx, 2,Bdihydroxyadenine +

Treatment
Correct risk factors: low urine vol, hypercalciuria. hypocitraturia. hyperphosphaturia
Correct dRTA w/ K citrate: i Ca. P release from bone. 1 urine Ca, R T urine citrate
t Urine pH w/ citrate may augment CaP crystal formation
Parathyroidectomy in 1 HPT with nephrvalithiasis/nephrocalcinosis. CrCI <60 or 24hr
urine Ca >400 mg with increased stone risk ljcm 1014299135611

URATE STONE AND NEPHROPATHY

Pathogenesis and Causes
pH decides :he form: insoluble uric acid in low pH: soluble urare in high pH
U r l n e pH is more imponan: than hyperuricosuria
 Tumor lysine syndrome in hematologic malignancy > solid tumor. seizure
Exerciseinduced AKI in familial renal hypouricemia (URAT 1 mutation 1 uric acid
reabsorption)
Clinical Manifestation
Usually asymptomatic AKI. random urine uric acidlcr >1 mg/mg; radiolucent stone
Preven t io n an d T reat m en t
Acute management; volume repletion, rasburicase for high risk for TLS
Chronic management: urine alkalinization with K citrate with goal pH 6.5 or above, L
animal protein and sak intake

CYSTINURIA
AR mutation of SLC3A1, SLC7A9encoding PT apical amino acid uansporten rBAT
s Cystinosis causing Fanconi syndrome and :ubuiar proteinuria
1st stone 24 y/o. 21% alter 40 ylo; 20% staghorn: CKD (70%), ESRD (9%) (qAsn zo1s:1 &12zs1
Cystinuria may be a/w Ca calculi UASN 2015:16§543); may present w/ sraghorn calculi
Dx: family history: stone analysis. hexagonal crystals on urine sediment
Cyanidenitroprusside test screening: purple color suggest cystine >75 mg/L
J urine cysteine level for diagnosis (>400 mg/d) and estimation of required fluid Intake
Bx: rarely done; imratubular cystine crystals (KJ 200s;691127)
Tx: T fluid intake to keep urine cystine <1 mmol/L (243 mg/L). urine alkalinization >7.5,
low protein. sodium diet.Tiopronin (2mercaptopropionylglycine). Dpenicillamine (can
cause MN.crescentic GN)

AdENINe PHOSPHORIBOSYLTRANSFERASE (APRT) DEFICIENCY

AR mutation ofARRT. purine metabolism enzyme -o T insoluble 2.8dihydroxyadenine
(DHA) crystals in urine -» CKD. radiolucent stone (can be misdiagnosed as uric acid)
Urine crystals with Maltese crosslike pattern under polarized microscopy
Kidney Bx: tubular interstitial deposits with strong birefringence (an be misdiagnosed
as oxalate) (NDT z01txzs=19o9)
Tx: allopurinol 1 eGFR decline aim 2016:67;4J1l. low purine diet high fluid intake
Txp: recurrence is commomfrequently diagnosed by graft biopsy

DRUG Po m1in G CRYST AL S AND ST O NES

Common risk factors: volumed depletion. high dose use. reduced kidney function
Clinical manifesto:ion:AKI with resolution of dlc of dr; frequency radiolucent
Drugs Forming Crystals
Antivirals
Acyclovir a/w high dose IV. volume deplecionaganciclevir has lower risk
Atazanavir In alkaline urine. Cryscalluria. Stone IA/xo zm 7;10.s7s1
Fosarnet AKI. crystal nephroparhies who Z015;6S:1$21
lndinavir In alkaline urine. 8% developed urologic symptoms: renal coli:
flank pain dysunia placelike rectangles and fanshaped or
scarburs: forms lAM :m 19w=1271119)
Antibaderlals
CiproNoxacin In alkaline urine.
Sulfonamides In acidic urine. esp. sulfadiazine
Other Drugs
Sulfasalazlne Andinflammatory agric used in RA and IBD an form crystals and
stones (A/KD 10 I7;70M9)
Triamterene
Mechotrexaw (MTX) In acidic urine. MTX precipice in the cubules (NEW 10\5d73:15911
Ephedrine Ma huang containing ephedrine W*D 1994311531
Pseudoephedrine Urolirhiasis (nm 1004.1%26!1
Dienkol Bean Meal in Southeast Asia: dienkolic acid forms needlelike crystal in
acidic urine;AKL needlelike crysuls
Mg crislllace Silicate urolidliasis u up: weusuzsl

Tx: d/c offending drug.volume repletion 1 loop diuretics. urine alkalinizadon with goal
pH 7 in sulfadiazine, MTX. Urine acidification is no: recommended
 URINARY STONE DISEASE

Conditions Associated with Urinary Stone

1 HPT CaOx > CaP (W mi 1009;1031e701; consider parathyroideaomy
Sarcoidosis CaOx > CaP
dRTA CaP. nephrocalcinosis common
CF CaOx; microscopic nephrocalcinosis 92% (NUM 19sa;J 1nsJ)
ADPKD Uric acid > CaOx we 1993:27;$13)
Dem disease CaP
Horseshoe kidneys CaOx
Metabolic syndrome Uric acid > CaOx

Clinical Manifestations
Acute. colicky Hank pain radiating to d 1e groin: CVA tenderness may be present
Hemaruria (9096): absence does no: rlo: Presence w/ flank pain is not dhgnosdc of stone I
26% of pos has persiszenr urereral stone after cessation of pain (I um:201B;19911011)
\ workup
rlo medicationinduced stone: triamterene. indinavir. atazanavir. sulfonamides, CAI
(topiramate). cipro. Mg Trisilicate antacids abuse, guaifenesin. and ephedrine
CT: preferred if urological intervention is planned: low dose CT may miss small stone
Dual energy multidetector CT may characterize stone composition (Rmnaiqy 2010.1$7394)
U/S: low sensitivity, no difference in important missed Dx dw CT (Nt/M 2014:37111100)
MRI if pregnant; KUB for flu: IVP: less sensitivity/speciNcity
S tra in u rin e to typ e sto n e . u rin e cu ltu re
24hr urine at home before dietary modification and after

Frecipitating Factors of Crystals and Stones -

Type Related Condition
A n y t yp e AKI. CKD

1 HPT.Vil D excess.
sarcoidosis.dRTA.
hyperdvyroidism.cancer.
Dem disease t Na.
animal protein intake
Hyperoxaluria CaOx Ox intake. i Ca intake
f
(<40 mild) 1 hyperoxaluria
Pyridoxine (vit B6) del.
Small bowl disease or
surgery
Hyperuricosuria CaOx. Uric T Purine intake. cell lysine.
(6 <0.B acid uricosuric aden:
9 <0.75 old) (probenecid. fenoNbrare.
losartan)
Hypocizraruria C a O x CaP T Nondairy animal protein, ; Nondairy animal protein/
(6 >450 mg/d Na intake. dRTA, hypoK. Na intake. Citrate.
9 >550 M8/4) UTI . bowel disease. watching SS CaP and pH
CKD (caution urine pH >6,5)
Hypercysdnuria Cysteine Genetic mutation Tiopmnin. Penitillamlne
Urea splicing Mg ammonium UTI (Proteus. Pseudomonas, Treat UTI
bacteria phosphate Klebsiella)
 High sodium CaOx, CaP High sodium die: l Sodium intake
(<100 m a)
Acidic urine Urlc acid. High protein die: Alkaliniudon (citrate.
(>6.5) Cysteine. bicarb)
MTX. 1 Prouin imzke
Sulfadiazine,
Triamrerene
Basic urine CaE Xamhine dRTA. CAI. urea splicing Antibiotic in urea splitting
organism (>8) organism UTI

MANAG E ME NT

Acute Management
IVF:T UOP; no A pain. rate of passage (1 emu¢uI 2006;20.71J1
Analgesics: ketorolac > meperidine (A~» HUH: m¢4 1996;2£:151)
Passage of stone: small and distal stone
u blockers: T passage of ureteric stones 25 mm (BMI 2016:355i6112); no difference in
small stone with mean diameter of 3.8 mm kw :m 20I 8;I78:I051)
Nifedipine: T passage of urezeric stones (Ann EmerlMe6 zoonsasszl
Urologic intervention: >10 mm. infectiomobstruction >4 d.uncontrolled pain
Exuacorporeal shock wave lithotripsy (proximaI.<2 cm). ureteroscopic removal.
"T percutaneous nephrolithotomy. open surgery
m
'i Longterm Management
2
vs PO fluid >2-2.5 Ud uvwi 199s=1s5=6391
Low Na diet; high Na -o hypercalciuriaz monitor w/ 24 hr
High K diet: Y urine citrate. pH.volume. i ss CaOx and ss Uric acid <oAs~ z01&11:1 n4l
Low protein diet: monitor urine sulfate. PCR
Sulfur containing animal protein -» T urine acid loading -» 1 urine citrate
Dairy protein is beneficial T urine citrate. 1 oxalate lcpsu 2016;111a341
Low ox diet avoid nuns. chocolate, dark green leafy vegetables. rhubarb. okra. beers
High Cz dies: low calcium - T oxalate absorption U um 1012;187116451
Avoid excessive vitamin D: high 1.25(OH);D is alw stone (qAsn 201s;1cr"7l
Diuretics with hypocalciuric effectszthiazide. amiloride
Citrate Supplementations
Used for inhibition of calcium stone formation and urine alkalinization ii uric acid stone
Plasma alkalinization T renal Ca reabsorption
L stone size. L new stone (Cuchmne Dalahdse So: no 20I 5;CD010057)
K citrate: start 30 (urine citrate >150 mold) - 60 (urine citrate <150 mold) mE/d
Compliance can be monitored with 24hr urine K amount (should be > dean prescribed
amount; should 1 ammonia)
It is normal to see K citrate tablet remnant in the stool
Side effect; metabolic alkalosis (keep urine pH <7.5 In Ca? sine),t K. NNID

Citrate and Bicarbonate Regimens

Lemon juice
K citrate :ab (UrocirK°)
K au-arecitric acid powder
(CPU°K°)
K citratecirric acid (CyvnK¢.
VirtrateK°)
Na dzratecitric acid (BIcil.ra°.
cm 2" l
Na citrateK citrateCitric acid
(Virtrare3°. Cyzra3°')
K bicarbonate:F(§)f1erK°.
KlorCon/E
120 mL (4 oz) contains 5.9 g (-90 mEq) citric acid:
urine citric acid by 142 mg/d u um: iwuisuon
5 mEq (540 mg). 10 mEq (1,080 mg)
1 packec K curare monohydrate 3.300 mg, citric acid
monohydrate 1,002 mg = K 30 mEq. barb 30 mEq
Solution: 1.100-334 my5 mL = K 10 mEq. bicarb
10 mEq
Solution:500-334 mg/5 mL = Na 5 mEq.bicalb 5 mEq
Solution:500-550-334 mgl5 mL = Na 5 mEq,K5 mEq.
bicarb 2 mE
1g = 10 mEq:2.Sg= 25 mEq
 INTERSTITIAL DISEASES
ACUTE INTERSTITIAL Nap:mms (AIN)
Interstitial nephritis may be acute, subacute. or chronic. Characterized by renal
function and an inflammatory infiltrate limited to the tubulointerstitial compartment.
AIN accounts for 12.9% of AKI: prevalence is increasing for 2013:18:112)
Causes of AIr who 2014;64.558. al 2010;77.956)
Drugs ( 70%): antibiotics (3576. PCN. FQ. cephalosporlns. sulfonamides, vancomycin),
PPI (10%), unSAIDs (7%). 5aminosalicylatesa checkpoint inhibitors (KJ 2016;90:638). thiazide,
allopurinol. Iamotrigine
Autoimmune (-2094): sarcoidosis. Sj6grens.TlNU. lgG4nelated disease. ANCAvasculitis.
MCTD. Sweet syndrome
Others (10%): infection et, E cd!i.TB, leprosy. histoplasma, Candida. Cryptococcus
(Ki 2009;761453). BK virus. Hantavirus; CLL mantle cell lymphoma. idiopathic
In 65 Mylo drug (87%) especially PPI (18%) and antibiotic are more common (KI z01 s8714ss1
Antibrush border antibody disease: immune complex TIN d/t andbrush border antibody
UASN 20\6:27380) against UASN 20lB:29:644)
Clinical Manifestations
Druginduced AIN may show triad (fever. eoslnophilia. and rash) in 10% (nor 2004119.81
Usually asymptomatic; NN malaise. arthritis
Oliguric or nonoliguric, gross hemawria (596), Dialysis requirement (40%) (KI 101W79956)
Laboratory Manifestations
Azotemia. pRTA. eosinophilia
Urine:WBC 1 WBC casts. eosinophilurla. occasionally bland sediment; microhematu
ria common: RBC casts not typically seen. High FENa. lsosthenuria (SG 1.008-1.012).
Tubular proteinuria. Nephroticrange proteinuria in NSAID induced MCD or MN
Serology:ANA, antiDSDNA. antiRo/SSA. antiLa/SSb. C3. C4,ANCA. lgG4. Other
systemic disease based on clinical manifestations (eg, chest imaging for TB. sarcoid)
T IgG4 levels. lm/pocomplementemia in lgG4RD; Renal and abdominal masses may be seen
Diagnosis
Kidney biopsy is diagnostic: interstitial edema. infiltrate ofT lymphocytes and monos/:es
> eosinophils. plasma cells and neutrophils. tubulitis: Interstitial fibrosis can be seen
wu 7-10 d after inflammation initiation (xi z010n7956i
IF: occasionally linear or granular tubular basement membrane (TBM) staining

Pathologic Clues in Tubulointerstidal Nephritis

Plasma cell rich infiltrate IgG4RD. Sj6grens. SLE, chronic pyelonephritis. HN BK virus,
chronic Tcell-mediated rejection
Nonnecrozing Drugs: unSAIDs. anzibiozics. thiazide. Iamorrigine. inzravesical
granuloma BCG for 1N0s;2\.14z7l. adalimumab we 2010;S6:e17)
Sarcoidosis,ANCA GPA, Crohn disease.TlNU. infections
Necrotizing granuloma TB we zooe:s 1:sz4). fungal infections
Linear TBM IgG staining AntiGBM disease and MIDD: wl GBM linear staining
unSAIDs. allopurinol. phenytoin, mechicillin
Granular or semilinear IgG4RD. MN. cryogiobulinemic GN. Hantavirus. autoimmune
TBM IgG staining (SLE.Si6gren). anribrush border antibody disease. Idiopathic
hypocomplemenzemicTIN WKD 200113723a8)

Gallium67 scan: Gallium binds [O Iacroferrin on WBC: not sensidvelspecillc

Treatment
d/c of inciting drug;TreaLment of underlying infection eg.T8. fungus
Glucocordcoidsz prednisone 1 mg/kg daily or 2 mg/kg god for 3-12 wk: long duration
is not alw improved outcome (cyAn Z01B; 13:1851). Poor response with co delay. severe
tubular auophylinnerscirial fibrosis and small kidneys (A/KD 2014.s¢25581.
MMF: - Cr in steroid imolerantlrelapsing cases LC/ASN 1006:1:71B)
Prognosis
Most recover after dl: d causative drug: median recovery time 3 wk in iluoroquinolone
associated AIN (map cu, Pix 201891151
Poor prognostic factors: higher degree of interstitial fibrosis/tubular atrophy. small
kidneys. longer duration of drug exposure. longer time from AKI onset or bx to
steroid treatment We 2014;s4s5sl.The majority of patients do no reach ESRD.
 Early steroid zreacmen: may improve recovery in druginduced AIN. Chronic dialysis
in 44.4 (wl steroid) vs 3.8% (w/o spheroid) (Kl1008:7J=940)

TINU SYNDRONE
Subset of patients with tubulointerstitial nephritis have uveitis (TINU)
HLADQA1*01, HLADQB1*05,and HLADQB1*01 may be associated
Monomeric CRP may be pathologically implicated
Clinical and Laboratory Features
Median onset 15 yr (9-74); female preponderance (Sury Opiiwimii 2001:4e19s)
Systemic symptoms: fever, wt loss. fatigue may be present
Uveitis: typically bilateral (unilateral or alternating may occur).Timing2 mo before,
concurrently,and up to 14 mo after TIN. Slit lamp examination to contirrn diagnosis.
TlN: usually AlN. Signs of proximal tubular dysfunction may be seen. On renal biopsy
nonspecific interstitial infiltrate. sometimes granulomas present
Treatment
Renal disease is though: to be selfIimized We 1999;34¢101s)
For progressive renal disease. prednisone 1 mg/kg/d (4060 mg) for 3-6 mo followed
by a taper (based on response). Limited experience with steroidsparing agents.

CHRO NIC TUBULO INTERSTITIAL DISEASE

Chronic tubulointerstitial injury can cause interstitial fibrosis. tubular atrophy (IFITA).
and macrophage and lymphocytic infiltration
I: can happen from primary tubulointerstitial injury or secondary to glomerular injury
The degree of IFITA predicts renal prognosis in all type of renal injury
Causes
Drugs: lithium. Cyclosporine, tacrolimus. cisplatin. indinavir (crystal nephropathy)
Toxins: aristolochic acid, heavy metals (lead, cadmium. arsenic, mercury. gold. uranium)
Analgesic nephropathy. radiation. obstruction
Chronic pyelonephritis.xanthogranulomatous pyelonephritis. malakoplakia
Vascular ischemia, renovascular disease
Metabolic hyperuricemia. hypokalemia. hypercalcemia. hyperoxaluria. nephrocalcinosis
Mesoamerican nephropathy, Balkan nephropathy
Progression ofAln and primary glomerular disease
Clinical Manifestations and Diagnosis
CKD, salt wasting. salt sensitive HTN; RTA pRTA, dRTA. type 4 all possible
Nephrogenic DI: decreased concentration ability dlt medullary dysfunction
Tubular proteinuria unless secondary to glomerular disease. bland urine sediment
Anemia: relatively early stage CKD dl: l interstitial erythropoietin production
Imaging: small kidneys w/ indented or irregular contour: papillary calcification in analge
sic nephropathy;cysfJc changes in lithium nephropathy; nephrocalcinosis on UIS or CT
T r eatment
Identify and stop insult If possible: manage CKD: prepare RRT
Hereditary Tubulointerstitial Diseases
Autosomal dominant tubulointerstitial kidney disease (ADTKD. aka medullar cystic
kidney disease). nephronophthisis (NPHP).and cystinosis can manifest with CKD
Hereditary Tubulolntersdtiai Disease 0KI>160 xr 101 ssas1s)
Disease Gene Pathogenesis and Manifestation
ADTKDUMOD UMOD NKCC2 expression water sodium loss -» T FT uric
acid absorption. FErrate <5%
1 Urine uromodulin excretion
Hyperuricemia.gouL and ESRD at median age 24. 40, and
56. respectively ic;As~ 2013;8:1349)
ADTKDHUC1 Mucin 1 Intracellular accumulation of rnucin1 frameshifi: protein
In distal lobule
ADTKDREN REN Childhood anemia. hypotension. frequent AKI. T K
Tx: avoid unSAIDs. low sodium die:
ADT KDHNF 1B HNF1B Mamriiy onset diabetes at die young type 5. neW cysts.
renal Mg wasting. pancreatic aunphy genial abnomnlides
NPHP (AR) NPHP1 10 Retinal degeneration
Cyszinosis (AR) crns Fanconi syndrome, photophobia (corneal cystine crystals),
CKDIESRD (c/Asn zaaeanil
 IMMUNOGLOBULIN G4-RELATED DISEASE
l8G4: higher rate of dissociation :han other IgG. does not fix complement by the
classical pathway. may bind other lgs and form immune complexes
Immunoglobulin G4related disease (lgG4RD): autoimmune intiiuatiwle condition that
involves multiple organs including the kidney with serum concentrations of lgG4
Virtually any organ may be involved including pancreas. biliary use (sdertasing cholangitis).
aorta. Iung.salivary and lacrimal glands.thyroid. pachymeninges.and kidney
Clinical Manif est at ion
Common in older, male,Asian. and Caucasian
Asthenia (26%), weigh: loss (21%), fever (4%) (MHZ an am z0\s9092n
From a renal sundpoinr pos present with worsening renal function. or kidney masses
Occasionally. NS from concominan: PLAZR Ab (-) MN no z0135sa14ssl
Obstructive uropathy from renroperkoneal fibrosis; lgG4RD was 54% (Muadae 2013;92=B1)
Workup
Azotemia. hypocomplementemia (60%. C3 and C4).eosinophilia (40%)
Variable proteinuria. hematuria.and pyuria
T IgG4 levels (typically 68fold ULN) in mos: patients
Typically needs a biopsy to confirm :he diagnosis Mia ramp 20\z;1s;1\s1).The 3 major
histology criteria are: (1) dense lymphoplasmacytic inNltratea (2) Fibrosis, arranged at
least focally in a storiform pattern: (3) Obliterative phlebitis
IF:TBM immune complex deposits (80%)
Nor all features are present simultaneously and some of :he features predominate in
some organs (eg. storiform Fibrosis in pancreas. not commonly seen in kidney). Further
the number of IgG4 cells may vary

Diagnostic Criteria for lgG4related Kidney Disease (at up ~=»»~w 2011;1s:s1s)

1. Kidney damage Abnormal urinalysis or urine marker(s) or decreased kidney function
widl either elevated serum IgG level. hypocomplementemia, or
elevated serum IgE level
2. Renal imaging a. Multiple lowdensity lesions on enhanced CT
(CT Sa n is th e b . Dif f u se kid n e y e n la rg e me n t
best) C. Hypovascular solitary mass in the kidney
d. Hypertrophic lesion of the renal pelvic wall without irregu
la rit y o f t h e re n a l p e lvic su rf a ce
3. Serum lgG4 >135 mgldL
4. Renal histology a. Dense Iymphoplasmacytic infiltration MM infiltrating lgG4
positive plasma cells >10/high power field (HPF) and/or ratio
of lgG4positive plasma cells/IgG positive plasma cells >40%
b. Characteristic "storiform" fibrosis surrounding nests of
lymp h o cyt e s a n d / o r p la sma ce lls
5. Extrarenal Dense lymphoplasmacytic infiltration with infiltrating lgG4positive
histology plasma cells >10lHPF and/or ratio of lgG4positive plasma cells
IgGpositive plasma cells >40%
De f in it e 1 +3 +4 a .b ; 2 +3 4 l.b l 2 4 ,5
P ro b a b le 1+4a.b:2t4a.b;2-5; 34a.b
Possible 1+3:2+3: 1+4a. 24a

T reat m en t
The optimal therapy is unknown (no RCT)
CS: 1st line: prednisone 0.6 mg/kg daily for 2-4 wk. tapered over 3-6 MO. Mos: authors
favor maintenance 2.5-5 mild for up to 3 yr (co open Rhematol 1011:2367)
Azathioprine and MMF: steroidintolerandrelapsing pts (aasziuenxuulugy 200¢;1J4=70s)
Rituximab in glucocorticoidrefractory or relapsing pts (Anhnus Rheum 2010<67;1755)
Unclear whether renal masses without symptoms need treatment
Prognosls
In giucoconicoidtreated pus. despite improvement in eGFR,there was progression
of renal atrophy on imaging In 2o13:s4:aza>
Relapses occur in ~20% pos
 SPORADIC CYSTIC DISEASES
Simple Renal Cysts
Benign renal cysts are rare in children. but occur commonly in advanced age
Most often simple cysts are asymptomatic and detected as incidenizl findings during
abdominal imaging studies; usually of no clinical significance
U/S: smooth walls.good sound transmission.and no inrracystic debris
II UIS is indeterminate/ CT On CT. benign cysts have homogenous attenuation, no
conrrasz enhancement, and smooth walls wirhou: calcifications.
The Bosniak Category Classification on CT Imaging luiuligy zausaswi
Features wlo Contrast Features wl Contrast Hanagement
I Water density (0-20 HU). thin No contrast
margins. sharp delineation with enhancement
d1 e renal parenchyma. thin and
smooth walls. homogeneous No furdier wvflwv or
II Presence of one or few thin No contrast an ukrascncgram
septations. small and fine enhancement. or in 6-12 mo
akiiiauonsz hypcrdaise cysts no measurable or
masuriig up no 3.0 cm (60-70 HU) perceptible
enhancement of septa
IIF More complex lesions which cannot Absent. dubious. or hair
be included in category II or Ill. like enhancement
Multiple septa.walls or septa
Continued
with nodular or irregular
surveillance
calciflations. Hyperdense cysts
>3.0 cm or with only 25% of
their walls visible (exophytic)
Ill Thickwalled cystic lesion, septum Wall or septum Conmuea surveillance.
irregularity and heterogeneous enhancement he neede biopsy.
septum and wall and/or contents: in nephiemmy
Gross and irregular calcifications
IV Lesions with all the Endings of Enhancement of wall Require surgery
category Ill. and solid component. and/or solid (malignancy in
soft parts. independent of finding component(s) 85-100%)
of wall or septa
Acquired Cystic Kidney Disease (ACKD)
Occurs in individuals with advanced CKD or ESRD
The occurrence of acquired renal cystic disease increases with the number of years
on dialysis,the majority of patients develop cysts after 5-10 yr on dialysis
The cysts in ACKD are more numerous than benign simple renal cyst,but share
similar radiographic features
ACKD is associated with increased risk of malignancy
Hypokalemiarelated Cystic Kidney Disease
Prolonged hypokalemia due to urinary K wasting (such as in primary hyperaldoste
ronism) predisposes to kidney cyst formation
Medullary Sponge Kidney
A congenital disorder;malformation of the terminal collecting ducts in the pericalyceal
region of the renal pyramids, Usually bilateral
Etiolcgyn unknown; not clear it the disorder has genetic basis
Clinical presentation: mostly asymptomatic. Incomplete or oven dRTA in >80% of
pts. Recurrent calcium kidney stones. gross or microscopic hematuria w/ or
w/o stones. UTI. flank pain wl or wlo an obstructing stone or UTI.
Usually remains undiagnosed or is discovered incidentally by a radiographic study.
The diagnosis can be made by IVP or noncontrast CT
Prognosis: renal function remains nl in most cases. However,there is a risk of renal
injury dlt recurrent stoneinduced episodes of obstruction and/or infections.
Treatment; manage UTls and recurrent stones
 HEREDITARY CYSTIC DISEASES
AurosomAL DOMINANT PoLycvsTlc Kinnsv DisEAss (ADPKD)
The mlc inherited renal disease affecting 1 in 500-1.000 individuals
Accounts for 5% of ESRD population in :he US
The penetrate is incomplete: family history is positive in only about 60% of cases
Clinical Manifestation
The clinical onset typically occurs from the third through the fifth decades of life
Massive enlargement of the kidneys due to the gradual development of cysts that arise
from the dim! nephron segments and gradually replace normal renal parenchyma.
ultimately leading to progressive functional impairment
Hypertension: die earliest and most prevalent manifestation: frequently predates the onset
of renal dysfunction: Likely caused by activation of die reninangioteisin-aldosterone
Flank or abdominal pain (compression by enlarged kidneys)
Macroscopic hemamria (cyst hemorrhage). lowgrade proteinuria (tubular dysfunction)
Fever and abdominal pain (cyst infection). kidney stones (stagnant urinary Row)
Decreased concentrating ability (distorted anatomy of the medulla)
Extrarenal manifestations:
Gastrointestinal system: hepatic cysts and colonic diverticula
Cerebral aneurysms: relatively rare (<10%)
Heart: patent foramen ovals (PFO). mitral valve prolapse (MVP)
Abdominal wall and inguinal hernia
Subcutaneous. ovarian. testicular: seminal vesicle. pancreatic. and pulmonary cysts
Diagnosis
The preferred diagnostic procedure is renal ultrasound: multiple bilateral kidney cysts
in the setting of a positive family history are typically diagnostic

Diagnostic Criteria ofADPKD (n r 100% specificity 100% PPM82-100%

sensitivity depending on the age group) (MW znonuzosl
Age Diagnostic Number of Cysts
15-39 ylo A: least :hree unilateral or bilateral kidney cysts
40-59 y/o At least :we cysts in each kidney
>60 lo A: least four cysts In each kidney

10yr ESRD risk can be calculated by total kidney volume (TKV) or kidney dimensions
(Available at QxMD app:}Asn z01sa6. 14o)
G e n e t ics a n d P a t h o g e n e sis
ADPKD is caused by mutations in PKD 1 (75-85%) or PKD2 (15-25%)
The proteins encoded by PKD 1 and PKD2.polycystin1 and polycystin2.are compo
nents of a multifunctional signaling pathway that regulates key cellular processes
including grovnh. differentiation. and orientation of tubular epithelial cells: polycystins
form signaling heterodimers that localize to primary cilia of all epithelial cells
Direct sequencing: because of high cost. primarily used for the evaluation of atrisk
individuals with equivocal imaging resuks. younger atrisk individuals being evaluated
for living kidney donation. and individuals with atypical cystic disease
Sanger sequencing of all exons and splice junctions of the PKD 1 and PKD2 genes is
the method of choice. Mutation screening of PKD2 is straightforward. but PKD 1 is
challenging because it is a large gene with its first 33 exons duplicated in six pseudo
genes. Current diagnostic sequencing protocols exploit rare mismatches between
PKD 1 gene and its six pseudogenes. If Sanger sequencing is ().one should test for
structural rearrangements. which occur in <5% of the cases.These can be detected
b y a d d i t i o n a l ML P A t e st i n g .
NextGen sequencing panels are gaining popularity and will likely replace Sanger
se q u e n cin g g ive n th e ir d e clin in g co sts
Patients w/ PKD 1 mutations have earlier disease onset and T progression to ESRD
T reat m en t
No curative ueaunenr. -50% of patients reach ESRDbefore the age of 60
Primarily directed toward complications: HTN, infections. pain,and hematuria
Dietary salt restriction: may slow eGFR decline (KJ 2017;91;493)
HTN: control w/ RAAS inhibitor
 In eGFR >60. intensive BP consol (95160-110175) i KTV Increase and urine albumin
excretion wlo AeGFR il4Aun(o NS/M 1014;371Q.255)
In eGFR 25-60. addition ofARB to ACEI did not aker AeGFR u4ALrn<o new zo\4s1men
V a so p re ssin su p p re ssio n n o in h ib it cyst g ro wth
f Fluid intake: >3 Ud (C/ASN 201015:-s); difficult to achieve daily for many patients
Tolvapun vs placebo L renal function decline in eCrCl >60 uwro NEJM zo 12;a67:z40n
Tolvaptan vs placebo L renal function decline in eGFR 25-65
t Liver enzyme (>3x baseline) in 5.6% of the tolvapmn vs 1.2% in the placebo group.
These changes normalize after d/c of tolvapizn. Up to 6.8% of patients do not tolerate
aquaretic side effects (polyuria. nocturia. thirst) inermse new 20 l7;377:1930)
Longacting octreotide: not statistically significant 1 AKW (lim to13;zaz14es)
Everolimus: l AKTV w/o effect on renal progression (NEW zo 1o.a6a:.:ol

AuTosor4AL Recessive PoLycvsTlc Klonsv DlssAse (ARPKD)

ARPKD is a rare AR disorder that usually presents in early childhood
The prevalence is approximately 1 in 20.000 individuals
ARPKD is invariably associated with liver fibrosis and portal hypertension
Both kidneys are enlarged w/ a cystic dilatation of the renal collecting ducts
Clinical Manifestacion: Bimodal
Newborns can be diagnosed by prenatal US and present with severe renal failure.
oligohydramnios. and lung hyperplasia (30% of infants die of respiratory failure)
• Older children and adolescents may present with complications of portal hypertension,
such as hepatosplenomegaly and bleeding from esophageal varies. Severe systemic
hypertension in the setting of renal dysfunction is also common.
G e n e t ics
ARPKD is caused by mutations in the PKHD gene encoding fibrocystin. a large ciliary
protein found in renal and biliary epithelial cells
Dysfunction of fibrocystin leads to altered ciliary signaling,which is normally required
for regulation of proliferation and differentiation of renal and biliary epithelial cells
Tre a t me n t
T her e is no cuntive tr eatment for ARKD
Infants surviving the newborn period should be monitored closely for decreased
re n a l fu n ctio n . h yp e rte n sio n , in fe ctio n s. a n d d e h yd ra tio n
Most cases progress to ESRD requiring dialysis or kidney uansplantatlon

NPHP is a rare AR disease :had presents as severe chronic tubulointerstitlal nephritis

Th e in cid e n ce is le ss :h a n 1 in 5 0 .0 0 0 in d ivid u a ls

Clin ica l Ma n if e st a t io n s
Low urinary osmolarity (<300 mOsmlkg) d/t reduction in the ability to concentrate
urine in early childhood causing polyuria and polydipsia
Urinary sodium wasting is also present and may cause hypovolemia
Progressive renal failure manifests as poor growth and anemia
ESRD develops at a mean age of about 13 yr but can also occur during adulthood
The most frequent extrarenal manifestation is retinal degeneration causing early
b lin d n e ss,with a n in cid e n ce b e twe e n 1 0 % a n d 3 0 %
Dia g n o sis
Renal ultnsonography is useful only in the advanced stages of the disease. when renal
cysts a re visib le . Kid n e ys a re typ ica lly h ig h ly e ch o g e n ic.
Although biopsy findings combined with clinical presentation can be suggestive of NPHR
genetic testing is the only definitive diagnostic modality
G e n e t ics
Mutations in several genes (NPHP1 through NPHP10 and likely many more encoding
various clllary proteins) are responsible for NPHP
The presence of die NPHP gene products in cilia of various organs (photoreceptor.
tubular cells.cholangiocytes) explains extrarenal manifestations in some patients
• Molecular testing by sequencing is now available, NPHP genes are included on several
kid n e y d ise a se Ne xtGe n se q u e n cin g p a n e ls

Treatment
No curative OC; Mos: cases progress to ESRD requiring dialysis or kidney uansplancation
 AUTOSOMAL DOMINANT TUBULOINTERSTITIAL
K IdN e Y D ls s A s e (A D TK D )
ADTKD.aka Medullary Cystic Kidney Disease (MCKD). presents as severe chronic
tubuloiniersdtial nephritis. similar (O NPHP
Distinct from NPHP by its AD inheritance and by the late onset of renal failure
Clinical Manifestation
Typically present after the third decade of life with advanced CKD
Exvarenal manifestations include hyperuricemia and gout
The kidneys have echotexzure. but there are no visible cysts by u/s
Kidney biopsy: chronic zubuloinrersddal nephritis. :ubular atrophy and mkroscopic cysts
in :he medulla or as the corticomedullary iuncdon (similar Findings to NPHP)
Genetic
Mutations in 2 genes encoding proteins produced by the renal tubular epithelium
MUC1 gene: encoding mucin1. a transmembrane protein expressed on the apical
surface of mos: epithelial cells.Among other functions, muslin provides a protective
barrier to prevent pathogens from accessing the cell. In the kidney. mucin1 is
strongly expressed in the loop of Henle. DCI and the collecting duct.A single cyto
sine insertion into one variablenumber tandem repeat sequence within the MUC1
gene cause ADTKD. Not detectable by standard genetic tests and can only be tested
in a research setting.
UMOD gene: encoding uromodulin (Tamm-Horsfall protein).This protein is produced
and secreted by TALH. Sanger sequencingbased mutational analysis of the UMOD
gene is commercially available and can be used to establish a molecular diagnosis.
Treatment
No curacive treacmenr for ADTKD
Xandmine oxidase inhibitors (allopurinol or Iebuxosrac) should be used for prevention
in pts with recurrent gouLThere may be a role for these drugs in slowing CKD pro
glession in asymptomatic pos if started early (Qin 20GZ:95:S97)
Summary of lnherleed Cystic Dlsorden
ADPKD (AO) ARPKD (An) NPHP (AR) ADTKD (Ap)
Gene PKD1,PKD2 M4401 NPHP 1-12+ MUC 1 (Mudnl ).
(Protein) (Polycystins1 (Fibfocystin) (Nephrocyslins. UMOD
and 2) other ciliary (Uromodulin)
proteins)
Localization Tubules (cilia) Tubules (cilia) Tubules (cilia) Tubules (avid)
Onset Adults >30 ylo Newborns md Children and Adults >30 lo
children adolescents
Imaging Massively enlarged Enlarged kidneys. cysts Normalsrted Norrnalsited
kidneys. multiple visible only in kidneys without kidneys without
large cysts easily advanced disease cyso. increased cysts. increased
visible echotexwre echotextaure
Pathology Massive cysts char Cystic dilatation of the Chronic Chronic
replace normal renal CDs tubulointerstitial tubulointerstitial
renal nephritis nephritis
parenchyma
Clinical HTN.1lank pain. Putter syndrome. Urinary Urinary
Features cyst infection, respiratory failure. concentrating concentrating
nephrolithiasis. hepatosplenarnegaly. deject. renal defect. renal
hematuria. Iow variceal bleeding. failure wlo allure wlo
grade hematuria. low hemawria or hematuria or
proteinuria, grade proteinurla. proteinuria. proteinurla.
renal failure. renal failure. lung =~=w=h failure. hypemnicemia.
hepatic cysts. hyperplasia. liver retinal gouty arthritis
cerebral llbrosis. portal HTN degeneration
aneurysms, PFO. (retinitis
MVR colonic pigmentasa).
diverticula blindness
 RENAL CELL CARCINOMA (RCC)
Background
Renal mass is frequently found with imaging during AKIICKD w/u
2 6 % o f RCC p t s h a d CK D b e f o re t u mo r nephrectomy (Lancer oȢul2006;773sl

Risk Factors and Pathogenesis

Smoking. H T N , C K D . obesity. Pl: F 1. 6: 1
A cq u i r e d cyst i c ki d n e y disease lqAsn 2007:z:7so): T wl dialysis duration or z011211:ae1

Type of Renal Cell Carcinoma

Type (94) Origin Associated Genes and Pathway
Clear cell (75-90) PT VHL.TSC 1/TSC2
BAP1 mu aw Res 101111:1061)
Papillary (1020) PT Type 1: MET
Type 2: NRF2ARE pathway (N£jM 2016;374:1351
Chromophobe (5) DT Fo llicu lin (FL CN): Bin -Ho g g -Du b e syn d ro me
Collecting duct (<1) CD
Medullary (<1) Medullary Sickle cell t rait > SCD

von Hippo-Undou (VHL) gene:encodes VHL protein. E3 ubiquity ligase: proteasome deg
radation of a hypoxiainducible factor (HIF). transcription factor of erydiropoietin gene
VHL syndrome:AD VHL mutation causing constitutive activation of HIF
Odmer malignancies: hemangioblastoma (CNS, retina). pheochrornocytoma. pancreatic
serous cystadenomas and neumeidociine tumor. middle ar endolymphadc sac tumors
VHL somatic mutation is found in 91% of clear cell RCC (an Canter Ra 200e;14:4726)
Tuberous sclerosis: angiomyolipomas > benign cysts, RCC, lymphangioma
Skin: forehead papules. plaques. lower trunk, angioiibroma
Birt-Hogg-Dube syndrome: mutation of folliculin gene; bilateral mukifocal RCC
Clinical Manifestations
Hematuria. flank pain. HTN. fever, fatigue. weigh: loss. anemia. hepatic dysfunction
Cxosteolytic metastasis. IL6 mediated PTHrp. PG mediated bone :sorption
Erythrocytosis: erythropoietin production
NS with M amyloidosis. Ig/NN
1/3 of diagnosed with metastasis
Diagnosis
UIS simple vs complex cyst
Contrast CT: standard imaging test; required for Bosniak classification of cystic disease
Surveillance of Complex Renal Cysts
Bosniak Classification u W z017:19mn)
Category: Imagining Features Intervention RCC Risk
I: simple cyst None
II complex cyst with din septations None
IIF: complex cyst with mulr.iple chin or minimal F/U 6-18%
thickening sepadons wlo masurahk enhancanent
III: complex cyst with thickened irregular or Surgery or dose FIU 51-55%
smooth walls. contrast enhancing (>1S HU)
IV: Ill + solid component. enhancing soft :issue Surgery 89-91%

80% continued surveillance and 20% (596 of Bosniak IIE 30% of Ill. 62% of IV) under
went surgery. mecaszasis, death rare. suggesting surveillance is safe (jUuI2018:1996JJ)
Renal Mass Biopsy it Ural 1017.198510)
14% nondiagnosticzvery high sensitivity. specificity. and PPV
Consider to rule our hematologic. metastatic. inflammatory, or infectious mass
US or CTguided multiple core biopsies
Not required if it would not A management (1) young pts who are unwilling to accept
the uncertainties: (2) older/frail patients who will be managed conservatively
No reported cases of tumor seeding in the contemporary literature
 RCC Staging and Primary Treatment
Stage TNM Treatment
I T1 ($7 cm, limited to due kidney) NO
T1a (54 cm) PN
T1b (>4. (57 cm) PN (or RN)
II T2 (>7 cm. limited to :he kidney) NO RN (or PN if clinically Indlazed) 4
Ill T1 or 2,N1 (regional LN) adjuvant treatment
T3 (major veins or perinephric tissues)
N T4 (beyond Gerota fascia) or M1 Nephrectomy + merastasectomy or
(advanced) (distant metastasis) Systemic therapy 3. cytoreductive
nephnectomy

Nephrectomy
Partial Nephrectomy (PN) vs Radical Nephrectomy (RN) WASH um: za11;19&5w1
PN Preferred RN Preferred
cT a (54 cm) renal mass High tumor complexity
Anazomic or functionally solitary kidney No preexisting CKD or proteinuria
bilateral tumors. familial RCC Normal contralateral kidney and new
Preexisring CKD. or proteinuria baseline eGFR will likely be >45
Young. have multifocal masses. or
comorbidizies Thai: are likely to impact
renal function in the future

Split radionuclide :wal San an be done co predict posuiephrectomy dialysis requiranent

CKD incidence after nephrectomy UASN 201 $.29:207): 7.9% (CKD45). 14.2% (CKD3b5)
PN (vs RN) was alw L CKD 4-S (x0.34).l CKD 3b-5 ()<0.15).. mortality (x0.55):
CKD Risk Acton: prop renal function. tumor >7 cm. old age
Renal function decline occurs within 12 mo after surgery
PN was a/w less eGFR fall than RN by 10.5 (qAs~ 201721z.\0s71
AKI postsurgery increasing co 10.4%. alw male. RN, older age. black race. higher
comorbidities. preoperative CKD stage (up: of 2016;34:293.e1)
Concurrent RN and IVC thrombectomy alw higher incidence ofAKl and CKD
Surgically induced CKD has less annual renal function decline than preop CKD (4.7
vs 0.7%). Postop mortality was higher in preop CKD x1.8 (CKD3).x3.S (CKD4).
and x4.4 (CKDS) Uu~l20u:1e9.1649)
Kidney biopsy review of nontumor tissue by medical renal pathologist in all pts with
preop CKD and proteinuria: 15% had renal disease: severe vascular sclerosis (>50%
luminal narrowing). global sclerosis >5% and IF/TA >10% was alw postoperative cre
atinine elevation wairuviu Lan M44 2013;137$31]
Systemic Therapy
Rand Toxicity of Systemic Therapy for Advanced RCC
IFNn2a (um 2007;]102 lOJ) Collapsing FSGS.TMA
Anziangiogenic VEGFl:7rosine kinase inhibitors TMA (prozeinuria and HTN)
Bevacizumab annul 2(ll7;]70:2103) HTN could be a biomarker of
Scnfenib we 10014512031 efficacy UNG 2011;103:763)
Sunizinib man 2857135611s¢n£w10\5:37S:1246)
Sunitinib alone no! inferior to nephrecromy +
Sunininib (NE/M zo1a1n4wl
Pazopanib (1 Cin Onan!201M8:1061)
Axkinib (num 2011:mmn
Cabozanzinib WSW 201S:J7J:1B141, Lenvaninib
Checkpoint inhibitors Tubulointerszitial nephritis
Nivolumab + ipilimumab (~=w 20\B.37&1177) (KJ2016;91k638}
Avelumab wl axidnib (NEW 201%38&1103)
P e mb r o l i zu ma b wl a xi r i n i b h e l m zoimmniq
roTOR inhibimrs
Everolimus AKI(AMC Cam 1014;l4:906)
Temsirolimus ATN un Once 1013:14:1411)
IL2 Capilla leak AIN
Transplantation
• RCC risk: KTR >other organ txp 1e cipient > general population UAMA 1011;306:1891)
alw graft failure: kidney function associated >immunosuppresslcn effect UASN 2016;27:1495)
Risk factors: black. prolonged dialysis predicting KT: 89% in native kidneys papillary
RCC risk is esp high or 20162163a4791

Transmission Risks of Donor RCC WT 201I;I1:1140)

Minimal (0.1%) Resected solitary RCC 51 .0 cm. well differentiated
Low (0.1-1%) Resected solitary RCC 1.0-2.5 cm. well differentiated
Intermediate (1-l0%) Resected solitary RCC T1b 4-7 cm.well differentiated
High (>10%) RCC >7 cm or stage II-Iv

Screening U/S wu 1 mo of exp. :hen q5y wlo cysts: q2y w/ cysts WT z011:11;a6)
Background
Common cause of CKD in children with CAKUT (mau nepmu 2016;31;l411)
In adults. more common in men due to prostatic enlargement
Pathogenesis
UTO an occur anywhere in the urinary USC! system
Renal tubular lniury is the consequence of mechanical stretching. hypoxia.and
exposure to oxygenfree radicals that result (1.um¢4 Res jin 2014:2014:303298)
Causes of Acute UTO
Oudlow obstruction: mechanical (narrow urethra) vs dynamic (i muscle zone)
Neurologic impairment: in sensory or motor nerve supply to detrusor muscle
inefficient detrusor muscle. following anesthesia
Medications. particularly anticholihergics and sympathomimetic drugs
Trauma: Urinary tract infection (UTI)
Causes of Chronic UTO
Children: posterior urethral valves. ureterovesical. or ureueropelvk junction obstruction
Young adults: nephrolithiasis
Older adults: BPH. malignancy, nephrolithiasis, retropericoneal fibrosis
Clinical Manifestations
Acute UTO: hemawria.AKl,+/- pain. abdominal distention. hypertension, UTI
Nondilated obstructive uropadiyc happen with volume depletion. hypotension. infilua
due metastatic cancer and reuoperkonml fibrosis: Percutaneous nephrostomy tube
placement and resolution ofAKl is diagnostic um Fu z010.122uu1
Chronic UTO: may be asymptomatic. Overflow incontinence sometimes. nocturia
Discovered during workup of renal insufficiency.
Workup
Renal UIS: false 1.) rate of mild hydronephrosis wlo UTO is 26%. NPV of 98%
Color duplex Doppler: intrarenal artery resistive index >0.7 in obstruction due to
vasoconstriction
Bladder ultrasound: can ald In evaluating for trabeculation of bladder wall and postvoid
residual. as well as bladder wall mass or bladder stone
Noncontrast CT scan: recommended for nephrolithiasis when presenting with signs
of renal colic (severe flank or groin pain. emesis. gross hematuria) or risk factors
(family history or prior renal stone) or in patients with polycystic kidney disease
Cystoscopy/retrograde pyelography: if UIS (-) and obstruction is suspected
Stenography:Te 99mMAG3 San with IV furosemide to differentiate collecting system
dilatation from obstruction
Cystoscopy and aerodynamics in patients with suspected oudlow obstruction
Differential Diagnosis of Hydronephrosis
Peripelvic cysts. exuarenal pelvis.dilated renal veins
Hydronephrosis without obstruction: notable in pregnancy
Obstructive Nephropathy (~flm i 9s1:104:37s)
t intratubular pressure - renal vasoconstriction. rapid ' in renal blood flow and
GFR.with interstitial fibrosis and nephron dropout if obstruction is prolonged
Chronic obstructive uropathy alw hyperkalemia and dRTA
Treatment
Dependent on location and etiology of obstruction
Oudlow obstruction: clean intermittent catheterization and bladder management
Nephrolithiasis: stone and urine analysis for mineral solubility Increase urine How
>2 L daily and low salt diet
Mass or obstructing stone. nephrostomy until obstruction removed
If bilateral chronic renal obstruction is relieved. may experience postobstruction
diuresis, monitor for hemodynamic instability if unable to keep up with urine output
Prognosis
If acute urinary retention is addressed <72 hr. likely complete renal recovery
If obstruction remains >2 wk, recovery less likely if not achieved at 12 wk
Risk factors for worse prognosis include recurrent obstructive renal disease. hyper
tension. diabetes. obesity. and albuminuria
 REFLUX NEPHROPATHY
Background and Pathogenesis limn 1015:J85:371)
VUR: the retrograde passage of urine from bladder into the upper urinary tract
1 VUR: incompetent closure of ureterovesical junction (UVJ). which contains a seg
men: of the ureter within the bladder wall. Reflux is prevented by bladder contraction
compressing the intravesical ureter and sealing it off with bladder muscle.
Congenital short intrayesical ureter. LowgradeVUR may improve with pt growth.
2 VUR:abncrmally high voiding pressure in the bladder results in failure of closure
of the UVJ during bladder contraction
Anatomic (posterior urethral valve) vs functional obstruction (neurogenic bladder)
Epidemiology
1VUR occurs in 1% of newborns. incidence higher in neonates with prenatal hydro
nephrosis, and in children with febrile urinary tract infections
White children are 3>< (than black children): : ,: = 2 : 1
Genetics: familial rate is higher for milder forms of 1°VUR.Although no single
gene mutations have been identified certain syndromes may be a/w VUR. eg. renal
coloboma syndrome (Cu Genaro 2016217;701
Clinical Manifestations and Workup
Prenatal hydronephrosis.with prevalence rate ofVUR of 16.2%; Febrile wl UTI
Renal and bladder U/S; Lab: serum creatinine. urinalysis. urine culture
Voiding cystourethrogram is the diagnostic procedure of choice. Radionuclide cystog
raphy is an alternative method and may be used to monitor pts.
Dimercaptosuccinic acid (DMSA) renal scan to detect renal cortical abnormalities
Grading of VUR (International Reflux Study Group)
Grade I Reflux fills ureter wlo dilatation
Mild
Grade II Reflux fills ureter and collecting system wlo dilaution
Grade III Reflux fills/mildly dilates ureter and collecting system w/ mild
blunting of calices
Grade IV Moderate
Reflux Wllslgrossly dilates ureter and collecting system wl
blunting of calices 4 Tonuosiry of ureter
GradeV Reflux dilates collecting system. calices are blunted wl a loss Severe
of papillary impression: + Ureteral dilation and tortuosiry

Prognosis I/ um: 1997;1571646)

1°VUR usually spontaneously resow when age of diagnosis is <2 lo. unilateral
I and II resolves in 80% of children by age 5
Ill with bilateral involvement at age 5-10 yr had lowes: spontaneous resolution (20%)
vs children presenting at 1-2 yr with unilateral disease (70%)
IV: 60% (unilateral) and <10% (bilateral) resolution despite age at presentation
V: spontaneous resolution rare.except in 6 infants (30% resolve in 1" year of life)
Recurrent UTI:giade III and IV (23%) vs grade I and II (14%) up new 2014:168t8931
General Treatment
Surveillance is recommended for mild Glade HIVUR as these usually selfresolve
Monitor for symptoms. best in children who are verbal and toilettrained
Prophylactic Antibiotics for Recurrent Pyelonephritis and UTI
Indications: not toilettrained or have bladder and bowel dysfunction, with any grade:
moderate to severe VUR (lll-V); recurrent febrile UTls regardless of grade ofVUR
TMPSMX or cotrimoxazole. nitrofurantoin. cephalexin, ampicillin. and amoxicillin.
although resistance to E coli UTls do arise (lam z01s¢sas;z11l
Stopping antibiotic: reevaluation ofVUR as child grows or after correction ofVUR
Prevention of Renal Damage:VUR Correction
Indications: IV-V beyond age 2-3, medical therapy failure wl breakthrough infections
Open surgical reimplantation (ureteroneocystostomy UNC); permanently corvectVUR
vs endoscopic injection (EI) of a biodegradable polymer (can have recurrent VUR)
Repeat imaging routine to flu endoscopic correction, and in setting of recurrent UTI
UNC more likely to have higher 30d GUrelated readmissions compared to El
(4.8% vs 1.1%. OR = 4.76): however. El demonstrated increased odds of repeating
antirefiux procedures (OR = 7.13) u haw Url 2017:13:S07.e1)
 URINARY TRACT INFECTION (UTI)
Definition (Imp on at" mum Ain 2014:281)
Asymptomatic bacteriuria (ASB): positive urinalysis and culture without symptoms
Acute uncomplicated cystitis: urine culture + with symptoms. UTI confined to bladder
Complicated UTI: special populations with acute cystitis: urologic abnormalities.
immunocompromise. poorly controlled DM, kidney transplant. or pregnant women
Pyelonephritisz inflammation of renal parenchyma +I- systemic illness
Common Microorganisms Causing UTI
Immune competent Immunosuppressed or immunocompromised
Enterobacteriaceae: Bcheridvia coli Candidaspp and mold
(mlc). Klebsida, Proteus spp Recent broadspectrum antimicrobial use
Pseudomonas ExtendedSpectrum BetaLactamase
Emerococci and staphylococci (MSSA. (ESBL)producing Enterobacteriaceae
MRSA) Carbapenemaseproducing gram
Staphylococcus saprophylkus negative bacilli
Clinical Manifestations
Cystitis: frequency. urgency, dysuria
Pyelonephritis: fever (>37.7 C); Chills/rigors, malaise or significant fatigue; costoverte
bral angle tenderness; pelvic or perineal pain in men
- AKI is rare: reported with solitary kidney and NSAID use swim Dis 1992.1411431
Complications of Acute Pyelonephritis (Infix Ds CM NoihAm 1997.116531
Renal cortical abscess/carbuncle: result from hematogenous spread of bacteria from
a primary focus of infection (bacteremia. osteomyelitis. endovascular infections)
Renal corzicomedullary abscess: alw underlying urinary tract abnormality. such as
?w
vesicoureteral reflux or urinary tract obstruction
Emphysematous pyelonephritis: suspect if DM + septic shock.worsening clinical status
despite aggressive medical therapy. known or suspected UTO (NE]M 20I 8;378:48)
• Xanthogranulomatous pyelonephritis a/w obstruction by struvite stone using
destruction of kidney tissue by granulomatous changes wl lipid laden macrophages;
frequently require surgical removal of infected tissue nephrectomy
Perinephric abscess: abscess between renal capsule and renal fascia, usually alw rup
ture of an intrarenal abscess. renal cortical abscess. chronic/recurrent pyelonephritis.
+I- obstruction. xanthogranulomatous pyelonephriUs. or renal carbuncle
Risk Factors
Urinary catheter use. UTONUR. DM. pregnancy. immunocompromised.ADPKD
Imaging: CT Scan with or without Contrast
Indicated for recurrent symptoms. acute pyelonephritis will\ sepsis. septic shock.
known or suspected urolithiasis. urine pH 27.0. new GFR $40 (NEW 1018:37s¢4s)
Management (IDSA;Gn lnfea Ds 2011:57;e103)
Empiric antibiotics based on severity of illness, risk factors for resistant pathogens.
previous susceptibility to antibiotics. local community resistance prevalence
Screen and treat all pregnant '2 w/ ASB (IDSA (Ja I»f¢<1 on 101%pmID 30e95zaa)
Acute uncomplicated cystitis: nitiofurantoin 100 mg bid x 5 d: superior to fosfomycin
(WM 10183319 17s1).TMPSMX DS bid x 3 d.or fosfomycin 3 s ><1
Fluoroquinolones x 3 d are efficacious but can have secondary effects
l3Lacnams should be reserved if no other options due to their lower efficacy
Pyelonephritis: oral fluoroquinolone (bid or extended release daily) x 7 d (+l- N initial
dose). IV ceftriaxone 1 g q24h dose or IV aminoglycoside q24h in lieu of IV lluoro
quinolone depending on community resistance patterns.
UTI in CKD (C/ASN 200s:1=3z7I
Nitrofurantoin: absent in urine if CrCI <20: FDA recommends against use if CrCI <60
Sulfamethoxazole: urine level is subcherapeutic if CrCl <50
Ciprofloxacin. levofloxacin. and trimedloprim: therapeutic level achieved in CKD
UTI in ADPKD iA;P Renal 2017313H0773
UTI, infected renal cysts. pyelonephritis: 3060% ofADPKD pts experience UTI
Prevention through flushing" of kidneys and preventing stasis through increasing
urine volume.vizamin C rich cranberry juice.and usual hygiene measures
Treatment targeted to penetrate renal ms, empiric IV fluoroquinolone or cefotaxime
or ampicillin plus gentamicin based on resistance panels
 MINIMAL CHANGE DISEASE (MCD)
Most common cause of nephrotic syndrome in pediatric population (2-7 cases/100.000,
accounting for -90% of nephrotic syndrome under age 10)
Third most common cause of nephroric syndrome in adults (10% of cases)
Usually idiopathic, bu: secondary MCD associated with:
Neoplasms: Hodgkin disease. NHL leukemia. renal cell carcinoma
. Medications: unSAIDs. interferon. gold. mercury. methimazole. penicillamine
Infections: syphilis. HIV. mycoplasma
Autoimmune disorders: sclerosing cholangiris, sarcoidosis
Other renal disorders: loAn (c;Asn Z014:9:10JJ). lupus nephritis (qAs~2016.1 \:§47)
Pathogenesis
Padwologic Tcell-medlaned circulating factor ("Shalhoub hypo:hesis") (jam l974;7aa0sss1
Activation of Fcell cosdmulatory CD80 (B71) on podocytes is a/w proteinuria in
MCD.and may be stimulated by cytokines such as lL13 (sewn ~=¢=»~=4201191324 144
Neplwul 201$130.469). t urinary CD80 during relapses of MCD. but not FSGS (KI 2¢10.78;296).
Role of B cells implied by eifectiweness of Bcell depleting agents (rituximab) and asso
ciations wide lymphoid malignancies. IL4-mediated mechanism nu 'win zowasiaae).
Pa t h o lo g y
LM: normal appearance: IF: no staining (unless secondary to other GN): EM: 280%
foot process effacement. no electron dense deposits (unless secondary to other GN)
Mesangial deposits of IgM 1r¢4n¢vn¢ulzua9;z4;11a7) or C1q may be seen in both MCD
and FSGS. and are associated with worse prognosis in MCD
C lin ica l M a n if e st a t io n s
Acute onset edema (LE periorbital. ascites); GI distress common in children (diarrhea.
nausea, pain: attributed to intestinal edema): often follows viral infection or atopic
episode
Complications: AKI/ATN, thrombosis
Wor kup
Labs: proteinuria >3.5 G/24 hr.l serum albumin, ' cholesterol (especially triglycerides),
hematuria in 10-30% of auks UAW z01 a.14:102l. May present with AKI.
Rul e out s e c onda r y c a us e s . a s a bov e
Consider genetic resting if age <1 yr. significant FHx. or steroid resisranz disease

Tr eatment
Prednisone 1 my kg (up to 80 mg) QD or 2 mg/kg QOD (up to 120 mg) for 4-16 wk:
if responding, taper over 3-6 mo
If unable to tolerate CS or FRISD. use CNI: CsA (3-S mg/kyd divided bid.goal trough
100-150) orT ac (0.05-0.1 mglkgld divided bid goal trough 5-7) x1-2 yn then taper
De finitions of Ste roid Re s pons iv e ne s s
Steroid resiscam: (SR) Fai l ed to achi eve r emi ssi on whh 16 wk of ster oi d
Ster oi d dependent (SD) Relapses 22 during steroid taper or wu 2 wk of dlc of steroid
Fr equency r el apsi ng (FR) Relapses 22 wu 6 mo or 24 wu 1 yr of achieving remission

For FRISD patients unable (O tolerate CNI. older guidelines suggest cyclophosphamide
(2-25 mg/kg PO daily) for 8 wk or MMF (1,000 mg bid) for 1-2 yr (KDIGO GN 1012>
Ri:uximab: effective for FR/SD MCD Intro;Asn zo14;zs¢sso; qAsn z01¢1\;710>

P r ognos i s
In pediatric popul a t i on. 9 0 % of cases are steroid responsive. but 60% develop FR/SD
state (I Pediatr 19e1 sss61: MIKE! 1988;85823W: inazau 1W§;l47:202)
20-30% of pediatric FR/SD pa t i e nt s c ont i nue t o have relapses into a dul t hood U mau
2005;147:202. 4:/Asn 2009;4.1$93)
88% of adult onset MCD respond to CS.w/ 56% having relapsing course (AjKo 201726%37)
Mos tFR/SD patients have good r e na l pr ognos i s but high risk of t r e a t m e nt r e l a t e d
complications (osteoporosis, cataracts. infertility) (qAs~100~r421s93). Few will progress
to ESRD WND z017;s&6311
FOCAL SEGMENTAL GLOMERULOSCLEROSIS
FSGS is a pathologic lesion that can be caused by a diverse set of diseases
Idiopathic FSGS also rolled "primary." usually presents refth nephrotic syndrome (NS)
Secondary FSGS: should be interpreted cautiously lt may refer to FSGS with cause
(KoiGo GN z01 z). nonprimary podocyte injury excluding genetic FSGS who 2018;62403),
or nonnephrotic syndrome wl foot process eifacemem. <80% (nbr 20 l§;]0:375)
Most common biopsy diagnosis in US. incidence rising WKD 101s;6a:53 31
Mos: common glomerular cause of ESRD (AJKD 2016:6&533)
Male:female incidence 1.5:1 (qA§N 20172125s021
Accounts for 20% of pediatric and 40% of adult cases of NS
Conditions Associated With FSGS
Infections HIV. Parvovirus B19. CMV. Malaria, SV40 virus. Schistosomiasis.
Strongyloidiasis [Ki Rev 201B.]:l4)
Malignancies Hodgkin and NonHodgkin lymphoma
Drugs Interferon, Pamidronate. Lithium. Heroin.Anabolic steroids,
HCV DM (fugaiaiqy z017:se:essl
Hemodynamic i nephron endowment (unilateral kidney agenesis. ' birth weight)
maladaptation Nephron loss (reflux nephropathy. nephrectomylablation.conical
necrosis. residual sclerosis from proliferative nephritis)
Hyperiltration (obesity. chronic allograft nephropathy. sickle cell.
cyanotic congenital hear! disease. HTN,diabetes mellitus)
Inflammatory disease SLE, HLH, MCTD. giant cell arteritis. adult onset Still disease.
sarcoidosis. systemic sclerosis
Genetic mutations Mostly monogenic mutations of critical podocyte genes
Genetic syndromes Charcot-Marie-Tooth.Alpon.Type I glycogen storage disease.
Branchiootorenal syndrome. Partial lecil.hincholesterol
aqrkransferase deGciency.Spondylometaphyseal dysplasia

Pathogenesis
Podocyte injury leads to detachment from GBM: parietal epithelial cells (PEC)
migrate from Bowman capsule. forming cellular bridges to the capillary wft. eventually
causing wft adhesion, loop obliteration. and segmental sclerosis (ACKD 1014221:40e1
Idiopathic: podocytes injured by circulating permeability factor of uncertain identity.
likely produced by immune cells. analogous to minimal change disease (Nat no.. wma
z01s;1 17sel. Evidence: (1) improvement of proteinuria wl PLEX: (2) resolution of FSGS
lesions upon retransdant to nonFSGS recipient one/m 2011:3£6:\648)
Adaptive lvyperfiltration: nephron loss leads to distention of individual glomerular
capillaries and increased glomerular pressure.causing GBM adaptation, slit diaphragm
widening, and podocyte detachment (now ~=»1~=l 1017:3293:405: KI 1017:91:118J)

Apolipoprotein 1 (APOL1) and the Kidney

APOL1 is a minor component of HDL synthesized in the liver and found in the kidney.
endothelium, pancreas. liver. brain. and hear:
APOL1 variancs G1 and G2, compared m reference variant G0. confer resistance against
zrypanosomal species and are more common in subSaharan Africa (MSN 2011:211098)
>50% ofAfrican Americans carry 1 APOL1 risk variant and 13% have 2 risk variants [Sam
~=1~=I201535122)
The occurrence of homozygosity Or double heterozygotes for G 1IG2 renal disease in
people ofAfnican heritage: 18% of FSGS and 35% of HlVAN U4SN 2011;2L1129)
Also alw HTN associated ESRD and sickle cell disease (Acne 2014;11:47.6; up zo 17;119;azs>

Pathology
LM: at least 1 glomerulus with lesion of segmental (partial) sclerosis. may see tubular
microcysts (esp in collapsing variant)
IF: typically no staining. Mesangial IgM may be seen.associated with worse prognosis.
Clq staining raises concern for Clq nephropathy. a rare variant of FSGS
EM: FP effacement typically diffuse (>80%). may be patchy in adaptive FSGS. Mesangial
EDD and tubuloreticular inclusions may be seen in secondary FSGS, especially immune
complexmediated disease. GBM wrinkling seen in collapsing variant
Histologic subtypes help differentiate primary from secondary lesions and may help
prognosticate disease course (ACKD 2014414001
 Histologist Subtypes of FSGS new 10141140m lo Miianiaua

FSGS NOS (68%) Z1 glomerulus with segmental increase in matrix obliterating

Collapsing variant (12%)
Tip lesion variant (10%)
Perihilar variant (7%)
Cellular variant (3%)
the capillary lumina.There may be segmental glomenilar
capillary wall collapse without overlying podocyte hyperplasia.
21 glomerulus with segmental or global collapse of Me
glomerular tuft with overlying podocyte hyperplasia or
hypertrophy. Mos: likely to progress to ESRD.
21 segmental lesion involving rip domain of glomemlus. Often
steroidsensitive. Best prognosis even if SR iqAs~ 7.0 lJ:B:]99)
21 glomerulus with perihilar hyalinosis,more common in
adaptivelhyperhlu-ation mediated FSGS
21 glomerulus with endocapillary hypercellularity without foam
cells or karyorrhexis

Clinical Manifestations
Proteinuria. typically nephrotic range (>3.5 old); Idiopathic FSGS usually presents as
full nephrozic syndrome: Adaptive FSGS less likely to have full nephrozic syndrome
May present as subnephrozic in collapsing and TRPC6related FSGS
Workup
Urine protein excretion.serum albumin, lipid panel
Rule out poizenzial infectious causes (HIV. Parvovirus B19. CMV). inflammatory diseases
(SLE. MCTD. HLH.gian: cell arrerizis. adult onset Still disease).drugrelated causes
(interferon. pamidronare. anabolic steroids. lithium. heroin)
Consider genetic evaluation in patients with significant family hx. steroidresistant (SR)
NS. pediatric onse: disease
RenalLir nited G enetic F SG S
Gene Pr oduct Gene Pr oduct

NHPS 1 (AR) Nephrin CD2AP (AD) CD2associated protein

NHPS2 (AR) Podocin ACTN4 (AD) Alpha actinin 4
PLCE 1 (AR) Phospholipase C21 TRPC6 (AD) Transient receptor potential cation
dlannel 6
Genetic FSGS With Possible Extrarenal Manifestations
Gene Pr oduct Associated Conditions
INf2° (AD) lnvened or r in 2 Charcot-Marie-Tooth: motor and sensory nerve
rnandesmtions wide dismal leg weakness. bot
deformities (yes avus. hammer toes)
WT1 (AD) Wilms tumor 1 Denys-Drash syndrome:Wilms tumor. male
pseudohermaphroditism
Frasier syndrome: gonadoblastoma, male
pseudohermaphrodidsm
mm, MT T L2, Mitochondrial :RNA MELAS syndrome: mitochondrial myopathy.
MTTY (mino encephalopathy. lactic acidosis. strokelike
chondrial) episode
LMX1b (AD) LIHHboxTF1 Nail-patella syndrome: hypoplastic patella.
dystrophic nails. dysplasia of elbows
Collagenofibrotic glomerulopathy
LAMB2 (AR) l.aminin be 2 Pierson syndrome: microcoria. NM junction
defects
lTGB4 (AR) Beta 4 integrity Epidermolysis bullosa
CD151 (AR) Tetraspanin CD151 Epidermolysis bullosa, sensorineural deafness.
nail dystrophy
SCARBZ (AR) Scavenger receptor Action myoclonusrenal failure syndrome: ataxia.
class B member 2 myoclonus
MYH9 (AD) Nonmuscle myosin Bleeding diathesis. macrodlrombocyropenia.
11a progressive sensorineural deafness. liver
enzyme, cataract

Moss common cause of generic SRNS in childhood

'Mon common cause of lamilual FSGS in adults, often subnephmdc (NDT 2011:178B2)
Treatment of Idiopathic FSGS
. Prednisone 1 mg/kg (up to 80 mg) QD or 2 mg/kg QOD (up to 120 mg) for 4-16 wk
or complete remission: if responding, taper over 6 mo
If intolerant of or resistant no CS. CNI: CsA (3-5 mgkgld divided bid w/ goal trough
125-175) orT ac (0.05-0.1 mg/kg/d divided bid w/ goal trough 5-10) for at least 12 mo
if responding by 6 mo
SR FSGS unable to tolerate CNl: dexamediasone and MMF lKl2011rS0:8681
Rituximab generally not recommended for treatmentresistant FSGS. but has been used
in small trials to treat resistant FSGS with improvement in protdnuria. relapse rate. and
need for IS (jAr 2014152850: Arn] Nephfnl 20l4:3932Z)
Conservative care with RAS inhibition. dietary sodium resr.ricdon.and BP control
particularly important if incomplete response to immunosuppression
Treatment of FSGS With Identifiable Cause
Treat underlying disease: eg. ART for HIVAN
Treatment ofAdaptiveIHyper1iltrationmediated and Genetic FSGS
No role for immunosuppression
RAS inhibition, dietary sodium restriction.optimize BP control
Prognosis
Patients with subnephrotic proteinuria are unlikely no progress to ESRD but are at
increased risk of cardiovascular morbidity and morality
Patients with nephrotic range proteinuria are more likely to progress to ESRD
Tiplesion FSGS associated with best outcomes and most steroidresponsive, more
similar to minimal change disease
Collapsing FSGS associated with worst outcomes and ESRD
Steroid resistance is most important predictor of poor outcome, regardless of histology
l;Asn 2004;1S:2169; 201718130551
Transplantation
idiopathic FSGS has high rate (-40%) of recurrence after transplant and can recur
within 48-72 hr (T~"=v!°M me 2017249111563 qAs~2016;111041)
Risk factors for recurrence include younger age. nonAfrican American race. heavier
proteinuria and low serum albumin pretransplant. and more rapid progression (D ESRD
Surveillance for recurrence necessary with frequent J urine protein excretion
Prompt initiation of plasmapheresis t rituximab may improve outcomes for recurrent
FSGS; prophylactic treatment may not be effective (fg 1npluntulian 201B1107;e115)

MEMBRANOUS NEPHROPATHY (MN)

Most common cause of nephrotic syndrome in nondiaberic Caucasian pts
Primary MN (PMN) (60-70%) vs secondary MN (30-40%)
Pathogenesis
PMN is an autoimmune disease in which antibodies (usually IgG4) are produced
against a podocyte antigen. most commonly the phospholipase A2 receptor (PLAZR)
Abs may also form againstAg rapped in the GBM (eg. bovine serum albumin), or
preformed AgAb complexes may in theory deposit from the circulation (not proven
in human disease). Complement activation then contributes to podocyte injury.

Identified Antigens of PMN

MType Phospholipase A2 Receptor (PLA2R) 74)80% of PMN. rare in HBV. malignancy
[new200%361:11I associated MN
Thrombospondin zype1 domaincomaining 2-5% Of PMN, 10% of PLAZR Ab (-) PMN
7A (THSD7A) (~£Im zoi 4:a71:zzm Expressed in GB cancer & LN meuszasisz
7/25 had malignancy luqm 2016.374.1995)
Neutral endopepridase ms//4 2o0za4s.zosal Rare: antenatal MN in fetuses of mothers
with deficiency of neutral endopepnidase
Bovine serum albumin (NE/M 2011:364:1101) Rare cause of childhood MN
Recombinant arylsuifatase B (MW 1014125167s1 Enzyme replacement for Pompe disease
 Ca us e s of S e c onda ry MN

Drugs unSAIDs. gold. mercury

Autoimmune SLE, RA. Sj6grens
Kidney allograft reiectlon, GVHD [nor z011;zs102s)
Alloimmunity
HBV (HBeAg, ansHBeAb present on immune deposit)
lnfeclion
Syphilis. malaria.? HCV (dubious causal relationship)
Solid organ tumors (lung. GI. breast. pros re. uterus)
Malignancy
Hematologic (Hodgkin and NonHodgkin. CLL)

Clinical Manifestations
Classically NS (80%) less commonly with subnephroticrange proteinuria (<3.5 old),
Onset of NS may be gradual compared no the rapid onset seen with MCD.
u If AKI is present. consider renal vein thrombosis or rare crescentic MN
CKD may be present after years of persistent highgrade proteinuria
Thrombosis is more common in MN (7%) vs other causes o( NS. Hypoalbuminemia
<2.8 gldL is a significant independent predictor of thrombotic risk (QASN z01z;7:43I
Diagnosis: Kidney Biopsy Is Gold Standard
LM: thickened glomerular capillary wall with spikes
IF: IgG and C3 granular staining
EM: subepithelial deposits. foot process effacement
In PMN 15% of patients will have glomerular antigenpositive PLA2R staining despite
negative serum antiPLA2R antibodies
Suggestive Pathologic Features of Primary vs Secondary MN
P r i m a r y MN S e c onda r y MN
Features
Leukocyte infikration in malignancy
LM
IKI zuas=1(>1s10i

IgG subtype IgG4: dominant in l8G1. 3 in LN

PLA2R.THSD7A lgG1.2 in malignancy
(+) in LN: can have andTBM ab with
Tubular basement (TBM) ()
tubulointerstitial nephritis
IgG staining
(+) in classy LN
Other Ig. C1 q ()
Subepitheiial, Additional mesangial. subendothelial
Electron dense deposits
lnmme mbnnous In LN
Endothelial tubuloreticular (+) in classy LN
()
inclusion

Serum antiPLAZR antibodies: the presence of has 96-100% specificity for PMN;
diagnostic. esp biopsy is connnindicazed and renal function is preserved ous One
2014;9:e1049362 KI 2019;95:429)

E v a l ua ti on
Serum antiPLMZR level; if negative consider ant.iTHSD7A resting v~d\ere available
If history and biopsy are suggestive of secondary MN: age and riskappropriate CBD
cer screening, especially in older aduks (age >6S yr) and chose who are andPLAZR
negative
Recommended Cancer Screening (USPSTF)

Colorectal 5 0 -7 5 l o
Breast Biennial mammography 5074 y/o

Cervical Pap smear q3y 21-65 lo

Annual low dose CT for 55-80 lo adults who have a 30 packyr smoking
Lung
history and currlendy smoke or have qui: within the past 15 yr

Serologic testing for autoimmune disease. including ANA and complement levels
Hepatitis B and C serologies. HIV. RPR
Consider GVHD in patients who have had a bone marrow transplant
If nephrotic: high index of suspicion for RW DVD or PE
RVT prevalence 30% in nephrotic MN lAmIa¢¢ \900:69:s191
RVT usually asymptomatic. but if acute may present with abdominallllank pain and if
bilateral may present as AKI. Raul stenography is gold standard to diagnose but rarely
done. No consensus on best radiologic test to use for diagnosis if suspected (CT angio.
Doppler ultrasound MRl).depends on local expertise but all have fakenegatives.
 Treatment
Antiproteanuric tx w/ ACEI or ARB: If secondary MN, treat underlying disease
If complications of die NS are present then initiate immunosuppression (IS)
If proteinuria >4 old persists after 6 mo ofACEI or ARB. consider IS
If eGFR <30. KDIGO 2012 suggests against IS (recommendation not graded)
Among immunosuppressive regimens. glucoconicoid monotherapy should not be used

Immunosuppressive Regimens for MN

Treatment Dosing Duration Efficacy
Alternating Glucocordcdds (mo 1.3.S) 6 mo 72-93% PRICR
Cydophosphamide IV methylprednisolone Relapse: 1025% by
(CYC) and 1 gon d 1.2.3followed 3-4 yr
glucocorticoids by PO prednisone
(aka modified Pont:icelli" 0.5 mgkg daily x 27 d
protocol) CYC (mo 2, 4. 6) 2.0-2.5
(nam wnnosc /ASN mg/kg PO daily
1998:9:444: 209798118991
Continuous CYC 1.5-2.0 MW PO 12 mo 92x PRICR. 36% CR
Cyclophosphamide x 12 mo Relapse: 28% by 5 yr
and glucoconicoids Glucocorzicoids for first
(nor z004.1,1142) 6 mo: prednisone
0.5 mgkg daily x 6 mo
with medwylprednisolane
1 g IV on day 1.2.3 of
mo 1. 3.5
Cyclosporine (CsA) CsA: 3.5-5.0 mg/kyd 12-1s mo $2-75% PR/CR
(MEN1OR NEW 201938\362 divided bid. :rough (stop if no Relapse: 36% by 1.5 yr
KI z001:sz14a»I 120-200 response
9; prednisone 5-10 mg by 6 m°)
QD or QOD
Tacrolimus (Tac) Tac: 0.05-0.075 mglkg/d 12-18 mo 76x PRICR
(KI2a01:71:914) divided bid, up (stop if no Rel-we 47% w zs Y'
3-5 response
2 prednisone 5-10 mg by 6 mo)
QD or QOD
Rituximab (MENTOR Rizuximab IV 375 mg/kg May repeat 60-65% PR/CR,
~£,m zoizael auusu Qwk x 4.or 1 g Q14d at 6 mo 27% CR
N1HJ1141$) x2 Relapse 28% by 5
PR, partial remission: CR camplexe remission

Anticoagulation for patients with known thrombosis. Prophylactic anticoagulation

should be considered for padenrs with albumin <2.8. Decision analysis tool can be
found at http:/Iwww.unckidneycentenorg/gnrools
Prognosis
Approximately 1/3 of patients have spontaneous remission. usually widlin the first 6-9 mo
Spontaneous remission is more likely in those widi preserved kidney function and subne
phrotic range proteinuria. but has been reported in pts MM highgrade proteinunia
Complete remission (<300 mg/d proteinuria) and partial remission (<3.5 Yd proteinuria)
is associated with a 10yr kidney survival of 100% and 90%
50% have persistent NS: of these. 3040% progress to ESRD within 5-15 yr
Proteinuria >8 g/d is a risk factor for progression regardless of GFR (Io 1997:51901i
AntiPLA2R Ab titers may predict disease course: low and falling titers are associated
with spontaneous remission. while high titers are associated with development of
persistent proteinuria iI*5N 1014;24:13S7; An, / ~¢piimI 101S;4170)
AndPLAZR Ab titers may be used to monitor response to therapy. Immunologic
remission typically precedes fall in proteinuria
Transplantation
Recurrence: 40-50%.
Risk factors: higher prev;xp proreinuria. (+) PLA2R Ab (Tnunspbnladun z011»10a1710)
Tx: riruximab or z009;9:2aoo>
De novo disease is rare and may be alw DSA and antibodymediated rejection
MembranousLike Glomerulopathy With Masked IgG
Kappa Deposits (MGMID)
Rare secondary form of MN where subepl deposits show C3predominant staining on
routine immunolluorescence of fresh tissue (may be misdiagnosed as C3 glomerulopathy).
by: reveal strong IgGk staining after protease digestion lx: 2014:B6:154)
Mos: commonly found in young women with positive autoimmune serologies.At least
one case recurred posttransplant (in Rep 2016;\:199)

MALIGNANCYASSOCIATED MN
The mlc glomerular disease in patients with cancer
Incidence of cancer in MN: ><2.25 We zwnwa9a1 - 9.8 (xi 1006;70:1s101
Reported case numbers: lung > stomach > kidney > prostate > colon, breast cancer
[Nat Rev Ncphml 2011:785)
Other reported cancer: bladder. pancreas. head.and neck.Wilms tumor. teratoma.
ovarian. cervical, endometrial. skin (melanoma. SCC. BCC). pheochromocytoma.
hematologic malignancy (Hodgkin disease. NHL CLL.AML CML); =/p HCT
10% of MN: 52% had symptoms of cancer at time of biopsy (xi 200e;701s1n)
Risk factors: age over 65 yr and history of smoking >20 p.y. in znoemmisiol
Biopsy leukocyte infiltration in 200e70.1s101. IgG1, 2 dominance (nor 2c04;191s741
THSD7A expressed in GB carcinoma and LN metastasis and serum Ab disappeared
with treatment (new z01s=374i99s1; 8 of 40 pts with THSD7Aassociated MN was
diagnosed with malignancy we 3 mo from die MN diagnosis (jAr 2017;28:S20)
Cancer surveillance in PLA2R ().THSD7A (+). or nonlgG4 MN UAS~ 101ma24z1 1:
Ac least age and risk factor appropriate screening: may need upper endoscopy.
colposcopy and PSA/prostate biopsy lclAsn z014:9zw9)
Remission with cancer nemoyal or remission; relapse with cancer recurrence

PAUCI-IMMUNE GLOMERULONEPHRITIS
Mos: common type of crescentic glomemlonephrids
Small vessel vasculitis distinguished from other vasculitides by the absence of immune
deposits. ANCA present in 885% of cases (1 Rheumaml 2W1:2B;1S84)
Predominantly affects older adults: mlc renal biopsy diagnosis in >80 (CJASN 20n9;4.10731
Incidence 20 uses per million annually, slight male predominance (sen n¢pne12017.37¢41s>
Clinical subtypes are defined histologically in the Table below (Chapel . Consensus
Cbnferenn Atwas Rheum 10\3z6S1), However. there is substantial overlap between MPA
and GPA.
Prognosis. genetics, epidemiology. and treatment response are better associated with
the specific ANCA antigen rather than histology mm n:vn1»¢w»-mi10141125101
Clinical Subtypes of Paulimmune GN 1~»1~i¢- alien you:ssI: up Z00e4471770l
Disease Histologist Features ANCA
Microscopic Polyangiizis Necrotizing vasculitis widiout 60% MPO or
(MPA) gnnulomatous inflammation. pANCA
Often renallimited
Granulomatosis with Necrotizing granulomatous 75% PR3 or cANCA
Polyangiitis (GPA). inflammation.
formerly Wegeners" Often involves kidneys. upper and
lower respiratory trac:
Eosinophilic Granulomawsis Eosinophil rich necrotizing 75% ANCA (mossy
with Polyangiitis (EGPA). granulomatous inflammation. MPO/pANCA) if
formerly "Churn-Strauss Usually involves respiratory tract. renal disease present
about half of cases involve 26% ANCA if no renal
kidney alw asthma and disease present
circulating eosinophilia

Antineutrophilic Cytoplasmic Antibody (ANCA)

Presence ofANCA was traditionally diagnosed by performing IF on ethanolfixed human
neutrophils incubated with ptS serum (indirect immunoNuorescence. IIF). Cyioplasmk
(C) ANCA pacxem is usually seen MM ab against serum proteinase 3 (PR3) and
Perinudear (P) ANCA is usually seen widl ab against myeloperoxidase (MPO).
Elevated PANCAJMPO ab can been seen with other autoimmune diseases such as
SLE or iniiammatory bowel disease
Pathogenesis
Distinct genetic associations exist for PR3 vs MPO disease (NEJM 2011:367:2I 4)
Formation ofANCA may be potentially triggered through the following
Environmental stimuli: silica.asbestos l;As~ 2001;12:134: Ref fun 20081726051
Drugs: hydralazine. propylthiouracil www; Rheum 200tt4:3340s1
Infection (NDT 101017531119. Coin RNeumalal 1010.29:B93)
Molecular mimicry 1n¢:m¢42008;14:10as). Epigenetic dysnegulatlon UG 1010;120¢32U9)
Loss ofT cell regulation rfmwww 201043064)
ANCA causes the development of vasculitis through several proposed mechanisms
activation of neutrophils via Fc receptors (!"'"'"*1"11 1994 ;lS]:l171)
Release of neutrophil extracellular traps (NETS) containing chromatin and granule
proteins that trigger damage to endothelial cells and ANCA antigen presentation
to immune system (num M¢4 2069:1$:623)
Activation of the alternative complanent pathway and generation d C5a.a nwuophil
chemoatuactant and activator In 1007;71:64e; jAN 200910:289)
Pathology
LM: fibrinoid necrosis of glomerular tufts +I- rupture of GBM. proliferation of epithelial
cells forming crescents
IF: no staining for Ig. no or mild complement staining (Pauci Immune)
EM: no electron dense deposits
Affected nonrenal :issue shows leukocytoclastic vasculitis
Clinical Manifestations
Constitutional: malaise. fatigue. fever, weight loss. night swears. anorexia
Renal: rapidly progressive glomerulonephritis (AKl. hypertension. edema. microscopic
hematuria. subnephrotic proteinuria over wk to mo)
Pulmonary: hemoptysis (from alveolar hemorrhage). cough. dyspnea on exertion.
alveolar infiluates on CXR
Sinonasal: sinusitis. otitis media."saddlenose" deformity (particularly GFA)
Dermatologic: palpable purpura (usually in lower extremities). petechiae, ulcers. nodules.
urticaria. ecchymoses. bullae
Ocular: iritis. uveicis, episclerltls
Gl: bleeding or perforation due to vasculkic ulcers
Cardiovascular: pericardltis. myocardids
Neurologic: mononeuritis multiplex.cranial nerve abnormalities
Comparison of PR3 vs MPO ANCA Diseue
PR3 Disease MPO Disease
Clinical manifestation Saddle nose. nasal ulcer/crusting, Renal limited GN
(lIdvm Rheum bone destruction Lung involvement w/o
201b6t3452) Epistaxis. hearing loss, Subglonic nodules
stenosis Lung involvement wlo ENT
Lung with cavities disease
Pathology Focal GN. Necrosis Global sclerosis. Interstitial
Z003;41539)
IA}KD fibrosis
Recurrence More frequent Less frequent
Workup
Lab: elevated Cr. hematuria (including dysmorphic RBCs and red cell casts), proteinuria.
normal complement levels. eosinophilia (in EGPA).elevated MPO or PR3 ab (or both).
positive PANCA or CANCA (O r both)
Rule our druginduced causes. esp if dual MPO and PR3 positivity or concomitant ANA
positivity Common culprits are propyldmiouracil. hydralazine. Ievamisole, allopurinol. and
TnFalpha agents <QAS~ 2015;10:1300)
Induction Therapy
CYC w/ CS (3d pulse of medlyIprednisolone 500 mg IV, then 1 mg/kg daily prednisone
up to 60 mg for 1 mo. then taper off by 6 mo)
CYC: in monthly IV doses (0.5-1 W) or dosed orally (1-2 mglkgld). Dose should be
adjusted for age >60.eGFR <20.and no avoid neuuwopena lxoico Gn). IV regimen has
lower eumularive dose and may be equally effective (qAsn 2013811191
Rizuxlmab (RTX) 375 mg/m' weekly x4 is an acceptable alternative lug;/14 2014361211:
1010:363:221: 101313693417: Ann Rhem Ds 2016;75:1166: KDIGO GN 1012)
Plasmapheresis x7 over 14 d for rapidly rising Cr. severe renal impairment (Cr >5.8 mg/dL
OR oliguria).AKI requiring dialysis. pulmonary hemorrhage. or concomitant antiGBM
disease (MEFEX JASN 2007:1s:z1sa Kolco GN 2012)
 RCTs of Rituximab (RTX) vs Cyclophosphamide (CYC) Induction
Trial RAVE RITUXVAS
RTX group RTX 375 mglm1 weekly xi wlo RTX 375 mglm' weekly x4 + CYC
maintenance therapy 15 mg/kg IV wl Is: & 3rd RTX
CYC group CYC 2 mglkgPOQD foIIowedbyAZA CYCN§or3-émoiollowed byAZA
Results RTX noninferior in inducing remission RTX not superior in sustained
by 6 mo (64 vs 5396). 12 mo (48 vs remission at 12 mo and severe
3996).and18mo (39 vs 33%) (nqrlI adverse even's www Zowssa:zin
zoimaeszzn 201z,369;4171 No difference in deadl, ESRD and
PR3 group respond berger no RTX relapse as 24 mo [Am Rhem o;
(Ann Rieum Drs 2016:75:1 i's) 101$:74:11781
All RAVE and RITUXVAS groups received corticosteroids

Maintenance Therapy
18 mo of maintenance therapy in patients who achieve remission. No further therapy
in patients who progress no ESRD without extrarenal disease 0tDIGo GN 10121
Azathioprine (AZA) 1-2 mg/kg/d or Mycophenolate mofetil (MMF) 1 g BID in
patients unable to tolerate AZA laI:>IGo GN 2011), MMF has been associated with a
higher rate of relapse in a single study (Ann's Rheum 1004511279i
Riuiximab 500 mg on d 0 and 14.mo 6. 12.and 18: more effective than AZA (AZA
group had HR 6.61 for major relapse) (MAINRITSAN N£)M 2014;371;1771)
Trimethoprim-Sulfamethoxazole (TMPSMX) should be considered in addition to
immunosuppression in patients with upper respiratory tract disease (KDIGO GN 2011)
Relapse
Rate 30-50% by 5 yr: Higher with PR3 disease. respiratory involvement. and nasal car
riage of S. aurous (in GPA) (Ann IM ZlX)5;8:170% nam 199s;3:1s:16: Ardine Rheilnuld zoiawesol
Reappearance or t ofANCA correlates strongly with renal relapse. Fersistently elevated
titer is al relapse (KI 2009;63:1079: lASN 2015:26:537; Anlmris Rheum 2004:51269)
Persistent hematuria >6 mo (x3.99). but not proteinuria is a/w relapse (qASN 20\&13:251)
RTX appears more effective than CYC in recurrent disease (NEW z01s;wx417l
Transplantation
Wait until 1 yr after remission of extrarenal disease before transplant. Presence of
circulating ANCA ab does not increase the risk of recurrence lxoico Gn 1011)
Risk of recurrence after transplant is estimated 10% and responds well to repetition
of induction therapy (Ki 2007;l 1i1296)
Recurrence after transplant may be more likely in PR3 disease (I Neplud 1017;3tt141)
Patient and graft survival 92% and 88% at 5 yr. and 68% and 67% at 10 yr, similar to
other nondiabetic kidney diseases (Car Open Rneun 2014:16:37)
Prognosis
Complete remission is attained in the majority (70-90%) of treated patients
Untreated disease is associated with 50% mortality at 1 yn Estimated 1 and 5yr
patient survival 84% and 76% who z008;41=176)
Presence of pulmonary hemorrhage is most important determinant of patient survival
(KDIGOGn2011)
20-25% patients will progress to ESRD war 7004;1m19s4)
Single most important prognostic marker for longterm renal outcome is Cr for
20041919541
Biopsy predictors of poor prognosis include degree of glomerulosderosls. interstitial
fibrosis. and tubular atrophy in 1001:61:17321
 ANTI-GBM DISEASE
Definitions and Pathogenesis
Characterized by ab against a glomerular basement membrane (GBM) antigen. often
crossreactive w/ alveolar basement membrane.causing RPGN +I- alveolar hemorrhage
AntiGBM disease: kidney involvement alone
Goodpastune syndrome: kidney and lung involvement ("puImonavyIenal syndrome")
Goodpasture disease: kidney and lung involvement + antiGBM serology
Principal antigen: (13 noncollagenous (NC1) region of type IV collagen
Trigger for autoantibody production is unclear. but may involve a conformational
change (eg. induced by airborne irritants such as cigarette smoke) that unmasks EA
and EB epitopes in 2008;64:1108)
Antibody binding jin rly along GBM induces crescentic glomenilonephritis
HLADRB1 alleles strongly associated with disease susceptibility (KJ 1999s6.16381
Epidemiology
Incidence: 0.5-2 cases/million/yn significantly lower than other RPGNs.eg. ANCA GN
Two peaks of incidence: (1) young adult males: (2) elderly women
Alw cigarette smoking, hydrocarbon. viral URI. alemtuzumab (NE/M zooeaswsel
Clinical Manifestations
Kidney: hematuria +I- proteinuria usually with rapidly progressive glomerulonephritis.
Symptoms include teacolored urine. and those related to kidney failure
Lung: hemoprysis due to diffuse alveolar hemorrhage (DAH): Other symptoms include
cough, shortness of breath, tachypnea
Constitutional symptoms (eg. fevers. fatigue, nausea, weight loss) are largely absent
Younger patients may present widi more fulminant disuse when compared m older adults
Pulmonary involvement a/w pulmonary irritants, eg,cigarette smite (jam 19aa;83b4;1390)
Diagnosis
Kidney biopsy: crescentic GN w/ linear IgG (usually lgGl and 3. rarely IgA. IgM) by IF §
Bronchoscopy (gold standard no identify DAH); Chest CT: ground glass opacities -4
AntiGBM Ab: diagnosis and for lacking disease activity Reasonably sensitive (63-93%) is
and specific (92-97%) 1!i¢<h¢v» MdMe4 1996;59:521. In a severely ill patient, the clinical I
manifestations plus (+) AntiGBM ab may be enough to make the diagnosis.
ANCA ah: in 15-50%, USU. PIPO, more common in the elderly
Disease Variants
. Dual (+) andGBM +ANCA disease: 47% d antiGBM disase.6.1% MANCA disease;
similar prognosis and clinical features of antiGBM disease. though may be alw clinical
features of vasculins and higher chance of relapse and renal recovery (KJ 201792693)
Atypical andGBM disease rare: (-) serum antiGBM antibody: usually milder. non
fulminant kidney disease; biopsy shows linear andGBM Mining (may be a monoclonal lg).
widmut crescents.Thought no be caused by antibodies co an alterative GBM protein
(je. not a3 NC 1 type IV collagen). Clinical course more indolent (KI 2016289:897)
Treatment
If kidneylimited. dialysis dependent on presentation and 100% cellular crescents or
>50% globally sclerotic glomeruli. chance of kidney recovery is exceedingly low
and is may be deferred lAn IM z001;13410331
Cyclophosphamide: 2-3 mglkg/d PO x3 mo. consider dose reduction in the elderly
Corticosteroids: mechylprednisolone pulse (0.5-1 g/d x3) followed by oral prednisone
1 mglkg/d (max 80 mold) tapered to 20 mg by 11-12 wk
Plasma exchange: daily for 14 d or until antiGBM ab undetectable
Alternative immunosuppressives: insudicienr day to recommend.case reports
using azathioprine. mycophenolate. and rituximab
Maintenance therapy: not required unless ANCA (+)
Prognosis
Outcomes in patients who receive appropriate therapy (Ami we 2001;I34:1033): 5yr
kidney survival 94% if Cr <5.7 on presentation: 50% if Cr >S.7 but not on dialysis
Predictors of ESRD: dialysis on presentation,% interstitial infiltrate.% normal
glomeruli lqAsn 201B:13:63)
Transplantation
Require () antiGBM ab for 6 mo; Recurrence 50% if andGBM ab (+) at time of txp
Low recurrence (3-14%). lower rates in current era likely dlt better :xp immuno
suppression (KI 2013:83:503: Cal Ylunsploflt zorn:ml
Alport syndrome wl large deletions in the COL4A5 gene: at risk of developing do novo
antiGBM disease after KT. since the wildtype COl.4A5 in the allograft will be immu
nolozically foreizn.Autoimmune conlormerona!.hy" (NUM 2010;363:3431
 Ep id e m io lo g y
Immunoglobulin A nephropathy (IgAN) is :he m/c glomerular disease (nor 20111zs14141
Disease prevalence varies by ancestry: highest in Asians and norther Europeans.
lowest in those with subSaharan African ancestry (Pl.oS Cenex 2011;B:e100176$)
In Whites. :he disease is more common in men than in women
Pathogenesis
Primary IgAN: immune complexes of galactosedeficient lgAl deposit in the
mesangium UCI 2009;119;1eea)
Galactosedeficient lgAl is a heritable :mir lx 2001;aa79)
GWAS have identified multiple susceptibility loci (naG¢nei 1014:46:I 1B7)
Up to 5% of patients with loAn have a relative with IgAN
Subclinical IgA deposits common in healthy individuals in highprevalence countries.
eg. up to 16% in japanese (Ki 1003:63:21861
Secondary IgAN associated with liver ds. HIV. seronegative arthritis (esp ankylosing
spondylius). inflammatory bowel ds.and celiac ds (Sem ~»»w- zcueze.zn
Liver dysfunction 1 clearance of circulating IgA, -» deposits in mesangium
Other causal relationships in secondary disease largely uncertain
C lin ica l M a n if e st a t io n s
Classically presents with hematuria (macro or micro). subnephroticrange proteinuria
and hypertension. Nephrotic syndrome is less common
Complements (C3 and C4) usually within normal limits: rarely C3 may be low
Recumbent gross hematuria.especially widl URIs (synpharyngitic") may be present
AKI during episodes of gross hematuria usually due to pigment nephropathy and
resolves once hematuria clan (3-S d): if no resolution of AKI after 5 d.then consider
kidney biopsy to evaluate for crescentic disease vs other fuse
Kidney Biopsy
The gold standard for diagnosis; reserved for those with hemaruria and one of :he
z following: (1) proteinuria >0.5-1 Yd: (2) i GFR:and/or (3) newonset HTN
'§ Pathology
The pazhognomonk finding is mesangial deposits of Ig/X. most commonly polymeric lgAl
Oxford Classification of loAn developed no identify prognosrically important. repro
ducible features across biopsies: used to generate "NESTC" score
Oxford Classification of loAn In z0w;91:1014)
Feature Score Clinical Implications
Mesangial 0 = <S0% M1 predicts worse outcomes (vs M0)
hypercellularity 1 = >50% gloms
Endocapillary 0 - None E1 independently a/w worse renal survival (vs
proliferation 1 =Any E0) only in studies where patients did not
receive IS
E1 NOT predictive of outcomes in studies diet
included immunosuppressed patients
E1 alw improved outcome in those treated
with corticosteroids
§_egmengl 0 = None $1 predictive of worse outcomes (vs S0)
glomerulosclerosis 1 =Any Podocytopathic features al proteinuria.
faster I GFR. bu: better survival with IS
Iubulolnzerscicial 0 I <25% Strongest independent predictor of adverse
fibrosis 1 = 2550% renal outcomes
2 = >50%
Qrescents. cellular/ 0 s None C1 predictive of worse outcomes if no IS
iibrocellular 1 = at least 1 C1 NOT predictive if IS used
2 = 225% gloms C2 predicmle d worse outcome regardless of IS

Disease Variants
IgAdominant infectionrelated GN staph infection in elderly diabetics UASN 2011.221s7)
leAn with minimal change disease: clinically similar to MCD. presents with nephrotic
syndrome and usually steroid sensitive. likely reflects dual disease (CJASN 201439 10331
IgAN widi ANCA vasculitis: / MPO and PR3ANCA in crescenric disease
Crescenric" IgAN variably defined: range from >10% to >50% crescents
Treatment (Recommendnucn Grade Band on KDIGO GN 2012 Gidelines)
ACEI or ARBs: for BP control (goal <130/80) and proteinuria reduction
Corticosteroids (CS): for patients who do not achieve proteinuria of <1 g/d with first
line therapy over 3-6 mo and have eGFR >50 (ZC)
Cyclophosphamide (CYC): considered for patients with rapidly progressive renal fail
ure. usually characterized by crescendc GN or nephrotic proteinuria (nor 2003;18:13111
Large RCTs of CS w/ or w/o alkylating agents and antimetabolites have not shown
consistent benefit
Key RCTs of Immunosuppression (IS) in leAn
Patients IS Protocol vs
Study Characteristics Placebo O u t co me s

STOP gAN >7 5 0 mg / 2 4 h r De t e r mi n e d b y G FR: No d i f f e r e n ce i n n u m

(NEW 2015: prot einuria eGeR >6& predni b e r e xp e r i e n ci n g 1 5
J7J:Z1l5} despit e ACEI or so n e Q O D x 6 mo loss of eGFR
ARB. st at in. BP 4 met hylpred 3 g T clinical remissions in
<125f 75 N at mo 1, 3. 5 I S group (UPCR <0. 2
NS a n d RP G N eGFR 30-60: PO wit h st able GFR)
excluded CY C + r e d severe inf ect ions in I S
N 162 random x3 mo t h e n A ZA I group
ized t o I S vs r ed x 3 yr
placebo
TE S TI NG i t * / m . Prot einuria >1 old Me t h yl p r e d n i so l o n e St udy t erminat ed early
2017;3184321 e G FR 2 0 - 1 2 0 0. 6-0. 8 mg/ kg/ a due t o serious inf ec
N 262 random P O x 2 mo t h e n t i o n s i n CS g r o u p
ized t o I S vs t a p e r e d o ve r (8. 1% including 2 f at al)
placebo 6 - 8 mo Fe we r co mp o si t e r e n a l
endpoint s (53% vs
15. 9%). slower rat e of
G FR d e cl i n e a n d . p r o
t einuria in CS group
(1. 31 old vs 2. 19 g/ d)

Fish Oils inconsistent benefit Studied doses range between 3,3 and 12 old. KDIGO
2012 suggests 3.3 g/d for those with proteinuria >1 old despite supportive care (20)
Tonsillectomy: a/w improved outcomes in observational studies (pardculady from
Japan); not superior to CS in randomized controlled trial mot z014.19¢1s46>
MMF: several negative trials despite one Chinese study suggesting benet (KJ 2010;77;54J)
RTX: in eGFR 30-90 dad not improve eGFR and proteinuria l;As~ 2017¢zs:130sl
Supportive care:for AKI in loAn with gross hematuria and kidney biopsy showing ATN
and intratubular erythrocyte casts (2C)
Prognosis
35-40% reach ESRD by 30 yr from diagnosis
Prognosis. from better to worse: episodic microscopic hematuria > episodic gross
hematuria > persistent hematuria > hematuria - proteinuria less than 1 old at dx >
hematuria + proteinuria greater than 1 old on treatment
Most important prognostic indicators. timeaveraged proteinuria. T BR and Tscore
Spontaneous remission may occur in patients with minor glomerular abnormalities.
In a retrospective study of children with leAn who did not receive IS. 60% achieved
5pgnqnegug remission (paint nwnui 21:13125.711
Transplantation
Postzransplant recurrence of gAN up to 30% of patients 10 yr posttransplanL Graft
loss due to loAn only 3-4%.
Predictors of recurrence posttransplant include precransplanr high levels of galactose
deficien: IgA1.earlier age of disease onset. and crescents lAM! :Mala 20 I7;45;99)
Maintenance CS aw recurrence in some.but no: all series WT 1011;11:164§)
For pos:transplant recurrence. highdose CS may be considered

IgA VAscuuTls (IgAV) Wons Rheumtol 2017;69t1862)

IgAV is preferred term of Henoch-Schdnlein Purpura (HSP) and anaphylaczoid purpura
Small vessel vasculizis afleczing skin (100%. palpable purpura). kidney (70%. hemaruria.
proteinuria. AKI). joints (6196). and GI tract (53%. bowel angina. bleeding, ischemia)
 Some IgAN progress to IgAV in 5 mo-14 yr (Min Nepnrol 101s;31;779)
Adult IgAV: cause CKD. unlike selflimiting pediatric gAv (SemnAnlnuis Rheum 10029211499
Kidney biopsy: indistinguishable from IgAN: extracapillary hypercellularity (crescents)
41X: fibrinoid necrosis 32%
Skin biopsy. leukocytodastic vasculitis (LCV) with IgA deposition: 30% of all LCV
(Mayo Gi Flo: 2014891151 So
TxCS:4 CYC wlo benefit (KI 2010;7s;495);possible role in severe (crescent >50%) disease
(nor z0a4:19:ase); MMF may be used as CS sparing agent (Ami ~=»»»~l2012:36z271)

Lupus NEPHRITIS
Renal involvement: 50% of SLE: mos: important predictor of death (Nnewnalaugy
2o0m4e:s4z)
SLICC included LN as a standalone diagnostic criteria for SLE (Animas Rheum 101 zs4;ze77)

Pathogenesis
Risk genes (jAuMirvnun 2013141¢251 and environmental factors (et infections. hormones.
UV light. drugs) -» cell death - delay in dead cell clearance -» activation of viral recog
nition receptors of the innate immune system, INinducible genes and autoreactive B
and T cells (Semn lnvnnopnlNal 1014:36:4431
Nonspecific trapping d circulating immune complexes. in situ formation, or by interaction
with f\°2s=iivel1 charged components of the giomenilar capillary wall -> formation and
deposition of immune complexes -» die binding and activation of complement -» the
ensuing inflammatory cascade
TMA w/ or wlo AFL ab can coexist and worsens prognosis
Lupus podocytopathies alw heavy proteinuria but no active inflammatory lesions
Interstitial or vascular renal disease
Clinical Manifestations
Variable asymptomatic hematuria. proteinuria. NS. RPGN
Workup
1 ESR.l CRR antidsDNA Ab. I C3,C4, CH50:APLA
Lab do not always correlate w/ LN class: Bx is frequently necessary
Bx if:T Cr wlo alternative explanation. proteinuria >1 old. proteinuria >0.5 Yd with
active urine sediment (dysmorphic RBCs or cellular casts) (Aruuws Can be 201L6A:7971
Pathology
IF: IgG dominant full, house pastern (glomerular slain 19 lim C3.and C1q codominance)
EM: endothelial tubuloreticular inclusion (TRI). subendothelial and subepithelial
deposits; extraglomerular immunetype deposits within TBM. the interstitium. and
blood vessels
Lupus Nephritis Classification l\snmps KI 20l)4:65?511: ;ASN 1004:15:241)
I (minimal mesangial LN): nl LM.wl rnesangial immune deposition on IF and/or
EM
II (mesangial proliferative LN): mesangial hypercellularity w/ Immune deposition
III (focal LN): inflammatory injury affecting <50% of :he glomeruli by LM wl cres
cents.fibrinoid necrosis. andlor subendothelial immune deposition
Classes Ill and IV are subdassified as A MM active lesions of proliferation and necrosis.
C with chronic lesions of sclerosis and fibrosis. or AIC widi a combination of these
lesions
IV (diffuse LN): inflammatory Injury affecting >50% of the glomeruli.agaln classified
as A. C. or A/C. This class is further divided into segmental (S) or global (G) depend
ing on the extent of inlury to the individual glomerular tuft. greater than 50% in the
latter category
V (lupus membranous nephritis): glomerular capillary thickening on LM wl sub
epithelial immune deposition on EM/IF
VI (advanced scleroslng LN):290% global glomerulosclerosis wlo residual activity
Upcoming proposed changes to ISNIRPS (Ki z01a:93.7a9)
Elimination of IVS and IVG subdivisions
Replacing the A/C subclasses wl a modified NIH lupus activity/chronicity scoring
 General Treatment
RAAS inhibition for all pronelnuria >0.5 gig Cr
Hydroxychloroquine (HCQ) for all LN: I renal disease and severity Imagine 1016:95:92891)
Max 66.5 mglkg IBW (Iipophobic): sle retinopathy (/ophthalmologic exam q 12m)
Crescents. interstitial and vascular Lesions:a/w renal progression. mortality (Lupus
2016:1S:1532)
Classes III and IV: consider activity and chronicity index for IS decision
Ciass VI: prepare for RRT
Treatment of Classes III and IV
Contraception in active classes III and IV LN

Induction Treatment of Classes Ill and IV LN

Corticosteroid (CS) Give CS plus any of below regimen unless otherwise specified
IV methylprednisolone 250-1,000 mg/d x 3 d -\ prednisone 1 mg/kg
qd with open
>70% remain on cs 10 yr after (Am ohm Do z01ms~zsn
NIH CYC 0.5-1 gm' BSA qm x 6. q3m x 4, q6m x 2 were 19a6:314¢n4>
Lowdose IV CYC 500 mg q2w x 6 w/ AZA maintenance = NIH dose 1ELNTArVmU¢ Mew
200z;4e¢z1 z1). Remain same after 10 yr um niim no 10 10.69;61i
Works on African American (Access Anil Mum 201444114441
PO CYC 2.5 mg/iq/d MMF MM zaoQ34a11ssl
MMF MMF wl target 3 old >< 6 m = NIH CYC lAuds up mozanos)
AZA CYC > CS only luqm 19a4.3111s2s): Option for pregnancy
Mulnirarger CS + Tac + MMF superior to CS - NIH CYC as 24 wk in class V+ (Ill
or IV) lAM :m 201S:16218)
Riruximab 2 g,x2 cycles addition to MMF and CS nor superior (LUNAR Aida
251 g xl, 2 wk Rheum zo 1z;so.1z1sl
apart Induces remission in refractory cases (NDT 201J.N:1M)
2 g + MMF w/o PO CS achieved CR in 52%, PR in 34% (RITUXILUP
Am Rheum M 2013:72:12B0)

If CYC doesnt induce remission. MMF and vie versa (use Annum Cae Res 1011:64:797)
Once remission has been achieved.maintenance treatment should be continued

Maintenance Treatment of Classes Ill and lY LN

cs Prednisone $10 mg/d with one of below
MMF 2 old superior ¢oAZA (ALMS of/m zoI 1;ass:1seo)
AZA 2 mg/kgld
CYC T Death. Cr doubling and sle (NEW 2004;3§09711; not recommended

Relapse: ueat MM induction agent

Treatment of Class V
 Treatment of ClassV

CS CS monotheraphy is not recommended ()ASN 1009120901)

MMF - NIH CYC in e4Gcacy and side effect profiles 1xl 201<x7711sz;

CYC Lowdose CYC is preferred

Remission 83% vs NIH CYC 60%. relapse is common. Promeinuria >5 g/d alw
CNI
no remission UASN 10a9:z(x9011.
Rituximab 2 z w/o PO cs induced CR in 38% PR in 24% \>Y 12 mo [Ann khwmbs zoimnzaol

OTHER Fonr4s oF GLOMERULAR Lesnon IN SLE

Renallimited LupusLike Nephritis (nm z01z4171z71
Renal biopsy with lupus nephritis features wlo systemic SLE
Some patients may develop SLE later: needs monitoring
Tx: co rre sp o n d in g L N cla ssifica tio n
Ne cro t izin g and Crescentic LN with ANCA (C/ASN 2008:3:581)
Necrosis and crescents exceeding the degree of endocapillary proliferation Et subendo
deposits
J ANCA ELlSA;Tx dlc hydralazine if taking;CYC
L u p u s Po d o cyto p a th y (q Asn 1 0 1 6 ;1 1 5 4 7 )
SLE + MCD or FSGS. mesangial proliferation wlo endocapillary proliferation. necrosis.
and/or crescents. Extensive too: process effacement wlo GCW deposits on EM.
Tx: 94% responded to CS wu 4-8 wk. Frequent relapse (56%) (qAsn 2016:11:585)
co lla p sin g Glomerulopathy in SLE 1c/As~101u9\41
CG and SLE (positive serologies +I- lupus sx at time of Bx)
Co mmo n in fe ma le (7 9 %) a n d A frica n d e sce n t (8 9 %)
Geneucs: strongly a/w APOL1 risk allele in AA with SLE (iAs~ 2013I24mI
Clinical: massive proteinuria with rapid progression of renal dysfunction
Pathology: global or segmental collapse of glomerular capillary tuft, with wrinkling and
reuaction of the capillary walls. overlaid by epithelial cell proliferation in Bowman
space (xi 1996:§0Ll734)
Tx: variable in series. irrespective of concomitant LN on histology. CS. MMF. NIG.and AZA
Prognosis: poor 7/13 went onto ESRD within 2 yr time

INFECTION-RELATED GLOMERULONEPHRITIS
POSTINFECTIOUS GLOMERULONEPHRITIS (PIGN)
B a ckg ro u n d
Poststreptococcal GN (PSG N), the prototype of PIGN is increasingly uncommon
in t h e d e ve lo p e d wo rld
» PSGN is more common in children: highest incidence between 4-15 yr old
PIGN formally implied antecedent infection and latent period of dwk after infection has
cleared (10-14 d for PSGN). Particularly for adults with nonstrep infections. GN often
occurs during ongoing infection:thus the preferred term is Infectionrelated GN (IRGN).
mlc organisms: Streptococcus (pharyngeal/skin infections). Staphylococcus (skin infections).
and rare gramnegative organisms (Pseudomonas, Escherichio.Yersinio, Pseudomol10s)
P a t h o g e n e s is
Nephritogenic antigens produced by pathogens stimulate an initial immune response.
Two streptococcal antigens have been implicated in the development of PSGN. the
sueptococcal pyrogenic exotoxin B (SPE B) and die plasmin receptor.a glyceraldehyde
phosphate dehydrogenase (GAPDHINAPlr) (KJ 1005;681120)
Immune complexes formed in circulation or in situ induce local activation of alternative
complement and coagulation pathways and recruitment of neutrophils to glomeruli
P a t h o lo g y
LM: diffuse endocapillary proliferative GN w/ intracapillary neutrophils (exudative")
IF: coarse.granular GBM and mesanglal staining of C3 alone or lg with C3 dominance
(st a rry sky a p p e a ra n ce " )
EM: large. scattered subepithelial electron dense deposits ("humps")
Clinical Manifestations and Workup
Acute GN including RPGN (with HTN).edema (80-90%),dark urinelhematuria
In PSGN.typically occurs 10-14 d following infection (pharyngitis. cellulitis. pneumonia)
 T Cr. Y CH50. C3 (90%), C4 (rare), t ASO (in PSGN). red cell asr.s.proteinurla (usu
ally subnephrotic)
Treatment and Prognosis
Supportive care ofAKl. HTN. and edema
Elimination of any ongoing active infection. Patients with PSGN should be :reared with
antibiotics to prevent carrier status. though limited evidence that this affects :he course
of PSGN.Antibiotics are indicated for prevention of PSGN when used to treat strep
tococcal infections in children.
Antibiotics should be used prophylacdcally for close household contacts of PSGN
patients and in epidemics of streptococcal infections UASN 200s;10:,6551
No clear role for immunosuppnession. though there are reports of success with cor
ticosteroids or cyclophosphamide in individual cases of severe/progressive disease
In children.complete renal recovery is likely within 2-3 wk. Persistence of low C3
should raise concern for C3 glomerulopathy. In adults. prognosis is guarded.

STAPHVLOCOCCAL AssoclATeo GNIIGA DOMINANT IRGN

Background and Pathogenesis
Risk factors: >S0 ylo. diabetes. malignancy, IVDU. and alcoholism (1ASN z0112z2..ian
Common site: skin. respiiar.oiy. hmm deep tissuelbone. urinary tract (Am y~¢pi~ii2o1s=41.9el
Causative organisms: MRSA >> MSSA > S. epide/midis/S. haemofyticus >> Enterobacter
species. Escherichia species
Typically during active infection (often chronic) wlo latency period (And 2015..6ssi61
Proposed mechanism: bacterial toxin (eg. S. aureus enterotoxin) acts as superantigen.
bind to MHC molecules _.T cell activation. cytokine release l~w»~»»» an f~n 1011:1m1ai
Pathology
LH: proliferative GN with endocapillary and mesangial proliferation +I- crescents
IF: mesangial C3 dominant or codominant staining with IgA +/- IgG
EM: subepithelial hump"like electron dense deposits
Clinical Manifestations
Renal: AKI. acute GN with elevated Cr. hematuria (including macroscopic), subnephrotic
proteinuria and HTN; up to 1/3 have nephrotic syndrome
Exuarenal: purpuric rash, signs of active infection
Workup
Cr. hematuria. subnephrotic proteinuria
J C3. C4 (hypocompleineitemia les common dlan with PIGN), ANCA (a/w ciesoentic GN)
Evaluate for active infection (blood cx. urine ex,sputum cx)
Treatment and Prognosis
Treatment of underlying infection and supportive care of AKI. HTN.edema
Retrospective studies suggest no benefit from immunosuppression (QASN Z006:11179)
Guarded prognosis: many patients have persistent renal dysfunction and up to 33%
of elderly pts remain dialysis dependent
Risk factors for progression to ESRD and death: age and diabetic nephropathy (;A$n
Z011;22:1S7: Median! Z008:B7:l 1: Anil N¢9hlI(201§:41:9B)

INFECTIOUS ENDOCARDITIS (IE)RELATED GN In 2015:87:1111)

Background and Pathogenesis
6:9 3.5:1.mean age an biopsy 48
Associated comorbidides: valve disease, IVDU. HCV. HIV. DM
Affected valves: tricuspid > mitral > aortic > pulmonic
Staphylococcus > Streptococcus > Banonella. Coxiella. Cardiobacterium. Gemella
Up m 18-24% of IE pos have ANCA (+) (Annrns slew 2014411672 Medan! 2o1a~>s:lzs4»4l
Mechanisms: (1) drcuhdng and in situ IC formation; (2) bacterial toxin activation d akena
tive complement pathway:(3) bacterial toxin activation ofANCA lading no acdvadon M
almemauwe complement pathway via activation of C5a In 201587112411 xmmssos; 2013;e3:m>
Pathology
LM: necrotizing/crescentic > endocapillary proliferative > mesangial proliferative GN
IF: C3 dominant (or isolated) staining. may have (+) IgG. IgM. IgA mining
EH: subendodlelial and mesanglal EDD
Clinical Manifestations
Renal: most common is AKI. may also see hematuria and signs of RPGN
Exvarenal: septic pulmonary infarcts (in tricuspid endocarditis).splinr.er hemorrhages.
fevers. weigh: loss. murmur. Osler nodes.]aneway lesions. Roth spots
Workup
Cr, hemacuria. proteinuria. i C3 z C4 (nl in 44%).may have (+) ANCA/ANA
Check blood cultures and echocardiogram for evidence of endoardizis
T reat men t an d Pro g n o sis
Treatment of underlying infection and supportive care ofAKl
lmmunosuppression: ANCA (+) and/or persiscenc GN despise antibiotics (OD 19991&10s7;
Case in Neill Url 2011421252 lndnn[ Nephrd 201333568: Gln N<PI"°1 Cdse Stud 20\7;5:3Z)
Risk of ESRD corvelates wish elevated serum Cr at diagnosis

SHUNT NEPHRITIS
Background and Pathogenesis
Complication of chronically infected yentriculoatrial (VA) or ventricukaiugular (VV)
shunts for hydrocephalus. Rarely seen in ventriculoperitoneal (VP) shunts
Organisms: S. epidermidislk acnes >> S. aurous >> Pseudomonas. Serration species
IC formation w circulating bacterialbiohlm activating complement padiway (nor 1997.1211431
Pathology
LM: MPGN or mesangioproliferative GN. may have ATN and red cell casts
IF: mesangial IgM. C1q. C3 deposition in 2/3 of cases (Case no n¢p»»ua 20\7=z011=1a¢7149)
EM: subendothelial EDD
Clinical Manifestations
Renal: elevated Cr. hematuria. red cell casts. proteinuria, HTN. edema. may be subacute
Weight loss. even arthralgia. hepatosplenomegaly. rash. so of T intracranial pressure
Workup
T Cr, hematuria. proteinuria. hypocomplementemia, elevated ESR and CRR anemia
May have (+) ANCAlCryolRF (nor 1997;1z1143)
Infection identification may be delayed dlt to poor growth of S. epidennidis and R acne
Treatment and Prognosis
Treat infection. removal of infected hardware is frequently necessary (NDT l997;111143)
Early dx.slwnt remcwal aiw beuer prognosis (nor 1997;17;1143: Can to NePhlu12017;2017:1B67349)

IMMUNE COMPLEX-MEDIATED MPGN

Background
Accounts for 7-10% of renal biopsies of GN in developed countries
Among the leading causes of ESRD from primary glomerulopathies (NEar 201136631191
Commonly presents in childhood and young adulthood
2 causes of immune complex (IC) MPGN include chronic infection (esp HCV). hema
tologk disease (eg, CLL NGRS), and autoimmune disease.True idiopathic is rare
Pathogenesis
AgAb ICS form in glomenulhddier after forming in the circulation or forming in situ fol
lowing glomerular Antigua trapping. ICS trigger an inflammatory response and activate
complement. leading to disruption of die GBM and endoapillary proliferation.
Pathology
LM: endocapillary and mesangial proliferation. leading to lobular appearance. Duplication
of basement membrane over deposits leads to"¢ram track" appearance of capillary walls.
IF: granular deposition of lg and complement in GBM.oMn mesangium. Chronic TMA
an mimic MPGN but will have no Ig staining. C3G will have almost exclusively C3 staining.
EM: GBM thickening and separation by elecr.ron dense immune complex deposits
Clinical Manifestations
Acute or chronic GN: hypertension, edema. microscopic hematuria.subnephrotic
proteinuria with CKD. Severe cases present as nephrotic syndrome.
Wo rk u p
Lab: elevated Cr. hemawria. subnephrodc proteinuria. low complement levels C3 or C4
. Seek our secondary causes:
Chronic infection: HCV. HBV. HIV. endocarditls. shun: infection. visceral abscess.
mycoplasma, parasitic injections
Autoimmune disease: Si6grens. SLE. RA. MCTD
Hemozologk disease: lymphoproliferative disorders. monoclonal gammopathy. plasma
cell dyscrasia (especially in MPGN with masked deposits present) In 101s;ea,a611
 Treatment
BP control and RAAS blockade as tolerated for all elected patients
2 MPGN: treat underlying causes
Idiopathic MPGN: immunosuppression if substantial protdnurla (et. >1 old) or falling GFR
Extended courses of corticosteroids have been used in pediatric patienfsahas not
been replicated in adults (m ~¢9h.vI 1992;6:113; 19953269
RTX (Clin Ntphml 1012:77Z90: NDT 2004:1931s0: 1007;11:I 351: 0» Neplvmf 20101731350
Rapidly progressive course: cyclophosphamide + corticosteroids (KDIGO GN 1012)
Prognosis
Pmgvessiverenaldiseasewid\l~erlalsurvival<50%at 10yrflamcb<.Risk facn>rs for pmgres
sion: GFR. proteinurh. HTN. age, severity of IFITA. crescents in 2006i69:504: nor 1noz17:1w3)
High rue of recurrence after transplant (19-4B%).confounded by studies grouping
different categories of MPGN (funspianmuan 1997;6]:152B; qAs~ 7.010:S:2363: pa 2010:77:711)

C3 GLOMERULOPATHY (C3G)
Background
Glomerulonephritis associated with dysregulation of alternative complement pathway
Defined on the basis of immunofluorescence: dominant C3 staining
Categorization of GN with Dominant C3 Staining In 201345440791

Morphologic appearance Glomerulonephritis with dominant C3

r
1
1

Disease category C3 glomerulopathy Poslinfectious GN Other

C3 GN

Specific
Specific genetic forms
genetic forms
Not for example Not
and/or
otherwise CFHR5 otherwise
specified nephropathy Specified
autoantibodies
and/or
autoantibodies

C3G may present as a nonresoiving postinfectious GN. (PIGN may show C3 deposits
beyond the acute stage: C3G should be suspected in such uses when dinial resolution
is incomplete.) Infection (including with streptococcus) may precipitate CJG.
Pathogenesis
Hyperactivity of the alternative complement pathway (normally constitutively active
at a low level) through hereditary or acquired defects (see table)
C3G is commonly associated with a circulating autoantibody called C3 nephritic factor
which binds to and stabilizes activated CJ. Other abnormalities of complement acti
vation may occur including genetic mutations of complement regulatory proteins and
other autoantibodies (see table)
Disease presentation and/or flares may be triggered by acute infection
 Mechanisms of Complement Pathway Disruption in CJG
Abnor malit y
Genetic mutations or
risk variants
C3 Nephritlc factors
CO Nephritic factors
C5 Nephritic factors
Factor H autoAb
Factor B autoAb
Descr iption
Implicated genes of the complement pathway include CFH, CFI, CFB,
CFHRS, C3. and MCP/CD46
Mutations of CFHR5 cause highly penetrant familial Cypriot
nephropathy (now 2013:1812B2)
Risk variants found in <20% of cases of C3G (al 20119440791
AutoAb stabilizing C3bBb.alterr\adve pathway C3 converse
( 50% of cases. DDD > C3GN)
AutoAb stabilizing C4b2a, classical pathway C3 convertase
AutoAb stabilizing C5 convertase
Prevent CFH from downregulating activity of CO convercase
Stabilizes C3 converse; prevents intrinsic and FHmediated deny

Monoclonal Likely ac! via autoAb activity: eg. one case documented a
gammopathies monoclonal 3. light coin dimer acting as a "miniaumandbody"
to FH (jumnwu 199215145901

Pa t h o lo g y
LM: proliferative GN (MPGN endocapillary. mesangioprcliferar.ive.or diffuse prolifera
live)
IF: C3 dominance and minimal or absent lg In 2014:85:450)
EM: presence (DDD) or absence (C3GN) of intramembranous highly EDD
C lin ica l M a n if e st a t io n s
May range from nephrotic syndrome (hypoalbuminemia. proteinuria >3.5 Yd. edema) to

Synpharyngtic hematuria (as seen with PIGN) may be seen reflecting increased activity
of the complement system during infectious episodes
May present as a nonresolving postinfectious GN
Retinal dusen (yellow gnnula on optic disc containing complanent). partial Epodystrophy
Complement Cascade Schematic
up
an
u

Man 0 a ( n, 0 )
c 1é binding leciln f or c a l l

CO Cowc t;1e

MCP

.13

CFHR5

FH, FI
11

C 5b9
(SMAI

Kay components of the complemau cascade an: diagrammed, In grey are various complement components. m
back are cumeruses ha: split C] or C5 into their activated brms.and in vivre an lqulazory molecule;
Workup
Labs: low C3 (40% of uses). normal C4. hematuria, pnor¢inuria.+/- elevazed crasinine
J Complement pathway abnormalities: C3nel. Factor H ab. Factor B level, Factor I
level, soluble membrane amok complex (SMAC) level
J Monoclonal gammopathy screen: SPEP/lFE, serum free light chains
Consider genetic mutation analysis: does not currently derange treatment bu: may
affect prognosis and risk stratification for pos:transplant recurrence
Treatment
Immunosuppression controversial: combination of srerolds and MMF may favor
clinical remission no 2015:881153: qASN 1018:13:406)
Eculizumab (antiCS mAb preventing its clearage): may be afflictive especially in
aggressive forms with elevated SMAC levels (qASN 201z17¢74s1 or crescents we 201692941
Plasma (FFP) therapy useful in case reports. eg, FH deficiency In 20as;m4zl
Prognosis
>50% progress to ESRD within first :we decades of diagnosis (Na: Reueprd201M:6341
Risk factors for progression: baseline eGFR and degree of interstitial fibrosis/
tubular atrophy on biopsy (al 201u2¢4s4;xi Z018;93;977)
Posttransplant: 2/3 recur.and 1/2 have allograft failure iIAsn z014:zs:11101.Another
cohort showed higher recurrence (10112 in C3GN, NU in DDD) and allograft failure
(3/12 in C3GN. 6/7 in DDD) (Aim zommio 304 mm

CRYOGLOBULINEMIA
Background/Pathogenesis
Cryoglobulinsz lgs :hat precipitate at <37C and redissolve upon rewarming
Cryoglobulinemiaz the presence of circulating cryoglobulins in serum
Mixed cryoglobulinemla (MC): cryoglobulin with 22 Ig clones
Pathogenesis of MC: antigen (eg. HCV) stimulation -» B cell clonal expansion -o non
neoplastic B cell lymphoprdiferative process -»Ab against Fc portion of IgG (RF activity)
» IC formation in vessel walls activate complement -» leukocytoclasdc vasculitis
Cryoglobulinemic vasculitis (10-15% of MC): predominantly involves the small
vessels. affecting the skin. ioims. peripheral nerves. and the kidneys we: mm 201s; 1zsoso)

Classification and Fear res of Cryoglobullnemla

Types Components Clinical Features Associated Diseases
Type I (simple) Monoclonal Ig. Hyperviscosity. WaldenstrOm
most often IgM acrocyanosis. macroglobulinemia
> IgG Or IgA Raynauds. gangrene. Multiple myeloma
arthralgias rarely Bcell lymphoma, MGUS
Type It (mixed) Monoclonal liM»: Wealmess (>80%) Infection
w/ RF activity Purpura (>75%) . HCM H8V HN
against IgG Arzhralgias (60-90%) IE Lyme
Type III Polyclonal IgM Neuropathy (2080%) Rickettsio, syphilis
(mixed) against IgG Nephritis (7.0-50%) Autoimmunity
Types It-Ill Both monoclonal Cutaneous ulcers S]6gren§ syndrome
(mixed) and oligo or (10-20%) . SLE. RA
polyclonal IgM Sicca (5-50%) Lymphopmliferative dz
against IgG "Meltzer triad idiopathic (essential)

Renal Manifestations
AKI/RPGN. subnephrotic or nephrodc proteinuria wl microscopic hematuria, NS. HTN
Renal injury is the most morbid manifestation of cryo vasculitis. typically manifested as
immune complex MPGN. However. only a minority of parents with MC show renal
manifestations at presentation w/ as least half developing them over followup.
Extrarenal Manifestations
Meltzer Mad: purpura, arthralgla (PICPs. P1Ps. ankles and feet). and weakness in 25-80%
Skin purpura. ulcers. Ravnauds and acrocyanosis. livedo (exacerbated by cold exposure)
Neuromusc: myalgias. peripheral neuropathy with paresthesia. mononeuritis multiplex
Pulmonary: rare: include dyspnea. cough. pleuris. rarely diffuse alveolar hemorrhage
A smoldering lymphoproliferative process can evolve into NHL 11/mana1 Hepaia z01s:e1on
Diagnosis
Serum cryoglobulins: measurable cryocrit ar protein concentration
Cryocrit: volume percentage of packed ciyoglobulins in blood after centrifugation as
4C: Quantity of cryocrit can correlate with disease severity
Draw in prewarmed syringe.transported and centrifuged at 37-40 serum then
stored at 4C for up [O 7 d as cryoglobulins precipitate out (hr to d)
Fake (-):common hearse of technical collection: repeat assays required if high suspicion
False (+): polyclonal cryoglobulins can be transient during infections
Immunofixation employed to identify type of cryoprecipitate
MC;T RF and cryoglobulins.and ii C4. more variably l C3 and 1 CH50
Kidney biopsy: typically MPGN +I- microthrombi (cryoglobulins appear as pseudo
thrombi). EM: subendothelial deposits wl fingerprint pattern substructure
T r eatment
MC a/w HCV: DAA iHei==-wiv 2016163.408: Gasziueniewiagy Z017:1S3:40G). Can recur despite
HCV eradicauon d/t ongoing ab production by Bcells We 2017;7&l011
Type 1 or 2 alw lymphoproliferative disorder treat it based on the type
IS: for organthreatening MC to inflammation and cryoglobulin production
CS: acute antiinilammatory benelir. Relapses are common upon withdrawal.
Rituximab: sustained response. Can be used before or after failure of HCV ueaonent
(always screen for HBV confection first) umm Umm 201u4.043i; Cyclophosphamide
Plasmapheresis: for severe vasculitis. RPGN, or hyperviscosity U angie 1o 16,31.149)
P rognos i s
Prognosis depends on associated underlying disuse and degree of organ involvement

gzip
Renal involvement carries particularly elevated morbidity
Overall survival 80% at 10 yr: renal failure 11% over S yr WKD 1007:49:59)
MC: 10yr survival rate <60% la" et Nnwmaiui z0o&ws10sl

AMYLOIDOSIS
Ba c k gr ound
Amyloid: extracellular deposldon of insoluble fibrils nesulrjng from abnormal folding
of proteins; >25 precursor proteins of amyloid found
Overall incidence 1.3-4% of renal biopsies (Am I So: PuMa! 2009939 is)
Clinical Manlfestadons of Amyloidosis: Depending on Involved Organ

Kidney Proxeinuria (NS common). CKD, NDI, :ype 4 RTA

Heart Nonisdlemic HF (nl or low LVEF. restrictive or dilated CMRAflb)
Nerves Peripheral neuropathy. carpal tunnel.or¢hosmk hypotension
Cooguhtion Easy bruisabiliry, Raccoon eyes, Factor X def
GI Malabsorpzion. ulcer. macroglossia
joint Ardmralgia

Dia gnos is
Biopsy fat pad or involved organ: kidney, liver. and heart are commonly involved
Congo red stain under polarized light; applegreen birefringence
LM in kidney biopsy. diffuse glomemlar deposition of amorphous hyaline material
EM randomly arranged fibrils. measuring 8-12 nm diameter
Amyloid typing IF staining of monoclonal light chains (AL) and amyloid A (AA) is
diagnostic. M protein in serum/urine is not (NE]M 2001:]46:17861. Mass spectrometry
gold standard In 10l 7.:B222b)

Other rarer forms are derived from following precursors: apolipoprotein CII (AApoCII)
qAs~20l 7¢um4:49). l ysozyme (ALys) UASN zol mssan. gel sol i n (Abel ) l x: 2017. 91:964)
 AL AHYL O IDO SIS
Precursor: monoclonal K (20%) or l (80%) LC produced by a monoclonal plasma cell
clone in :he BM. Rarely heavy (AH) and heavy and LC (AHL)
Only about 10% of padenrs have concomitant multiple myeloma at presentation
Localized form: 12% Produced by a local. selflimited plasma cell clone. w/ (-) SIFE/
UIFE. mlc sires: GU nracc. larynx.skin.and upper respiratory yacc Tx is local excision,
RTF No systemic progression but recur locally esp In the GU tract w~=»»ov~ nm 2017192.90m
Systemic form: affects the heart. kidney. liven and nerves (autonomic/peripheral)
Manifesuitions: NS. fatigue. weight loss. bleeding tendency orthosmsis. CHF symptoms
Renal Scage and Pmgnosls of Renal AL Amyloidosis (um zounmazsl
Stage Definition Dialysis Dependence 3 yr alter dx
I Proteinuria $5 gl24 hr and eGFR 250 0%
II Proteinuria >53/24 hr or eGFR <50 7%
III Prozeinuria >5 g/24 hr and eGFR <50 60%

T reat m en t
AutoHSCT eligible (low risk) pts autoHSCT w/ highdoGe melplnhn (Anal IM Z0041140i851
or standard dose mdphalan plus dexamethasone (NEIM 2007;357:10s3)
Criteria: physiologic age <70. troponin T <0.06 fig/mL, NTproBNF <5.000 nglL. CrCl
>30. NYHA functional class 1 or 2. $2 organs involved. not oxygen dependent
AutoHSCT ineligible (intermediate or high risk) pts: combination chemotherapy: eg.
melphalan + dexamethasone or CyBorD (CYC. bortezomib,dexamedusone). CyBorD
achieved renal response in 25% (Nina 2015;126:mi.
Daratumumab: human mAb against CD38 on plasma cells. if refractory (Sim 2017;130:9001

Prognosis orAL Amyloidosis by Treatment Response (am z0\4;1z41azs1

Criteria Definition ESRD Risk
Renal Progression L eGFR 225% HR 4.56
Renal Response l Prozeinuria 230% or 0.5 8124 hr
HR 0.15
wlo renal progression
Hematologic Very Good Partial Difference between involved and
Response (VGPR) uninvohred fLC (d1LC) <4 mgldL
wl baseline dfLc 25 mgldL HR 0.47
Hematologic Complete () SIFE. UIFE. nl FLC ratio
Response (CR)

Transplantation
15/19 survived after median flu 41.4 mo (nor 1011:z6:20321
Median graft survival 5,8 yr: Pt survival was 8.9 yr if CR ( SIFE. UIFE. nl FLC ratio)
or PR (dFLC <50% of prerx) vs 5.2 yr in NR (dFLC >50% of pretx) WT 1013;1!;433)

A A A MYL O ID O SIS
Precursor: serum amyloid apolipoprocein A (SEA) produced by the liver. vascular
endothelial cells. monocytes. macrophages. It is induced by proinflammatory cytokines
including IL1. IL6. and TNFa (Mad Khan 2014;241405)
Reactive amyloidosis to:
Chronic inflammation: RA, juvenile idiopathic arthritis. spondyloanhropazhies, IBD,
FME hidradeniris suppurativa, IgG4related disease <~ElM 7.017¢376=5991
Chronic Infection: bronchieccasis. IV drug abuse. infected pressure sores. osteomy
eliris
Neoplasm: RCC. lymphoma
Organs involved: kidneys. GI rracc (including liver), heart. autonomic nerves
Tx: great underlying disease
Tocilizumab: humanized andlL6 receptor Ab. inhibits SAA production.Appmved for RA
1 Amyloid load by SAP scimigraphy. i SAA. proteinuria (an Exp Meum 2015;33:S46)
In FMFAA amyloid. l proreinuria, ESR. CRP 10wn0mij Nan M 20 I7:Iz\os)
Canakinumab: humanized anuIL1 mAb 4 proceinurh in children (haul numb Z016:J 1:6J3)
Txp: median graft survival 10.3 yr: recurrence 19.5% or 201J.1314331
 ALECT2 AMYLOIDOSIS In 2014:86:370. 2014x6¢m1
Precursor: leukocyte chemotacdc factor 2. a cytokine produced by the liver
Etiology of :he hepatic upregulation of this proteins production is unclear
Strong ethnic associations: Mexican Hispanics. Punjabis.Alabs. Israelis. Native Americans
Organs involved: kidney, Iiver.heart (rare); DM. HTN common
CKD. proteinuria (33% nephrotic range). ESRD (39%) over flu of 22 mo
Concurrent renal disease on bx: DN (21%), MN (5%)
Monoclonal protein in 9.6%: monoclonal protein + amyloid z AL amyloid
Tx no specific tree¢ment:Txp: recurrence 1/5 wlo graft demise

AFla AMYLOIDOSIS row# 2o13a¢1s\s=;Asr4 z0a942a4441

Precursorzfibrinogen n chain, synthesized by the liver

AD mutations with variable penetrate. Family history absent in 46%
Poor prognosis: presenting creatinine 4.1. 62% reached ESRD in 4 yr.
Txp: 7/12 gray failure in 5.8 yr including 3 recurrence. Combination liver-kidney top
appears to be more effective QM 2000:93:169)

ATTR Amy Lolnos ls

Precursor: transr.hynetin transport teuamer protein that carries T4 and retinolbinding

protein; 90% produced by :he liver
Accounted for 1.4% of renal amyloid uses submitted to Nephrocor (KI 20\4,e6)378)
The most common form of hereditary amyloidosis
Mutant forms (>100 known) destabilize the native TTR quaternary structure. leading
to mislddinglaggregation of the protein, resulting in amyloidosis
VVT (nonrnurant) fonnzaflects che heat in elderly men. Endemic in Fioruigal and Sweden
Organ involvement: nervous system. heart. kidney. and Gl uact
Manlfesmdon: neuropathy -» micrcalbuminuria 3-5 yr later - oven nephvapaclly 2-3 yr
later -» ESRD about 10 yr after neuropathy lqAsr4 1011113371
Tx: liver or liverlkidney txp: tafamidis. aTTR stabilizer. oilers possible improvement
cardiovascular outcome (NEW z01a;:n 1007)

ABZM Ar4 y Lo1 oos 1 s

Precursor: 152 microglobulin, LC of the MHC class 1 molecule.excre1.ed by Me kidneys

Clinically affects :he osteoanicular structures. je. scapulohumeral periarthrirjs and
carpal tunnel syndrome (Semen our 2017;30:19J). Occurs in long:erm dialysis patients.
Cleared by high flux HD membranes along with convection U Lau on m¢4 1991;\1s1i531
Also helpful: use biocompatible HD membranes and ultrapure dialysane to minimize
proinflammatory state UASN 1lX)Z;\3972)
Treatrnenr time is important: slow imzercompartmenral mass transfer llmins 152 micro
globulin removal (KI 200666921431)
Higher prevalence with longer dialysis vintage
Overall decline in disease prevalence in Europe (n 1997:51:1017) and Asia (nor 2016:J\:s9s)
Tx: renal rransplanurion is die best prevention and treatment
 NONAMYLOID DEPOSITION DISEASES
Fibnillary GN and Immunotactoid GN uuz00su»z:14so. qAs~ zmwns; nor z0na7»4131)
Fib rilla ry G N (FG N) l mmu n o t a c t o i d G N (I T G N
Prevalence <1% of native bx 0 .0 6 % o f n a M b x
Marifestation HTN, proteinuria (NS 50% in FGN, 69% in ITGN). hematuria. CKD
MG. low C 15-17%. 2% 63-66%. 46%
Associated Cancer. MM Lymphoproliferative disease
CGodili¢f\s Autoimmune: Crohns. Graves.SLE. ITP. (esp CLL)
PBC. Si6grens. ankylosing spondylids. HIV +/- hep C (at Ntphiul
scleroderma z0112751a01
Infection: HCV w~ z011;4s=24al.TB.
osteomyelitis
LM Diffuse proliferative. membranous. Membranoprolifemive. diffuse
Mesangio/membranoproliferative. proliferative. and
diffuse sclerosis, crescentic (rare) membranous pattern injury
IF IgG (esp lgG1 and 4). N and A light chains Deposits contain IgG or IgM.
(mostly polyclonal) and complement monoclonal ac or 1. and
complement
EM Randomly arranged fibrillary deposits: Micro tu b u le s: 3 0 -5 0 n m in
1 6 -2 4 n m in d ia me te r in th e diameter in parallel
mesangium and capillary walls arrangement, in the subepi
and subendothelial space
Cryo deposits an be
indistinguishable from ITGN
ESRD 44-45% 17%
Transplantation 5/14 recurred. 2/5 became ESRD again Recurrence 25% WN
iqnsu 2011:47751 1015;42:I77) - 59% (Am;m¢a
1/13 recurred w~201S:41:177) 1990189:91)
wl MG: 5/7 recurred.3 reoqa. 1 recurved
again. 2 died wl hematologic malignancy
w/o MG: 0/5 recurred (m zoous:4z0l

Dna] Heat Shock Protein Family B Member 9 (DNA]B9) in FGN

A heat shock protein; detected by immunohistochemistry (King 101&3;$6) and mass
spectrometry i}Asn 2015429511 in glomeruli with high sensitivitylspecificity
May be used for diagnosis. particularly if EM is not available
Treatment of FGN:Treat Underlying Disorder
Various IS agents have been tried with suboptimal response
In group w/ mean Cr of 3.1. IS (CS, CYC. CsA) was not a/w outcome (xi 2003:6314s0)
In group w/ mean Cr of 2.1. IS use resulted in PR in 10%.persistent renal dysfunction
in 38%. ESRD in 52% ic1As~ z011:s:77$i
6 (5 RTX. 1 CYC)l13 had L proteinuria by >50% w/ stable GFR) WK. 201341:679)
RTX use was a/w nonprogression in 4/12: nonprogress had lower Cr (nor 1014129:19151
In crescentic FGN treated w/ CS.CYC.6/8 wen: on to ESRD (I/mn/i4¢1»~iz017.z7..1519
Treatment of ITGN:Treat Underlying Disorder
7/14 (Cr 1.5) had B cell disorder. Chemo#-HSCT led no NS remission in 5 us zoorsziuq
A PR of the hematologic disease led to complete renal remission (Ann Henuiul 2007;B6.927)
7/12 w/o MG were treated wl CS+/- CYC. 3 achieved PR (NDT 1017;27:4137)

Rar e Nonamyloid Deposition Dlseases

Disease P a t h o lo g y Clin ic a l Ma n if e s t a t io n s

Fibronectin GP Mes. subendo Hbronectin AD, proteinuria. HTN. ESRD

deposition Can recur (an Tiuiiplani zoizzsssi
Collagenofibrodc GP Mes. subendo type Ill AR. proteinuria. ESRD
collagen deposition
Nail-patella Type III collagen deposition AD, prozeinuria. <$% ESRD nail and
in lamina denser paella abnormality
Upopmtein GP Lipoprotein diiombi w/i Proreinuria. T VLDL LDL. app E
g io me n ila r ca p illa ry irin a
 HEREDITARY GLOMERULAR DISEASES
Background
• Mutations of genes encoding proteins involved in glomerular filtration barrier can
directly fuse glomerular diseases
Generic systemic disease (eg. sickle cell disease. generic aHUS) may indirectly cause
glomerular injury
Monogenic causes identified in 30% of steroidieslstan: NS in <25 y/o IJASN 2015:26:U791
Relatively common generic causes in 19-25 y/o: lNF2,TRPC6, NPHS2 l1Asr4 20151642791
Clinical manifestations: proteiriuria 1 steroidresisxznt NS t hemaruria i CKD
Pathology of congenital NS in children: FSGS (5696). MCD (21%), mesangioproliferatiwe
GN (12%), diffuse mesangial sclerosis (3%) (QASN 2015110 59z1
lmmunosuppression is generally ineflecdve in generic podocyiopadiymediazed glomerular
disease UAS~2015:2b:130)

Pathogenesis
Deficiency of the enzyme agalactosidase A (nGalA). encoded by GLA on Xq22
Accumulation of globotriaosylceramide (Gb3) within lysosomes in a wide variety of :do
Renal Manifestations
Proteinuria: nephrotic range uncommon: a/w renal progression (C/ASN 2o1ans:222al
pRTAIFanconi: polyuria and concentrating defect in distal nephron involvement
ESRD in 14% of cl. 2% of 9 an 38 ylo: alw cardiac even: and stroke (nor 1010'1537691
Multiple renal sinus cysts
Renal variant: later onset. renal limited wlo other organ manifestation (KI 100J;64;B01)
Heterozygous female: asymptomatic carrier all manifestations including renal mani
2 festations: eGFR <60 (1994). proteinuria >1 g/day (22%) (mu 6¢-1m¢10b 2008;93\12>
g Extrarenal Manifestations
E . Cardiovascular: nVc muse of death; premature CAD, LVH. arrhyizhmb, mimic hypertrophic
cardiomyopathy

I3
M
Angiokerawmas: ziny painless papules. esp bashing suit area. :elangiecrasia
Hypo or anhidrosis. hear intolerance. acroparesthesia in hands and feet
Cornea verricillasa (vortex keracopachy)
TIA. stroke. neuropathic pain
Diagnosis
/ Leukocyte RxGalA activity in 6: <3% diagnostic. 3-35% requires GLA mucasion
analysis:
. Not recommended for 9; low to normal regardless of disease manifesucion
GLA mutation analysis: diagnostic if known mutation
Tissue diagnosis: if genetic test nondiagnostic
Kidney Biopsy
LM vacuolization of podocytes. DT cells > PT cells,endozhelial cellscglomerulosderosis
EM: Zebra or myeloid bod lf osmiophilic inclusions in lamellated membrane stnicuires
(enlarged secondary lysosomes)
Other causes of Zebra body. silicosis. amiodarone (lu 200e;74:1354), gentamicin (PT cells).
chloroquine. hydroxychloroquine IAjKl> 20061488441

Enzyme Replacement
Recombinant uGalA: agalsidase ii (Fabrazyme°) 1 mg/ug or agalsidase G (Replagal°.
available in Europe) 0.2 mglkg IV q2wk
Indicated for all males and symptomatic females even with ESRD
1 Gb3 deposition in mos: cell types including podocytes uAsu zo1n4¢ 137: qAs~
2017:12:1470)
Maximal impact if eGFR >5S (A~» IM 2a07;14u71:1 severe clinical events 0 m4¢G¢»¢
1016;SJ;49S)
s/ez neuualizing antidrug antibodies development; may need dose adjustment and
immunosuppression UASN 101819122651
Other Treatments
RAASi to treat HTN and proteinuria
Migalasuc pharmacologic chaperone, t trafficking of RxGalA to lysosomes -» T aGalA
activity: 1 kidney and plasma Gb3: improved LV mass index (NEIM zu1@37s:s4s1
Transplantation
5yr graft survival similar. T death (x2.1$) (rfumpIamauan 200957:N0)
Recurrent deposit is common UASN 2002:13:S134)

COL4AASSOCIATEO NEPHRQPATHY
Background
Hereditary diseases caused by mutation of COL4A genes encoding type IV collagen
COl.4Aassociated nephropathy includes benign familial hematuria, thin basement
membrane nephropathy.Alport syndrome, COL4A associated FSGS (KI 2014.s612sa1
62% of patients with COL4A mutations were clinically not diagnosed with Alpon syn
drome or thin basement membrane nephropathy luqm 20195801142)
Genetics
Type IV collagen: component d basement membrane (BM) in gk>merulus.cubules. and sloan
6 genes are located at chromosome 13 (COL4A 1 & 2).2 (3 & 4).and X (5 & 6)
COL4A5 (classic XL) mutation in male or heterozygous female >> COL4A3, COL4A4
(heterozygous AD or homozygous AR)
Expression Collagen lY
Location Normal XL Alpert
Immature GBM. BC.TBM ulu1rx2 + u1u1u2 u1 a1a2 + 01 u1n2
Manure GBM. dTBM u3a4u$ + /13114415 u1u1a2 + 11 a1u2
BC. dTBM. skin BM u1u1a2 + /15415116 at rx1a2 » u1a1 u2

BC. Bowman Capsule: GBM. Glamerular Bm:TBM.Tubular BM; dTBM. rlinalTBr*l

Large deletions and nonsense mutations: progress to ESRD faster (90% at age 30).
more frequent hearing loss and eye abnormalities
Missense mutations: variable course (50% reach ESRD at age 30)
De novo mutations: -15%
Mutation of lamina B2. component of GBM modify Alport phenotypes (jAsn 201&29:4149)
Clin ica l Ma n if e st a t io n s
Hematuria, proteinuria: ESRD before 40 ylo:90% in male: 12% in female (MSN 1003;14zwJ).
Age of ESRD a/w type of mutation in male ()A$n 2010:2\:B76)
Risk factors of renal progression in Xlinked female:gross hematuria. proteinuria
Bilateral anterior Iendconus is pathognomonic; dotandfleck retinopathy sphero
phakia. corneal erosion
Highfrequency sensorineural hearing loss
Skin and Kidney Biopsy
Skin epidermal basement membrane up stain:
(-) In male XL disease: segmental (-) in female is C/w COl.4A5 mutation
(+) In COL4A3. COL4A4 mutation
LH: normal or FSGS; interstitial (oam cells (nonspecific. present in other proteinuria)
IF of collagen: mosaic. skipped a5 in female
EM: GBM thinning (early); thickening, laminationibasket waving (late). elecuolucent zone
Can have normal GBM appearance in early stage (Hum Anna: 2ma,a1;z19»
Treatment
RAASi: i progression. ESRD (mau nquvua 1017;31:131). Stan early (n 2012;81=4941
Transplantation
No recurrence. LRKT is possible (NDT 200911421s1s1
De novo antiGBM antibody against a5 or 113 detected in 5-10% (cyAsr4 101711z11621
Associated with crescentic GN and subsequent graft failure
Commercially available antiGBM as NC1 region Ab does not always detect this Ab
Retransplanmionz high risk for graft loss (KI 2004,6s167s)
Thin Basement Membrane Nephropathy (Benign Familial Hematuria)
Mutations of COf.4A3 and 4: benign side of the spectrum ofAIport (xi 10143611 0611
None or minimal proteinuria unless concurrent FSGS
Rare ear/eye involvement
Biopsy. diffusely thin GBM 150-225 nM; indistinguishable from early Alport
Tx: RAASi especially for proteinuria
 ANTIPHOSPHOLIPID SYNDROME (APS)
Antiphospholipid syndrome (APS):an autoimmune disease resulting from :he presence
of antiphospholipid antibody (APLA) which exert a pathogenic role resulting in arre
rial and/or venous thrombosis +I- pregnancy morbidity (num R¢vRl»¢umaml2011;1,330)
Causes of transient APLA: infection. medications (hydrazine, amoxicillin. minocycline.
and propranolol) (Can Rlewnnd Rep 1012;14:71: Lupus 2017185921901
alw autoimmune disease. SLE: APLA is found in about 1/3 of SLE and is an independent
risk factor of premature death and progressive renal disease IAP<D 1004143:281
APLA present in 9% of pregnancy losses. 14% of strokes. 11% of Ml.and 10% of DVT
I,4/u»¢n¢ Cave Res2013:65:1869)
The common final pathway is that of endothelial injury exposing phospholipid binding
protein, attachment ofAPLA and the initiation of an inhammatory cascade that activates
complement (Blew 2016;127=365), leading to vascular thrombosis and organ dysfunction
APLA chronically upregulates roTOR in vascular smooth muscle leading to proliferation
and obliterative vasculopathy luzym 1014:37130])
Clinical Manifestation and Diagnosis
Diagnostic Criteria o¢APS:21 Clinical + 21 Laboratory uniumo llama 1006;429§)
Clinical Cr iter ia
Vascular thrombosis 21 arterial, venous. or small vessel thrombosis (imaging or
histopathology)
Pregnancy morbidity 21 unexplained feral deadl (at or beyond 10th wk of gestation)
21 premature birth (before 34 wk) due to eclampsia. severe
prteclampsia, or placental insufficiency
23 consecutive miscarriages (before 10th wk of gestation)
Labor ator y C r iter ia: 22 tests, 12 wk apart
r
Lupus anticoagulant Positivity
T' Anticardiolipin Ab loG and/or IgM >40 U or >99!h percentile
1~

n
AntiB2 G P1 Ab IgG and/or IgM in medium or high titer (je. >99th percentile)
a ..
q
Renal manifestation: depending on the vessel caliber that is affected
Large renal artery/vein thrombosis/infarcdon:sudden flank pain.hema:uria.and AKI
Small vessel thrombi in the inzersritiumrsubacute AKII CKD with mild proreinuria
Glomerulus: proxeinuria. active sediment +I- renal dysfunction (an Sinful 2005.63 471)
Biopsy: acuzely.TMA. and in chronic stages oblirerazive arzeriopanhy. fibrosis and FSGS
Od1 er lab: dimmbocynopenia. AIHA. hypocomplemememia (case :up M 24 z017;z0ws797w>
10yr survival probability was 90.7%.The top causes of death: severe thrombosis.
infection. and carasuophic APS (Ami linen" of 201517421011)
T reat m en t
Ancicoaguladon; heparinlwarfarin co maintain INR 2-3 (new 20014349 11331
Rivaroxaban (factor Xa inhibitor) if intolerant of warfarin (lance: Haemuud Z016;3:c426)
In SLE w/ APS. hydroxychloroquine 1 secondary thrombosis (Aruvan Rheum 1011261.8631
Transplantation
Anticoagulation during the periopenrive period in renal :up to 1. the risk of postLxp
thrombosis and graft failure (llansplanralmn 2000:69:1348)
roTOR inhibitor: recurrence of APSassociated vascular lesion (NEW 201413718031

CATASTROPHIC ANTIPHOSPHOLIPID SYNONOME (CAPS)

Diagnostic Criteria of CAPS: Definite if all 4 (up 1003;I2:sl0)

1. 23 organs. systems. and/or tissue involvement; clinical assessment +I- imaging. Renal
involvement: a 50% Cr rise. HTN >180I100 and/or proteinuria >500 mold.
2. Development of manifestations simultaneously or in <1 wk
3. Histopathologic confirmation of small vessel occlusion in >.1 organ or tissue
4, APLA ( )x2 26 wk apart
Probable 2 organ involvement + 2 3 4
1 + 2 + 3 » absence of lab confirmation death to the early death
1+2+4
1 » 3 4 . 3rd event in >1 wk. <1 mo.despite anticoagulation
 VVdespread thrombosis and mulriorgan failure. very high morzaliry In a cohort of
1.000 APS patients followed for a decade. 9 developed CAPS and 5 died. (Am Rumen
Drs 2015;741011)
Tx: anticoagulation.corcicosteroids. plasma exchange +I- IVIG (l"P"* 1014:231283)
For resistant cases. consider the addition of riruximab (AulammuneR¢v2013:11:108S; so;
MeumuW 1017:4:145) or eculizumab (Anhriux Rheum 1012;6A:2119; Case My Hemauw 1014;7/4371)

HUS AND TTP

H eMO L YT lC U R Er4IC SYN D R O ME ( H U S)
Background
Pathogenesis: ShigaToxin
Caused by Shiva toxin producing bacteria ennerohemorrhagic E coli 0157:H7 (mlc).
many more Shiga toxinproducing E coil (STEC) and Shigella dysenteriae serotype 1
Complicates 6-9% of STEC cases
Food source:beef (cattle GI tract),spinach,Iettuce,sprt>uts.fruit.iaw milk too z01¢xs1;\411i.
cookie dough (cm 2012154151 ii. flour (NE/M 1017;J77:1036)
Shiva toxin is absorbed by the gun epithelium The toxin binding to the glycoprotein
receptor globotriaosylceramide (Gb3), expressed in the kidney and brain -v the toxin
entrance into the tissues inflammation. lysine. and destruction
Gb3 is also expressed in platelets. causing activation/aggiegation (microthrombi) and
thr ombocytopenia in thimbu mwhmi 2016:100:\597)
Upregulated complement activity (CJASN 2009;12;1920) » + membrane attack complex
(MAC) - endothelial injury and microthrombi formation (Blood 1015;125.3153)
Clinical Manifestation and Workup
Mainly children w/ abd pain. NM diarrhea that precedes HUS by 5-10 d (NEJM 19951333>64i
End organ involvement: kidney and CNS
Labs:anemia.schistocytes and helmet cells on peripheral smear. T indirect bilirubin.
. haptoglobin, T LDH, thrombocytopenia. renal dysfunction
Stool culture (selective media required for 0157:H7 and non 0157 serotypes). ELISA/
PCR of stool for shiga toxin, also serology against the most frequent STEC serotypes
Kidney Bx:TMA; cannot distinguish from other causes: not required for Dx
Prognosis: in pediatric cases w/ 43% of non0157 serotype. temporary HD needed in
61%.CNS effects (seizures) seen in 25% and mortality rate of about 4% urn 1001418644931
T reat m en t
Supportive Treatment: IVF. pRoC if severely anemic or symptomatic. transfuse platelets
if clinically significant bleeding occurs. BP control (CCB) if HTN. dialysis as needed
Antibiotics (ciprofloxacin.TMPlSMX) have the potential to T production of shiga toxin.
Although azithromycin and meropenem J, toxin production WEIM 2000,342119301
Plasma exchange (PLEX): no benefit
Eculizumab a mAb against C5 that i production of MAC: In STEC related HUS w/
severe renal (requiring dialysis) and neurologic impairment, early use may improve
neurological outcome (NE;M 1011364.1561i Meakine 201S:94.e1000)

THRor4soTlcTHRor4aocyTorEnlc PunpunA (TTP)

Pathogenesis: ADAMTS13 Deficiency
Functional ADAMTS13 (A Disinnegrin And Metalloprotease with aThrombospondin
type 1 motif. member 13) activity.This enzyme cleaves large vWF multimers on :he
endothelial surface.Accumulation of these structures cause TMA.
Heredity disease (<5%):genetic mutation of the ADAMTS13 gene
Acquired disease (most):AutoAb against ADAMTS13
Clinical Manifestation and Workup
Rare, 3/1 million adults/yr (wav Una Can z0 n=w.1e7sl
Diagnosis: i ADAMTS13 activity (<5%), (-) inhibitor before any plasma transfusion
Only 5% have all components of the pentad: MAHA. thrombocytopenia <20K. renal
impairment. CNS involvement and fever luau 1010.116.4040)
Rare severe renal injury 4% AKI requiring dialysis. 6% CKD.no ESRD lal¢¢4A4 2017:1 s9ol
Kidney Bx:TMA; cannot distinguish from other TMA; not required for Dx
Untreated.a progressive course of neurologic and cardiac deterioration - death
Treatment
PLEX: immediar.ely;daily until plt >150K and hemolysis markers normalize: removal
of a potential inhibitor and replacing ADAMTS13 from the donor plasma
Plasma infusion: in case of delay in plasma exchange
Concomizann cs (IWPO) 0~4m 1991;3254981
Add Rituximab (RTX). if severe disease or no improvement after a few days of PLEX
and CS or in relapsing disease want 2015;125.152sl; ofatumumab (~=1m 101B:378:92)
Cyclophosphamide: for disease refractory to PLEX. CS, and RTX (Ink Herms z004»w941
Bonezomib: for refractory disease to all of :he above (NE/M 2011;3681901
Caplacizumab, humanized variable domain of lx against vWF: faster platelet recovery.
l TTP related death. recurrence. and thromboembolic event (NE/M zowaurnasi)

COMPLEMENT-MEDIATED HUS
Atypical HUS (aHUS): HUS not mediated by Shiva wxin: aka diarrhea (-) HUS
>50% of aHUS are cornplememmediazed HUS (al z017.91:sz9)
Other forms of HUS include coagulationmedicated TMA. eg. DGKE mutations
Pathogenesis
The complement system is part of our innate immunity that defends us against inlec
:ion and maintains internal inflammatory homeostasis.The 3 arms no the system
(classic. alternative. lectin) are each tightly controlled by regulatory proteins.
In complementmediated HUS. there is disturbance of this balance in the adeemadve
pathway. -» pathologic overactivation and ultimately :issue destruction and injury
Types
Hereditary. gene mutation of die regulatory complement factor(s): complement factor
H (CFH.m/c). complement factors I. B. C3. thrombomodulin (THBD).and CD46 (MCP).
Often require another hit," eg. infection. pregnancy (C/ASN z007a¢s911.
Acquired:Abs to CFH (<10% of aHUS). CFB. Many pts have concurrent mutation(s).
Epidemiology and Clinical Manifestations
Incidence: 7/million in children (B1H z010.140¢:i7). Can occur sporadically wlo FHx.
Age of onset: variable from <1 to >20 y/o. 60% were adult onset Adults progressed
to ESRD (4 6 %), d e a th (6 ,7 9 6 ) w/i th e 1 st ye a r o f disease. re g a rd le ss o f d ie typ e o f
complement dysregulation (CjA$N zo13x;ss4).
Ischemic injury to organs: renal (mlc).gangrene of fingers and mes,hean. lung. Gl.death
(Nat Rev Nephml Z014;1ll1174)
Wo rku p
Labs:TMA (MAHA, thrombocytopenia). Complement mutation and Ab in select labs:
nl complement levels do not exclude complementmediated HUS
Diagnosis of exclusion: rlo STEC,TTP (normal ADAMTS13). other causes ofT MA
Kidney Bx:TMA Cannot distinguish from other causes
LM: mesangiolysis. GCW duplication. vascular onion skinning.: Nbrln thrombi
IF: fibrin staining thrombi; no immunoglobulin (In) and C3 staining
EM: endothelial cell swelling. subendothelial electron lucent space
Eculizumab
AntiC5 monoclonal Ab. FDA approved. Efficacious in 80% of pts that were either
PLEX dependent or refractory genetic testing not performed (n6/M 2013;3681169)
C5 blockade with eculizumab can predispose to encapsulated bacterial infection. Pos
should be given meningococml (both quadrivalent x2 and serogroup B). pneumococcal
(PCV13 and PPSV23), and Haemophilus influenzas type b vaccine. Penicillin VK 500 mg
bid or erythromycin until 2-4 wk after last meningococcal vaccine
Optimal duration therapy is unclear. Attempts to d/c the drug can lead to relapse.
d/c can be considered in seroconversion of CFH Ab (KDIGO KI 2017935191
When stopped after 18 mo therapy 31% (72% of CFH. 50% of MCR none of no variant)
relapsed during 22 mo flu. Roan we 2 day of drug was therapeutic (qAsn 2017;1Z50>
Other Treatments
lmmunosuppression if Ab (+): cyclophosphamide 1/qxo 201ass9m2 xoico KI 1017.91519)
Plasma exchange (PLEX): use if eculizumab not available. About half respond (compieteiyl
partially). Pos w/ CD46 mutation do not benefit (rom PEx since 90% of episodes
resolve whether they received plasmatherapy or not LC/ASN 2010.5;l844). Pts w/ ab to
CFH do better with the addition of immunosuppression (CS wl cyclophosphamide
or RTX) who 2gl0:$§;923; our run zootzasel.
Transplantation
Before ecullzumab use. recurrence was -80%. esp w/ CFH mutation Laura 100s;10812677
Eculizumab +I- PLEX: prevention and tx of recurrence in allografLTleatment may have
to be lifelong (qAs~ 2011;6:\4881 A/r zoiznuaavl.
Combined liver-kidney Txp (rarely done): liver produces modulating proteins.
Perioperatilely. there is an intense upregulation of the complement systan. often leading
to allograft demise with widespread microvascular thrombi in the liver sinusoids and
kidney graft Wr z00s5=114sl. Perioperative F'Ex +I eculizumab may circumvent dis problem
(mau ~¢vl=-il2014;29:477).
 GENERAL HYPERTENSION
About 103 million us adults have HTN (ACC/AHA;ACC 201B:71:e1Z7)
45.6% prevalence of HTN among US adults >18 yr; pharmacologic treatment is rec
ommended for 36.2% of US adulr.s: 53.4% of Pts receiving treatment for HTN have
BP above goal (cauuauni 2018;137:109)
As of 2010. 80.7% are aware of the diagnosis of HTN UAMA 201ik30:2043)
Prevalence increases with age: >twothirds of US aduM >60 yr of age have HTN
HTN is prevalent in B085% of pts with CKD:prevalence of HTN T inversely with GFR
Risk of CVD doubles for every 20/10 rise in BP above 115/75 (una:2002;3&19031
Risk factors for primary HTN: age. obesity. family history. black race. excessive dietary
sodium i»»==\<=.8'-w alcohol intake. physical inactivity. reduced nephron mass
HTN in black pls is more common.develops earlier in life, is more severe. and is
associated with greater risk of CV complications in comparison to whites
Complications LVH, HF w/ reduced EE HF w/ preserved EF. ischemic heat disease.
ischemic stroke. intracerebral hemorrhage. CKD, ESRD
2017 ACCIAHA Definitions of Hypertension UACC 201t71»127)
Normal BP SBP <120 and DBP <80
Elevated BP SBP 120-129 and DBP <80
Stage 1 HTN SBP 130139 or DBP 80-89
Stage 2 HTN SBP 2140 or DBP 290
Isolated systolic HTN SBP >130 and DBP <80
lsokced diastolic HTN SBP <130 and DBP 280

Pathogenesis
Hundreds of generic risk variants have been identified: number of risk alleles corre
lates with likelihood of developing primary HTN: effect on BP is modulated by envi
ronmental factors
High sodium intake leads to t intravascular fluid volume.cardiac output.peripheral
vascular resistance, and BP;elevation in BP leads to T renal perfusion pressure and
T excretion of excess sodium and fluid (pressure natriuresis"). If sodium excretion
is impaired (aging, obesity. kidney disease) -> HTN
Other factors: reduced compliance of large conduit arteries. impaired endothelium
mediated vasodilation (T PVR). T activation of local reninangiotensin systems (heart.
kidney, adrenals, vasculature),T activity of sympathetic nervous system
Evaluation
Ensure proper measurement technique: patient sitting widi back supported for >5 min and
arm supported at level d heart; length of BP cuff bladder >80% and widdi >40% of dr
cumference d upper arm; take average of 22 readings (additional if readings vary by >5):
measure BP in both arms: assss for postural hypotension
Exam: optic fundi. thyroid. heart. lung. kidneys. peripheral pulses. neurologic system
Testing: electrolytes. Cr. glc. Hb. lipid profile. U/A. UACR. ECG. echocardiogram
Evaluate for causes of secondary hypertension
BP Measur ement
Strategy C omments Cr iter ia
Ambulatory blood Device takes BP measurements at regular Daytime average
pressure intervals over 12 or 24hr period 2130/80 OR nigh:
monitoring (15-30 min during daytime and 3060 mi time average
(ABPM) during sleep) 2110/65 OR 24hr
Predicts CV outcomes independently of average 21251275
office BP: stronger predictor of all
cause and CV mortality than office BP
(NEW zoiezmsoel
Reference standard for confirming
diagnosis of HTN w. :m 101s¢1s3r/s)
Home BP May predict CV outcomes as well as ABPM Repeated readings
monitoring Multiple mouing and e~ening measurements 2130/80
(HBPf1) should be taken over a period 21 wk
Alternative method of confirmation if
ABPM not available
Oncebased BP Can be done routinely (manual or semi See above: based upon
measurements automated) or via automated average of 22
(OBPM) oscillomeuic BP (AOBP) device (ukes readings at 22 o1&ce
multiple consecutive readings while pt visits
is sitting and resting alone. better
approximates daytime A8PM)

- Secondary Causes of HTN (amuuuin 10aa11171a101

Lifesryie factors Obesity. excessive dietary sodium intake. heavy alcohol nuke
Medications unSAIDs. sympathomimedc agents (decongeszanrs. cocaine),
amphetaminelike stimulants. oral contraceptives. glucocordcoids.
herbals (ephedra). licorice (l metabolism of cortisol). Curls. ESAs.
VEGF ligand inhibitors. antiangiogenic TKIs
Renal disease CKD. acute GN. vasculitis. HUS
Renovascular dz Renal artery sxenosis
Endocrine disorders Primary hyperaldosteronism. pheochromocytoma. Cushing
syndrome. hyperparathyroidism, reninsecrezing rumors
Monogenic HTN Glucocorticoidremediable aldosteronism (GRA). Liddles.
syndromes pseudohypoaldosteronism type 2 (Gordons). syndrome of apparent
MC excess (AME). congenital adrenal hyperplasia (CAH)
Other OSA (discussed below).aonic coarctarion. intracranial rumors

Evaluat ion of H T N in C KD
Masked HTN Elevated ambulatory but normal clinic BP ("isolated ambulatory HTN")
a/w * longterm risk of sustained HTN and higher risk of allcause
(HR 2,83 vs 1.80) and CV (HR 2.85 vs 1.94) mortality than in Pts wl
sustained HTN in large registrybased study (NUM z0\a;37e1 s09l
Occurs in 15-30% of US adults with normal oNce BP
More common among prs wl CKD: 70% of pos wl controlled clinic BP in
the AASK Cohan had masked HTN: masked HTN was aw LVH and
proteinuria and lower eGFR 1H»~w~»»w~ zooesaizol
Nondipping Absence of the normal (10-20%) nocturnal decline in BR may be related
to impaired ability to excrece sodium during daytime
Up to 80% of pts with CKD are nondippers
Risk factor for LVH. HE proxeinuria. CKD progression
Independent predictor of CV events and CV and allause mortality in Pts z
wl resistant HTN qo
Chronotherapy can restore normal dipping (discussed below) H

Tr e a tm e nt
Lifestyle As: wt loss (maintain BMI 18.5-24.9 kg/m').die:ary sodium restriction
(<2.4 old or 104 mmol/d Na or 6 old NaCl), DASH die: (rich In fruits. vegetables,
and lowfat dairy products). T physical activity (230 min/d. 5 d/wk). moderation of
alcohol intake
DASH diet + dietary sodium restriction: high sodium (3.5 g or 150 mmol/d) -> low
sodium (1.2 g or 50 mmol/d) DASH diet a/w L 7 in SBP: high sodium control -» low
sodium DASH die: a/w is in SBP (N£IM 2010.361:z10z)
Pharmacologic dwerapyc in -2/3 of HTN. 22 drugs are required to achieve target BP

Tre a tme nt a nd Bl ow up 1 ;Ac c a o1 a m1 2 1 )

Normal BP Encourage healthy lifestyle As w maintain normal BR reassess in 1 yr

Elevated BP Recommend healthy lifestyle As. reassess in 3-6 mo
Sa ge 1 HTN If 10yr ASCVD risk <10%: healthy lifestyle As. reassess in 3-6 mo
If clinical ASCVD or DM or CKD or 10yr CVD risk >10%: start
1 BPlowering medication. monthly followup until goal achieved
Stage 2 HTN Recommend healthy lifestyle As and 2 BPlowering medications of
different classes. monthly followup until goal achieved
 HYPERTENSIVE NEPHROSCLEROSIS
Background
2nd m/c cause of ESRD: usually a/w longstanding HTN (HTNattributed nephropad\y")
In black pts,r.here is a high incidence of renal disease progression despite intensive
antihypertensive therapy (3fold T risk in incidence of ESRD among African Americans
with HTNattributed nephropathy dw European Americans)
Pathogenesis
Apolipoprotein L1 (APOL1) risk variants are significantly associated with kidney dis
ease (FSGS and HTNattributed nephropathy) in black Pa. OR 2.57 In 20131834141
Chronic HTN - medial hypertrophy and intimal thickening -» luminal narrowing of
large and small arteries and glomerular arterioles; ischemic injury global glomeru
Iosclerosis nephron loss. compensatory glomemlar hypertrophy and hyperGltra
:ion -» rise in inuacapillary pressure -» FSGS; ischemic injury -» severe interstitial
nephritis

BP Targets and Choice of Antihypenensive Agent

Population Goal BP and Benefit
CKD and Target <130/80 (Acc t¢A;Acc N1&7I:e127)
others with In 250 y/o wl T CV risk (excluding Pos
known CVD wl DM. oven HE stroke. or 21 old
or 10yr prozeinuria). intensive treatment (SBP
ASCVD risk <120) is a/w l in allcause moruliry
210% (HR 0,73) and Ml.ACS. stroke. HE
CV death (HR 0.75) dw standard
treatment (SBP <140) (shunT ~=1m
z01 s.am1o:l
In CKD subgroup (eGFR 20-59):
intensive BP control is alw 1 in all
cause mortality (HR 0.72) and CV
outcome (HR 0.81). No A in kidney
outcome (25096 . in eGFR or ESRD)
(SPRINT ASr 10\7;2&Z812)
In ps wlo baseline CKD: t incident CKD
(HR 3.5) and AKI (HR 1.64) but early 1
eGFR may be reversible hemodynamk
effect(9*$N Z01&13:I575)
In metaanaiysis of RCTs: intense BP
lowering is a/w 14% i risk of allcause
mortality in Pa widl CKD stages 3-5
(WM IM 20177171:1498)
CKD with More intensive BP control alw 1 risk of
proteinuria CKD progression in pts with:
>1 old proteinuria in longterm flu of
the MDRD study (Ann :m z00s;14z34zI
>300 mg/d proteinuria among black pts
in cohort phase AAS( (NUM 1010l]63:918)
and in longterm flu 1 ESRD in pos wl
>1 old pmteinuria (Msn lOI7;18t67 l)
Diabetes (with Target <130/80 (AccrA»4A;Acc 201B:7\:l127)
and without In¢ype2 DM CvDa22adn»tiomlrisk
CKD) lectors for GQ imenswe comrd (SBP
<120) a/w no A in CV morbidity/
morulimy or allause mortality but
slgnbiiam m wal (HR 059) a1d nonhnl
sunle (HR 0.63) dw sundard dwipy
(<140) (Accoar>epr4gpu zola=Jea;1slsl
Intensive BP conunl 1 incidence d
microdbuminuria (HR 0.84) but no A in
renal failure Of 1ezinopazhy of zolzsl so
Choice of Agent
In pos who require 2 drugs:
Benazepril-amlodipine 1
CV morbidity. morulizy
(9.6 vs 11.896, HR 0.80)
and 1 CKD progression
(HR 0.52) dw benazepril
HCTZ 1A€COMPIJS14 nqfa
1n0eus9z4m
Chlorthalidone 1 me of HF
and CVD outcomes. but
no A in primary outcome
(fatal CHD. nonfatal MI) or
morality dw lisinopril.
amlodipine Al.uIAT (MMA
zo0z.zs8m1l
ACEi or ARB L rate of
progression to ESRD in Pts
wl >500-1.000 mild
proteinuria; benefit extends
no PU w/ advanced CKD:
no benefit and . adverse
effects wl combination
ACEilARB lo~rAnGs1 we
N08:)S&1$47]
In pa wl albuminuria ACE or
ARB
In pos wlo albuminuria:ACEi.
ARB. thiazide. or CCB
In pts who require >1 drug
ACEr or ARB Q longacning
CCB
ADPKD Target $130/80: in young pts wl intact
kidney fun. urge: <110/75 may L CV
events and me of is: growth
In pos 15-49 yr w/ eGFR >60. low BP
goal (95160-110175) alw 1 A in total
kidney volume. LVMI. urinary albumin
excretion. no overall A in eGFR dw
standard (120170-130180) (HALTPKD
NE[M 2014;]71:1155)
General ACC/AHA: clinical Lrial evidence Black and elderly respond
population strongest for <140/90. but <130180 beuer so nhiazide:ype
wlo above may be reasonable yAcc 201B:71:e127] diuretics or longacting
conditions JNC8: <150l<90 in 2 6 0 lo. SBP <140 in CCB than ¢oACEi or
<60 ylo up 2014;311:S07) ARBs
Isolated syscolk HTN: may need tO
accept SBP >140 to keep DBP >60

HYPERTENSION IN ESRD
Background
Prevalence of HTN in dialysis Pts is high>50% and up co 86%1A~»}m¢4 100s;11s:2911;
the majority are :reared with antihypertensive agents but not controlled
DeGnicions: 1wk avenge predialysis SBP >150 or DBP >90 OR 44hr interdialytit
ambulatory BP 2135/85 OR use of any antihypertensive medications
In 10-15% of Pts. BP paradoxkally increases during dialysis ("intoadalytic hypertension"):
this is ails volume overload. interdaiylic hypertension.and increased shonteam morality
Pathophysiology
Volume overload is the major fuse of HTN in dialysis Pts;T activity of RAA6 and SNS:
arteriosclerosis. T in intracellular Ca2,t in endotheliumderived vasoactive substances
ESAs: incidence of HTN correlates wl dose but not RBC mass or viscosity: may
involve T in vasoactive substances such as endothelin; more likely wl IV than SC
Evaluation
There is uncertainty about how to accurately measure BP in dialysis Pts
BP Measurement Strangles
Predialysis and postdialysis BP Highly varialsle inaproverdmezagleepoorlywidiiuuvhlyUc
measurements alnbdawry BPmaybe t but predialysis BPL
dq,1en¢1ilg on Me degree and race d duafiluation
Ambulatory BP monitoring Gold standard for diagnosis bu: generally nor used clinically
(ABPM) Measurements men over the 44hr interdialytic interval
Amb. BP T by 2.5 for every 10 hr elapsed after HD
Home BP monitoring (HBPM) Correlates more closely with ABPM and better predicts
longterm outcomes (CVD, allcause mortality)
Home BP T by ~4 for every 10 hr elapsed after dialysis

Tr e a tm e nt
Guidelines are scarce target predialysis BP <140190 and postdialysis BP <130/80
iKVOQ¢A1»<D 2005:45:51)C no recommendations made by KDIGO up 20!3;B3:377)i using
incerdialytic home BP to target BP <13S/85 may be more reasonable
No doubleblind RCTs evaluating :he target BP or optimal agen: in dialysis pts
Giving anrihypenensive drugs at nigh: may occurrence of inrmdialytic hypotension

Tr e a tm e nt S tr a te gi e s
Nonpha rma c ol ogi c
Dietary Na resticrion <1.5-2 old Na no target imerdialytic we gain (IDWG) <2-3 kg
Optimizing die dialysis (1) Individualize dialysare Na; Hypertonk dialysaze may allow
prescription t Huid removal and improve hemodynamic stability BUT leads
to T whirs: and T inrerdialytic WI gain
(2) Increase length and/or frequency of dialysis: A from
conventional co frequent/nocturnal HD is alw L BR number of
andhyperrensive medications, and LV mass
 Optimizing the Dry weight should be achieved via gradual reduction in post
management of dry dialysis weigh: (0.2-0.5 kg/session) no :he lowes: tolerated
weigh! weigh: that J, sis of hypo or hypervolemia
Reducing EDW can improve BP in majority of Pls
Probing EDW can 1 ambulatory BP even in Pts w/o oven sis of
volume overload (Hyperwaniun 11109;5}:5001
P ha rma c ologic
ACEr or ARB Well tolerated but may T risk of hyperkalemia and anemia
L In LV mass: no large RCT has demonstrated benefit on CV events
or mortality
Lisinopril, enalapril, benazepril are dialyzable and should be given
after dialysis: other ACEi and ARBs are not
Dihydropyridine (DHP) Effective and well tolerated; not dialyzable and do not require
CCB supplemental dosing
Bblocker Openlabel RCT showed CV events with atenolol vs lisinopril
(nor 2o14;29¢sn»:A:enolol is moderately dialynblezcan be given
TIW after HD (25-100 mg)
MR antagonist (MRA) 36wk RCT showed SPL welltolerated at $25 mgdajly, T me of
K >6.5 mEq/L at 50 mg daily In z01s¢d°e 10.101sl "
Metaanalysis suggests benefit on CV and allcause morality but
lowquality evidence We 10154681591)

RESISTANT HYPERTENSION
Background
Defined as BP Mat remains above goal despite adherence to treatment with 23 anti
hypertensive agents of different classes prescribed at optimal doses. ideally including
a diuretic. OR BP at goal but requiring 24 agents (aiaiIauan 200B;117:510)
Epidemiology iHn=¢iteiuion 201\;57:\076)
Using data from NHANES from 2003 to 2008: (1) 8.9% of US adults with hyperten
sion and 12.8% of US adults on treatment with antihypertensive drugs met criteria
for resistant HTN; (2) 72.4% of all drugtreated adults with uncontrolled HTN were
taking drugs from <3 classes: (3) 85.6% of adults with resistant HTN used a diuretic
but 64.4% of those used the weak thiazide diuretic HCTZ
Prevalence of resistant HTN in nephrology clinics may rise to >50%
Adults with resistant HTN are more likely to be older, nonHispanic black. and have
higher BMI,albuminuria, CKD.CAD, HE stroke. and DM
P a thoge ne s i s
Factors do T prevalence of resistant HTN in CKD: impaired Na handling. chronic
fluid overload. T activity of RAAS and sympathetic systems. impaired NO synthesis and
endodieliummediated vasodiladon. arterial sdflness. inflammation, renovascular ds

Definitions of Resistant Hypertension

Apparent resistant Uncontrolled BP despite being prescribed 23 antihypertensive agents
HTN or controlled BP despite being prescribed 24 agents
True resistant Uncontrolled BP despite adherence with 23 antihypenensM agents at
HTN optimal doses or controlled BP despite adherence with 24 agents
Pseudoresistant Appearance of treatment resistance
HTN Causes: poor adherence to therapy. complicated dosing regimens:
suboptimal dosing of medications. inappropriate combinations of
agents. physician inertia; improper BP measurement technique.
difficult to compress calcined arteries in elderly: white coat HTN
White coat HTN Elevated BP during clinic visits with normal BP in nonclinic settings
and absence of target organ damage (isolated clinic HTN")
Pts an at lower cardiovascular risk compared with persistent HTN
but white coat HTN may not be benign. alw HR 1.79 for allcause
mortality in large registrybased study 1n£/m z01s.3n.1 solI
Occurs in 15-30% of pts with elevated office BP
Mon common among patients with resistant HTN
Refractory HTN BP unable to be controlled despite optimal medical therapy under die
care of a hypertension specialist
Evaluation
Accurate measurement of oNce BP attention to environment. body and arm position.
and appropriate cuff size: obtain avenge of multiple measurements at least 1 min apart
Confirmation with ABPM or HBPM
Identify contributing lifestyle factors: age, obesity.family history. black race. excess dietary
sodium intake. heavy alcohol intake. reduced nephron mass
Identify substances that interfere with BP control: unSAIDs, sympathomimetics. stimu
lants. alcohol, oral contraceptives. glucocorticoids. natural licorice. herbal substances
Screen for secondary causes of HTN
Treatment
Optimize volume Dietary sodium restriction and use of appropriate diuretics:
status Chlonhalidone 25 mold is twice as potent as HCTZ 25 mgld.has a
much longer duration of action. and is effective at a lower GFR
Use of loop diuretics in advanced CKD
Combining loop diuretic with thiazide or lowdose Ksparing diuretic
Adequate RAAS Use of mineralocorticoid receptor blockers (MRBs. spironolactone and
blockade eplerenone) as addon therapy:
Addition of spironolactone 25-50 rngld is superior dw placebo (-8.7 1 In
home SBP).doxazosin (4 .0 3 .),and bisoprolol (4 . 4 8 ) esp. in Pts wl
low plasma renin;low incidence of hyperkalemia though Pts had GFR
>45 lPAYHWA!2 linier zoisaaazns9l
Chronotherapy Bedtime dosing of BP medications can restore the nomtal dipping p a r e r .
improve nocturnal and 24hr ambulatory BP control. reduce proteinurh.
and may be a/w l risk of CV morbidity and mortality UAW 2011:2Z;13131

HYPERTENSIVE EMERGENCIES
Background
Hypertensive emergency: significantly TBP (SBP 2180 and/or DBP 2120) with s/s of
acute. ongoing, endorgan injury: requires immediate BP reduction
Severe asymptomatic HTN ("hypertensive urgency"): BP can be lowered within hr to d
BP usually severely elevated in pts with chronic HTN but can develop at lower BPs in Pts
without preexisting HTN if there is an acute rise in BP (je,acute GN or pieeclampsia)
Pathophysiology
Release of vasaconsukting substances (angiotensin II. notepinephnine) -» abrupt rise in
vascular resistance -> endothelium releases vasodilator molecules but dlis compensatory
response is overwhelmed - endothelial damage and furdier rise in BP
As MAP increases (esp >180).cerebral vascular autoregulation is overwhelmed -» cerebral
vasodilation and edema - hypertensive encephalopathy
Clinical Manifestations and Evaluation
Symptoms chest pain (Ml or aortic dissection):back pain (aortic dissection); dyspnea
(pulmonary edema or HF): neurologic sx. seizure, or AMS (hypertensive encephalopathy)
Exam: ./ for BP A between arms (aortic dissection): T JVR $3 (HF): flame hemor
rhages, exudates. or papilledema on funduscopic exam (hypertensive retinopathy)
Causes: renal (acute GN, vasculitis. HUS. renal artery stenosis): endocrine (pheochro
mocytoma.Cushings): CNS (head iniury.cerebral infarction. cerebral hemorrhage);
drugs (cocaine. sympathomimetics. Curls. ESAs. sudden withdrawal of antihypertensive
medications): other (preeclampsiaJeclampsia.TTP)
Reversible Posterior Leukoencephalopathy Syndrome (RPLS or PRES)
Associations: HTN.TlR HUS. eclampsia,vasculitis. immunosuppressive drugs (CyA.Tac)
Imaging MRI shows symmetric white matter edema in posterior cerebral hemispheres
Tre a tme n t
Hypertensive emergency: admission to ICU for monitoring and parenteral therapy
MAP should be i by 10-20% in die first hr and addtl 5-15% over next 23 hi:after 24 hr
of BP at target levels.oral medications an be started and N mediations tapered oil
Tre a tme nt Approa c h for Cl l ni c a l S c e na ri os

Acute ischemic Labeialol and nicardipine (fursline). Ninroprusside (secondline)

stroke Lower BP if Z2201120 (or 21851110 if IPA candidate)
Hypertensive Nicardipine. clevidipine, fenoldopam, niuoprusside. Iabetalol.
encephalopathy enalapril. hydralazine
 Loop diuretics, vasodilators (niuoprusside, nitroglycerin)
Avoid hydralazine (T cardiac work). Bblockers (i contractility)
Acute MI Nitroglycerin. nicardipine. esmolol (T coronary perfusion. 1 MVO;)
Acute aortic First: Bblocker to L HR and wall shear stress (esmolol. labetalol)
dissection then vasodilator (nitroprusside or clevidipine)
SBP should be rapidly l to 100-120 (within 20 min)
Pregnancy (pre Methyldopa. hydralazine. Iabezalol. fenoldopam nicardipine
eclampsia. IV magnesium sulfate for prevention of eclampsia
eclampsia) Delivery of baby and placenta
AKI (acute Calcium channels blockers and Rxblockers (preserve renal blood
hypertensive flow):fenoldopam (causes renal arterial dilation > maintains or
nephvosclemsis) increases renal perfusion)

Dr ugTr veaunent
Drug Mechanism Dose Adverse Effects
Sodium Arterial and venous Sun ac 0.25-0.5 - Cyanide toxicity if Rx
nitroprusside dilawr max B-10 ug/kg/min prolonged >24-48 hr
Nitroglycerin Venous > arterial 5-100 up/min Headache. reflex
dilator tachycardia
Clevidlpine Shortaczing CCB 1-21 mglhr Reflex tachycardia
Nicardipine CCB 5-15 mg/hr Reflex tachycardia
laberalol B and ublocker 2080 we bolus or Bradycardia.
0.82 mglmin infusion bronchospasm
Fenoldopam Dopamine1 0.1-1.6 pglkglmin Headache. flushing,
receptor agonist . IOP
Hydr azine Vasodilator 10-20 mg IV bolus Reflex tachycardia

ANTIHYPERTENSIVES
F eatur es and Dose o( Andhyper tensives
Class Feacunes Dose
AC Et and Beneficial efleccs in proreinuric
ARBs CKD. HE pos:MI
Synergistic eifecc with diumics
Remains beneficial in advanced CKD
(NEW2M;]§(;U\)
Contraindicated during pregnancy
sle: K
ACEi 1 formation of angioiensin II (All), Lisinopril: 10-40 mg (1:Id)
vasodilation (dl: 1 kin in levels) Benalepril 1040 mg (1-2>Id)
sle: cough. angioedema (rare) Fosinopril: 1040 mg (1-2x/d)
due to kin in levels Ramipril: 2.520 mg (1-2xld)
Quinapril: 10-40 mg (1-Zxld)
ARBs Impair binding olAll to AT1 Losarran: 50-100 mg (1-lx/d)
receptor Valsartan: B0-320 mg (1>Jd)
Losarlzn: las effective ac BP lrbesartan: 150-300 mg
lowering dun oder ARBs. T uric Telmisanan: 4080 mg
acid excretion and L plasma uric Candesar¢an:8-32 mg
acid levels Azilsamn: 4080 mg
Thiazides Inhibit apical NCC in DCT
<~+;1m sle. K. J. Na. t Ca.. uric acid.
za o mw sa ) glucose intolerance
HCTZ Most effective at GFR >50,tin 10 hr; Start at 25 mg/d and citrate Io
(rhiazidezype) reasonable choice in frail older 50-100 mild: can be given
Pts <10 above goal BP 1-2 x/<1
Chlorthalidone Can be effective to GFR of 3 9 4 0 : Star: as 12.5-25 mg/d and
(thiazidelike) i n 5 0 6 0 hr, 2 x more pote nt t i m e (D 50 mild
than HCTZ; greater L in
nighttime and 24hr BP; l HE
CVD IAU.HAT #mi 2007:zae:19sn
Mezolazone Retains efiecxiveness at GFR Sun as 2.5-5 mg/d. ckrace to
(xhiazidelike) <30 mUm in; TM 14 hr 10-20 mg/dc can giveTlW
Loop diure tic Inhibit apical NKCC in THAL Normal renal fxn. Bum.1 mg =
(NEW sle: L K. rash. AIN. otozoxiciry as Euros. 40 mg = tors. 20 mg
19981339:J07) high doses Severe CKD: Bum.1 mg = furos.
20 mg tors. 20 mg
Funosemide Maximal response in severe
CKD: 160-200 mg IV. Should
be given 2-3x/d
Torsemide Bioavailability 100%;tm ~3-4 hr Maximal response in severe
CKD: 50-100 ms lVlPO: Can
be given 1-Zx/d
Bumetanide Maximal response in severe
CKD: a-10 mg IVIPO
Erhacrynic acid Only nonsulfa diuretic but T
ototoxieity
Ks pa ri ng Act in the principal cells of the
diuretics CCD
Spironolactone Competitively inhibits MR. Tm >15 hr 25-100 mud; risk of
(SPL) (active metabolite). hyperkalemia is predicted by
sle: gynecomastia. 1 libido dl: baseline eGFR $45 mUm in
nonselective binding to steroid and baseline K >4.5 mEqIL
receptor
Eplerenone (EPL) Competitively inhH>its P1R.tm 3-6 hr; Starr at 25 mg/d. drrare to
t specificity for MR. 1 incidence 50100 mg/d in daily or
of sle but more expensive and divided doses: risk of
may be less effective than SP1. hyperkalemia as above
Triamzenene Inhibits ENaC. 37.5-75 mg/d in combination
sle: crystalluria. stones,AKl pills wl H C T Z
Amiloride Inhibits ENaC;prolonged to Scar: as S mg daily and drrare to
(100 hr) in CKD:few side effects 10 mg daily
Ca lc ium Inhibit Ltype cab channel
channel sle: peripheral edema. constipation,
blockers gingival hyperplasia (dose
dependent)
DHP Potent vasodilators. AModipine sur! as 5 mold
(amlodipine. s/e:as above plus headache and (15 mg in small prs).¢iu1ce to
nifedipine) flushing edema is more common. 10 mg/d after 7-14 d.
Amlodipine: longer to (30-S0 hr Nifedipine: Sir: 3060 mg/d.
vs 2-7 hi):studied in ALLHAT da me w 9 0 -1 2 0 ma . ma y
and ACCOMPLISH trials need no be given rwke daily
NonDHP Negative inouopes. less potent Dilciazem: 120-360 mold
(diltiazem, vasodilators. May : proteinuria. VerapamiI: 120-480 mold
verapamil) s/ea: above plus L CO. HR. Cause T
levels d CYP3A4 substrates (incl.
CNI)
Bblockers sle: hyperkalemia, T Glc and TG.
bradyardia. ischemic sx wl acute
withdrawal, depression. t weight
Selective (p.1) Atenolol: excreted by kidney: to
(atenolol. prolonged in CKD
bisoprolol. Atenolol and metoprolol are water
metoprolol, soluble and dialyzable; should be
nebivolol) administered postdialysis
Nebivolol produces NOdependent
vasodilation
 Wsodiladng pmperdes. Carvedilolz no Carvedilol: 12.5-50 mild (2>¢Id)
impact on glycemk control. may Labezalolz 2001.200 mg/d
v renal vascular resistance and (2-3,/d)
T renal blood How and GFR
t HDL and insulin sensitivity
May have benefit in men wl BPH.
sle: postural hypotension. dizziness.
In ALLHAT,doxazosin alw t risk
of CHF UA/M 1001;28&2981)

sie: sedation. dry mouth. sexual

dysfunction. withdrawal
hypertension (esp w/ clonidine).
Methyldopa is safe in pregnancy
bu: rarely used in other servings
sie: headaches, fluid retention. reflex
tachycardia
sl e:as above pl us dr ugi nduced l upus 25-100 mgldose (2-3>(Id)
and ANCApositive vasculitis
Minoxidil s/e: as above plus hirsudsm

Indications for Specific Drug Classes

Indication Drug Class
HF ACEi,ARB. diuretic. Bblocken MRA
Pos:MI ACEi. Bblocken MRA
Aerial 6brillaxion Bblocker. nonDHP CCB
DM ACEi.ARB. diuretic. iiblocker. CCB
Proreinuric CKD ACEi.ARB. nonDHP CCB
Fluid overload Thiazide diuretic, Iaop diuretic. Ksparing diuretic
BPH ablod<er
/Osteoporosis Thiazide diuretic

Background
A sleeprelated breathing disorder characterized by repetitive partial (hypopnea) or
complete (apnea) cessation of airflow caused by collapse of the pharynx during sleep
repeated arousals and hypoxemia
Common but frequently undiagnosed disorder
An independent risk factor for HTN: in generaI.the more severe the OSA.the more
prevalent and severe the HTN
Moderatelsevere OSA is a/w widl nearly3fold T risk of incident HTN lnqm zouasazmal
OSA may be present in >70% of Pts wl resistant HTN
Epidemiology
Prevalence is 10% in middleaged individuals (-5% in women, -15% in men)
Risk factors: obesity craniofacial or upper airway soft tissue abnormalities. age. male
gender. smoking.» family history
Prevalence T w/ T BMI and markers of obesity (neck circumference.waisttohip ratio)
Presentation
Common presenting complaints: daytime sleepiness. fatigue. snoring. restless sleep,
poor concentration, mouing headaches. nocturia
Common exam findings: obesity.crowded oropharyngeal airway. HTN
Frequent apneic and/or hypopneic episodes can end with arousals with spikes in BP
lasting several seconds » T the risk for"nondipping" HTN.a strong predictor of CV
risk: nearly 90% of Pts w/ nondipping HTN patterns may have OSA
Complications: T mortality. sustained HTN. pulmonary artery HTN. HE stroke. insulin
resistance. impaired daytime functioning. impaired cognition. depression
Diagnosis
Screening in Pts w/: Excessive daytime sleepiness; snoring + 22 additional clinical fea
tures of OSA: resistant HTN; unexplained pulmonary HTN;secondary pciycyzhemia
The STOPBang questionnaire can help idenzify Pro w/ OSA
STOPBang Questionnaire laId 1012410a16s)

s Do you snore loudly!

T Do you often feel ¢ired.fatigued. or sleepy during daytime?
o Has anyone observed you stop breathing during your sleep?
P Do you have or are you being treated for high blood pressure?
B BMI >3s Up/ml
I Age >50 yr old
n Neck circumference >40 cm

8
Gender: Male?
01 pos. nsponsas = low risk. 3-4 pos. responses = intefmediane risk. 58 pos. responses = hgh risk d OSA:
probability of moderatefsevuu OSA = 36% for score 23. 60% for score 27

Polysomnography (sleep study) evaluation performed in a sleep disorders un: is :he

gold standard for an accurate diagnosis of OSA
Criteria: 25 obstructive respiratory events per hr of sleep in a P: w/ 21 associated
symptom or comorbidity OR 215 eventslhr regardless of symptoms or comorbidities
Apneahypopnea index (AHI) 5-15 eventslhr = mild. 15-30 eventslhr = moderate, >30
evencslhr of sleep or 02 saturation <90% for >20% of total sleep time - severe OSA
Treatment
Behavior modificationweight loss. exercise.and avoidance of :he supine sleep position.
alcohol, and medications that can worsen daytime sleeping or cause weigh: gain
CPAP to stabilize the airway and prevent hypopnea and apnea events due upper airway
collapse is the mainstay of therapy
Surgical procedures to relieve nasal obstruction (turbinate reduction.septoplasty rhi
noplasty). upper airway obstruction (uvulopalatopharyngoplasty [UPPP]. tonsillectomy.
adenoidectomy), and lower airway obstruction (somnoplasty)
Successful treatment of OSA can lead to a modest bu: clinically significant i in BP and
neducdon (rather complete elimination) of the need for antihypertensive medications
Among Pts w/ OSA and resistant HTN, use of CPAP is a/w greater i in 24hr mean BP |
(3.1) and 24hr DBP (3.2) dw no CPAP and f percentage of Pts displaying a"dipper"
pattern at 12 wk (35.9 vs 21.6%. adjusted OR 2.4) up 1013=310n40n
Number of hours of CPAP use alw greater in 24hr mean B 24 hrlnight likely needed
Predictors of a greater BP response to treatment with CPAP: OSA severity, presence
of excessive daytime sleepiness. presence of uncontrolled HTN

RENAL ARTERY STENOSIS (RAS)

Baekgr ound
RAS: narrowing of one or both main renal arteries or their branches
Renovascular HTN: . BP resulting from renal arterial compromise. often due to
occlusive lesions in the main renal arteries
Ischemic nephropathy: CKD that results from atherosclerotic RAS due to diminished
renal blood flow to the poststenotic kidney
RAS is an anatomical descriptor: the presence of lesion(s) does not necessarily
translate to the lesion(s) being responsible for BP or renal dysfunction
If systemic hypertension is related directly to an arterial lesion. then relief of the
obstruction. presumably. should lead to reversal or improvement of the hypertension
Ep id e m io lo g y
Atherosclerosis accounts for 90% of cases of renal artery stenosis (discussed in this
section):hbromuscular dysplasia (FMD) accounts for -10% (discussed below)
Risk factors for renoyascular atherosclerositic lesions: DM. HLD. aortoiliac occlusive
disease.CAD.and HTN
Prevalence of atherosclerotic renal artery stenosis ° wl age. may rise as high as 30%
among Pts with CAD and to 50% among elderly Pts or those wl diffuse atheroscle
rotic vascular diseases; 10-15% among patients with endstage kidney disease
Pathophysiology
Decrease in renal perfusion pressure -» activation of the RAS. impaired sodium
excretion. activation of the sympathetic nervous system.T intrarenal prostaglandin
concentrations. L nitric oxide production -» renovascular HTN
Initially plasma renin activity t due to activation d the RAS: but when HTN is sustained.
plasma renin activity L
Advanced vascular occlusion (>70-80% stenosis) -» hypoxia widiin the renal cortex
-» activation of inflammatory and oxidative padiways -» irreversible interstitial fibrosis
and loss of renal function (ischemic nephropathy")
Presentation
Renovascular disease is more likely to accelerate or impair control of preexisting HTN
than to cause newonset HTN
Features that suggest renovascular hypertension: resistant HTN. onset of HTN
(>160/100) in a Pt >50 yr. presence of diffuse atherosclerosis. atrophic kidney or asym
merry in kidney size. absence of family history of HTN. recumbent flash pulmonary
edema. unexplained refractory HE acute rise in serum creatinine (z50X) after the
administration of ACEi or ARB. presence of abdominal bruit
Atherosclerosis usually involves the ostium and proximal 1/3 of the main renal artery
and perirenal aorta: segmental and diffuse intrarenal disease may also be seen
Stenosis is progressive in the majority of patients
Diagnosis
Testing is indicated in pa w/ clinical findings suggestive of renovascular disease who
have a high likelihood of benefiting from an intervention should a clinically significant
srenoric lesion be found
Renal arteriography is the gold standard but less invasive options are available

Diagnosis of Renal Artery Stenosis

Modality Features
Duplex Doppler Provides both anatomic (direct visualization of the main renal arteries)
/ ultrasonography and functional assessment (systolk flow velocity via Doppler) of the
severity of stenosis
Nonirwasive and relatively inexpensive: bu: time consuming, may be
technically difNcull. operator dependent
CT or MR Accurate and noninvasive: better for proxdmal disease
angiography May be limited by pt.related factors (presence of cadmium or scents)
Toxicity associated with use of contrast media in pts with CKD
Captopril Oral captopril is given 1 hr before a marker of glomerular fikradon.
stenography such as DTPA is injected - ACE inhibitorinduced decline in GFR
in the stenotic kidney and equivalent increase in GFR in the
contralateral kidney - A between kidneys is enhanced
Functional test to compare RBE GFR between the two kidneys
Low predictive accuracy for renovascular hypertension
Can be unreliable when baseline kidney function is abnormal as
asymmetries in renal flow and function can be present for
reasons other than renovascular disease
Measurement Of PRA measured 1 hr after the administration of oral captopril - Pts
peripheral plasma w/ a functional lesion should have an exaggerated . in PRA
renin activity Low predictive accuracy for renovascular hypertension
(PRA) PRA is in only 50-80% of pts wl renovascular hypertension
PRA may be suppressed by high dietary Na intake. bilateral renal
artery disease. volume expansion.various medications

Tr e a tm e nt
Treatment goals include: blood pressure control (rather than reversal). preservation
or salvage of kidney function. and prevention of flash pulmonary edema
Options include (1) medical therapy with ACEr or ARB other agents as needed.
(2) percutaneous angioplasty +I- stent placement). (3) surgical revascularization
Revascularization vs medical therapy alone
(1) In 1,000 Pts wl adierosclerotic renal artery stenosis widl 260% narrowing and sys
tolk HTN despite 22 antihypertensive medications and/or eGFR <60 no A in pri
mary outcome (composite of dam from CV or renal muses. CVA. Ml. hospitaliza
don for CHE progressive renal insufficiency. or die need for permanent RRT)
between those randomized to medical therapy alone vs medial dtevapy plus stent
(CORAL NEIM 2014;3741J)
 (2) In 800 Pts w/ average 76% stenotic occlusion of the renal arteries and entry
serum creatinine >2,0 mg/dL randomized to medical therapy with or without stem
ing - no A in blood pressure control. kidney function. heart failure hospitalizations.
or mortality over a median followup period >2 yr lAs1rzAL new zcoraernrsai
Features that suggest benefit from revascularization: short duration of BP elevation:
inability of optimal medial therapy to conuol Be intolerance of optimal medical therapy.
including ACEi orARB: progressive CKD in a pt with bilateral renal artery stenosis or
unilateral srwosis to a solitary kidneys recumbent flash pulmonary edema: refractory HF
Risks of revascularizationz renal artery dissection. thrombosis, perforation; restenosis.
AKI due to atheroembollc disease; reaction to ndiocontrasr: agent
Calculation of the renal resistive Index (RI) may help predict the outcome after revas
cularization: t Rl is alw greater degree of intrinsic renal damage. Rl ([1 - (enddiastolic
velocity + maximal systolic velocity)] x 100) 280 identifies pts wl renal artery stenosis
in whom angioplasty or surgery is not likely to improve renal function. blood pressure.
or kidney survival (Ne/M z001:344:4ro).

FlaRomuscuLAn DYSPLASIA (FMD)

Ba ckg r o u n d
FMD is much rarer than atherosclerotic diseasecaccounts for <10% of cases of RAS
Classically.diis disease has been described as a cause of HTN in younger females.some
times first presenting during pregnancy
Prevalence drops markedly with age:among pts with renovascular HTN. FMD accounts
for up to 50% of cases in children but <15% of cases in adults
Among adults. FMD is far more common among females (10fold higher prevalence)
Pr e se n t a t io n
FMD =dpi==lIy affects the distal 2/3 of the renal artery and its branches ("soing of beads")
Extracranial cerebrovascular (carotid. vertebral arties) involvement is common
Only rarely does FMD lead to complete or segmental occlusion of d\e renal arteries.
wick most individuals presenting w/ normal kidney function but significantly elevated BP
Diagnosis
Duplex ultrasonography. CTA.and MRA (less preferred) are noninvasive options
Renal aneriography (dagiia1 subtraction angiography [DSA]) should be the first diagnostic
tat for Pts at high risk for FEDassociated reno vascular hypertension.as this imaging
modality allows for simultaneous treaunent wrih percutaneous transluminal angioplasty
T reat m en t
FMD and uncontrolled HTN: conventional balloon angioplasty
Rate of restenosis following angioplasty ranges from 12-34% over followup intervals
of 6 mo-2 in but restenosis does not always lead to recurrent hypertension
Likelihood of cure of HTN is more likely in Pts w/ FMD than in those w/ atheroscle
rotic renal artery stenosis (60% vs <30%)

HYPERALDOSTERONISM
Ba ckg r o u n d
Aldosterone: hormone primarily involved in the regulation of extracellular volume
and potassium homeostasis
Sites of action: epithelial cells in distal nephron > colon. salivary glands. and swear girds
Regulators of secretion: plasma K+. All. ACTH
Binds to cytosolic mineraloconicoid receptors -v T number of open ENaC channels in
apical membrane of CCD principal cells -» T sodium reabsorption electronegative
lumen creams a laivorable gradient for poizssium secretion via ROMK. BK channek
Primary aldosteronism (PA): reninindependent hypersecrecion of aldosterone. non
suppressible by sodium loading
Ep id e m io lo g y
Prevalence of PA: 4% in primary are clinics. 40% among Pts referred to HTN specialty
clinics; 43% among Pos wl severe HTN. Prevalence of elevated aldosterone to renin
:ado (ARR): 46% in primary care clinics. 20% in specialty clinics UMM 101e101:1ss<n
Causes of PA: bilateral idiopathic adrenal hyperplasia (IHA: 60-70%). unilateral
aldosteroneproducing adenoma (APA: 3040%). less common: Unilateral
hyperplasia: familial hyperaldosteronism type I (GRA). type II. and type Ill: and adre
nocortical carcinoma
 Somatic muradons cause aldosterone hypersecretion in 50% ofAPAs: KCNj5 (most
common. -40% of APAs). ATP 1A 1, ATP2B3. CACNA 1D. CTNNB 1
Presentation
Persistent volume expansion, severe & resistant HTN. hypokalemia (in <50% of pts).
metabolic alkalosis. hypernauemia (mild). hypomagnesemia (mild)
T CV morbidity/mortality clw pts wl same degree of BP elevation: ¢ LV mass and
myocardial fibrosis.. LV function. risk of arrhythmias, Ml. stroke. CV death
Renal effects: T GFR due to glomerular hyperNkration, T urine albumin excretion
Pts widl APA: usually younger (<50 yr). T aldosterone secretion rates, plasma and
urinary aldosterone concentrations. more severe HTN and hypokalemia
Evaluation
Casedetection testing w/ plasma aldosterone to renin ratio (ARR = PAC/PRA) should
be performed in Pts with: severe HTN (SBP >150 or DBP >100). resistant HTN, HTN
and spontaneous or lowdose diureticinduced hypokalemia. HTN and adrenal inciden
talorna. HTN and sleep apnea. HTN and family history of earlyonset HTN or CVA at
<40 ynand HTN with firstdegree relative w/ PA
Screening for PA should be done in all Pts w/ resistant HTN. regardless of K level.
although the likelihood of positive results T in pts w/ hypokalemia
PAC and PRA should be measured in a mouing blood sample while seated
Definition of abnormal ARR is assay dependent: PRA is generally undetectable (usu
ally <1 ng/mUllr): PAC is >15 ngldL in most pts w/ PA,ARR >20 is suggestive of PA:
ARR >30 is the most commonly used cutoff
Antihypertensive medications can be continued during testing as long as pt has been
on stable doses for >3 wk
(1) EXCEPT mineralocorticoid receptor blockers (MRBs, spironolactone. and eplere
none) which should be stopped for 26 wk unless Pt is hypokalemic and PRA is
suppressed
(2) ACE inhibitors and ARBs can T PRA thus a detectable PRA or low ARR does not
exclude PA: undetectable PRA will be strongly suggestive of PA
( 3) Bblocker s can l PRA and ARR but PAC >15 still suggestive of PA
(4) Drugs with minimal effects on PRA and PAC: verapamil, hydralazine.ablockers
2
as
Dlagnosls of PA
5
Findings Diagnosis
1 PRA,T PAC.. ARR Suspect primary hyperaldosteronism
Proceed to confirmatory resting (see below)
If spontaneous hypokalemia.undeteci:ible PRA. and PAC >20 my dL
confirmatory testing may not be required
T PRA. T PAC.ARR <10 Suspect secondary hyperaldosteronism (renovascular disease.
diuretic use. malignant HTN. reninsecreting wmor [rare])
1 PRA and 1 PAC wl Suspect Liddle syndrome OR nonaldosterone mineralocorticoid
HTN and excess (syndrome of apparent MC excess [AMEJ. Cushing
hypokalemia syndrome, chronic licorice mot ingestion. congenital adrenal
hyperplasia)

Confirmatory resting to demonstrate inappropriate aldosterone secretion

(1) After consumption of a high sodium diet for 3 d. if 24hr urine collection
shows UM >200 mmolld.then urine aldosterone >12 pg/24 hr is confirmatory
(modern practice): (2) IV saline suppression test or fludrocortisone suppression
test (cumbersome. difficult to implement): (3) captopril challenge test (high false
negative rate)
Subtype classification is the next step once primary hyperaldosteronism is con
firmed. to distinguish a unilateral APA from bilateral hyperplasia and to exclude
adrenal carcinoma
 Studies for Subtype CIasMcation
Adrenal CT Preferred imaging modality
Superior spatial resolution dw MR with contrast
Imaging findings:APAs usually appear as small hypodense nodules (<3 mm
diameter); in bilateral hyperplasia.adrenal gland may appear normal or
nodular; adrenal carcinomas usually >4 cm in diameter and have
suspicious imaging phenotype
Limitations: imaging findings may be misleading: absence of a mass does
nor exclude adenoma (can be missed if lesion <1 cm): solitary
unilateral adenomas may be nonfunctioning and cannot be
distinguished from APAs
Adrenal vein Gold standard zest to distinguish whedier excess aldosterone
sampling production is unilateral (ie.APA that is a candidate for adrenalectomy)
(AVS) or bilateral (je. IHA that should be treated medically)
Sensitivity and specificity (95 and 10014) superior to adrenal CT
Indications: pts with PA who are candidates for surgical management and
have adrenal CT showing normal findings or bilateral abnormalities
or unilateral abnormalities in pts >3S yr: may not be needed in pts
<35 yr w/ spontaneous hypokalemia. marked hyperaldosteronism. and
unilateral lesion dw adenoma on CT
Limitations: expensive. invasive. technically diiiicuk
Method: J conisol to confirm successful cannulation of both adrenal
veins:wl cosymropin infusion, the adrenal vein to IVC cortisol ratio is
typically >5:1; J aldo and conisol hom 3 sees: right adrenal vein, left
adrenal vein.and IVC; then compare adrenal vein cortisolcorrected
aldo ratios (PAGconisol): ratio >4:1 suggests unilateral aldosterone
excess: >10:1 in mostAPAs; ratio <3:1 suggests bilateral adrenal
hyperplasia
Treatment
Treatment goals: reverse cardiovascular morbidity caused by aldosterone excess.
normalize serum potassium, normalize BP
For unilateral disease (APA or unilateral hyperplasia). Rx is laparoscopic adrenalectomy
For pts wl bilateral hyperplasia or in Pts with unilateral disease who are not surgical
candidates or unwilling to have surgery. treatment is with MR antagonist
Unilateral adrenalectomy » marked L in aldosterone secretion and cornectlon of
llypokalemia in nearly 10054; HTN improves in nearly 100% and is cured in 35-80%
Postoperative management: / PAC and PRA to assess biochemical response. d/c
potassium supplementation and MR antagonists. and lower other BP medications;
risk of T K postop d/t hypoaldosteronism 2/2 chronic contralateral adrenal gland
suppression
Adnenalectomy more likely to cure HTN in Pts withzyounger age. shorer duration elf
HTN. use of $2 antihypertensive agents. t ARR,T urine aldosterone.lack of FHx of HTN
Spironolactone or eplerenone.titrate dose to achieve midnormal serum K
Ksparing diuretits (amiloride. triamterene) are an alternative but do not address the
CV morbidity caused by persistent hyperaldosteronism and activation of the MR

Rare Entities of MR or ENaCtlndueed HTN

Liddle syndrome
Glucocorticoid Remediable
Aldostervonism _ Familial
hyperaldosteronism type 1
Syndrome of apparent
mineralocorticoid excess
(AME)
AD: ENaC function and Na reabsorption in CD: classic
triad of HTN, hypokalemia.and metabolic alkalosis at
young age: J. PRA and l PAC
Tx: amiloride or tniamcerene
AD; ACTHdependent activation of aldosterone synthase;
typical onset of HTN <age 21: 1 PRA and T PAC
Tx: glucocorticoid
AR: deficiency in 11DHSD2;T cortisol binding [O MR:
T urinary free cortisol [0 cortisone ratio,J. PRA, L PAC
Tx: amiloride or triamterene or MRA +I dexamediasone
 PHEOCHROMOCYTOMA
Background
Neuroendocrine tumors derived from chromafNn cells of the adrenal medulla that
hypersecrete catecholamines (epinephrine. norepinephrine. and/or dopamine)
Paragangliomas or extraadnenal pheochromocytomas" arise from chromatin cells
of the sympathetic paravertebral ganglia in the thorax. abdomen. or pelvis
Rare form (<0.2%) of secondary HTN
Presentation
Classic symptoms:palpkations.headaches.dlaphoresis.and paroxysms of hypertension
Pts do not always present w/ all of these. but paroxysms of BP spikes are common feature
Pheochromocytoma can occur at any age
There are no known risk factors except for the presence of certain genetic syndromes
including: multiple endocrine neoplasm (MEN) type ZA or 2B. von Hippel-Lindau (VHL)
syndrome.and neurofibromatosis type 1 (NF1)
"10% tumor" because it was commonly thought that 10% of pheochromocytomas
are malignant: -10% are bilateral: 10% are pediatric; 10% are extraadrenal: and
-10% are familial: but more recent data suggests that up to 25% of pheochromocyto
mas are inherited
Evaluation
Indkations for testing: classic symptoms. onset d HTN at young age. resistant HTN. FHx of
pheodiromecyioma. presence of familial synd, or adrenal incidemaloma (>10 HU on CT)
Testing for plasmafree metanephrine levels has become the most efficient screening test
A positive screen for plasmafree metanephrines should be followed by more
involved 24hr urine tests for fractionated metanephrines and catecholamines
After biochemical confirmation: imaging studies w/ CT or MRI to locate the tumor
II imaging is negative '"IMetaiodobenzylguanidine (MIBG) nuclear scan or
"Ffluorodeoxyglucose (18FFDG) positron emission tomography (PET) scan should
be done to search for adrenal tumor too small to appear on CT/MRI
MIBG also indicated for palagangliomas or large tumors (>10 cm) due to T malignancy risk
FOGPET Is more sensitive than CT/MRI and MIBG for metastatic disease
Genetic testing should be considered for Pts wl: paraganglioma, metastatic or bilateral
or multifocal dz. + family history. syndrome presentation. onset at young age (<4S yr)
Treatment
Once a tumor is found. it must NOT be biopsied;can lead to a pheochromocytoma
crisis and possibly death
Definitive therapy is surgical removal of the tumor; adrenalectomy if tumor is in the
adrenal gland: specialized approach required for paragangliomas
Most pheochromocytomas can be removed Iaparoscopically except for large tumors
(>68 cm) and those that are clearly malignant
Perioperatively: combined u and Badrenergic blockade to control blood pressure
and prevent intraoperative hypertensive crises
Pedoperative Medical Management of Pheochromocytoma
xxadrenergic blockade Given 2 wk preoperatively to normalize BP and expand intravascular
volume (co prevent severe hypotension after minor ieinoval)
Nonspecific Phenoxybenzamine: preferred. conventional drug; longacting
uadrenergic and irreversible; initial dose is 10 mg once or twice daily -»
blockade increase by 10-20 mg in divided doses every 48-72 hr as
needed to control BP » final dose is often between 20 and
100 mg daily: side effects are common and include ordiostasis.
nasal stuffiness, fatigue. and retrograde ejaculation (men)
Selective u1adrenergic Prazosin. terazosin. doxazosin
blockade Associated with fewer adverse effects and lower costs
Badrenergic blockade Initiated AFTER adequate nblockade to control nclvycardh: usually
2-3 d preoperatively; NEVER first because this an lead to
unopposed aadrenergic receptor stimulation. hypertensive crisis
Calcium channel Alternative regimen: can also be used as addon drug or as
blockers intravenous infusion Intraoperasively (je. nicardipine)
Metyrosine inhibits catecholamine synthesis: may be used in combination with
ablockade for short period to further stabilize BP
FoIlowup:Annual biochemical messing to assess for recurrent or mezastadc disease
 CARDIOLOGY
CANi:>iORSNAL SvnoaomE (CRS)

Classification of Cardlorenal Syndrome

Type 1 Acute HF leading to acute kidney injury

Type 2 Chronic HF leading to chronic kidney disease
Type 3 Acute renal failure presenting with fluid overloadlHF
Type 4
Chronic renal failure contributes to hem disease (je. associated with LVHI
diastolic dysfunction. coronary artery disease. arrhythmias)
T s
Systemic disorder causes both cardiac and renal dysfunction (je. sepsis)

Background
CR :the interaction between kidney and CV systems where acute or chronic changes
in one organ leads to adaptive (or maladaptive) changes in the other organ system
Risk factors for HF and renal insufficiency overlap. 38-55% of patients had DM
(more frequent wl worsened renal function). 70-80% had a lo HTN. and advancing
age was more common with increasing cneatinine (ADHEREJ cne Fdi 1007;13;422).
Chronic HF is al CKD.Among 80.098 pts wl HF 63% had any renal dysfunction
with 29% being rated as moderate to severe." Mortality was higher in those with
renal dysfunction wl a stronger effect in those w/ worse renal function (RR 1.48 for
any impairment and 1.B for mod-severe dysfunction) (yAcc 2006;4711987)
Pts admitted with acute decompensated heat failure (ADHF) may experience worsening
renal function (WRF). 27% of 1.004 pts with ADHF experience WRF yacc 2004.43.61).
High Rsided venous pressures correlated best (Mc zoomsrsssi
WRF may occur in the setting of diuretic use. although some pts may show
improvement. In a study of 443 patients ADHF. only 10% worsened wl diuresis
while 27% improved. Larger BP drop was predictor ofWRF with cardiac index (Cl)
and change in RA pressure not being predictive (Et:/Hwt rm12013;1$:43J).The fre
quency ofWRF with diuresis varies between studies. ranging from 10-40%.
In ESRD patients. LVH is very common (>70%) and 40% carry a diagnosis on CHF
Pathogenesis
NeurohormQnal: reduction in cardiac output leads co arterial underfilling -» activation
of the RAAS. sympathetic nervous system. and endothelin release -o arteria) vasocon
striction with a reduction in renal blood flow
Reduced cardiac oq§p115: perhaps an overstated contribution to GFR decline,as changes
in intraglomerular pressure work to maintain GFR.at least when Cl >1.5. In 575 patients
MM PA athetefs in place. :heine was no association between Cl and GFR or WRF UACC
zoiesnisstan effect that was confirmed when looking at UNOS registry of patients listed
for heart transplantation (;Acc 201614»818741
V_€D9LI§L9ngg§xi9n: backward flow from RV dysfunction -» venous congestion in an
encapsulated kidney - mechanical compression with T in interstitial and intratubular
pressure -» L GFR. In addition. there is a redistribution of blood How from the cortical
tissue (where glomeruli are) to the medullary compartment. In human studies of HF
with renal dysfunction, there is a stronger correlation with RA pressure than Cl. an
effect that may be modified by systemic arterial pressure.With lower SBP sensitizing
patients to a reduction in GFR alw venous hypertension (Hun few Rer 201B;23;29\)
Renal adapution to HF: in the setting of chronic hypoperfusion.the iuxtaglomenilar
apparatus hypertrophies. glomerulus may undergo ischemic type atrophy with associ
ated progressive interstitial fibrosis or"thyroiditation" where tubular atrophy is out
of proportion to the degree of fibrosis.These effects an Iikeiy worsening by elevated
levels of neurohormonal factors (eg.AlI) and cytokines (eg.TGFB)
Cardiac adaptation to AKI:AKI is a/w fluid retention that results in increased LV end
diastolic pressures. In addition.alteration in Cal. K. HCO;.all i cardiomyocyte
connactility and predispose to arrhythmia. Cytokine release from inlury renal tubules
have independent effects on mitochondrial oxygen consumption as well as increase
pulmonary capillary bed permeability,
Cardiac Idantation to CKD: chronic fluid overload and HTN lead to progressive LVH.
Elevations in RAAS markers,alterations in FGF23 signaling through the IGF receptor
and oxidative stress all contribute to cardiac fibrosis and impaired relaxation. leading
to the rates of CHF >40% in the ESRD population
Treatment
Loop diuretics: standard of care for ADHF even in renal dysfunction.Torsemide and
bumetanide have lower inuapatient and interpatient variability in absorption.
Torsemide (cl: furosemide) is a/w 1 readmission rates 17% vs 32% (Am}M¢4
2001;111:51])
IV loop diuretics are preferred. In one study there was no difference in outcomes at
72 hr between continuous vs bolus. However highdose group (received x2.S their
home dose) were x2 as likely zo be able to convert to an oral regimen ac 48 hr than
lowdose group (continued on their home dose given IV) (Doss new 10113641971
Add a thiazide diuretic (hydrochlorothiazide, chlorthalidone. or metolazone).
spironolactone, or CA inhibitor if refractory edema despite loop diuretics
ACE ihhibition: a mainstay of therapy in HF w/ reduced EF and improves long.term
survival. However. its use in these patients has not resulted in reduced risk of renal
insufficiency
lnotropic support: dopamine.dobutamine. or milrinone (requires dose adjustment
for CrCl. may 1 BP with vasodilation) may be considered in persistent CHF despite
maximal dose diuretics and/or evidence of low output state
Prognosis of HF With Associated Renal Dysfunction
Lower eGFR in HF is consistently alw worse mortality t RR independent of EF: eGFR
30-59: 1.13: eGFR 15-29: 1,85: and eGFR <15: 2.96 (Open Heart N 1&8:¢0003241
WRF during treatment of acute HF is a/w a worse prognosis.wid\ an RR of 1.48 Mm
eGFR declines by 11-15 and 3.2 with a decline >15
DetongesUon (despite WRF) may be a/w improved survival (annum zoi0 iuzosi
Prognosis of Renal Failure With Associated Cardiac Disease
In ESRD pts the presence of HF alw a doubling of mormliq at 2 yr - 16,6% vs 33%
(USRDS 1018 Annual Day Report)
Compared to the general population. patients with CKD are less likely to undergo
rensculariution and have worse outcomes after cardiac catheterization and CABG.
However. revascularized patients do better than those who do not undergo these
procedures (reviewed in CAD and CKD)

CononAny ANTEIW DlssAsE (CAD)

Background
Patients with CKD have much higher rata of CAD than the genes population: 39.4%
of adults >65 yr old have CAD compared no 15.6% in those wir.hou: CKD
Even young paniamrs are at risk for CAD. Among patients aged 2040. 18% on HD carry
diagnosis of CAD (USRDS 2017AfuunI Dan Rayon). as opposed to only 0.6% of general
population 4c~um=w» 1015;131:e29)
Albuminuria on its own is a marker of T risk of CV death. Hazard ratio for CV death
(compared to Um <10 mglg Cr): 11-29 = 1.63. 30-299 = 1.82, >300 = 4.77;an effect
do was present zhroughour all stages of CKD lcxo Conw4num.IAn¢e¢ 1010;37§;2073)
Pathogenesis
Risk Factors for CKD + CAD Uremiaspecific Factors
Hypertension Diabetes Inflamma[l9n FGF23
Smoking
Hyperlipidemia Age . Phos. - PTH Indoxyl sulfate
Metabolic syndrome Carbamoylzdon of Asymmetric
LDL dimechylarginine
Risk factors for CAD and CKD overlap. but uremia plays a role as well
Treatment of CAD in CKD
CKD not on HD
Srazin Use
Metaanalysls showed a 1 cardiac morality No clinical benefit in 1255 dialysis pts wl
RR 0,8 lAM :m 20I1;I$7151) DM(4)new100$;3$3:238)
Simvasratin 20 mg qd Ezezimibe 10 mg qd: Subgroup pts w/ starting LDL >14S had l
17% risk . for major atherosclerotic primary endpoint (HR 0.59). cardiac
events. driven mainly by 1 ischemic stroke death (HR 0.48) (4oqAs~ 20111611319
and revascularizations 4SHANP was No difference in primary outcome at: 3.8 yr
10l 1i]77:2I8l) (AURORA NEWzau9=ua1a9si
B lo o d P re s s u re Co n t ro l
4 CV events wl similar efficacy as in nonCKD
wl 17% risk L per 5 of . SBP wlo class
di f f er enc e j am z o\ a: J 47: r s s s ol
Target <130180 (140/90 if UACR <30 mg/g)
( K D I G O C K D 2 0 1 2 ) . or perhaps 120/80
(SPRINT ngu 2015:373:1103: piss z017;1ezs12i
Percutaneous Coronary Intervention (P
CKD p a wl NSTEMI a re mu ch le ss like ly to
undergo PCI (41% st age 4, 20% st age 5)
even though CKD pts who undergo PCI
are twice as likely to survive to discharge
U W 201817 ¢00m 01
I n pt s w/ eGFR <60. drug eluung scent s (DES)
vs bare met al st enrs (BMS). revealed a
. a llca u se mo rta lity (RR = 0 .8 ).i ca rd ia c
deat h and t arget vessel revascularizat ion
( I l ner taw l oi 201B.3l :319)
Coronary Artery Bypass Graft Surgery
No RCI Observational day suggest a U or
Jshaped curve widl T mortality at lower or
higher BPs. PreHD BP dw the best
outcomes differ between studies and
range from SBP 130-159 with DBP
60-99 (al 2012;8Zz570)
cl)
Angiographic success is similar between HD
patients and nonuremic controls. but
longterm survival is much worse for
ESRD patients. with a 3-4 fdd T mortality
at 1 yr
Similar to CKD not HD population, ESRD
patients receiving DES have a 18%
relative risk reduction in death and a 13%
risk reduction in death. MI, and target
vessel revascularization yAcc 201&61:1459)
(CABG)

: Mortality, risk of myocardial injury. deep Inhospital mortality (12.2 vs 1096).

t issue inf ect ion, prolonged I CU st ay. mediasninitis (3.6 vs 1.2%). stroke (4.3 vs
v ent i l at i on ( N D T z 0\ az s as s 4i 1.7%) 1oullum 2(100.102:297!l
t Renal progression at 3 mo (compared to Despite T early monalkya ESRD Po undergoing
PCI or medical t herapy). but no CABG have lower 1 yr mornlity
d iffe re n ce a t 2 yr.Th e mo ra lity risk a t compared w ESRD pos wl CAD who do
24 mo was lower (3.9%) dw PCI (14.5%) not undergo CABG.and lower risk of
or medical t herapy (16. 4%) (CnmnAmry Ds revascularization compared xo patients
201&19;B) undergoing PCI

Prognosis
After ACS (NSTEMI or STEMI). CKDnon HD patients have a higher mortality at
180 d (10.3% vs 3.4%). CAD risk factors are also more common in CKD.after
adiusunenr-each 10 .. in CrCl T 180 d morralizy with RR = 1.1 (Grtulamiun 1001:106:974]
There is a graded decrement in 2yr survival patients with CAD, widl worse outcomes
among patients with worse CKD. 2yr survival: no CKD:87.476, Stage 1-2: 81.1%.
Stage 3: 77.6%. Stage 4-5: 67.4% mans Z018 AnnuaI Day Kwon)

CARDIAC CATHETERIZATIO N

Backgr ound
More than 1 million cardiac catheterizations performed in :he US annually
Since risk factors for CAD and CKD overlap, many patients requiring catheterization o
have underlying renal dysfunction. Stage 3A: 17%. 3B: 91%. 4-5: 2.9% gAil 2014a:¢00us01 .4
Reported rates of AKl after cardiac cath range from 3-20% depending on patient risk
factors, procedural factors (eg. contrast dose).and definition of AKI used
From 2001-2011. number of postcatheterization AKI cases has f 3fold UAHA
1016540027] 91

Pathogenesis of Kidney Injury

Renal hypoperfusion in ACS. hypotension related to cardiogenic shock
Cholesterol emboli from procedural manipulation of vasculature
RBC breakdown products/pigment related to hemolysis from IABP or lmpella device
Ris k F a c t o rs o f K id n e y I n ju ry
CKD Graded increased risk by starting eGFR with values <30 mUm in alw
h i g h e st r i sk o f A K l o r A K I D
Diabetes 1.5-2x increased risk compared to nonDM with same eGFR
Age Each 10 yr increase alw relative risk 1.1-1.1 for CIN
Hemodynamics CHF (at presentation or prior). hypotension.and need for intraaonic
balloon pump, all independently increase risk ofAKl
Indication STEMI >> NSTEMllunstable angina >> elective procedure
 Contrast High osmolar >> Low or soosmolar
Contrast volumexnaOnine Clarance ratio: risk dAKar begins no increase
as ratios between 2 and 3
Others Hyperglycemia (w/o diagnosis of DM). anemia. proteinuria
(independent of eGFR). unSAIDs. multiple myeloma (possible),
complex coronary lesions
Predicting AKI after Catheterization
Risk of CIN ranges from <1% to >50% in individual patients
Stratification can identify patients who benefit from additional interventions (see
below) to reduce risk of AKI. or identify patients in whom catheterization should be
deferred IAHA (ulddine for ac: ;Acc 1011;S8:14)
Many prediction equations exist but were generated on data obtained prior to renal
sparing interventions. newer contrast agents. and low contrast volume PCI
Mehran Risk Stone includes 11 clinical and procedures factors and has been externally
validated (acc 2004:44:1393)
National Cardiovascular Do Registry (NCDR) AKI score was developed using
>900.000 patients and has been validated in US and overseas.with AKI defined by the
Acute Kidney lniury Network criteria. using a modern ueatrnent cohort. 11 clinical
characteristics for AKI and 6 clinical characteristks for AKIDialysis UAHA 1014;3:e0013B0)
Prevention
Modifiable risk factors with the largest impact are volume ams and volume of contrast
used. Volume resuscitation avoids hypotension and prevents renal vasoconstriction that
could be worsened with contrast administration.
Frequent examination required as shine administration can be limited by CHF symptoms

Intervention for AKI after PCI

Fluid Randomized trial data limited but suggest N better than
unrestricted oral hydration (though oral salt loading may have
benefit). Regimens vary ranging from 3 mUg for 1 hr to 1 mU
kg for 6 hr prior to cath.continuing postprocedure at 1 mUkg
for 4-6 hr
Type of IVF NaHCO; solutions have theoretical benefit of altered urine
pH - lower free radical generation -» lower AKLClinic trials
comparing to NS have been mixed with () welldesigned trials
(new201&]78:603)
LvEDpguided fluid Direct measurement of LVEDP during cash detects underfilling as
well as avoids giving fluid to patients already ac risk for HE
LVEDPguided fluid administration reduced risk ofAKl by 60%
(POSEIDON lance! 2014;]83:1B14)
Acetylcysteine Free radical scavenger with mixed results in RCTs. Unlikely to be
effective. IV preparation has 3-5% risk of anaphylactoid reaction.
Prophylactic dialysis Several studies have shown NO benefit of dialysis or
hemohltration prior to contrast or postcatheterization dialysis
to remove contrast in hopes of reducing renal toxicity (ln»}I4ed
1011;11.661
5BUH5 Mixed results when compared to NS alone. though patients likely to
be initiated on statin at time of discharge legandless.nuy be worth
initiating prior to contrast exposure
Diuretics Diuretics alone do not . risk of AKI and may worsen. Forced
diuresis matching IVF to urine output using RenalGuard system
may lessen AKI (MYTHOSWC Cntimt In 10115,901
Access Radial access may reduce risk ofAKl over femoral access; OR 0,57
(0.35-0.91) (Am}cnuzo17:1m141)
Evaluation
DDx: prerenal AKI from hypoperfusion/cardiogenic shock.volume depletion in
patients who have postprocedural bleeding. cholesterol emboli syndrome
Unlike other nephrotoxic AKI, urine Na and FEn. is frequently low or unchanged from
prior to procedure (NE}M 1989;320¢149)
Cholesterol embolilrenal atheroemboli: presentation is usually subacute over 1-2 wk
w/o improvement.Approximately 213 will have eosinophilia and 1/3 will have reduced
complement levels. Skin findings of livedo reticularis. digital infarcts, and new neurologic
deGcits are strongly suggestive but not always present.
Prognosis
In hospiizl mortality for AKI 5-10%.with mortality forAKlD 20% UAHA 2016;55¢001739)
At 1 yr. risk of death remains higher in patients who experienced postcath AKI. as are
rates of reinfarction and target vessel revascularization (Cn CmUiniwclnierv2015;8:s00247§)
Of all. patients with a 50-99% increase in creatinine between days 3-7. 28% will con
unue to have elevated creatinine 3 mo later.Those with more severe early AKI. >50%
will have sustained loss of function and a more rapid rate of decline in renal function
between mo 3 and 24 after exposure Kl 2010:78B03)

ATRIAL FIBNN.LATIO N ( AFIB)

Background
The annual incidence d being newly diagnosed widi AFlb * as renal function declines:40%
of stage 4-5 CKD pts wall develop AFib over 2 yr (usaos 1017AilmI Dao Revoll)
18% w/ CKD had AFib (25% >70 lo). ><2-3 of nonCKD picnic AHA zoirkis9.1I01)
AFib is al a 67-80% T in rate of J. of renal function. including progression to ESRD
Patients with CKD and AFib are at higher risk (or stroke than patients with either
condition alone, with those on dialysis having the highest risk. Proteinuria itself is ailw
an almost 50% increase in risk lAT MA awl¢Inn 2009;119:1s63)
Pathogenesis
AFib and CKD share common risk factors. In addition.CKD contributes to HTN
(largest populationbased risk factor for AFib).yolume expansion + LVH -» t left atrial
volume. electrolytes abnormalities. myocardial fibrosis. and adierosclerosis-all of which
may contribute to die T risk.
Patients with CKD have slower atrial appendage emptying. T frequency of spontaneous
auial appendage echocontrast T platelet aggregation in response to cAMP and ET1.
markers of inflammation and activation of tissue factor pathway. all of which have
been alw an T risk of thrombotic events (;Acc Z016:6B:145Z)
T r e a t m e n t C o n sid e r a t io n s
In addition to having an t risk of thrombotic events, ESRD pts are at higher risk of
hemorrhage,wl x10 T risk of intracranial bleeds and x3-4 T risk of GI bleeding
In nonendstage CKD pts, balance of risks and benefits favors warfarin use (HR of
thrombotic event 0.7 and death 0.65). However, multiple cohort studies in ESRD
patients suggests no reduction in stoke (in some studies. higher risk). no reduction in
mortality, and a consistent increase in risk of bleeding (Own 201e; 149.9s11
Data regarding Novel Oral Anticoagulants (NOACs) is dialysis patients are limited
since most are at least partially eliminated by the kidneys and patients with advanced
CKD were excluded from randomized trials.Apixaban at a dose of 2.5 mg BID
appears to show similar pharmacokinetics to the 5 mg BID dose in patients with
normal renal function UASN 2017;282241) but efficacy studies are not available yet

SunkEn CAnoiAc DEATH (SCD) AND AICD

Background
Wadi eadx sage d CKD. patients experience higher morality rats (no CKD:43. sage 1-2:
79.sizge 3:97.smge 4-5: 170 per 1.000 patientyr).And among those wide ESRD.40% at
these deaths are amibured no SCD/Arrhynhmia lusaos 7.017Ann\»l Dao R=o°f4
Common in 15: 2 wk of chronic dialysis (c;Asn 201116:zs4z)
Pathogenesis
Rates of ischemic hear: disease approach 40% in dialysis patients.At least part of the
elevated risk of SCD related to ischemic events from underlying atherosclerosis. as
SCD risk is higher in patients with known CAD and diabetes.
Electrolyte fluctuations lead to abnormalities in cell membrane stability and polarlza
tion. Low K dialysate (<2 mEq/L) was alw )<2 t risk of SCD in zoonwasm1011:79=21a)
Low Ca baths have been a/w QT: prolongation and cardiac death (qASN 2013.8:7971
Abnormal fluid balance leads to development of CHE and rapid removal of fluid
during dialysis may lead to myocardial hypoperfusion and microvascular ischemia.
Increased rates of fluid removal (>13 nUke/hr) are alw T allcause and CV mortality
(Ki 1011991501
The combined impact of additional fluid and electrolyte overload manifests in HD pts
as an ' risk of morality during the long (72 hr) interval between dialysis sessions.
Compared to other times during the week. the 72hr interval is al a 36% T CV
mortality, 23% T in allcause mortality. and a 90% T risk of dysrhythmia i~€lm
201 l:J6S:1099)
Prevention

Avoid 0 or 1 K lx: 2001;m3s0. 2011791181. <2.5 Ca and high bicarbonate (Doors um

2013;62:738) dialysate;Avoid digoxin (in 2010321:15S0)
ii blockers: in ESRD wl cardiomyopathy, addition of carvedilol was alw a 21.5% | in
mortality over 2 yr u/irc 20oa=4114ssl.Among >40.000 pts followed in :he Gambro
dialysis system. B blocker was alw an T likelihood of surviving arrest (qASN 2007:2491).
However. other observational trials have given inconsistent results We 201B;71337),
Use nondialylable p blockers (carvedilol) instead of dialyzable p blockers (atenolol.
acebuwlol. bisoprolol. or metoprolol) ac/Asn 1018:13:604; ;As~ 2015216387)
ACEr/ARBs: fosinopril did not I CV events in ESRD w/ LVH lFoslmAI. xizoos;1o13\si
Automated Implantable CardiovertervDelibrillator (AICD)
Remains controversial in patients with renal disease
Patients with renal failure have higher arrhythmia event rates but also higher rates of
competing death
Patients with CKD and eGFR >30 likely benefitThose with eGFR <30 or advanced
age are much less likely to benefit (qAs~ 201S;10;l 119)
ldeally.should be placed on side opposite AV access to reduce venous congestion and
allow venoplasty or venous stent placement if needed to maintain access patency

PULMONOLOGY
Interorgan crosstalk between the kidneys and lungs IS not limited topulmonary-renal
syndromes.AKl/CKD may affect lung function and acute/chronic lung disease may
affect kidney function.
Reduced lung function is a/w several factors that may contribute to the development
of CKD: hypoxia ( HIF1u. RAS activation. SNS activation); RV dysfunction
(1 perfusion due to T renal venous pressure): chronic inflammation (A;xo 1017;70c615)
Impaired lung function is common in CKD. In CKD (eGFR 15-60 or ACR 230). 15.6/9.8%
had obstructivelrestricxive lung function. In pts w/ ACR 230. OR for obstructive lung
function 1.42 and OR for restrictive lung function 1.43 (niIAnes Ain: 2016:68=4141
Reduced baseline lung function (esp. ; Xpredicted FVC) was alw T risk of incident
ESRD and t risk of CKD progression lAxic Also 20 17:7a675)

AcuTe Lun¢s Inlulw (ALI)

AKI is common in patients with ALl:AKlN stage 1: 54.1%. stage 2: 12.3%.stage 3: 15%.
AKI defined by change in Cr may be masked in presence of fluid overload.When
adjusted for fluid balance. incidence ofAKl increased to stage 1: 61.8%. stage 2: 19394.
stage 3: 17.2% Patients with AKI that was only diagnosed after adjusting for fluid bal
ance lead similar mortality to other patients with AKI. and higher mortality than those
without AKI (Ados Network sAcrT on Care mm 2011.]9:2665).
ALI managed wl low tidal volume (46 mUkg) ventilator strategy Low volume
respiratory acidosis -> acidemia. Patients in ARDS network study less likely to develop
AKI if treated with low tidal volume,Treatment w/ HCOi may worsen acidemia in
this setting. so earlier initiation of RRT may be needed to prevent complications of
acidemia p:jAsn 2(l(8.3:57B)
In AU,conserva6i»e fluid strategy (CVP <4, PCWP <8) alw improved oxygenation index and
lung injury vs liberal fluid strategy (CVP 10-14, PCWP 14-1B). Baseline Cr good in bodi
groups (Cr 1.24 vs 1.29) and no difiiefence in new for RRT betweai groups (10 vs 14%).
Impact on course of preexisting AKI or CKD not studied (FACTT NE/M 200sJs41zs641
Inhaled NO. used in ARDS.a/w T AKI (RR 1.52) in dosedependent fashion. Risk MMI not
present with low or medium cumulative dose. or when iNO used in absence cARDS.
Possible mechanism: reactive nitrogai species -» oxidative injury icunailCaft z01s. \$.1371
Prone positioning may be used in severe ALI » t intraabdominal pressure. but no
effect on renal perfusion or renal function wew-A»d¢2001:92:\126)

COP D
The prevalence of CKD is T in COPD. occurring with 2-3x Frequency dw pos wlo
COPD. Presence of achexia and muscle wasting in COPD may mask diagnosis of CKD.
as patients may have low GFR with normal creatinine. In pts with COPD exacerbation.
more advanced CKD a/w T rnorraliry (lm 1 corn zmsnazoln
 AKI more common in COPD (1.4 vs 0.6%). esp. among patients with preexisting CKD
or CHEAKI occurring during COPD exacerbations alw T short.term mortality urn!
COPD 2015;10;2017: 2013;B:1271
T Inflammation -» enW lhl dysfunction _ albuminuria. UACR higher wl more advanced
COPD and albuminuria in COPD alw t mcruliq loa m1s;1 41w iw f i mu n sn w zi
C O PD a n d D ia lysis
COPD is common (75% prevalence) in ESRD on dialysis. Mortality is higher Mr ESRD
w/ COPD (RR 1.20).esp. in active smokers (RR 1.28). COPD pa w/ ESRD are less
likely w receive a KT (RR 0.47 for aW smokers, 0.54 for nonsmokers) WN 20\1;u;M.
COPD HD paUenu are more likely to have prolonged inzradialytic hypoxemia.which
is associated with risk of hcspicalizarion and T mortality (clAw 101s;11.616l
Wim standard HCO; dialysate, Pco, T. HCO; T and pH r during HD. PO; l and Aa
gradient T during treatment M m lah so 2011:41:3\S)
Fluid removal >3% of body weight during HD may T FEV1 and FVC temporarily in
COPD (Hmnulal i! zoisaofeai
COPD pts sining on CAPD may have L WC.lVC,LTLC that ieversu within 2 wk.
without changes in PO w. mo or pH ( 19u;u:s74)

SMOKiNC AND IMOPATHIC NonuLAa GLOHERULOSCLEROSIS (ING)

Chronic ischemiclhypoxlc conditions can cause ING wl nodular mesangial sclerosis
wl accentuated glomerular lobularity. mimicking diabetic nephropathy. MPGN, dys
proteinemias. organized glomerular deposition diseases (/ASN 1007=18:20321
ING linked to chronic HTN and cigarette smoking. Patients more likely no be older.
white, male: 95.7% with HTN and 91.3% wl lo heavy cigarette smoking. Nephrotic
range proteinuria common (70%) but NS uncommon (21%). Mean time from biopsy
to ESRD 26 mo. T IFlTA and vascular disease alw progression to ESRD. Smoking ces
sation and RAAS blockade aw better survival (Human nntnulqy 2oo2.nam
Smoking may cause ING via T AGEs.1 oxidative stress, T angiogenesis. T sympathetic
activation (JASN 2007;18:2032)

PULMONARV HYPeaTENSlON (PHTN)

PHTN is common in CKD, and CKD is common in PAH, PHTN (PAP >25 mmHg)
occurs in 23% of pt w/ CKD.and severe PHTN (PAP 245-50) in 7-29% of HD pos.
PD < HD. likely due to differences in comorbidinies lA/KD 20 1a1717s1 xv Z01 J.e=ee1l
PHTN in CKD , v morzalicy (RR 1.4 CKD, 2.3 ESRD, 2.1 after KTx).. CV event
(RR CKD 1,7. ESRD 2.3). CV morzaliry (RR 2.3) We z01a:n75)
CKD occurs in 4-36% of PAH. Prevalence of CKD higher in PAHassociared connec
:ive tissue disorder: esp. SSc. CKD in PAH - t risk of death (num ci<z017:17:.a). In pos
with PAH and CHF exacerbazion.AKl is common (2394). more common if CKD (OR
3.9) and alw T mornalicy (OR 5.3) U ci~llia¢r¢,im 201147533)
Mechanisms of CKD: SNS activity T RAAS aczivicy -» pulmonary/renal vascular
remodeling T RA pressure » t renal vein congestion; t endothelial dysfuncuon in
uremia -» T pulmonary vasoconstricrionc I PCWP mum of 201711738: KJ 20 u:a:m)

OasTnucTlvs SLEEP APNEA (OSA)

Common in ESRD (>S0%) with similar prevalence in HD and PD. No studies on
whether CPAP reduces CV risk and mortality in ESRD patients with OSA. although
switching to nocturnal HD alw improved symptoms (See 0m12013;16:2731
More common in CKD. seen in up to 65% Nocturnal hypoxemia in OSA is alw more
rapid decline in GFR. Possible mechanisms: endothelial cell dysfunction, oxidative
stress. RAS activation (c/As~ 201I:8: 1S02)
T Risk of albuminuria independent of the presence of DM or HTN. T UACR may
correlate wl severity of OSA.Treaunent of OSA with CPAP is alw a l in UACR
(Aledkme1016:95:26).
Risk factor for developing HTN (risk increased nearly 3fold in OSA). OSA is a common
fuse of resistant HTN. OSA patients wadi resistant HTN treated with CPAP show
improvement in BP (. 4.7811.53) uwwiwm 20161511531

C v s nc Fm nos ls ( C F)
Nephrocalcinosisz 23.2% on uls. 92% on biopsy mf*1 m2w;u;n= new im:3i9.263)
Nephrolichiasisz 3,063%. Possible mechanisms: far malabsorption -o T GI oxalate
absorption -> hyperoxaluria -» 7 CaOx saturation in urine: hypocitraluria
 l O. forrnigenes in GI tract -» J, breakdown of oxalate in GI tract -> T GI oxalate
absorption -» hyperoxaluria - T CaOx saturation in urine (A)K0 2003¢42:11
Prevalence of CKD (stages 3-5) in CF 23%. Disease prevalence doubles with every 10yr
increase in age. imdiing 19.2% in patients over 55. Risk of CKD greater in CFrelated DM.
but not widi increasing pulmonary exacefbaticns of CF (AIRCCM 10019541147i
CFrelated DM: microalbuminuria in 14-21%. Patients wl CFrelated DM more likely
to have microalbuminuria and less likely to have retinopathy than patients with DM1
II Cyst Fibiuils 2000;7:S15; Dabeles Care 1007:3(M056)
Other causes of intrinsic CKD:AA amyloidosis. loAn (qASN 2009;4:921)
AKI in CF most commonly druginduced from nephrotoxic antibiotics (aminoglycosides.
polymyxin B.colistin). unSAIDs used in pediatric patients. may cause AKI if acutely
volume depleted la Can Hanan: 200e=1 z3o9).
AKl rarely due to acute oxalate nephropathyzfat malabsorption - t GI oxalate
absorption -» hyperoxaluria » T calcium oxalate deposition in kidney luff 100a;a119011

SARCOIDOSIS (Ap(o z0as;4a£54>»

Granulomas and maaophages make 10 hydmxylase » T 1.25(OH)2 vitamin D (ddtriol)
Hypenakiuria: Um >300 mild. 50% (mlc renal manifestation); t calcitriol -» 1 PTH -»
L tubular Ca* reabsorption
Hypercakemix 10-209411 cakitxiol -» T Gl Ca* absorpdonf bone iubsorplion -» ' Ca"
Prednisone 20-40 mold can improve hypercalcemia and hypercalciuria dh L macrophage
1a hydroxylase activity
Noncaseadng granulomatous interstitial nephritis: 7-23% on autopsy. mos: uses clini
cally silent Treatment with prednisone 1 mykg/d for 6-12 mo improves renal function
but most left with CKD. Relapses uncommon (1S%). more likely no occur after
prednisone d/c. but also respond to prednisone (Meda: 1009;BB:98).
ESRD rare; KT safe if ESRD develops, but sarcoid GIN can recur in KT (nos of 201440
Renal tubular dysfunction: common: polyuria from Calinduced NDI.CDI in neuro
sarcoidosis: piTA. dRTA, or Fanconilike syndrome from tubular damage from T Cal or
GlN.Tubular abnormalities improve with steroids.

TUBERCULOSIS
ExuapulmonaryTB more common in HlV or organ transplants. 27% of extrapulmonary
TB are GU. GU TB occurs in 2-20% of pts with pulmonary TB. GU TB primarily
involves the collecting system and less commonly causes parenchymal lesions.
TB seeding of GU tract an occur widi primary infection or racti~»ation.TB bacilli form
granulonias in medulla -» rupture into tubular lumen widi exaction into collecting system.
Descending infection can lead KO papillary necrosis. ureteral stricture and obstruction.
hydronephrosis. and renal dyslunction.Typically unilateral: if bilateral an lead to ESRD.
Urinary symptoms common. systemic symptoms uncommon
Labs sterile auria and gross or microscopic hematuria
Renal parenchymal lesions:AA amyloidosis from chronic iniiammationz lnnerstitial
nephritis; postinfectious GN
Diagnosis of renalTB: isolation of TB from urine culture or tissue biopsy
Treatment; antiTB antibiotics. If obsuuctlon present and renal dysfunction reversible.
may require ureteral stenting or nephrostomy. Partial or total nephnectomy may be
required in UP to 55% (A~»1f~» M 44 we 2013:B8:54)

IN Te N STi Ti AL L u n g D l ssAss (IL D )

CKD is common in IPF. with 30% of patients having eGFR <60. CKD more common in
older patients and patients with HTN. CKD associated with .. DLCO and 1 distance
on 6min walk test. eGFR independent predictor of survival in IPF after adiusdng for
age and PFls aw-wili" 2017:94:3461
ILD alw ANCA: usually >65 lo. MPO (+); pulmonary fibrosis occurs concurrendy or
predates by several mo to 12 yr: usual interstitial pneumonia is the m/c radiological
pattern; ILD has an adverse impact on :he prognosis (Auiuaivmn Rev 1017;!6:712)

roTOR InhibitorAssociated Pneumonitis 1r-~=--salini-=w~ z004;77121s: Ann it

100611448051 Transplat Pwr 1018;159331
In up to 4.3% of :xp pts receiving everolimus and up to 11-17% receiving sirolimus
Not related to drug levels; S0% of cases occur after >6 mo of drug exposure
Symptoms: cougltfatigue. levers.and dyspnea. Pulmonary infiltrates are common and
resemble BOOR
 No formal diagnostic aiteria. so r/o infectious etiology BAL shows lymphocytic alveolitis.
Treatment: permanent withdrawal of roTOR inhibitor +I- steroids
Clinical and radiographic recovery zypically occur w/i a few weeks of drug dlc

DIFFUSE ALveoLAr HEMORRHAGE (DAH)

Caused by disruption of tile alveolarapillary basement membrane: small vessel vasculitis
can cause injury co glomerular capillary wall together causing pulmonary renal syndrome
Lifethreatening condition requiring prompt diagnosis and treatment
Conditions Associated With DAH With Renal Impairment r~Elm 2u11;:67:1540)
. ANCAassociated disease.AntiGBM disease. SLE +I-, antiphospholipid syndrome
HSR mixed cryoglobulinemia. polymyositis, progressive systems sclerosis. MCTD
HIV. disseminated cryptococcosis, Legionnaires disease. CMV. strep or staph infection
. Uremic pneumonizis: cardiogenic pulmonary edema dl: HTN and/or volume overload
Clinical Manifestation and Diagnosis
Hemopzysis may be absent in ~1/3 of cases: should suspect vnth radiographic opadcies
(either localized or diffuse) and falling Hb level: PFT:T DLCO
Confirmed when lavage aliquots are progressively more hemorrhagic
/ ANCA, antiGBM,ASLO. CO. C4,ANA. RE cryocrit.APLA,and blood culture
Biopsyi lung, skin (if rash present). or kidney
Tr e a tm e nt
Invasive or noninvasive mechanical ventilation. correct coagulopachy transfusion pm
Pulse glucoconicoid + PLEX: empirically when autoimmune conditions are suspected

PLEURAL EFFUSION
Nonmalignant pleural effusion + renal failure 1yr morzaliry is 46% (do z017;1s\.1099)
20% of hospitalized HD pts. commonly from hypervolemia (fmusglanxllnc 1007;39.8891
Pkuroperitoneal leak in PD: 1.6-1098; pleural fluid/serum glucose >1 (nbr 2011;27211121
Urinothorax: caused by obstructive uroparhy (pelvicureteral, bladder outlet, pelvic
mass). GU procedure. trauma; pleural fluid Cr/serum Cr >1 (An»1m¢a s¢z017;Js4;44)
Transudadve: hypervolemia. nephrodc syndrome. HE pleuroperitoneal leak
Exudadve uremic pleuridc. parapneumonic effusion

EXTRACORPOREAL MEMBRANE OXYGENATION

Background
Extracorporeal Membrane Oxygenation (ECMO) provides gas exchange for hypoxemia I
and hypercarbia as well as hemodynamic depending on configuration and indication
Venovenous (W): respiratory support
Venoanerial (VA): respiratory and hemodynamic support
ECMO use has increased dramatically in recent yr. from 253 in 2006 to 4.297 in 2016
iecis r-gsm. 1rz0171
AKI during ECMO
AKI is common. ranging from 2986% (pooled estimate 55.6%) with renal replacement
therapy (RRT) required in 7-86% (pooled estimate 46%) (Am Thom: sw:2014;971610)
AKI requiring ECHO is a/w with high mortality (78% vs 20% nonAKl) (NDT 1006;11:ZB67)

Pathogenesis of ECMOAssodaned AKI (c¢1uw¢i Abu 1016.4s0)

Patient Factors ECMO Related
Hypotension.SIRS. Nephrotoxins. Blood flow changes. RAAS dysregulation
Hypoxia, CKD Blood-air interface. Cardiorenal syndrome, Homo/
myoglobinuria,Aor¢ic disseWon (VA). Embollsm (VA)

In 50-60%. renal failure precedes :he initiation of ECMO fnaiaucni Cae M44 101617:115n
In severe ARDS, ECMO use was a/w more days free of RRT and renal failure (EOUA
num 2018;378;1965)
Renal Replacement Therapy (RRT) during ECMO
RRT frequently initiated earlier for control of volume status
In one survey. indication for RRT was fluid overload in 43%. prevention of fluid
overload in 16%.AKI in 35%. and electrolytes in 4% (A$Aloj 20121581407)
 While intermittent HD and PD can be used during ECMO. CRRT or SLED is
recommended at least Initially until patients are stabilized
CRRT can be used via a separate double lumen dialysis catheter but central access
may be taken by other catheters (cannulate for ECMO plus catheters for medication
administration) and placement may be risky if on systemic anticoagulation
Hemofilter may be placed inlihe with ECMO circuit distal to ECMO roller pump
(providing blood flow) with the venous return line proximal. Effluent needs to be
continuously measured with replacement fluid administered to maintain the net
filtration balance. In practice. this configuration provides less accurate assessment of
fluid balance and more nursing work lqAsr4 2011;7I 32B)
CRRT machine can be spliced into the venous limb of ECMO circuit directly If a
centrifugal ECMO pump is used, place the CRRT machine after the pump because of
the risk of air entrapment. Return line of CRRT must be prior to oxygenator to trap
air or clots (cow Cae 10149816751
High blood How used for ECMO an tause high pressure on CRRT circuit. Line pressure
adaptor or placanent of CRRT access line * return line before the pump has been tried
without air embolism event (ASAIOJ 2017;63:4G)
Prognosis
Adult patient survival to discharge in setting of ECMO AKl ranges from 25-45%
with slightly better survival when respiratory failure is the indication iscLs R=¢»1'"y
Report.112017)
PostcardiotomyAKl requiring ECMO is alw high mortality x30.8 in AKlN stage 3, x12.6
in RIFLEF (Emf Caldiadwiu( So: 101&37:3341
Renal prognosis among aduk ECMO patients requiring RRT is poor.widi 74% continuing
to requiring dialysis in one study for 2013:7.8:86)
Among 200 pediatric ECMO 4 CRRT patienis.68 survived to discharge widi 18 requiring
continued dialysis (mau on Core Med 201 111211s31
In pts who survive episode of AKl on ECMO, CKD is common: 12% have proteinuria
and 19% have HTN at 8.2 yr. though eGFR >60 lqAs~ 2014910701

GASTROENTEROLOGY
GASTROINTESTINAL SYMPTOMS inn iv Nephfd 1010;61480)
Most common symptoms include nausea. vomiting.abdominal pain, constipadon.and
diarrhea; divided into organic (causal lesion) and functional (no histopathologic) basis
and influenced by psychological factors. visceral hypersensitivity and altered GI motility
8 Prevalence: 70-79% of pos wl CKD and ESRD; trend toward increasing Sx w/ duration
§ of renal failure: similar rare of sx in CKD. HD. and PD
5 Etiology: uremia/ureinic retention molecules. comorbid anxiety.and depression
g Constipation
5 Prevalence: 63% HD patients and 29% PD patients
O Etiology: l activity. L fiber. l liquid. phosphate binders. and other comorbidities
Tx: la1ati\¢es.stool softeners.enemas;avoid magnesium and phosphate laxatives and enema
Gastroparesis
Prevalence: up to 36% of padenrszr prevalence vs general pop
Etiology medications. DM; related no intraabdominal fluid in PD
Clinical Sx: nausea. vomiting. abdominal pain. bloating. and weigh: loss
Tx: meroclopramide and erythromycin: t dialysis doesnc help

GASTROINTESTINAL BLEEDING (Nat Rev Ntpllld zo1 o.¢4ool

Background
Prevalence: (+) fecal occult -19%
Causes: anglodysplasia. GI erosions. ulcers. divertlculosis. and mesenteric ischemia
Upper GI Bleeding
T Upper GI lesions in renal failure vs general pop
Duodenal lesions in 61% of ESRD patients wl (+) fecal occult
Angiodysplasia and GI erosions most common cause of upper bleeding; angiodysplasia
-20-30% of episodes of upper GI bleeding and cause Y: of recurvenx episodes of upper
GI bleeding in patients with ESRD lAM IM 19as;1uzsaal
No higher risk of ulceration or H. Pylori
 T Acute upper GI bleeding w/ estimated frequency of 21 bleeds per 1.000 patient
years: cause 3-7% of ESRD deaths: anticoagulation and andplatelets are not a risk
factor
Lower GI Bleeding
Angiodysplasia and colonic neoplasms are common causes; angiodysplasia
20-30% of episodes of lower GI bleeding and are the m/c cause of recurrent
lower GI bleeding
diverticulosis and diverticulitis in PKD vs general pop
Pancreatitis (Na: Rn Nepal 1010z614B01
Prevalence: T pancreatic abnormalities: T risk of acute pancveatitis, PD > HD
• Etiology: similar causes general pop in HD. In PD: chronic exposure to icodextrin and
high dextrosecontaining dialysate are risk factors
Diagnosis: L clearance of pancreatic enzymes with renal failure -> look for
amylase >3x ULN. lipase >30O kg/L (>60 IU/L). in PD distinguish from peritonitis:
effluent amylase level >100 UIL: inhibitory effect of icodextrin on serum
amylase levels
Tx: no heparin w/ PD and HD to i risk of pancreatic hemorrhage; stop icodextrin If
new
Acute Mesenteric Ischemia imp Rev nepal z010.s24a01
Incidence: higher in HD: frequency 0.3-1.9%Ipt/yr; 14% of HD pts on autopsy
Etiology: typically nonocclusive; intradialyzic hypotension w/ atherosclerosis
Common Sx: abdominal pain. fever. guarding. leukocytosis. bloody diarrhea or rectal
bleeding: can mimic peritonitis
Dx: colonoscopy. CT with an opaque enema. surgery, vascular calcification on
imaging
Prevention: avoid excessive UF and normal fluid balance with acute abdominal pain
Monaliry rates from 33-73%
Encapsulating Peritoneal Sclerosis (no: no mam:20104:4410: ia 2010=172s041
Peritoneal thickening - encapsulation of the bowel and obstructive ileus in PD pts
Incidence: up to 4% of PD pos: >15% in pvs on PD for >15 yr
Risk factors: PD vintage. prolonged exposure to high glucose dialysate. repeated
peritonitis, PD -> HD conversion, and no RRF
Clinical Sx: early satiety, abdominal fullness. obstructive symptoms. UF failure
Diagnosis: abdominal UIS and CT are not sensithfe or specilic.gold standard laparotomyl
laparoscopy -> peritoneal thickening encases intestines
Tx: tamoxifen: nesting peritoneum w/ switch to HD: morality rates 20-93%. T when
on PD for >15 yr

INFLAMMATORY Bowel. DisEAse (IBD) (Ioun»»c=wu¢2o1e.1azzs»

Kidney Bx findings: gAN > interstitial nephritis > arrerionephnosclerosls > acute lobular
injury > proliferative GN > AA amyloidosis lqAsn 101491551
Nephrolithiasis
Prevalence: 12-28% in IBD: ileocolonic disease > leal disease (Crohns > UC):t in Ca
Ox and UA stones
Pathogenesis
Alkali los: with diarrhea - metabolic acidosis -» aciduria - UA stones
Low urine volume (especially with colon surgery) - CaOx and UA stones
Bile Sal: malabsorption 4 enteric hyperoxaluria (>45 mg/d) (Ca binds to fa: and not
oxalate) . oxalate reabsorbed - oxalate stones
Less Oxafobacter formigenes - L intestinal oxalate catabolism -» oxalate stones
Risk factors: bowel surgery. ongoing diarrhea
Tx t liquid intake and citrate to alkalinize urine
G lo m eru lo n ep h rit is
T IgAN in IBD: mucosal inflammation and chronic immune stimulation -» dysregu
lated IgA (qA$N 201419:165)
Other GN: IgM nephropathy. membranous. mesangiocapillary, FSGS.AntiGBM
disease
GN T w/ intestinal disease activity
T u b u lo in t erst it ial Nep h rit is ( T IN)
5ASA and sulfasalazine - CINlchronie interstitial fibrosis >TNFalpha
) Related to underlying disease vs Tx, seen in pediatric population wlo Tx
 5ASA Associated TIN
Prevalence; CKD in 1-7.I1.000; 10% of cases progress to ESRD
Nonspecific sx, +I- malaise.fever, skin rash. eosinophilia; idiosyncratic often w/ 12 mo of
saning
Tx: d/c:szeroids improves function in 4085% if dx within 10 mo and only 1/3 if dx
after 18 mo
AA Amyloidosis
lncidence:0.3-10.9% in CD and 0-0.7% in UC: dx 10 yr after IBD diagnosis
Clinical Signs: m/c AA manifestation renal (9096): Proceinuria. nephrotic syndrome
Tx: control underlying IBD

Soolun PHOSPHATE BOWEL PREP (no: 0. ¢~¢phvu z01ae 4aoi

Pathophysiology and Risk Factors

T Serum [Po.] + volume depletion -» T intratubular [POW] -» precipitation and :issue
deposition of CaP salts -i luminal obstruction + direct tubular epithelial injury
Risk factors for AKl:Age, HTN, volume depletion. CKD,ACEi/ARB. unSAIDs. Diuretics
Clinical Manifestation and Diagnosis
1-4% w/ oral sodium phosphate prep develop AKI
U/A often bland sediment. modest proteinuria; Normocalcemic
Renal BX: Interstitial pattern of CaP deposition won Kossa stain
Prevention
Avoid use in patient with CKD
Use balanced electrolyte solutions containing polyethylene glycol for bowel prep

proTon Purr INHIBITOR lx: Rep 1017;1297)

Pathophysiology and Risk Factors

AIN »AKI,also linked to CKD and ESRD I through unresolved AKI
Duration of exposure up to 720 d uAs~2016:27;3153)
Clinical Manifestation and Diagnosis
AIN: idiosyncratic. not dosedependent. recurrence an occur wl 2nd exposure
2-3x TAKI: 1.2-1.8)< t CKD l x f ne p 1017929n
UIA: +I- sterile pyuria, +I- prot/einuria with AIN; Renal Bx:AIN
Prevention
dlc if possible: consider H2 receptor blockers lranicidine or famotidine)

SHONT BOWEL SYNDROHE

E RouxenY Gastric Bypass.Jejunoileal bypass -\ Rapid intestinal transit -» fat malay

sorption l, soluble Ca in the GI trac: and insoluble CaOx -> 6x T absorption of solu
ble oxalate and oxaluria
up Bacterial overgrovnh. fermentation of unabsorbed carbohydrates -> t Dlactate
Risk factors: CKD and HTN are risk factors for AKl
Clinical Manifestation and Diagnosis
lntratubular deposition of CaOx crystals with giantcell reaction and tubular damage
+ interstitial inflammation and fibrosis; CaOx nephrolithiasis;AKI and CKD
Dlactic acidosis: AMS. slurred speech, seizure.anion gap metabolic acidosis
Prevention
Consider restrictive procedures if CKD, eg. sleeve gastrectomy

So 1:»1ur4 POLYSTYReNE (SPS) +I- SORBITOL

Pathophysiology: cation exchange resin -4 inreszinal necrosis
Clinical Manifestation and Diagnosis
Ileal and colonic necrosis w/ bov.h oral and real SPS-sorbkol reported
Incidence of bowel necrosis 0.4% Lon nehru z016;as:3a)
Risk Factors
Sorbitol containing sodium polystyrene
CKD. recent surgery. ileus. opiate use. bowel disease and obsuucdon. use as enema
Prevention
Use laxatives without sorbitol or alternative potassium binding resins
 Electrolyte and AcidlBase Disorder In GI Diseases (qASN 2naa;310s1)
(Normal stool:0.15 Ud Na 20-30 K 55-75 CI 15-25 HCO; 0)
GI Scare F luid C omposition Electr olyte AcidlBase
VomiringING 0-3 Ud. Hypotonic Hypokalemia: Metabolic alkalosis
suction Na 20-100 K 10-15 renal loss
ci 120- 160 HCO ; 0
Inflammatory 1-3 Ud. Hypotonic None +I- Menbolic
diarrhea Na 50-100 K 15-20 alkalosis
C l 50- 100 H co; 10
Secretory diarrhea 1-20 Ud. Hypotonic Hyponaxremia Menbolic acidosis
Na 40-140 K 15-40 Hypokalemia
CI 25-105 HCO x 20-75
Congenital 1-5 Ud. Hypotonic Hypokalemia Metabolic alkalosis
chloridorrh . Na 3080 K 15- 60 +I- Hyponanremia
C l 120- 150 H co, <5
Villous adenoma 1-3 Ud, Hypotonic Hypokalemia Metabolic alkalosis
Na 70-150 K 15-80 CI
50- 150 Hco,
Unknown
Ileostomy drainage 1-1.5 Ud Hyperkalemia w/ Metabolic acidosis:
(new) Na 115-140 K s-1s acidosis HCOa loss
C I 9 5 - 1 2 5 H co ; 3 0 Metabolk alkalosis:
Cl loss.vol
depletion
Ileostomry drainage 0.5-1 Ud
(adapted) Na 40-90 K 5
C l 2 0 H co ; 1 5 - 3 0

HEPATOLOGY
HEPATORENAL SYNDROME (HRS)
A variety of causes ofAKl/CKD exist in pos wl cirrhosis/decompensated liver disease
The approach to dilhrential diagnosis ofAKl and CKD can be challenging,as renal biopsy |
is difficult to perform in cinhotic pts due to concerns about bleedingcoagulopaizhy
Relying on complement testing or FEel is problematic due to the altered physiology
of advanced cirrhosis
Pathogenesis
Release of vasoactive mediators by failing liver leading to splanchnic vasodilation and
renal vasoconsMcdon: portal hypertension -» T nitric oxide production -» splanchnic
arterial vasodilatation- hypotension -\ baroneceptor activation -» T renin.All.AIdo.
NE,vasopressin renal vasoconstriction - impaired Na excretion - ascites -
impaired H20 excretion - hyponatremia -» l RBF - progressive renal dysfunction
Precipitants: bacterial infection, GIB. SBR CKD. acute alcoholic hepatitis. large volume
paracentesis with no albumin repletion (NE/M 199k341=403)
Clinical Manifestation and Diagnosis
Classification of Hepatorenal Syndrome uiqnuinligy 1996:1!164:2015a61'i86)
T ype ( T iming) Findings
Type I (<2 wk) Rapidly progressive renal failure. Doubling Scr. >2.5 mgldL
UOP <400-500 mud. bland urinalysis. <S00 mglg prvoteinuria
No response after 2 consecutive d of diuretic withdrawal and volume
expansion with albumin
Often precipitant factor(s)
Absence of shock, infection. urinary obstruction. nephrotoxlns
Type II (indolent) Steady and progressive impairment of renal function
Related to diuretic resisianr ascites
Bland urinalysis and <500 mg/g proteinuria
Chronic kidney disease
 Differential Diagnosis: Other Common Causes of AKI in Cirrhosis
Volume depletion: large volume paracentesis particularly if done without albumin replaae
rent. bleeding, over diuresis. Responds quickly no holding diuretics and vokirne expansion
ATN: prolonged prerenal azotemia.bleeding. shock. nephrotoxins. prolonged renal
ischemia in HRS lA;Ko 19azz13szl. Expect muddy brown ;asts.AIso bile casts (below)
Glomerular disease: hepatic IgA nephropathy. hep C associated MPGN. expect an
T UPCR.active urine sediment
Abdominal compartment syndrome: massive ascites. high bladder pressure. bland UA
Prevention
Use of albumin with large volume paracentesis (8 YL of ascites removed)
Primary prophylaxis of SBP with riorfloxacin . HRS (Cusimenwuiqy 2007;13J81a1
SBP pls should receive concentrated albumin (1.5 g/kg on d 1.fdlowed by 1 g/kg on d 3),
Albumin was a/w lower renal impairment (8.3 vs 30.6%) and mortality (16 vs 3S.4%)
(On Gasunemerd 14¢f1°1°12013:11123)
SBP pts should dlc nonselective B blocker <G¢=~»=~~=»-ww 2014;146:16B0)
Management (I Hpazol 1016.647171
Hold diureticszvolume expansion with crystalloid solutions as initial fluid choice in
volume depletion (10-20 mUkg)
Albumin 1 Ykg (up to 100 g) on d 1 then 20-40 old + vasoconstrictors
V a s oc ons c r i c r or s f or HRS

Teriipressin T HRS r ever sal :han al bumi n onl y (23. 7 vs

No e pi ne phr i ne w / MAP god T 1 0 - 1 5 m m Hg
Oc zre otide (1 0 0 2 0 0 ug SQ TID or IV in
$0 kg/ hr ) and Mi dodr i ne (7. 5 mg and
1 dose at 8hr inzervals up no is mgTlD)
15.2%) (6anuemelnlu¢y 201445015791
t Renal r ecover y dw ocl r eozi del mi dodr i ne
(70.4 vs 28.6%) iuepuwllgy zo1s»z=s¢m
Si mi l ar outcome w/ r er l i pr essi n U Hqmnl l
1011156:1Z93)
Octr eor i de i nhi bi t gl ucagon. spl anchnk
vasodi l ator
Up to 3 d. can be aaempzed pr i or no
nor epi nephr i ne

Other:TlPS. liver transplant. hemodialysis as bridge co transplant Lu£Gj 20173811001

Re na l Re pl a c e m e nt The r a py
Withhold RRT unless there is reversible component or a plan for liver transplantation
l ocal Coe 201Z:16:R23)
Q 30d and 1yr morality 73% and 90% U Cammi Hmm# z004:19:13649
1; 64mo mortality is 84% if not listed for liver =XP vs 39% if listed for liver txp (qAsr4
> 2019:1l&16)
§ Hemodialysis an T ICP worsening hepatic encephalopathy: CRRT preferred

8 BILE CAST NEPHROFATHY (Kl 2015;87:§09; WIG 20\6:12:27)

4
Can occur when bilirubin level >25 mg/dL Pathology demonstrates pigmented casts
occluding tubular lumens, pigmented granular casts seen on urine sediment
Renal manifestation: direct toxicity to :he nephron leading to elevated Scr levels. pig
mented bile crystals on urine. natriuresis, and [32 microglobinuria
Dx: T bilirubin.bland u/a.trace protein and AKI.jaundice.renaI biopsy
Tx: directed at bilirubin reduction which may improve renal function 1 hemodialysis

I gA NEPHROPATHY SECONDARY To LIVER DlSEASE (Sem al Nepal 109818271

loAn occurs in association with liver cirrhosis and portal HTN due to poor clearance
of In/\ by hepatic Kupffer cells :hat circulate and deposit in the kidney. Most frequendy
bu: not exclusive seen widl alcoholic liver disease.
Renal manifeszadon: proteinuria. microscopic hematuria
Renal biopsy mesangial proliferation with IgA deposits
Tx: :r ear under l yi ng l i ver di sease

ABDOMINAL COMPARTMENT SYNDROME UTHIMG 2000:48874. ;Acc 1013.61485)

Definition: sustained intraabdominal pressure (IAP) >20 mmHg and abdominal perfu
sion pressure (APP) = MAP - IAP <60 mmHg causing new organ dysfunction
Epidemiology: occur in liver Lransplanrarion. massive ascites. abdominal surgeries.
i nt r a pe r i t one a l bl e e d. pa nc r e a dds
 Renal manifesracions: renal vein compression - 1 venous resistance - impairs venous
drainage -» progressive reduction in renal blood (low both -» t renin.All.AIdo. NE.
vasopressin - l Un, and Uci -» T abdominal pressure -» renal dysfunction/ATN
Dx: / intraabdominal pressure by bladder pressure: 1 mmHg = 1.36 cmH to
Tx: reversible if recognized and decompression is done early (large volume paracen
tesis. surgical decompression): Larger APP :60 mmHg

ACETAMINOPHEN-INDUCED NEPHROTOXICITY (KID 2015:11:316)

Renal injury in :he setting of acetaminophen toxicity
Epidemiology: acetaminophen remains mlc cause of acute liver failure in the US.ATN
can occur in up to 10% of patients.
Renal Manifestations of Acetamlnophen Toxldty
ATN: possible mechanisms include direct tubular damage from the wxrc metabolite
Nacetylpbenzoquinoneimine
Anion gap metabolic acidosis: 5oxoproline (pyrogiurzmic acid) (qAs~ z0 I4;9,191)

DX clinical.biopsy often not needed

Tx: supportive management of acetaminophen intoxication

KIDNEY TRANSPLANTATION IN ENDSTAGE LIVER DISEASE

Indications for Liver and Kidney Dual Organ Transplantation
(C]A$V2017;12:84B)
CKD: GFR <60 for >90 consecutive d and eGFR or CrCl $30 at or after registration
on kidney waiting list or Dialysis (in the setting of ESRD)
AKI: dialysis for 6 consecutive wk or eGFR or CrCI $25 for 6 consecutive wk
Metabolic disease: aHUS from mutations factor H or factor I. hyperoxaluria.familial
nonneuropathic systemic amyloidosis, mediylmalonic aciduria may be cured by dual
organ transplant
CKD must be verified by a nephrologisr
Evaluation of MELDNa score (Acxo z015:zz=391)

ELECTROLYTE AND ACID-BASE DISTURBANCES IN CHRONIC

ALcoHoLUse DiSOROER MM 20 l7:377:1]6B)
A variety of electrolyte disturbances occur in patients with chronic alcohol use
Most severe w/ proteincalorie malnutrition and vitamin deficiency
Hypophosphatemia (<Z.5 mgldL)
Causes: phosphate deficient diet. deficits in body stores. increased urinary excretion.
vitamin D deficiency
Clinical presentation: skeletal muscle weakness.:t rhabdomyolysis. metabolic acidosis.
hemolytic anemia. respiratory failure
To: oral supplements preferred: 42-67 mmol phosphate over 6-9 hr not to exceed
90 mmol/d: IV 10-15 mmol. Check calcium and magnesium levels
Hypumagnesemia (<2.0 mg/dL)
Causes: intracellular shift from correction of acidosis.administration of glucose
containing fluids leading to insulin release. loop dysfunction and acute pancreatitis
Clinical presentation. neuromuscular irritability weakness.anorexia. nausea.tremors.
arrhythmias. apathy
T>c oral supplements preleried. slow oral replacement 2-8 tablets (S-7 mEq/tablets)/d.
parental administration over 8-24 hr, to maintain Mg >1.0 mgldL in pts with arrhyth
mias or neuromuscular irritability. Proper replacement of Mg paramount in die effec
tive correction of hypokalemia and hypocalcemia deficiencies
Hypocalcemia (<B.5 mgldL) (AmI 200e;JJs119a)
Causes: intracellular shift from correction of acidosis and administration of glucose
containing fluids leading to insulin release
Clinical presentation: neuromuscular irritability.weakness, tremors. arrhythmias.
Trousseau sign, Chvostek sign
Tx: oral supplements include calcitriol 0.25-0.5 ug twice a day and oral calcium car
bonate 1-4 old. IV calcium gluconate 1-2 g can be infused over 20 min
Hypokalemia (<3.5 mErelL) (Dpi Akal<>iR¢»2001.2I;73)
May occur in nearly 50% of hospitalized pts with alcoholuse disorders
 Causes: inadequate PO intake. GI and urinary losses. Coexisting hypomagnesemia can
cause kaliuresis
Clinical presentation: weakness, paralysis. arrhythmias
Txcoial suspaision is pieierred; if N KCI is needed give 4080 mE/L as rare <20 mEqlhr;
administer K before bicarbonate in acidemia disturbance

Sodium Disturbances vcxo 201512z 376)

Hyponatremia: Na <135 mEqIL commonly seen in about 17% in patients MM chronic
alcoholuse disorders-causes: poor solute intake, hypovolemia, release of vasopressin
- T urine osmolality -r free water clearance - hyponatremia
Cllnlcal presentation: fatigue. nausea. dizziness. vomiting, headaches, confusion. coma
Pseudohyponatremia: alcohol consumption is often associated with hypertriglyc
eridemia. hence pseudohyponatremia may occur
Beer potomania: vasopressinindependent mechanism of hyponatremia in individu
als who drink large quantities of beer without adequate food intake
Reset osmostat syndrome: abnormal osmoieceptcr activity due to defective cellular
metabolism. Persistent hyponauemia Usom <100 mOsm/kg and natriuiesis >40 mmol/L
Hyponatremia in Cirrhosis: dlt hemodynamic changes resulting in an impaired
ability to excrete water.Vasodilatation~ activation of endogenous vasoconstrictors
T ADH release -» L free water clearance -» hyponatremia
Alcoholic Ketoacidosis
Seen in malnourished pos w/ chronic alcoholism after 1-2 d of drinking cessation
Present in 25% of pa admitted w/ alcoholrelated disorder
Responds quickly to holding diuretics and volume expansion
Presentadonzabdominal pain. NN tachycardia. HTN.: pancreatitis and volume depletion
(*"/M¢4 1991:91:119)
Dx:AG metabolic acidosis. due to ketoacids and fact acid. T Bhydroxybutyi-ate
Tx: directed at correcting hemodynamic instability and ketogenic pmcess.Volurne expan
sion with 5% dextrose in 0.9% NS. Repletion of coexisting electrolyte abnormalities.
Lactic Acidosis
Favors the conversion of pyruvate to lactate
If lactate is >3 mmol/L; consider alternate diagnosis; sepsis or thiamine deficiency
Tx: volume expansion with 5% dextrose in 0.9% NS
Hyperchloremic NormalGap Metabolic Acidosis
Lowered bicarbonate concentration due to loss of ketoacid salts in urine. which is
counterbalanced by an equivalent plasma chloride

HEPATITIS B VIRUS (HBV)

HBV infection affects 2 billion worldwide. HBVrelazed renal disease is rare in :he
US and Western Europe dl: the lower prevalence of chronic HBV infection and
lower likelihood of childhood infection dl: widespread vaccination. HBVrelated
glomerular diseases are mlc in endemic areas with high chronic carrier incidence
(hepb.og)
HBVAssociated Membranous Nephropathy (MN)
Laboratory and Histology Findings of HBVAssociated MN ran nephml 201118459
H BVR e la t e d MN Pr imar y MN
Younger onset age Steady and progressive impairment of
High occurrence of microscopic hematuria and renal function
renal failure, more nephrotic Proteinuria 2 nephrocic syndrome. *
Severely low C (C3 and C4). Neg antiPLAR2 hematuria. - antiFLAR2
LM: more segmental glomerular damage. mesangal More severe hyperlipidemia
proliferation, rulzuloinrersddal elanor LM: thickened capillary wall and GBM
IF: polyclonal immunoglobulin and polytypic IF: granular IgG, C3. and some IgM
complement: Granular IgG, CO. and some IgM staining along the GBM
staining along :he GBM EM: subepithelial immune deposits:
HBeAg in immune deposits IME/M 197%100:8144 extensive podocyte too: processes
EM: extensive poclocyte foot processes effacement
effacement
Other Renal Manifestations
MPGN: microscopic hematuria (dysmorphie RBC and RBC casts). 1 C4 2 1 C3. normal
RF. proteinuria 2 nephrotic syndrome. i GFR and HTN
PAN: necrotizing vasculitis of small and med vessels. T ESR. T CRR neg ANCA.Nw HBe
antigenemia and high HBV replication. HBsAg/Ab detected in vessel wall wjriuu
1978;90:619). Can lead to renal infarct. variable degrees of i GFR and HTN.
Less commonly IgA nephropathy (advanced liver disease) and FSGS
Diagnosis and Workup
Hepatitis serologies in all patients with CKD
Kidney biopsy no confirm a glomerular process. For PAN. a diilerent tissue site may
be biopsied for diagnosis (skin, nerve. muscle) or renal angiography
Treatment and Immunosuppression
Acute hepatitis B: supportive treatment
Antivirals: tenofovir or entecavir. Lamivudine or adefovir monotherapy cause resistance
Tacrolimus may have synergistic effect with entecavir (Am jYmnslR¢s 2016:B:1S9J)
MN: 50% children spontaneously remit IFN l proteinuria (¢~~~=~»¢=f=¢=¢v 199s:10~rs40)
Antivirals therapy 1 proteinuria, T HBeA,g clearance (lnbiidj Gmuwiwa 1010=1617701
immunosuppression is generally not recommended
Mild PAN: antiviral therapy plus short course of immunosuppression (prednisone
0.7-1 mg/kg QD, tapered over 4-6 mo) and PLEX (2.5-4 Usession x6-10. QD or
QOD over 2-3 wk) www anew 2004:s1¢4m
Moderate-severe PAN: antiviral therapy and PLEX + prednisone + cyclophosphamide
(oral or IV) (Anhnus Nlem 2001944661
ESRD
About -1% of dialysis patients are seropositive for HBsAg
Nosocomial transmission is a risk in HD pts. Machine segregation and proper cleaning
and disinfection procedures among H8sAg + pos at HD is essential in the prevention
in HBV incidence (Semn Oval Z00§;18:$2)
Regular 2-3 mo monitoring of liver enzymes and albumin. liver US annually
All pts with ESRD should receive HBV vaccination and have HBsAb titers monitored
HBsAb + after vaccination is alw 1 allcause mortality in dialysis pts (man 2017135:814)
Kidney Transplantation and HBV
All HBVinfected pts should be further evaluated prior to transplantation in order to
determine risk of reactivation (HBeAg. serum HBV DNA, and preferably a liver biopsy)
HBsAg+ a/w 1 allograft survival. No change in patient survival (hnnspiant Proc 201s;47=94z1
There are cases of de novo HBV from receipt of kidney from infected donor
Isolated HBcAb + pts are prophyfaxed with lamivudine posttxp to prevent HBV
reactivation with IS irlunipimn hue Z007;3&3121; Can Open own Timsplml zoosn uses;

HEPATITIS c VIRUS (HCV)

HCV infection affects 2.8% of the worlds population. HCV infection is a risk factor for
proteinuria and/or impaired renal function (cm,n n¢phml2012174101
HCV infection incident CKD and prevalent CKD lqAs~101247¢$491
HCV infection doubles :he risk of progression to ESRD (l4¢W"1l°IY 101541114951
HIWHCV confection: high risk of CKD progression wxo 2009254:431
HCV . the risk of morbidity and mortality of dialysis patients (/vuviH:94n 2007:14:697)
Renal Manifestations
Maced cryoglobulinemia syndrome (MCS): 30.1% of HCVinfected pts have circulating
cry globulins (c¢=~~~~~~v 2016;1SQlS99). Symptomatic MCS anil -2% uwu Hoi: zoaa7 nasl
Up to 90% of MCS is due to HCV MCS caused by type It or Ill cryoglobulinsz polyclonal
IgG and monoclonal IgM or lg/l (type II) or polyclonal IgmllgA (type III).The IgM has
RF activity against Fc portion of the polyclonal IgG. HCV RNA and antiHCV antibodies
have been identified in cryoprecipitates (no/vi 1m.31s4ss)
Renal manifestations d HCV MCS: nephritic syndrome. HTN.mar/ also halve NS or RPGN
Symptoms: palpable purpura, arthralgias. neuropathy. weakness
. C3. J. 1 C4. +RF and +cryocrit
Biopsy: MPGN pattern on LM with mesangial and subendothelial proliferation.
Pseudothrombi" are classic. IF positive for IgM, IgG.and C3. EM shows subendo
thelial deposits w/ fingerprintlike substructure
Mesangioprt>lillaatlve GN:deposits/proliferation in mesangium. Mild hematurh/proteinuria
Membranous nephropathy proteinuria 1 nephrotic syndrome. normal C3/C4. normal RF
 PAN: 19% of HCVassociated vasculids; more severe. variable degrees of l GFR and
HTN. Small. medium vessel disease (ANCA neg). T ESR, t CRP nufan Cannes 201\;63=4z7)
IgA Nephropathy: can be seen in HCVinfected patients with cirrhosis
Fibrillary and Immunoxaccoid GN: several cases reported. Hematuria/proteinurialrenal
insufficiency with normal C3lC4 and RF US/AN 1990.9122441
FSGS: :he mlc lesion seen in pauiem: coinfected w/ HCV and HIV (a» Nfpniu 7.01327ns51
Renal manifestations may be underdiagnosed.autopsy studies and kidney biopsies
taken at liver :xp show GN In 45-85% (Inter M44 1999237834 AM :m zcoe4144.1as>
Diagnosis and Workup
All patients evaluated for CKD be screened for HCV
Evaluate for proteinuria. hematuria. HTN. eGFR. cryogtobulins. complements. RF
Kidney biopsy recommended if there is hemarurialproteinuria
Treatment of HCV Infection
J CrCI.or GFR prior to HCV treatment
IFN and RBV are renally eliminated. lFN associated with collapsing FSGS and drug
induced lupus. RBV must be dosereduced for CKD, can cause hemolytic anemia.
Because of lack of efficacy and because IFN/RBV so poorly tolerated. only 1% of
HCVinfected dialysis patients ever received ueatlnent (Amy new#2o1ne405i
Directacting antivivd therapies (DiAs) target the HCV viral proteins widl cure rates >95%
DAys have many drug-drug interactions (an Phamacy Dew Div 2017:6,147]
D AA T r eaunent O ptions for H C Y

Drugs Use Comment

Elbasvir - Grazoprevir
(Zepatier°)
Ombiusvir 4
pariraprevir +
ritonavir + dasabuvir
( Viekin PMI
Sofosbuvir + simepnevir
Sofosbuvin-ledipasvir
Sofosbuvir-daclalasvir
Sofosbuvir-velpansvir
Glecaprevir-pibrentasvir
(M=vyf°=°)
Tesv.ed in Stage 4-5 Cured 94% of patients with advanced
CKD/ESRD CKDIdialysis
Genotype: 1a. 1 b. 4 s/e: headache, nausea, and fatigue
acsunru Lance: 10 15886115371
Tested in Stage 4-5 sle: anemia, nausea. fatigue. diarrhea.
CKDIESRD headache. peripheral edema
Genotype 1b,add (C°""=°1°°l°l7101&1sa1s901
ribavirin for pos wl 1a
Genotype 1a and 1b sie: insomnia. photosensitivity
(simeprevir)
Genotype 1a . 1b, 4 sie: headache. fatigue. nausea
Genotype 1-3 sle: headache, fatigue. nausea
Genotype 1-6 s/e: headache. fatigue. nausea
Genotype 1-6 Cured 9B% in advanced CKDIdialysis.
No treatmentrelated SAEs
(NEW10\773773144B)

Treatment of Cryoglobulinemic Glomerulonephritis lnipfmalqy 2016;63;468:

1016:641473; Gm Gauunenlemd Hepalol 20I 7;15.5751
DAAs are safe and effective; curing HCV in >90% patients with MCS
D»°iAs alone lead to nomnlizadon d complement. and reduction d cryo level in die majoiiny
DAAs cause complete or partial remission of MCS in 70% :r ear ed with DiAs
lmmunosupplession (Riuiximab, steroids 4- PLEX) should be added in patients w seven
systemic vasculitis (pulmonary hemorrhage. CNS vasculitis. RPGN) or nephrodc syndrome
Riruximab does no: reduce antiviral efficacy (Aida 2010416943) and does no: lead to
heparins flares or increase in uremia (Andrus Rheum 20\2;64:843:2011:64:835)
Management of Patients With HCV and Kidney Disease
Presentation Treatment
Asympwmatic hemaruria DAA therapy
Normal kidney function
Minimal proteinunia
Suspected GN DAA therapy
Subnephrodc proteinuria
Suble renal function. eGFR >30
Suspected GN DAys recommended for eGFR <30
Subnephrotic proxelnuria grazoprevir + elbasvir
Stable renal function. eGFR <30 giecaprevir + pibrennsvir
Nephroxic syndrome Biopsy -» Rizuximab steroids. DAAs
Rapidly P , . ressive GN (5%) Biopsy - PLEX. Ricuximab + Steroids. DAAS
Rend Side Effects of DAAs
Sofosbuvir is no: FDA approved for eGFR <30. however analysis of offlabel use sug
gests reasonable safety and efficacy (um nu 2017137974)
Sofosbuvir linked to increased rates ofAKl mum in patients with eGFR <45 compared
to those with eGFR >45 (um I( zoo s;36¢a07)
Lupuslike immune complex-mediated GN: sofosbuvirbased therapies (va up 201a111351
FSGS may occur wir.hlafter DAAs (H=»=~~=w zo11=e4¢¢se¢~.t;m z017;a76:z394)
ESRD
HD is a major risk factor for HCV. HCV prevalence is 10-13% in US dialysis patients
HCV outbreaks are still reported in dialysis units due to breakdown in infection con.
trot techniques iImJAfvfofl¢"= 2015:3B:471)
HCV associated with 1 survival on dialysis uwrai Heps 2007:14.697) and T morbidity
(t hospitalizations.T transfusions. 1 QOL) on dialysis lclAsn z011:1z:2s7)
Liverrelated deaths t in HCV+ dialysis patients UASN 200n11:1a9s)
Kidney Transplantation and HCV
HCV is a/w T NODAT. T de novo glomerulopathya T chronic allograft nephropathy.
1 allograft survival, 1 patient survival postKT (An 200§:5:1452;200\;1:171)
INbased therapies for HCV can provoke acute rejection trialupialuaiian 19B&45:401)
No T acute rejection risk with DAAs (al 2018915601
Sofosbuvir/ledipasvir: 100% elective in KT recipient wid genotype 1/4 (Am IM 2017.16a109)
Transplanting HCV positive kidneys (genotype 1 or 4) into HCV negative recipients
followed by pos transplant elbasvir/grazoprevir treatment may be safe. and is under
active investigation mum 2017:376:Z394)
Timing of Kidney Transplantation
HCV infection dramatically i waittime for KT WT 2010.1&12J81
Current recommendations are to treat HCV ;fig transplant in patients on dialysis
waiting for a deceased donor transplant in centers utilizing HCV+ organs
Timing ofTreatment of HCVInfected KT Candidates on HD In 201&9nss01
Favors Treating PreKT Favors Treating PostKT
Excellent cure rates for all genotypes Excellent cure rates for all genotypes
i liver disease progression Does no: T risk of rejection
l nosocomial transmission in dialysis units i KT waidist time
1 posttransplant de now GN T orpn utilization (i discard of HCV+ organs)
1 NODAT risk l cost by shortening time on dialysis

HEMATOLOGY
Possible Hematologic Manifestations of Rend Conditions
AKI + anemia: hemoglobin 1 hemosiderin pigment nephropathy from hemolysis. light
chain cas: nephropathy wkh myeloma.TMA. lupus nephritis. undiagnosed CKD
AKI + :hrombocyzopenia:TMA including anziphospholipid syndrome. HIT with renal
artery ischemia, lupus nephritis. Hancavirus infection, leptospirosis
AKI + eosinophilia:AIN. renal adieroemboli
GN + eosinophilia: EGPA
NS + eosinophiliz parasitic infection, et. Strongyloides szercoralis (Ra Rep 2018;3114)
Potassium Charges in Hematologic Conditions
K Hemolysis. tumor lysine syndrome
Spurious: leukocytosis dl: cell fragility (a. Cn.mA¢w zuommosl. zhrombocywsis
(./plasma) upco l99B;l1:116)
LK Hemaropoiesisz GMCSE folaze, vitamin B11 Lrearment
Spurious:AML (T cell uptake)

HEMOGLOBIN AND ERYTHROPOIESIS

Hb: heme (iron + porphyry, synthesized in BM and liver) + aglobin + Bglobin
Anemia is defined as Hb <13 (d) and 12 (9) (WHO.KDlGOAnemin z012)
Erythropoiesis:The Production of RBC at Bone Marrow
Erythropoietin (EPO).a glycoprotein is produced in kidney peritubular Interstitial
fibroblastlike cells (90%), liver and brain pericytes
L local oxygen tension inactive HIF prolyl hydroxylases » Y HlF -» T EPO -» binds
to EPO receptors on erythroid precursor cells -» T erythroooiesis
 T Loal oxygen tension active HIF prolyl hydroxylases 4 hydroxylated HIF binds
to Von Hippel-Lindau (VHL) protein -> ubiqukinarion and degradation of HIF -» i
eryzhropoiesis
Roxadusrac HIF prolyl hydroxylase inhibitor T Hb in CKD ND and CKD SD
(NE/M 2019;PMID lII400891 J13401 16). Need long :erm safety dana, eg. RCC risk

A N £ t4 IA oF C K D
Diagnosis of exclusion: rlo other cause of anemia
T as GFR declines: 113 (6)-2/3 (Q) at eGFR 15 ln14Anes/vu- IM z001.\s2:1401; pAsru am
MUM Open 2aa4;1011s01); l 3% in Hot allw t 7% death (ac zoouamssl
Pathogenesis
EPO deficiency and resistance: level is not low in CKD. bu: inappropriate
Acute and chronic inflammation: t IL6. lL1.TNFa. INFy -» .L erythropoiesis
Hepcidin: 1 by chronic inflammation. lL6 and L renal clearance of hepcidin
Inhibitor of iron tiansporten ferroportin - functional iron deficiency
Folate, vitamin Be nutritional deficiency 2 HD removal -w ineffective erythropoiesis
and 4 survival of RBCs
Blood loss during HD and phlebotomy
Uremic bleeding: abnormal hemosrasis in CKD dl: defects in platelet function
Aluminum toxicity: BM accumulation -» microcytic anemia
Clinical Manifestations
Dyspnea at vest/on exertion.fatigue. L QOL LVH (strongly alw hasphaization, morality)
Hb variability is a/w morality (NDT 2010.2s=3701: Ayer 1011:5711661
Diagnosis and Monitoring
J Hb quo mo in CKD3-S including pts on PD: qlmo in CKD5 pts on HD
./ Iron profile iron.TIBC.and ferritin (reflects storage) periodically
rlo other causes of anemia:/ stool occult blood, res. MCV. platelet, monoclonal
protein/ folate.vitamin Be if t MCV. J res. LDH. and hap to to rlo hemolytic anemia
J PBS if accompanied by thrombocytopenia to rlo TMA
Homocysteine and methylmalonic acid levels elevated in CKD (NE/M 1013;36B:149)

IRON DEFICIENCY
Goal and Strategy
Consider iron initiation ifTsat $30% and ferrite $500 in CKD (KDIGO Anemia 2012)
lV iron if ferrite 500-1.200 and Tsar $2596: T Hb and Tsar lows,/Asn z0o7;Is;97s) and
L ESA requirement (DRIVEILjA$N 100941913121
iron sucrose high dose (400 mg monthly unless ferrite >700 orTsat 240%): l ESA dose,
vs low dose 0400 mg monthly reactive to ferrite <200 or Tsat <20% (NE}M zo1nso44n
Iro n Ad mi n i stra ti o n
In nonCKD. multiple PO iron dose is inefficient dlt T hepcidin. QD or QOD dose is
recommended (aim 201s¢126=1se1i. Hepcidin is further T in CKD: consider QD or QOD
PO iron is generally ineffective in dialysis pts
Ferric citrate (?0) approved for hyperphosphatemia in dialysis pts and IDA in
nondialysis CKD. 1 IV iron and ESA requirement in dialysis pos UASN 101s1zs¢493:
2015;16:Z578). T Hb and Tsar in CKD (;As~ 1017;Z8:l851: um 201$;65:NB)
IV Iron Agents and Dose
Iron sucrose (Veno4er°) HD: 100 mg HD x10; PD: 300 mg on d 1 and 15.
then 400 mg on d 28; Nondialysis pts: 200 mg x5
Sodium ferric gluconate HD: 125 mg HD x8
(Ferrleci¢°INulecit°)
Ferumoxyrol (Feraheme°) 510 mg xi then 510 mg in 3-8 d
Iron dextran (INFeD°l IV or IM:test dose require¢05 mL (25 mg).wait for 1 hr
DexFerrum°) then 100mglhendose 1.000mgx1 or 100mgx 10
Ferric carboxymaltose (lni=¢0f¢r°) 750 mg x 2 (at least 7 d apart)
Ferric pyre phosphate citrate Added to dialysate: reduced ESA and IV iron dose (KA
UM¢c zo1s;sa11sn
Side Effects of IV Iron
Infection: bacteremia x2.5 in HD pos with Tsar 220 and ferritin z100 (an N»1ioo»s
z004;3e;w90); injection is a/w high ferritin In z01 w61s4s1
No direct evidence of t mortality, CV event. iniecdon. and hospitalization at a systemic
review and mereanalysis lqAs~ 2018;l3:4$7)
 Iron overload: deposition i injury in liven heart. pancreas. gonad. and skin. rare with
iron administration. bu: possible Lem; Hmml0l Z01 l89:B7)
L POW w/ ferric carboxymalrose (mc n4pn~4201J;l4=167):anaphylaxis wl iron dextrin

ERYT HNO PO ISSIS ST IMUL AT INC AG ENT S ( ESA)

BeneGr.s: J, RBC transfusion.l iron overload. improve QOL. LVH (qASN 2009445755)
ESA Regimen and Dose
Epoetin a (Epogen°. Procrit°) SCIIV r.iw; sur! with 50-100 uniulkg
Epoetin aepbx (biosimiiar. Rencrit°)
(qASN20181111200
Darbepoetin u (Annesp°): x3 longer half $GIV q1-4wk; in with 0.45 up/kg qwk
life than Epoetin u or 0.75 Wks q2wk in dialysis pa and
0.45 kg/kg quo wk in nondiaiysis pts
Methoxy polyethylene glycolepoetin p SCIIV q2-4wk: start with 0.6 uglkg q2wk
(Mircera")
Peginesatide (Omontys') Withdrawn for anaphylaxis and death
Epoetin and Darbepoetin Dose Conversion
Total Weekly Weekly ToW Weekly
Epoetin a (dw, units) Aranesp (pg) Epoetin a/Aranesp Mircera (ug)
<2.499 6.25 <8.0001<40 120 quo or 60 q2wk
2.5004,999 12.5
5.000-10,999 25 8.000-16.000/4080 200 quo or 100 q2wk
11.000-17,999 40
18.000-33.999 60 >16.000l>80 360 quo or 180 q2wk
34.00089,999 100
gzip

290.000 200

Clinical Trials on ESA Use With Hb or HcrTarge¢

NHCT (U5) HD pos Mth CHF or CAD. Hot larger 42% vs 30%. 28% T death
or nonfatal MI (NEW 199a=J39§84. K1 zmzewsl
CHOIR (U$) CKD (eGFR 15-SO): Hb target 13.5 vs 11.3. 34% T death, MI.
CHF. CVA (num zoos:ass:zcasl
Pos:hoc: inability to reach target Hb and high doses of ESA
were each a/w death. MLCHF. CVA (DOI the high Hb) (KI
10ae.14.7<m
CREATE (Europe) CKD (eGFR 15-]5): Hb urge: 13-15 vs 11-12.5 no difference in
CV event: improved QOL; T HTN and headache (NE/M
2ccs.assz011l
TREAT (lnzernadonal) CKD (eGFR 20-60) widl T2DM; Hb target 13 vs rescue if <9 no
difference in death or CV event and dash or ESRD; T nonfanl
CVA (NEW zco9;sm01~>)

ESA dose can be increased no avoid blood transfusion

Recommendations (or Target Hb With ESA lxmcu Menu 1011)
For nondialysis CKD w/ Hb <10. choice of starting ESA is individualized
For ESRD. use ESA (D avoid Hb drop <9
Do not use ESA to keep Hb >11.5, but ok to individualize for QOL if pt aware of risk
Do not use ESA to keep Hb >13

Side Effects
Hypertension: endothelial cells express EPO receptor -> T endothelin - vasoconstriction
T Mortality and/or tumor progression or recurrence in pts with breast, head/neck,
lymphoid. cervical and non-small cell lung cancer (FDA): insufficient evidence on tumor
response (Cachvne omuw Sys Re 1012;12:CD€03407: M Canal 1012;106:1149)
Highdose ESA a.lw T Incidence of cancer diagnosis (NDT 1016;32:1047)
AVFlAVG thrombosis (new 199e¢339:sa4l
Pure red cell aplasia (dlt antiEPO Ab) with Epoedh a (Eprex°.available in Europe)
ESA Resistance
Iron deficiency (could be alw blood loss). infection. inflammation. inadequate dialysis
Hyperparathyroidism (A}KD 10091518131 Can Nepluul zo1 l;16:99)
 INTRAVASCULAR HEMOLYSIS WW z01o.ss¢7aiz 2015:65:337)
TMA: glomerular endothelial injury: MAHA (1 hapto,T LDH. reti.a>schis:ocytes) +
thrombocytopenia (could be absent making it difficult to diagnose wlo renal
biopsy)
Free Hb from intravascular hemolysis is bound to haptoglobin: glomerulus cannot 6Mr
Once haptoglobin is deplezed.flee Hb is filtered: reabsorbed by megalith-cubilin in PT
AKI by direct heme effects (renal vasoconsuiction. mitochondrial toxicity, cell
damaging enzyme activation) and/or intratubular Hb cast and tubular obstruction
Hemosiderin: FT cell deposition (brown on PAS. Prussian blue Q) :AKI

BLOOD TRANSFUSION
Indication
In CKD. should be determined by symptoms and clinical conditions (acute hemorrhage.
unstable myocardial ischemia), not Hb threshold (KDIGO Anemia 2012)
A restrictive threshold, Hb level 7 is recommended for hemodynamically stable
hospinilized adult patients UAMA 1016;316:1025)
Side Effects
Volume overload. t K. transfusiontransmitted infection. immunologic sensitization
on transplantation candidate. iron overload. transfusion reactions,TRALI
Acute (<24 hr) and delayed (5-7 d) hemolytic transfusion reaction - AKI
TX: IV fluid z loop diuretics according to volume status
Transfusionassociated circulatory overload (Am 1m¢42013;116e29)
Risk factors:CKD (x27). HE hemorrhagic shock:alw T mortality (x3.2).hospiulACU stay
Leukocytereduced blood still increases sensitization (lvansplanmau 2011:93:41s)
Iron overloadzchelators are required for conditions requiring chronic transfusion
Defer.sirox:AKI and Fanconi syndrome are common (mm n¢inmi 1011:27:2115: nor
2011r1s:z37e app z014;167:434). reversible wl dlc w/o longterm kidney injury laps
2011;154:lB7). Dosedependent hypercalciuria (Bone 2016;8S:S5). CaOx stone (Ann Heinalnl
10139Z2s3).Avoid in renal dysfunction
Deferoxamine:AKI from tubular injury l~or 200a;23:10s1i
Defeniprone: no significant renal side elect; preferred in L GFR (n£)M 201B¢379:2140)

SicxLe CELL DlssAse (SCD)

Background
Glu toVal substitution as 6th AA of 13globin chain of HbA -» sicided hemoglobin (HbS)
SCD Genotypes: HbSS. HbSC.HbSBthalassemia, HbSD, HbSE. HbSO
Sickle cell anemia = HbSS (homozygous): most common and severe form of SCD
• Affects millions worldwide. ml in ancestry from subSahara Africa. Latin Americal
Caribbean. Saudi Arabia. India. Italy. Greece, and Turkey
Renal disease was attributed to cause of death in 16% ireduv lined Cancer 101J.w: 14e2)
Pathogenesis (no: lu new# 2015;11:1611
HbS molecule is insoluble upon deoxygenation causing rigid deoxy HbS polymer in
RBC
Leads co hemolytic anemia.inflammation,vasoocclusion.endorgan damage, and
death
Renal vasculopathy -» medulla h/popefusion + cortex hyperperfusion + vasoconsulction
C lin ica l M a n if e st a t io n s
Crisis: vaseocclusive painful,aplastie, sequestration.and hemolytic
Acute chest syndrome (ACS). pulmonary HTN. asthma, myocardial ischemia. HE CVA
Renal disease develops in 5-40%;CKD -» ESRD in 4-12% immune 100594:3531
AKl during vaseocclusive episode <5%, a/w ACS and pulmonary HTN for 2010.152524>
Glomerular hyperfiltration-» T GFR,albuminuria. protieinuria -o glomerulopathy. CKD
Kidney biopsy: FSGS > MPGN >Tr4A (m<¢s¢»¢ 10\o1sa~ma1
AKI. ns and red cell aplasir parvovirus B19/FSGS (lance: 1995;346:475: app 2010=149=za9)
Proximal tubule hyperfunction -» T uric acid and Cr secretion: Crbased equation
overestimate GFR (pies One 201m»699z2),t PO. reabsorption -v hyperphosphacemia
 Dis ml tubule and collecting duct: metabolic acidosis.l K secretion (incomplete dRTA).
enuresis, hyposthenuria 2/2 impaired urinary concentration (Max Uosm after 8 hr HxO
de pri v a ti on 4 0 0 4 5 0 mO s ml k g)
Interstitium: hematuria (common). papillary necrosis (painless gross hematuria). renal
medullary carcinoma.chronic interstitial disease -» CKD
Renal infarction: gross hematuria. pain,vomiting.fever. renlnmediated HTN, T LDH
. Dx : c ontra s t CT. ra dio is otope s c a n.c ontra s t MRI

Treatment
Fluid for volume depletion: blood transfusions: may T level panel reactive antibody
Potential l, proteinuria with ACEI (Caduvne Diabase Sys: Rev 2015:CD0091911
Hydroxyurea for 6 mo 1 albuminuria l;As~ 1D16:27:lB47)
Blood transfusion with Hb goal 10 for stroke.TIA.acute chest syndrome and preop
AlloHSCT: curativezsickle nephropathy is an indication iuianuiuiqua 2014598s111
Prognosis
ESRD alw x2.8 1yr mortality we 1012:1s9n60)
HD. high 5yr mortality (46336 vs 6.4%) from cardiac Ernest and septic shock low chance
to get transplantation (MH 1016;174:1481
Kidney Transplantation
Better survival than being on dialysis
6yr survival 70%. improved but lower than other disease (NDT 2013;2a=10391
Vascular occlusive crisis on graft (Human rauiuiqy 2011142110272 al 1008;74:1219) is possible
Sickle Cell Trait (SCT)
Heteitazygous sklde cell muiadon on one allele of [3globin chain of HbA. producing HbAS
Albuminuria x1.86, CKD x1.57 up 1014:312:21151. ESRD x2.03 (IAS~2017=ua1a01
Microscopic hematuria. papillary necrosis
HD patients with SCT requires higherdose ESA (;ASN 201411518191
Medullary Renal Cell Carcinoma in SCT
Rare, aggressive form of RCC: almost exclusively in young SCT patient
Hemawria, flank pain. palpable mass: survival 4-16 mo (IJiulily 100717a878)
Dx: contrast CT or MRl;ultrasound can miss

E RY THRO CY TO S I S
Polycythemia: t red cell mass
. Hb >1B.5 or packed cell volume >0.52 (6): Hb >16.5 or packed cell volume >0.48 (9)
Clinical Manifestations: Hyperviscosity
Chesdabdominal pain, myalgias. weakness. fatigue. HA. blurry vision, paresthesia
Causes and Pathogenesis un] n¢pl\\I 2013:37:333)
Excess EPO production (so 2018:347l6667)
Tumors: renal cell carcinoma. hepatocellular carcinoma. hemangloblastoma P
Gastric carcinoma. parathyroid carcinoma. pheochromocytoma, uterine leiomyoma N
w
PKD (from epithelial lining of renal cysts). hepatitis (Am]Med$¢i 1984;287:56)
Chronic hypoxia (via HIF1); OSA. R- L cardiac shunt. chronic pulmonary disease.
high altitudes. carbon monoxide poisoning. smoking. hemoglobinopathies
Polycythemia Vera: acquired ]AK2 V617F mutation in 95%
RAAS Activation: posttransplantation. RAS. chronic severe hypotension
Idiopathic: rare. treated with phlebotomy and close attention to iron levels
PostTransplantation Erythroeytosis
Incidence Hb >17 decreased from 18.7-8.1% (a»Tfaiaa4unr 2009:13;B00)
Risk factors: male. simultaneous pancreas kidney transplantation Wr 20l0:1&9ll8). primary
disease; PKD and GN
Pathogenesis: muitifactorialzactivation of RAAS (angiotensin II type 1 receptor activation
stimulates EPO mediated wydirvid prdiferadon).local renal hypoxia. hematopoietic growth
factors. eg. IGF1. serum soluble stem cell factor. endogenous androgens
Tx:ACEI or ARB. phlebotomy
 ANTICOAGULATION
Nonvalvular Atrial Fibrillation (NVAF) in ESRD
Prevalence ofAF 10-15% in ESRD l;Asn 1a11:12;349)
1yr mortality in HD patients with AF is twofold that of HD pos in sinus rhythm
AF risk scores have poor predictive value for stroke for the CKD/ESRD population
and underestimate woke risk (qAs~ 1016;11:2085)
Anticoagulation for NVAF in CKD and ESRD
For eCrCI 30-50. noninferior efficacy in prevention of CVA and rhromboembolism
and Iikeiy superior safety of DOAC compared [O warfarin lKolGo an Ileon 12019.39 11141
Convicting recommendations on anticoagulation in CKD 4-5.AHA supports for
CHAR;DS;VASc score >2, KDIGO does not support
Anticoagulants for NVAF yacc m01ws=zzn; we zmsn L:om lOl1;I2:1\76)
Dr ugs ( Pr otein
Bound) Comments CKD ND ESRD

Warfarin (99%) Overanricoagulazion: xi .2 No adjustment Avoid for primary

ND( dialyzable in CKD and x 1.5 for prevention
Renal elimination ESRD UAS~ 2oo9:zwml (KDIGO n
<1% INR variability in ESRD: 2011:sa571>
CYPZC9 metabolism <4S% of time
to inactive Lherapeutic (Hedvl
meuboliue Z01l;l0]:8lB)
CKD: L CVA (qAsn
Z°\6:ll12W§)
ESRD: 30% * major bleeding
wlo 4 stoke/mortality
(Gia:201$;149951)
Stop in calciphn/Iaxis
Dabigatran (35%) Major bleeding t 48% in CrCI 15-30: Avoid
50-65% dialyzable ESRD lcauniun zoisnavzni 75 ms BID
Renal elimination HD WH 2015:\69:603) CrCI <15: avoid
80% of dose or idarucizumab WE!"
1017;377:431) can be used
for reversal in bleeding
Rivaroxaban (95%) Noninferior to warfarin in CrCI 15-50: 15 mg daily:
Not dialyzable CrCl 230 (nocxE\=AF 15 mg daily I 10 mg daily
35% renal elimination is;/u 201 \;Jus=seJl CrCI <15:avoid we 101516630
CYP3A4/5 and t 38% major bleeding in
CYPQ12 metabolize ESRD;no T wl 15 mg
50% no i1acdw¢e daily <a¢n»u- zomuwn)
metabolite
Apixaban ( and) Nonlnferlor to warfarin in Cr >1.5 and ZW 5 mg BID:
7% dialyzable CrCI 225 (ARISIOTLE new lo or <60 kg ! 2.5 mg BID
34)40% renal N11:365!981) 1.5 mg BID we 2011a&1241)
clearance 1 bleeding dw warfarin CrCI <15: avoid
CYP3A4/S (CJASN z01a \I:w1~n Guulludun
mexabollsm to 201B;138:1S19)
Inactive meobolire

Prophylactic Anticoagulatiori in Membranous Nephropathy

Pts with MN have increased risk of thrombosis (KVI PE.and DVT)
No RCT addressed question of prophylactic as
Risk faccor:Alb <2.8 a/w RR of 2.5 for thrombosis. x2 Increase for further 1 albumin
of 1. Proteinuria does not correlate with risk (qAsn 201 z7431
Broad spectrum of clinical practice regarding prophylactic anticoagulation in MN
Alc if low/intermediate bleeding risk and albumin <3 lx:10141as1i41z1
Alb <2.0 w/ prophylactic dose LMWH or lowdose aspirin;2.0-3.0 wl lowdose aspirin
was successful (C1ASN 1014:9.47B)
AnticoagulationRelated Nephropathy (WarfarinRelated Nephropathy)
T Cr by >0.3 wlo other obvious etiology in the setting of INR >3.0 in case of warfarin
33% of CKD and 16.5% of noCKD had T Cr w[i 1 wk after INR >3;a/w 1yr (31.1 vs
18.9%) and 5yr mortality (42 vs 27%) and CKD progression In z0 n¢s4x1a1l
 5/9 did no: regain baseline kidney function (Aixo 2609454111219
More common wu 8 wk of starting warfarin
Gross or microscopic hemacuria air an anticoagulant overdose. minimal proteinuria
Dx: r/o other causes of AKI (esp RPGN); Bx in Cr does not improve with moderation d
anticoagulation; consider risks of bleeding and dwombaemboiism while off anticoagulation
Bx: giomerular hemorrhage with RBCs and numerous occlusive RBC casts in tubules
Dabigatran caused similar pathology in rat (NDT 10141n228)
Rx: d/c or moderation of anticoagulation

MONOCLONAL GAMMOPATHY (MG)

Background
Monoclonality: the abnormally high proportion of one type of light chain (LC) or heavy
chain (HC) on serum/urine immunofixation or FLC assays
M protein: monoclonal protein; B]P: urine M protein
The type of monoclonal protein determines d1e type of kidney disease lnqm 19911324;1s451
lg do not cross GBM. LCs are filtered and reabsorbed by PT cubilin-megalin complex
lgG3: strongest complement activation, highest (+) charge
sFLC >ULN a/w t mortality (x1.45) and ESRD (x3.25) (mapan nu¢2017:<n:1671l
CD19,CD20 (+) B cells differentiate into CD27. CD3B. CD138 (+) plasma cells

HEMATOLOGIC CONDITIONS (lnncet Ondnl 2014:15:¢$38: NEW! 2006:J55:2765)

Mu lt ip le Mye lo ma ( MM)
Diagnosis: clonal BM plasma cells 210% or exuamedullaq plasmacytoma AND any
of the myeloma deNning event:
. Evidence of end organ damage char an be amibutM to MM: Ca > 11 or > 1 higher
than :he ULN, Renal insuMciency (CrCI <40 or Cr >2, LCCN). Anemia (Hb <10)
Bone (osteolwc lesion; MRI or CT more sensidw than plan radiography)
Biomarkers: donal BM plasma cells 260 M 2100 or $0.01 or >1 focal lesions on MRI
17% of newly diagnosed MM had eGFR <30 I 201329134n
Renal biopsy. 3/4 showed MG associated renal disease: LCCN 33%. MIDD 22%
Amyloidosis 21% (Aim 2012:s9:7u)
Tx: auwHSCT if eligible. Proreasome inhibitor (bone. aril ixammjh), immunomod
ulamq drugs (knalidomide. pomalidomide). cytotoxic 4ens.and CS. Mmmmunnb
and elowzumab J. disease progression or death (NW N1&3N:S\&1015;373:611)
Morality in ESRD:86.7.41.4,and 34.4/100 personyr in the 1st 3 yr (WN mlmrwn
Other Hematologic Conditions Causing MG
Smoldering MM (SMM): serum M protein IgG or IgA 23 gldL or BJP >S00 mg/24 hr
and/or clonal BM plasma cells 104M wlo myeloma defining events or amyloidosis
Waldenstmm Macroglobulinemia (WM): serum monoclonal IgM and 210% BM |
lymphoplasmacytic infiltrate: hyperviscosity syndrome; almost always B cell (CD 20+)
Clinical manifesmdon of IgM subtype of lymphoplasmacytic lymphoma (LPL)
Renal biopsyQAL Amyloldosis > IgM deposition/cryoglobulinemia > lymphoma infil
uation > LCCN, MIDD up 2016;175:623:c1As~ 101841311037)
Chronic lymphocytic leukemia (CLL): MPGN (20%) > interstitial infiltrate (12%) >TMA
(12%) > MCD (10%) innmttalqea z01s;1001 1s0)
Monoclonal B cell iymphocytosis (MBL): B lymphocytes <S.000l1IL w/o Iymphadenopathy
MG of Undetermined Signillcance (MGUS)
Dellnition: serum M protein <3 gldL.clonaI BM plasma cells <10%. no elo CRAB or
amyloid that can be attributed to the plasma cell proliferative disorder
1-2% of adults: more common in older age.female.African American
Progression to MM or lymphoid disorder -1%/yr (18% at 20 yr. 28% at 30 yr)
Risk factors (RF): M protein >1.5 g/dL. abnormal FLC ratio. Progression in IgM/non
IgM MGUS at 20 yr: 5s/30% (2 RF),41/20% (1 RF), 19/7% (no RF) (nom201B:37B1241)
ilu pts wid\ IgM MGUS. M protein >1.5 my dL or abnormal FLC ratio wl labs annually
flu pts with nonIgM MGUS. M protein <1.5 mgdL and normal FLC wl history and PIE
MG of Renal Significance (MGRS) ll1(mG Consensus Row Nor Rev n¢pnmI 201<r1s¢4s)
Any B cell or plasma cell clonal lymphoprolilleiation wid\ both of the following diaracterlWcc
One or more kidney lesions that are related to the produced monoclonal lg
The underlying B cell or plasma cell clone does not fuse tumor complications or meet
any hematologic criteria for specific dweraplr: including SMM, smoldering WM. MBL
Frequently more than 1 type of renal diseases coexist
MG of Clinical Significance (MGCS) uuw4201&m:14n)
MG with related organ damage (kidney. nervous system. or skin) that would otherwise
mee: criteria for MGUS

DIAGNOSIS AND Woaxuv

t Ca in MM: Igs have Cobinding sire: may T :oral Ca:./ iCe
T Globulin (total protein _ albumin). Low complement in PGNNlD,immunotactoid
AG: L In T IgG (+ charge), t in ' IgA ( charge) (clAw 101l;6:1814}
Urine albumin to protein ratio (UAPR) <25% in LCCN. Sensitivity 0.98. specificity
0.94 vs >25% in amyloidosis and MIDD (qAs~ 1012:7:1964)
Urine dipstick: hematuria and proteinuria. Nor sensitive to BJR
3% Sulfosalicylic acid precipitation: detects albumin. BjR and lysozyme
SPEP: M protein on 1>> Ll Low level Ann be missed. 1 fraction in LC disuse is common.

SIFE: more sensitive than SPER quantitative

FLC: reference i</) ratio varies according to renal function. NonCKD (0.26-1.65).
CKD (0.37-3.1). HD (0.69-2.57), PD (032-2.35) (cjAsn z00a;311ea4l
UPEPIUIFE detects BJP
Cryoglobulin, RE C3, C4: HCV. SSA, SSB (Si6grens)
RF:ab against the IgG Fc portion: can be (+) in MG
Fat pad biopsy or aspiration: used for systemic amyloid diagnosis and typing. Fat
pad or other organ amyloid - proteinuria >0.5 g/d w/o other explanation (DM or
hypertension) is diagnostic for renal amyloidosis WW 2005;793191. Underutilized and
can obviate the need for invasive kidney biopsy (Mn ma z011:49s4s).
BM biopsy: evaluate lymphocyte or plasma cell clone. May detect amyloid.
Kidney biopsy: frequently only way to prove MG is responsible for kidney disease
Mass spectroscopy types amyloid from formalinfixed paraffinembedded specimen
Unnecasary if diagnosed as AL amyloid. MM.WM. or CLL and in AKI wl FLC >1S0 mg/dL
AL amyloidosis a/w factor X deficiency /factor X before biopsy (Biased 2001197218851
Pseudoabnormalities in lab: 1 Na. CI.Alb. BUN: T Ca: L or f Cr. CQ, po. (xi 20123116031
 LIGIIT CHAIN CAST NEVHNOrATHY (LCCN)
Tamm-Horsfall glycoprotein: synthesized at TAL. binds to LC to form LC cas:
aka myeloma kidney:>95% has MM, rarely CLL and B cell lymphocytosis
Urine dipstick (sensitive co albumin) protein discrepancy
Urine albumin/protein ratio: usually <10%,<25% sensitive and specific (qAsn 1011;7;19641
Not otherwise unexplained AKI with LC >150 mg/dL is diagnostic for LCCN: consider
kidney biopsy if <50 mgldL (Lam Omni 1014:15:eS38: Not no nqmmi 20111B:43)
Kidney biopsy: eosinophilic distal tubular easts with IF staining of associated Ig chain.
Local inflammation with giant cells
Tx: MM treatment. IV fluid: l LC concentration and correct hypercalcemia
PLEX: remove LC: didnt improve outcome (Ann :m z00s.143=177)
High cutoff HD: remove LC (c/i$~ zoom.74s);didnt ' HD dependence up z017=J1&20991.
Unavailable in the US.
L FLC is linearly a/w renal recovery:60% reduction by day 21 alw 80% renal function
recovery Pt survival is al renal recovery ()ASN 201l.Z2:11291.
Survival on dialysis: 16 mo; 28.9 mo in AL amyloidosis, 18.4 mo in MIDD (qASN 20161\1A31)

LIGHT CHAIN PROXir4AL TUBULOPATHY (LCPT) UASN 2016;2711555)

aka LC Fanconi syndrome; mlc cause of adult Fanconi; Fanconi in 38%
MM 25%. smoldering myeloma 15%. MGRS 53%. rarely B cell lymphoma or CLL
Biopsy: crystalline or noncrystalline inclusions of LC in proximal tubular cells

CRYSTALGLOBULINEMIA (ISSN 2015:16:515)

Monoelonal crystals in vessels or glomeruli; kidney infarction
Painful purpuric nonblanching rash (occlusive vasculoparhy), corneal. BM deposition
LM: inrracapillary crystals; IF: monoclonal Ig: EM: parallel linear array

MONOCLONAL Im4ur4ocLosuun Dsposmon DisEAss (MIDD)

LC >> LHC, HC. I( > J.; M protein 90-97%, MM 34-59% (qAsn zo1r7.zJ1;el¢¢az019.ms1¢)
NS. CKD; heart. liver involvement: low complement level in HCDD
LM: nodular mesangial sclerosis. MPGN
IF: diffuse linear GBM,TBM.and mesangial monoclonal LC or HC
EM: unorganized (nonfibrillary).finely granular powderylpuncure EDD
Tx: borzezomibbased regimen. melphalanconditioned autoHSCT (Aland 2015;126:2a0$)
Hematologic response was alw good renal out:ome
Txp: no recurrence with sustained remission (Bland 2015:126;2805)
Prognosis: pt and renal survival MIDD > MIDD + LCCN - LCCN; 33% ESRD. 29%
death after 4 yr up* lyvnghamu 2015;563357)

PGNMID (1ASN 20o9;zoz0ss)

Proliferative GN w/ monoclonal immunoglobulin depositszglomerular injury related
to monoclonal Ig deposition that cannot be assigned to any other conditions
lgG3 >> G1 > G2 >> G4. s: > 1.: IgA In z0 n:91no). IgM (WM) who 201$;66:756)
Monoclonal protein in -3094: BM clone -3098: hematologic malignancy $-3574; can
develop during f/u; 22% progressed to ESRD
LM/IF: endocapillary or mesangial proliferative GN. MPGN (lgG3) > MN (lgGl) (QASN
2011:6:1A09>. EM: mesangial and subendothelial deposits
Tx: clonedirected therapy: B cell lymphoma treatment (eg. RTX + prednisone) for B
cell clone. MM treatment (eg, CyBorD) for plasma cell clone (Vu 2018;94:1991
Transplantation
Monoclonal protein (+) 4/11 of recurnm MPGN vs 2/15 nonrecurrence (no 20 m77:n1)
Recur w/ same IgG deposition w/ native PGNMID wlo monoclonal protein (cum wnmzzl
Recurrence caused graft failure in 11/25 (44%) during7yr flu (KA 2018:94159)
Filgrasdm (GCSF)induced crescenzic RPGN (}ASN z016227:1911)

RENAL LESIONS WITHOUT MONOCLONAL IMMUNOGLOBULIN DEPOSITION

TMA with MG (au 201791690
Direct or indirect endothelial injury by monoclonal protein
13.7% ofT MA patients had MG: 21% in z 50 y/o.x5
50% progressed no ESRD vs 33% TMA lo MG
coG with MG (awe 1011.129 14m
IgG x (71%) > IgG 7. (2278); MGRS (60%).smoldering MM (3094). symptomatic MM (4%)
Renal survival was worse in C3G 250 lo w/ MG than w/o MG
Bortezomibbased regimen induced hematologic response:A/w better renal outcome

GENERAL MANAGEMENT
Fluid: imporvznt in T Ca.volume depletion. and LC cast nephropathy
BP: /orthoslasis in AL amyloidosis. Avoid overdiuresis and ablockers. Consider
midodrine.
RAAS blockade: little evidence supports its use for albuminuria
Clonedirecred therapy may improve renal prognosis. No RCI AutoHSCT in eligible
PLS Nauru 2018:122:3583).
Plasma Cell Directed Treatments
Cyclophospharnide Requires adjustment based on renal function
s/e: hemorrhagic cysnius (give with MESNA). SIADH
Bortezomib (V) No renal dosing, require HZV prophylaxis
s/e:TMA Mph AKI wH n16=91:EJ4s). peripheral neuropathy.
thrombocytopenia
Lenalidomide (R) CrCI >50: 25 mg qd 30-50: 10 mg qd <30: 15 mg q48h
ESRD: 5 mg qd after HD
sle: birdl defects. rash. myelosuppnession
Dexamethasone (D) No renal dosing
Melphalan High dose: 100-200 mg/mzaszandard dose: 10 mg/m'
CrCI 10-50: 75% <10: 5096: HD: administer after HD PD: 50%
CRRT:75%

HEMATOPOIETIC STEM CELL TRANSPLANTATION

Background
Hematopoietic stem cell uansplanmtion (HSCT) is classified into autologous HSCT
(autoHSCT) and allogenic HSCT (altoHSCT) by donor type
All autoHSCT requires myeloabladve regimen to replace abnormal replace hemato
poietic system. AlloHSCT can be done with myeloabladye (causing pancytopenia).
reduced intensity.or nonmyeloablative (lymphopenia w/o significant cytopenia) regimen
AKI
Mortality of pa with AKI requiring dialysis 83% In 2o0s;s7:1wa)
AKI and mortality decreasing; Cr x2 50 -» 33%, x3 18 -» 10%. dialysis 8 - 5% from
reduced intensity of conditioning regimen. reduced hepatic SOS. seven GVHD. iniecdon.
amphotericin use (num 20i0;363:2091)
CKD
CKD3-5 after myeloablanive altoHSCT 17%: ESRD 4% (nor z01o,zs 278)
Risk factors: hlo AKI. GVHD. 245 ylo. baseline eGFR <90. HTN. highdose TBI In£iM
1016:374:2}56)
CKD risk was similar in reducedintensity and myeloablazhre doHSCT (as/wr 2UOS.14.6$8)
All renal biopsy: MN (36%) >TMA (21%) > MCD (12%) lAvA»~¢¢ Pau1¢120I4:2I:330)
Types of HSCT and Associated Complications
TAutologous Allogenic Allogenic
Myeloablative Myeloablative Nonmyeloablative
Indications MM.AL amyloidosis. Leukemia. lymphoma. MDS. aplasdc anemia.
WM.AML. sickle cell anemia
lymphoma
AKI + 44+ 4+
sos 4+ +44

Causes of AKI Hyporension, volume depletion. sepsis.TLS,TATMA. drugs

Typespecific causes TAutologous GVHD CNI zoxidcy, acuze GVHD
of AKI
Causes of CKD Chronic GVHD. MN. CNI :oxiciry
TAutologous GVHD (One Type of Engraftment Syndrome)
Within days of neutrophil engraftment in autoHSCT. usually 8-20 d after HSCT
Fever. rash. pulmonary edema, weight gain. capillary leak
Biopsy of involved organ: skin. colon: mononuclear cell infiltrates
AKI Is common; 28% required dialysis. 72% recovered (Am) Hfnwwl 2011;87=511
Tx: IV corticosteroid (BSMT 2015:11:2061)

SinusoioAL OBSTRUCTION SYNDROME (SOS)NENOOCCLUSIVE DlssAse

Risk factors: myeloablation (busulfan. cyclophosphamide. and TBI). preexisting liver
disease. age. specific treatment (eg. gemtuzumab. ozogamicin) 4aam12016124001
Less common with less intensity conditioning
Pathopmiology: thrombosis. sinusoidal obstruction. portal HTN. microvascular
intrahepatic portosystemic shunting
Clinical presentation: hepatorenal syndrome (t bilirubin, ASK ALT. PI 1 urine sodium),
hepatomegaly. fluid retention. weight gain
Doppler U/S: reversal of portal vein How
Tx: defibrotide
TransplantAssociated Thrombotic Microangiopathy (TATMA) lamr 201s:s::119)
30-35% of alloHscT;45% of all biopsy proven TATMA was autoHSCT mum iiiuiii
z014,z 1.as01. a/w high morality.
Risk factors: GVHD. HLA mismatch. highdose TBI. CNI. genetic (Blow 201s=117=9891
Clinical manifestation:AKI. proteinuria. edema. HTN
Arteriolar C4d deposition (Transpkniauan 20131962zm
TX: conservative. eculizumab (riunqiimpow so 2016Z54:1B1). rltuximab
Other Causes of Renal Dysfunction
Recurrent hematologic disease associated (amyloidosis. MIDD). lymphoma infiltration
Pigment nephropathy from ABO incompatible HSCT; BKV nephropathy (nor 2013:ze:6z0)
Nephrotic Syndrome After AlloHSCT lumr z016=n297s>
MN (6$.S%): PLAZR Ab (+) is rare > MCD (19%) > FSGS (7.7%)
87% was a/w acute or chronic GVHD:often a/w immunosuppression reduction
Tx. reinidation of immunosuppression. rituximab
Renal Transplantation
Kidney from HSCT donor or combined txp (NEW 20G8;358:362) may allow iS dlc

ONCOLOGY
Tur4oR Lvsis SvnonomE (TLS)
Background and Pathogenesis
Spontaneous vs induced wmor cell lysine by cytotoxic therapy (chemodlelapy;Ab therapy
or radiotherapy)-> Release of intracellular electrolytes (K and Phos) and nuclei acid
Nucleic acid is metabolized as below by xanzhine oxidase (XO) and orate oxidase (UO)

Water solubilityc xamhine < uric acid < allantoin

UA: precipitation in the distal par! of the renal tubules in acidic urine (acute UA
nephropathy), renal vasoconstriction
Hyperphosphatemia: calcium phosphate (CaP) deposition in the renal tubules (alw
hypocalcemia); the deposition starts when Ca x P >60 mg*1aL'
Xanthinuria: XOl used for TLS prophylaxis can cause accumulation of xanthippe ->
Xanthine stone. Xandiine nephropathy (cum, an 19B1:412273)
CairoBishop Definition ofTLS we 2004.1z7s)
Laboratory TlS:2 or more lab changes within 3 d before or 7 d after cytotoxic therapy
UA 28: K 26; P a4.S: Ca 57 or any change 225%
ClinicaITLS: laboratory TLS +AKl. cardiac arrhythmlalsudden death or a seizure
Risk Assessment U a- anal 2uue.zs:z1s7l
Risk Factors of TLS
PatientRelated TumorRelated
Precreaunenr UA >7.5 High tumor cell proliferation rate
CKD Chemosensilivizy of :he malignancy
Volume depletion Solid tumors: rare: mainly when tumor diameter is >10 cm
Acidic urine Hematologic
WBC >50K:Aggressive NHL;ALL: Burkitt lymphoma/leukemia
Veneroclax for CLL; Obinutuzurnab for diffuse large Bcell
lymphoma: Dinacidib/Alvccidib for ALL or AML

TLS Risk Stratification lqu mo,\4ms1s)

High risk (>5%)
Prophylaxis IV fluid v rasburicase
AML WBC > 100K
Burkina lymphomailleukemia. Burkitt leukemia
lymphoblastic lymphoma Stage IIL IV lymphoma
LDH 2 2X ULN
ALL WBC > 100K
LDH 2 2X ULN
CLL
Adult Ttell lymphoma. Aduk bulky, LDH > ULN
DLBCL. peripheral Tcell, Child $Ug€ 11IIN LDH z 2X
transformed or mantle cell ULN
lymphoma
Others Intermediate risk renal
dysfunction.T UA. K
or P04
Inter mediate r isk ( 1- 594)
IV fluid allcpurinol
WBC 25-100K
LDH 2 ZX ULN
Early stage lymphoma + LDH
<2X ULN
All others
Fludarabine. rituximab
WBC > 50K
Adult nonbulky LDH >
ULN
Child stage lllllv. LDH < 2X
ULN
Child anapestic large cell
lymphoma lllllv
Lymphoma I leukemia +
renal dysfunction
Some solid tumors*

Treatment
IV fluid to maintain UOP 80 to 100 mum': lurosemide only for hypervolemia
Urinary alkalinization no longer muzindy recommended! Ca? deposidon.Could consider
initially in padenzs with lvypenlricemia w/o hyperphosphatemia (et. spontaneous TLC)
Blockers of UA formation through XO inhibition: allopurinol or Febuxosran Used
mainly when UA is still <8.Allopurinol 100 mg/m' qBhr.
Metabolism of UA Lo allantoin (water soluble) using exogenous UO: rasburicase
0.2 mg/kg once daily for 5-7 d or 3 mg daily (/G6PD activity)
Sle of rasburiase anaphylaxis widl repeated courses. mezhemaglobinemia in G6PD def
RRT if Ca x P 270 mg'/dL2;AKl with elecuolyres imbalances or hypervolemia

CHEMOTHERAPY
Background
In oncology patients. GFR estimation using BSAadjusted CKDEPI is accurate for
medication dosage. MDRD tends to underestimate GFR (j au- ami 2017;35:2798)
Nephrotoxicity is potentiated with: volume depledon.usage of other nephrotoxic agents.
obstructive uropathy
5yr incidence of AKI in cancer patients receiving systemic therapy: multiple myeloma
(2694). bladder (1996). leukemia (15.4%) u~c» zo18 m1o 304231601
Cisplatin
Mechanisms: organic cation uansponer2 (OCT2) mediated cellular toxicity primarily
of :he $3 seg of the proximal tubule.vasocons:ric¢ion, proinflammatory effect
Progressive AKI. hypomagnesemia, salt wasting, Fanconilike syndrome.TMA (when
combined with neomycin or gemcitabine). anemia secondary [O epo deficiency
AKI is dose dependent. nonoliguric
4, Dose: 25% for CrCl 46-60: 50% for CrCI 31-45 (Can¢efTnalRev 1995;21;J3)
 Agents to decrease toxicity: (1) amifosdne (organic thiophosphate): concerns about
possible interference with :he antitumor efficacy of cisplatin: (2) sodium lzhiosulfate for
prevention of systemic toxicity of intraperitoneal cisplatin

I f o s f a mi d e
The metabolite chloroaceizldehyde is directly toxic to the tubular cells
The metabolite atrolein causes hemorrhagic cysUtis (ifosfamide and cyclophosphamide)
Partial or complete pRTA/Fanconi: hypophosphatemia.glucosuria. bicarbonaturia.
aminoaciduria. tubular proteinuria (T beta2microglobulin excretion). K wasting
d RTA. n e p h ro g e n ic DI
The cumulative dose (>60 x/m'). nephrectomy and concomiuint dspladn T nephrotoxicity
Me t h o t r e xa t e ( MT X)
Precipitate in acidic urine for high doses MTX: transient afferent arteriolar constriction
Preventlon:50% of dose in CrCI 10-50 and avoid in CrCI <10; avoid drugs inhibiting
MTX clearance via OAT1/3: unSAIDs. PCN. salicylates, probenecid.gem8brozil.TMPSMZ,
N fluid: Urinary alkalinization (target pH 27) before starting infusions; leucovorin
Leucovorin: reduced form of folic acid; competitive inhibitor of MTX
Leucoworln Dose Based on Serial Serum Methotrexate Levels and AKI
MT X L e v e l Al te r
Condi ti on Adm i ni s tr a ti on Le uc ov orin Dos e
Normal elimination 101ll*1 as 24 hr.1 pM at 48 hn PO. IM. IV: 15 mg q6h x10 beginning
and <01 lIM as 72 hr 24 hr after die sun of infusion
Delayed late >0.2 l,iM at 72 hr and >0.05 pM Continue 15 mg (oral, IM or IV)
elimination as 96 hr q6h until <0.05 pM
Delayed early 250 uM at 24 hr. or 25 pM as 150 mg N q3h until <1 .uM.then
elimination and/ 48 hr. or a doubling of 15 mg q3h until <0.05 l,IM
or AKI serum creatinine at 24 hr

Glucarpidase metabolizes folic acid: used in patients with AKI leading to delayed MTX
elimination co decrease systemic toxicity
HD: limited utility due to the high volume of distribution of MTX leading to rebound

Pa thoge nesis and Clinical .

Me di c a ti on P re s e nta tion P re v e ntion a nd The ra py
P la tinum
CarboplaUn Less AKIIATN than Cisplatin Calves formula* to estimate
. Mg: Sal: wasting the dose
Cisplatin AKI. RTA, L Mg IV fluid, lower dose. amifostine
TMA (combination with
neomycin or gemciubine)
Oxalipladn Rare ATN No adjustment for GFR >20
Alk y la ting Age nts
Cyclophosphamide SIADH with high IV dose Dose reduction far CKD
Hemorrhagic cysrkis IV fluid. MESNA
Nitrosoureas Chronic interstitial nephritis Delayed noxicizy (onset several
(carmustine. (aikylalion of tubular cell mo or yr :her stopping :he
Iomustine, proteins - Glomerular medication)
semusline) sclerosis. interstitial fibrosis) Forced diuresis
Slreproxocin Chronic inzerszicial nephritis Forced diuresis
Proteinuria (65-75%)
Proximal tubular damage
Ifosfamide pRTA, dRTA IV fluid, Nacerykysreine.
Nephrogenic DI (polyuria) MESNA
Hemorrhagic cysriiis Toxicity can be delayed
O the rs
Minomycin C TM/N cumulative dose
dependent. delayed clinical
onset (few mo)
Mezhozrexare Inkarubular deposition of IV fluid
(h ig h d o se 1 -1 5 a m') crystals Urine alkzlinization (keep urine
SIADH pH 27.0)
Gerncitabine Cumulative dose dependent
TMA
 Cabazicaxel AKI . hemor r hagi c cysti ti s

Lenal i domi de AI N
I nter fer on Pr otei nur i a (MCD, FSGS)
TMA ( m os dy w i t h CML) . ATN
Al l tr ans r eti noi c aci d Capi l l ar y l eak wl edema.
( ATRA) . I L2 wei gh: gai n and AKI . Aka
"di ffer enl i adon syndr ome"
I n ATRA

BIOLOGIC AGENTS
Bevacizumab
Risk factors for sle: CKD. renal cell carcinoma
Usually mild asymptomatic proteinuria; only 2-6% develops nephrodc range proteinurla
Histology<TMA: local binding of :he podocyteproduced VEGF leading to aVEGFR
medicated glomerular endothelial damage (NEW 100e;3$*r205)
HTN wfl days of starting the dierapln the mechanism of HTN seems to be independent
from the proteinuria (T peripheral resistance; i Na excretion: .L NO production;
1 Endothelin1)
Rapidly of the HTN onset depend on the potency of the VEGF inhibitor
HTN is a surrogate for anticancer efficacy
TMA rare. reversible in most cases after stopping the drug. Eculizumab is a potential
therapy for persistent TMA
PathogeneslslClinic.l
Medication Presentation Prevention and Therapy
VEGF Pathway Blockers
AntlVEGE bevacizumab. Proteinuria. ns. HTN.TMA. Proleinuria monitoring
afiibertept reversible posterior Hold for U,..,. >2 old
leukoencephalopathy Discontinue for NS
(RPLS)
AKI with sunitinib or
sorafenib
Tyrosine kinase inhibitors:
axitinib. pazopanib,
sorafenib, sunitinib
An ti EGFR
Cetuximab. panitumumab. Hypomagnesemia dl: wasting. Reversible after stopping the
necitumumab, matuzumab (sunnite of better therapy
outcome) - i Ca. K
Others
Rituximb (antiCD20) TLS.PRES
Bosutinib AKI. CKD Monitor kidney function
Crrzotinib AKI Monitor kidney function
(first few weeks)
Ibnninlb AKI Oni fluid
Vemurafenib and dabrafenib AKIICKD (mainly with
Vernurafenib)
Ch¢CIQQint inhibitors: AIN (Immunenelated Prednisone
PD1 (pembrolizumab. adverse effects) The medication can be
nivolumab) resumed after prednisone
PDL1 (atezolizumab. therapy
avelumab. duryalumab)
AntiCTLA4 (ipilimumab.*
tremelimumab)
Epacadostat
lpiliinumah camblned will anocher checkpoint inhlbhors like niwaklmab (andPD1Ab) induces AIN wish
aggressive inilzruion of cytaloadc l1¢dI;:he1py requires camhlnadon on sword and/or MMF (KI 2016:9&63€).
 ELECTROLYTES AND Acne-BAs£ IHBALANCES

Hyponatnemla
Pseudohyponarremia Paraproreinemia
Tumorinduced SIADH Small cell carcinoma of the lung and other organ, Head
and neck cancer
Therapyinduced SIADH Cyclophosphamide, ifosfamide: occurs and resolves within
24 hr of drug discontinuation
Melphalan, Vina alkaloids (Vincnisdne. vinblasdne. vinovellaine).
Methotrexate
Therapyinduced sak wasting Cisplatin. carbopla:in: Sal:wasting through direct tubular
damage mainly the loop of Henle
I lyp e ma t n e mla
Nephrogenic DI ifosfamide
Hypokalemla
Pseudohypokalemia Leukocytosis
Tumor related ACTH secreting tumor: SCLC. thymus or bronchial
carcinoid. thyroid medullary carcinoma, or
neuroendocrine tumors
AML (M4 and M5): lysozymemediued tubular Injury
Leukemia blast crisis: cell build up
Light chain proximal rubulopadiy (LCPT) In monoclonal
gammopathy
Therapyrelated GMCSEVit B12: cell buildup
Hypomagnesemia
Therapyrelated wasting Cisplatin
AntiEGFR inhibitors (ceruximab and paniv.umumab)
disrupt TRPm6medicazed distal reabsorprion of Mg
Hyper calcemla
Humeral PTHrp: squamous cell carcinoma (lung. head and neck),
renal cell, ovarian. breast. and esophageal cancers
1,25(OH)1Vit D: lymphoma, dysgerminoma
PTH (rare): parathyroid, lung (small. squamous cell). d thyroid
papillary carcinoma, ovarian cancer
Oszeolytic tumor Osceosarcoma, MM. solid (breast) cancer with osceolydc
metastasis
Hypophosphatemia
Proxima! tubulopachy Ifosfamide, cispkzin, imacinib
Tumorinduced osteomalacia FGF23 is release by the rumor (hemangicpelicy\omas.gam
cell tumors. and osteoblastamas) .I ding to phosphamria
Metabolic Acidosis
AGMA Lactic acidosis: leukemia, lymphoma,Warburg effect
pRTA (NAGMA. glycosuria. lfosfamide: NDI and dRTA can accompany
aminoaciduria.. K. POW) Cisplatin
Lich: chain proximal tubulopazhy (LCPT) in monoclonal
gammopamhy
dRTA lfosfamide
 INFECTIOUS DISEASES
SsrslsAssoclATsn AKI
AKI is common In sepsis. and incidence increases with higher severity of sepsis (>50%
in patients with septic shock) llnlj infer m 1009;13:176)
AKI typically occurs early in clinical course (often wu first 24 hr of presentation)
UASN 1003;14;1021) and is a/w T morality. although outcomes are improving over time
(A]KD201§.65:B70l
Although septic AKI is alw T morality and T length of hospitalization dt nonseptic
AKI lm Care zooe.1 zR4n, it may carry better renal recovery prognosis in survivors
(qA§N2007:2:431)
Pathogenesis and Workup
AKI results from both impaired glomerular filtration and lobular dysfunction
l RBF only if L cardiac output. otherwise T or normal Lon can 200591R363)
Altered intrarenal blood flow and microcirculatory changes can lead to J. glomerular
capillary pressure independent of RBF 1 GFR (lu 2017;91:45)
Systemic inflammatory response syndrome. tissue hypoxia. 1 perfusion -v tubular cell
apoptosis/necrosis
FEn, >1% and "muddy brown" ass on microscopic sediment
Prevention and Management
Although maintenance of MAP to preserve renal perfusion pressure is key. no advan
tage to raising MAP about 65-70. except in subset of patients with chronic HTN
(NEW2014:310:1S83)
Use of dopamine to increase RBF does not reliably protect against AKI
Prophylaetic fenoldopam results in smaller T SCr. but not 1 mortality
Aggressive IVF is alw inferior outcomes (Ki 200~m:4z2) and conservative fluid administra
tion strategy after initial resuscitation may be renoprotectiwe (umune Cnem¢4 z01e42.1 a9s1
Balanced cryszalloids may provide marginally better renal outcomes compared to NS in
critically ill adults (NS has supraphysiologic chloride concentration). although benefit for
balanced crystalloids is small (major adverse kidney event [death, new RRT. or persistent
renal dysfunction] 14.3% for LRldasmalyte vs 15.4% for NS. p = 0.04: no difference in
need for new RRT or persistent kidney dysfunction) SMART new zoiaanxzvy
Artificial colloids (eg, HES) ahv tAKl and T mortality: should be avoided (NEW 10113611141
No evidence to support highvolume hemohltration to clear inflammatory mediators
(lnleidne Care m¢420138911535)

Ideal timing of RRT initiation is controversial: early initiation does no: appear to provide
increased survival or better renal outcomes in septic critically ill patients with AKI
In patients Who require RRT, d\ere is no benefit to highdose RRT over lowdose RRI
and efliuent flow rare of 20-25 mUkglhr is considered sufficient (Table)
. Consider higher-dose RRT if refractory acidosis or hyperkalemia
Key Cllnlcd Trials Regarding RRT Management
Study Companson Primary Out come Fi n d i n g s

A TN Hi g h i n t e n si t y RRT 6 0 d mo r a l i t y No dif f erence in

(NEW z0a855mn ( 6 xl wk HD o r morlaliry. RRT
CWHDF wi t h dependence.
3 5 mUkg l h r e f f l u e n t ) organ f ailure
vs l o wi n r e n si cy RRT
( HD 3 x/ wk o r
CWHDF wi t h
2 0 mUkg l h r e l l i u e n z)
RE NA L CWHDF wi t h e f f l u e n t 9 0 d mo r t a l i t y No dif f erence in
(NEW 2wt u1=1sz1) f l o w 4 0 vs 2 5 mUkg l h r mo r t a l i t y RRT
d e p e n d e n ce .
lengt h of
h o sp i za l i u zi o n

2o\
I VOI REx; ». 1sss) Hi g h vo l u me HF vs 2 8 d mo r za l i r y No d i f f e r e n ce i n
(lnwnne Cure m¢4 st andard HF in mo r a l i t y.
crit ically ill pat ient s h e mo d yn a mi cs
wi sh se p t i c sh o ck a n d
AKI
 ELAIN Early vs late RRT 90d mortality Early RRT 1
(lW* N16;3I§2190) inidadon in critically mor:ali:y.l RRT
ill pazienrs with stage durazion.l length
2-3 AKI (primarily of hospitalization
surgical patients) Extended followup:
early RRT L
mortality and T
renal recovery
ax 1 yr UAW
m1nm01 n
AKIKI Early vs lane RRT 60d monalicy No differences in
INEJM 2016z375:\21) inidacion In critically mortality, RRT
ill pazienu with stage dependence.
3 AKI (80% patients length of
had sepsis) hospinlizadon
IDEALICU Early ys lace RRT 90d mortality Stopped orly: no
wire 20IB:J7%I431) initiation in early difference in
septic shock and mortality, ICU
failurestage AKl by days. vent d.
RIFLE criteria Delayed -» L RRT
time

A N T I MI C R O B I A L S

An ti b i o ti c D o si n g i n AKI
Patients with AKI display variable alterations in antibiotic pharmacokinetics. so close
drug monitoring is required to ensure drug efficacy while avoiding increased drug
toxicity (Cm Can an 1006;211255)
Intravenous route is preferred due to variability in oral drug absorption
Although some antibiotics will experience i clearance in AKI. thirdspacing of
fluids. hyperyolemia.and 1 drugprotein binding can T volume of distribution
-» t dose needed to reach therapeutic drug level (Cm Care Med 2009;37a40)
Early renal recovery can lead to underdosing dlt T renal drug clearance
In patients requiring CRRT. antibiotic clearance is highly variable concur z01s;19:a4).and
suggested dosing may be inappropriate due to (Nat RevNephlul 20l 1:7226)2
. Heterogeneity in extraction coefficient: due to variable drugprotein binding
Mode of clearance (hemodialysis vs hemoliltration vs hemodiafiltration): convective
methods increase clearance of larger solutes
Filter adsorption differs based on filter composition
Variability in dialysis dose delivered: dosing recommendations are based on stan
dardized dialysis dose. but there is practice pattern variation in CRRT dosing; in
addition. only 68% of patients receive prescribed dose of dialysis
Consider antibiotic characteristics P
w
Concentrationdependent antibiotics (C) require high peak levels: may require U
increased dose due to factors above. and avoid RRT immediately after dosing
Timedependent antibiotics (T) require prolonged time above MIC: consider
prolonged intermittent antibiotic infusions or continuous infusions
Pharmacodynamic Profile and CRRT Monitoring ofAntlblodcs
Drug CRRT Monitor ing/Consider ations
Vancomycin (T) Daily serum concentration. redose for level <15 mg/L
Continuous infusion may be superior in CRRT UA¢lun¢mb Oianadnf
2013;6828$9)
Linezolid (T) No established drug level monitoring parameters. although there is
large variability in pharmacokinetics in patients receiving CRRT
(Imnmnu aienavw z016:11:4a4)
Daptomycln (C) Although trough concentrations correlate with peak levels, not
routinely checked, as adequate peak levels achieved MM 8 mg/kg
q4Bhr Lou Cae Me4 201 189119)
Increase serum CK monitoring frequency (institutiondependent)
Cehzroline (T) No data available
Tigecycline (C) Nonrenal elimination. poorly dialyzed. No adlustrnencs required U a»
Mdm1¢¢=IN1M2:l3N1
Piperacillin No puri ne drug level monitoring. Higher doses (12 g/d) associated
mobamm m with achieving drug targets, and extended infusion preferred
regardless of dose (qAs~ 1016;1 l:\)I7l
Cefepime (T) No routine drug level monitoring, although variability in pharmacddneiics
in pacienvs on CRRT u~vw»w==»~~»= z0\s;4ew1>l results in risk of
undeureazing inlecdon or risk d neurologic side effec is
Cefnzidime Limited day (case report) lA»uwvuA¢¢m Oumiam 2017.6l:100164)
Avibaczam (T)
Meropenem (T) No routine drug level monitoring. Consider loading dose prior to
dose reduction for CRRT given pharmacokinetic variability um I
Kldy Dx 10 I4:63(1):1701)
Gentamicin (C) Peak drug level monitoring 30 min after dose delivery (goal 6-8 kg/mL
or 8-10 kg/mL depending on severity of sepsis) and redose when
level <2 kg/mL (or <3 kg/mL depending on institution and severity
of sepsis) (J avow 2012;24:107)
Amikzcin (C) High loading initial dose (225 mglkg) preferred.with peak drug level
monitoring (xo adjust dose) and extended dosing interval (goal
trough <2.5) (Minden We oieniiim 10164049011
Polymyxin B (C) No routine drug level monitoring. No dose adjustment needed for
patients on CRRT 4/umienb Oimain 2013:681674)
Coliszin (C) No routine drug level monitoring. Potential role of loading dose (in)
Annrmcwb IB 10\5:4&337)
Tobramycin (C) Peak drug level monitoring 30 min alter dose delivery (goal 6-8 purL
or 8-10 pglmL depending on severity of sepsis) and redose when
level <1 kg/mL (or <2 kg/mL depending on insdtudon and severky
of sepsis)
Ciprofloxacin (C) No routine drug level monitoring. Given reliance on achieving desired
AUC/MIC ratio for elhcacy. consider exceeding recommended dose
in severe infection (can nm of 2005;41;\159)

Rend Complications of Antimicrobials

Risk factors of antibioticrelated AKI: CKD. DM.advanced age. other nephrotoxins
Direct tubular toxicity (ATN) is most common mechanism of injury
Crystal formation (sulfa.acyclovir) more likely to occur in volume depletion
Acute interstitial nephritis can complicate therapy with any antibiotic. but commonly
widi penicillin antibiotics or fluoroquinolones. Classic AIN triad of "rash, even and
pyuria" occurs only in the minority. Need high index of suspicion or kidney biopsy.
Dlactic acidosis due to bacterial overgrowth of acidproducing enteric bacteria 4
anion gap metabolic acidosis
AntibioticAssociated Renal Toxicity (num lu ~=»~w auovsnsal
DruglCIass N ephr otoxicity
Trimethoprim AIN: ENaC inhibition o hyperkalemia. volume depletion induced
Sulfamethoxazole hyponatremia WKD zoixsziissi
Trimethoprim . tubular Cr secretion 4 T SCr wlo AGFR
Amphoterlcln B ATN: L Aquaporin 2 - hypernatremia (nephrugenic DI)
T Membrane permeability to cations -» hypokalemia.
hypomagnesemia. nephrogenic DI. distal RTA
Aminoglycosides L Microsomal protein synthesis, mitochondrial injury (especially in
proximal tubule) » ATN. L K. POW. L Mg. Fanconi syndrome
luiiiwaia we Glanulliet 1999;431003)
t CaSR -» Bartterlike syndrome (L K. metabolic alkalosis)
Linezolid Mitochondrial toxicity » lactic acidosis INfJM 1005.35323051
Tetracyclines Proximal tubule ribosome injury v Fanconi syndrome
Lactic acidosis
Penicillins t 5oxoproline, pyroglutamate o anion gap metabolic acidosis
AIN: penicillins and other BIactams can provoke allergy
Fluoroquinolones AIN: crystal nephropathy (Ciprofloxacin)
Vancomycin Cellular uptake ATN
Vancomycin cast formation -» ATN UASN 201723:111!I
Polymyxin B Tubular cell apoptosis -»ATN
Daptomycin Rhabdomyolysis: possibly via plasma membrane disruption (mvw cur
on Gunn 2010c46.613) »» ATN
 Antibiotic Toxicity if Inappropriately Dosed for Renal Function
DruglCIass Toxicity in Renal Failure
BIactams Neurotoxicicyn encephalopathy seizures
Aminoglycosiries Ozoroxiciqn AKI
Vancomycin AKI

HUMAN IMMUNODEFICIENCY VIRUS (HIV)

Prevalence: 38.8 million worldwide and 833.000 in the US (wu HIV 20 1s,3.¢z611
HIV causes primary kidney diseases and is also a risk factor for progression [O ESRD
AKl is common in HIVinfected patients (sepsis.ARVtoxicity) was 201$:29;1061)
Glomerular diseases may result from direct infection of podocytes causing HlV
associated nephropathy (HIVAN). immune complexmediated glomerular disease and
endothelial inlury causing thrombotic microangiopathy (TMA) (not Rev n°p"iu z01s;\1:1S0)
Incidence of HIVAN decreasing with widespread use ofAR11 although prevalence is
increasing as patients live longer (1ASN 2005,16:241z1.The incidence of FSGS increasing
in such patients (NDT 2011:27:2349)
Increasing survival of HIVinfected patients leading to rise in CKD from other
comorbidities (DM and HTN) found in HIVinfected patients and ART nephrotoxicity
W o r ku p a n d E va l u a t i o n
Recent HIV diagnosis (HIVAN) vs chronic HN (immune complexmediated GN)
Rate of GFR decline: rapid (HIVAN) vs subacute (immune complexmediated GN)
Risk factors: HCV coinfection. high viral load
Workup HIV activity (CD4 count. viral load), Ula, proteinuria quantification
Fanconi syndrome (glycosuria without hyperglycemia, NAGMA, hyperphosphaturia):
drug toxicity especially tenofovir disoproxil fumarate (TDF)
Kidney biopsy. recommended for suspected TMA. nephrotic proteinuria. or atypical
presentations of other renal lesions (typically does not change management)

HIVASSOCIATEO GLOMERULAR Dis£AsE

- Glomerular Diseases Associated With HIV

I mmu n e Co mp le x
HI V A N Me d ia t e d G N TMA
Risk factors Advanced HIV. Black Variable stage of HIV Advanced HIV
race/APOL1 we 101358115141 ($Om4Iln\murlnl
genotype No racial predilection 2UUM8L3JTI
(MSN 2011:17;1\29)
Clinical findings NS.fast GFR decline. GN (p ro te in u ria . 1 pit. MAHA (often nl
large echogenic hematuria). low ADAMTS13)
kidneys on UIS complement
Collapsing FSGS. I mmu n e co mp le x G N Thrombosis. Ischanlc
Be vw
microcystic tubular (variable: lupuslike. glomeruli and
dilation, tubulitis Ig o r. MP GN. IRGN. tubules. RBC
TRls (IFN fo o tp rin t) MN, ITGN, FGN) fragments
Treatment ART, RAASi. GC for A RT » l- GC PLEX and CS if low
rapid progression ADAMTS1 3 ,ART
Prognosis Poor widiout ARV No n lg A N fo rms h a ve Mixed
better outcome
than loAn. HIVAN
(NDT 2016;31:Z099}

The :erm HIVassociated immunecomplex kidney disease (HIVICK) is not recom

mended for its heterogeneous disease spectrum and potential nonHIV reversible
causes [KDIGO KI 101B9]:54$)
 HIVAssoclATeo TUBULOINTERSTITIAL DlseAss
11-26% of kidney biopsies from HIVinfected patients show mbuloinzerstirial disease
ac/Asn 10105179812013;8:930). Of diese:
70% have a second major diagnosis. M of AIr attributable to drugs
Hematologic (je, lymphoma) and infectious (TB. MAI) etiologies should be considered
Immune Reconstitution Inflammatory Syndrome (IRIS) 1s¢~-~~~=i~~ zooaamsssm
Systemic inflammatory response that typically occurs in setting of ART initiation early
in course of opportunistic disease (and severe immunocompromised)
Kidney Bx: granulomatous inflammation
Tx: steroids
Diffuse Infiltrative Lymphocytosis Syndrome (DILS) In 1007711191
Multiorgan lymphocyte infiltration that occurs in xetdng of uncontrolled HIV infection:
commonly affects salivary gland .
Kidney Bx: CD8+ lymphocytic infiltration
Tx;AR1Z steroids

Anvenss RENAL EFF£CTS oF ART

Small T Cr w/o true renal dysluncuon dl: L tubular cr secretion: dolutegravir
(integrase and OCT2 inhibitor) up an nwmmi 201J:7ss90). cobiciscat (CYP3A4
and MATE inhibitor) UAIDS 20 izs1:32). T Cr >0.4 should be evaluated for its fuse
(NIH hapsl/aidsinlo.nlh¢ovI).
Nucleoside/tide reverse cranscripase inhibitors (NRTIs) stavudine and didanosine may
cause lactic acidosis and rhabdomyolysis. Rarely used in developed world.
Proximal Tubulopathy
Tenofovir disoproxil fumarate (TDF) and Adefoyir inhibit mitochondrial DNA
7polymerase and fuse renal tubular mitochondrial toxicity and Fanconi syndrome.
TDF is most common cause of Fanconi syndrome.
Secreted by OAT1 (basolateral) and MRP4 (apical) in the PT (Lab :in z011:91=ssz>
Lab: L PO¢.glucosuria,aminoaciduria. nonalbumin proteinuria was 20151z9194n
Kidney Bx: tubular damage; EM w/ change in mitochondrial shape. enlargement, or
depletion
TDF causes osteopenia d/t hypophosphatemia. 1 1ahydroxylase activity, and loss of
vitamin D binding protein in urine
Early detection and dlc may prevent further decline of renal function U10 2011107113591
Tenofovir alafenamide (TAF): newer formulation wl safer renal and bone sle profile due
to 90% lower serum tenolovir levels. Less renal adverse events and proteinuria with
TAF than TDF (;Alos 20162711s301
Z Crystalluria
:: Protease inhibitors (lndinavir and Atazanavir) can cause nephrolkhiasis and inrrazubu
lar crystal formation. Indinavir caused renal colic in 8%,Atazanavir (case reports)
Radiolucent stones comprised of the medicine We IM 1997:127:119)
HIV DrugAssociated Nephrotoxicity Jun in ~=I»~~I 201s:11¢1soi
Drug Class Comments
Tenofovir NRTI ATN from mitochondrial toxicity
Proximal tubulopathy (TDF>>TAF) w/ tubular
proteinuria: failure no reabsorb low MW proteins
Fanconi syndrome: phosphaturia. glucosuria. acidosis
(insulNcient ATP to power sodiumglucose
cotransponer and perform ammoniagenesis)
Renal osteodystrophy: PO 4 wasting. loss ofVinmin D
binding protein, low 1uhydroxylase production
Biopsy:ATN and characteristic mitochondrial
enlargemenddismnion
Treaunenc drug discontinuation - good prognosis
Didanosine NRTI Fanconi syndrome. Lactic acidosis. Rhabdomyolysis
Lamivudine. Stawdine NRTI RTA
Efavirent NNRTI Nephrolithiasis um) M 44 So 20163518131
lndinavir.Atannavir Pl Crystals. stones,AKI
 KIDNEY TRANSPLANTATION
Transplantation improves survival compared to HD in HIV+ patients with ESRD
HIV viral load should be undetectable prior to transplantation
No increase in HIV progression after transplant is;/A 201ck361220041
Safety and efficacy of HIV+ no HIV+ transplantation established IN£]M 20155372;6131

Drug Interactions
Generally continue with same pretransplant ART regimen
CYP4503A inhibited by CNI and Pl: expect to use 20% of typical CNI dose via
extended dosing interval (fiunsplonmuon 1999;se¢a071
Avoid MMF - zidovudine or sravudine myelosuppression. 1 zidovudine efficacy WT
10099Suppl45263)
Outcomes
Pr a graft survival worse :han nonHIV. bu: similar no other highrisk INEJM
10\(x:ss:.004>
Increased rates of rejection compared to HIVnegative recipients
Worst outcomes if HCV coinfected UASN 20l5;26:ll2Z)

DIABETES MELLITUS
D IA s e Tlc K lons y D is e A s E (D K D )
Background
Most common cause of CKD and ESRD in die US (USRDS)
Abeu: 34 of diabetic patients develop DN
Albuminuria with strong predictive value for CKD progression
Microalbuminuria on spot morning void: HR 4.4 for progression (NEW 1001;345:B611
A/w allcause morality, CV events an all GFRs UAMA 2010230314n1
Moderately increased albuminuria (microalbuminuria): 30-300 mg/g or mg/d
Severely increased albuminuria (macroalbuminuria): >300 mg/g or mild
Of diabetes with eGFR <60. 16% have microalbuminuria. 61% macroalbumlnurla
Of those with microalbuminuria. 20% progress in 8 yr. 50% stable. 30% improve
Possible to progress directly to ESRD without evidencing oven proteinuria
Pathogenesis and Risk Factors
Hyperglycemia and advanced glycation end products drive diabetic complications:
glomerular hyperfiltration UASN 2017;28:102])
;Afferent arteriole resistance from tubuloglomerular feedback (TGF) inhibition.
NO bioavailability. hyperinsulinemia
. Efferent arteriole resistance from TAII. endothelin 1, ROS
lnflammationlfibrosis from cytokines and growth factors (eg.TNFa.VEGF.TGFll)
Direct podocyte effects.eg. nephrite expression.podocytespeciic insulin signaling
Older age.African ancestry. smoking.and obesity increase risk for DKD
No single gene has been identified.familial clustering is common
Screening
Annually from DM2 diagnosis. annually S yr after DM1 diagnosis
/ Cr. eGFR calculation. urine microalbumin to creatinine ratio (UACR) (ADA.KDIGO)
Workup and Diagnosis
Urinalysis: bland sediment. although hematuria can be seen.especially in severe DN
Urine protein measurement
Dipsticlc affected by urine concentration. usually "+" indicates >300 mold
24hr collection: gold standard
Spot UPCR and UACR: acceptable and easier for patients. accuracy affected by
creatinine generation (large muscle mass. cachexia)
Urine microalbumin sensitive for low levels of albuminuria
Protein electrophoresis: distinguishes albumin and nonalbumin proteins (light chains)
Biopsy ac,IAs~ 2013;8:1718)
Of biopsied diabetic patients. 1/3 with DN. 1/3 with nondhbetic renal disease (NDRD).
and 113 with both DKD and NDRD
mlc NDRD:ATN. FSGS. lgA nephropathy. HTN glomerulosderosis
 Kidney Biopsy Decision In Patients With DM
Pursue Biopsy Defer Biopsy
CKD of show duration Stable proteinuria
Rapid worsening of GFR Inactive sediment
Vasculitit symptoms Known retinopathy
New onset nephritis/nephrosis
Low C3IC4
Monoclonal mmopa

Pathologic Classification of Dlabetlc Nephropathy unsuzoiwsssy

I: GBM thickening II: mesangnalexpansion
III: nodular (Kimmelsdel-Wilson lesion) IV: advanced sclerosis (>§0% global
sclerosis (<50% global glomerulosclerosis) glomerulosclerosis)

Interstitial fibrosis and small vessel disease frequently coexist UASN 1010:z1s56l
Treatment
Nephrology referral: GFR <30. UACR >300 mg/g. 25% drop in GFR (KDIGO)
Lifestyle changes: exercise. BMI <25; no clear benefit w protein restriction
BP goal <140190 :Ace l<olGoilnc). <130/80 if proteinuria 1KD°GO1. <130/80 (1017 ACC/AHAI
Every 10 mmHg drop In SBP L mortality (x0.87).albuminuria (x0.83). CV events
(x0.89), stroke (x0.73), retinopathy (x0.87) llAMA z01 s;m¢w3)
Diuretics usually necessary to achieve BP control. loop preferred in advanced CKD
(eGFR <30. or heavy protelnuria)
RAS inhibition:first line for BP and proteinuria conuol; i intraglomerular pressure
ACEi or ARB: renoprotective UDNT num 2001:345:851: RENAAL N£jM 2001:345:861)
30% Cr: acceptable. /BMP, risk of AKI T wl diuretics. unSAIDs or volume depletion
T >30% Cr: consider workup for renal artery stenosis
Continue in advanced CKD unless *. K (try l dose + diuretic) or sudden ' eGFR
Not recommended for primary prevention in normotensive. UACR <30 mglg
ACEi +ARB a/w worse outcomes and no benefit lON1AaGE1: new 2013;369:1892)
MRA + ACEi or ARB for further antiproteinuric and antiHTN: can initiate K s4.S and
eGFR 230; T K frequent: lowK diet. loop diuretic. no NSAlD. close BMP monitoring
Glycemic control: strict control prevents onset of microalbuminuria (NEW 1993;129:977)
A1c <8% appropriate in CKD to avoid complications of hypoglycemic (ADA. KDIGO)
A1c correlates widi Hub and pH.an be confounded in CKD due to anemia, acidosis
w

Y . Fasting and postprandial fingers\jcks generally more reliable than Alc

Q Proteinuria control: 1 50% albuminuria. i 18% CV event (at~AAi. KI z004:6s:-:09)
. CCB: nonDHP more andproteinuric than DHP (KI 20041651199\l
Pentoxifylline L eGFR decrease.albuminuria [MSN 201 $:26:220)
CV comorbidities: statin with LDL goal <100, smoking cessation, aspirin 81
 Liraglutide
Lixlsenaride
Semaglutide
a gluc os ida s e inhibitors

G LUCO SE DISARRAY IN PATIENTS O N DIALYSIS

Susceptible to hyperglycemic episodes
No urinary glucose excretion posrprandially. adsorption of insulin by dialyzer
Hypoglycemic episodes -» counrenegulatory hormones :had are poorly cleared
Susceptible to hypoglycemic episodes
No renal gluconeogenesis. no renal clearance of insulin - prolonged halflife
Recommended target for Hgb A1 C: 6-8% (nm Rev ~=1~~°lw 201s¢11¢:02)
Treatment no glucoselree dialysare
Aim for p:s glucose to be wnl before HD to prevent shifts during trearmenn
Titrate insulin to nutritional status as malnunridon/inflammacion -> Tinsulin resistance
Increased pr selfmonitoring on dialysis days no catch postHD hyperglycemia

DIABETIC KETOACIDOSIS (NEjM 10151372:546)

Pathophysiology
Insulin dehciencylresistance -\ impaired peripheral tissue glucose metabolism. T f===v
acid oxidation and lipolysis, T glycogenolysis and gluconeogenesis
Fatty adds overwhelm Krebs cycle and excess Acetyl CoA - Acetoacetic acid
Loss of ketones in urine -» ECF contraction v AG acidosis when ketoacids retained
in severe volume depletion
Clinical Manifestations and Workup
NN abd pain. AMS: / Insulin use. ischemic symptoms. ingestions. infection
Exam: volume depletion (orthosiasis. flat neck veins, dry axillae). hyperventilation
Labs:+urine/serum ketenes,AG acidosis. sGlu usually 400-800 although can have
euglycemic DKA especially in setting of SGLT2 inhibitors
Tre a tme n t
Monitoring: hourly glc, q2hr BMR cardiac monitor
Volume resuscitation: bolus 1-2 L NS via largebore access; continue fluids 250-500 cdhr
Potassium repletion
. If K <3.5. hold insulin until repleted >3.5
If K <5.0. 40 mEq KCI with each L of NS
If K >5.0, monitor q2hr
Phosphate repletion:avoid.unless phosphate <1.0 mg/dL.then 20 mEq Naphos
If pH<6.9, 100 mEq NaHCO; in 500 cc w/ 20 mEq KCI and repeat until pH >7.0
Insulin: 0.1 u/kg regular insulin lV bolus. then 0.1 ulkyhr continuous Infusion
Repeat bolus if sGlu does not drop >50 mgldL in Grst hr
Once sGIu <200 mg/dL change IVF to D5 36 NS at 250 cclhr
When AG acidosis resolves. start subq rapid acting 0.1 ulkg q2hr
Overlap 2 hr of insulin GTT with subq plt stopping GTT
Treat potential underlying disorder: infection.ACS. intoxication

METFO RMIN ASSO CIATED LACTIC ACIDO SIS

P a thophy s i ol ogy
conversion of glucose to lactate in GI tract and inhibiting mitochondrial respira
tory chain complex 1 -» 1 lactate use in hepatic gluconeogenesis
Diagnosis
History: NN abd pain.AMS. dyspnea: documented metformin use when eGFR <30
Exam: tachycardia and hypotension in setting of severe acidosis
Labs:AG acidosis. negative wlu for infection or other causes of severe lactic acidosis
Treatment (Cru Core Med 201554317161
Volume resuscliadon with isotonic IVF if hypotensive: avoid bicarbonate administration
1 glkg IV dextrose if hypoglycemic
Dialysis if: lactate >20. pH <7.0. shock despite fluid resuscitation, ongoing AMS >2 hr

P a t h o p h ysio lo g y
Chronic interstitial inflammation and effect of hyperinsulinemia on WNK4 signaling
lead to low renin levels and hypoaldosteronism (NEJM z01s;373:$4a).Volume expansion
from CKD can elevate aural natriuretic peptide which directly inhibits renin and
h yp e rka le mia in d u ce d a ld o st e ro n e se cre t io n ,
Hypoalldosteronism - * Na absorption -» L lumen electronegativity -v l K/H excretion
Hyperkalemia -» impaired excretion of ammonium H re t e n t io n

Dia g n o sis
r/o a lt ca u se s o f h yp o a ld o ste ro n ism:
Primary adrenal insufficiency: chronic interstitial nephritis: HlV.Tb. sarcoid. EBV/CMV
Drugrelated: unSAIDs. Curls. heparin,ACEl/ARB, Ksparing diuretics. trimethoprim
Labs: nonAG acidosis, hyperkalema +UAG. urine pH <S.5, low plasma reninaddosterone

Tre a t me n t
If plw HTN or edema. low K diet with thiazide or loop diuretic
If not then patiromer (potassium binding resin)

ELECTROLYTE DISORDERS IN DIABETES (NEJM 2015;373:548)

Dysnatremia: inua -i extracellular fluid shifts and osmotic diuresis from hyperglycemia
Hyperkalemia potassium shifts due to insulinopenia and acidosis.Type IV RTA
Hypomagnesemia: renal Mg wasting due to osmotic diuresis
Hypophosphatemia renal Phos wasting due to osmotic diuresis
HypermagnesemialHyperphosphatemia: in DKA due to acidosis and insulinopenia

HYPERLIPIDEMIA
CVD is alw death in ESRD (50% of deaths. 20% of which is related to CAD)
Dyslipidemia is alw incidence and progression of kidney disease
Risk srranificadonz 10yr risk for atherosclerotic cardiovascular disease (ASCVD)
(Cu lu wn 2014;1Z&511; available AHA/ACC websir.e. app (ASCVD Plus. QxMD')

HMG CoA Reductase Inhibitors (Stalin)

Intensity of Stains (mg) (ACGAHA o-ww z01m 39=\04q
Low Mo d e ra t e Hig h

L LDL goal <30% 30-49% 250%

Srarin dose A t o rva : 1 0 2 0 A ro n a : 4 0 -8 0
Rosuva: 510 Rosuva:20-40
Simva: 10 Simva: 20-40
Prava: 10-20 Prava: 40-80
Lover: 20 Lover: 40
Fluva: 20-40 Fluva: 40 BID or XL so
Picava: 1. 2, 4
Bold: Recommended dose for CKD 3-5. including CKD SD or w/ KT IKDQGO Lipid sum
2 (18 ylo) and 1 (40-75 ylo) Prevention ofASCVD (AcclAHAa.mliun z01%1m104el
Co n d it io n s Tre a t me n t
Multiple major ASCVD or 1 major Maximal tolerated statin: if LDL 270 add
ASCVD + mu ltip le h ig h risk co n d itio n s* ezetimibe :hen PCSK9I
Histo ry MA S CV D e ve n t High or moderate srazin
LDL 2190 Maximal tolerated surinz if LDL >100 add
ezenimibe :hen PCSK9l
 LDL 70.189 and DM Moderate satin; if multiple ASCVD risk
(50-75 lo) high statin
LDL 70-189 and 10 yr ASCVD 220% High snazin
LDL 70-189 and 10 yr ASCVD 27.5 co Moderate szadmconsider risk enhancers" and
<20% coronary artery Ca score
LDL 70-189 and 10 yrASCVD 25-<7.5% Selective moderate sauna risk discussion
considering risk enhancer'
LDL 70-189 and 10 yr ASCVD <5% Lifestyle and risk discussion
LDL <70 Assess lifetime risk
CKo>4 (eGFR 15-59) is one of hi¢risk conditions* and risk enhancing heron'

S t a t in M yo p a t h y
Dosedependent. lowes: with prava and iiuvastatin
Prava, fluva. pitava. and rosuvastatin are less affected by CYP3A4 inhibitors
Drugs causing myopathy with statin: Cyclosporine. gemfibrozil. protease inhibitors
S t a lin a n d A K I
No L kidney failure but 1 proteinuria and rate of eGFR decline W02016:67ea1)
Preoperative use is not alw l postoperarJveAKl Isa rep z017:7:10091)
Szatin should not be recommended solely for renal protection and proteinuria
H yp e r lip id e m ia in C KD
Cholesterol level is predictor of mortality in HD pts: lowest in 200-219 (KI 2002:61:i887)
Prayastatin 40 mg 28% . CV death or recurrent nonfatal Ml in CrCI <75 w/ previous
MI (cAns Am :m 2003;1:a:98);23% i new MI. CV death. or cardiac intervention in eGFR
30-60 (mean ss) (PPP aannxan z004:110:1ss1)
Simvastatin 20 mg + ezetimibe 10 mg 22% l 1st major atherosclerotic event in non
dialysis Cr >1.7 <3 >1.5 9: no effect in dialysis population lsr.lARpi»»<=i 1011;377:2181)
Simvasnatin + ezetimibe: better than simvastatin alone (MSN 2017aa30341
Atorvastatin 20 mg did not lower CV death. nonfatal Ml.and stroke in HD pts with
T2DM.There was 18% i cardiac events (40 NEW 1005;353=23B). If LDL >145. 31% 1 cardiac
death. nonfatal myocardial infarction, or stroke lcpisn z011:6:1a1¢)
Rosuvasladn 10 mg did not lower CV death,nor\fatal MI. or nonfatal spoke and allcase
mortality in HD pts (AuroRA num z009;3se1 i9s). In post hoc analysis of DM pts. 32%
reduction in cardiac events (AURORA/ASN 1011:22:1335)

Pharmacologic Treatment of CKD (xouco ups42013)

18-49 lo. CKD Srazin if CAD. DM. prior ischemic stroke or 10yr risk >10%
250 ylo. eGFR 260 Sratin
250 ylo. eGFR <60 Skin or srarin/ezenimibe
ESRD If pr is already on a satin. continue in. Do not routinely iniziane it

OBESITY
Background and Definition
By BMI (kg/m1): overweight 25-29.9: class I 30-34.9; class II 35-39.9; class III 240
Prevalence increasing;33.7 (2007-2008) -» 39.6% (2015-2016) (}M4A 201e;J19¢\713)
Waist circumference is alw mortality in CKD who 20\1;5B:\77)
a/w low GFR and albuminuria in 2017;911224). inflammation who 10l7:70:B17)
Risk factor of ESRD: overweight x1.87, class I x3.57. class II ><6.12 (Am. :m 1004144911
M e d ica l C a u se s o f O b e sit y
Cushing (including iatrogenic), hypothyroidism. PCOS. hypothalamus injury
Atenoiol. metoprolol, propranolol. MAO inhibitors.TCA, paroxetine. lithium. escitalo
pram. clozapine. olanzapine, risperidone. valproate, divalproex. mirtazapine, progestins.
insulin, sulfonylureas. thiazolidinediones, meglltiriides (émdnuon 10122125116951
N o n su r g ica l T r e a t m e n t
Bdiavioral intervention: dietary changes (energy deficit 2500 kalld). physical activity.
selfmonitoring and inperson counseling (uspsTF AM in 20121157373; ;Acc 1014:63229B5)
Orlistac lipase inhibitor;AKI (ArtN :m 1011:171:703), oxalate nephropathy We 2007:4e 1s3)
Phentermine: used with topiramate: sympathomimetit;T BR HR: avoid In glaucoma
Topiramate: cause hypokalemia. distal RTA -» nephrolithiasis
Liraglutide: I, new albuminuria (NE;M 2017:377¢s39>
 Lorcaserin: serotonin agonisu: no signMcanz CV side effect luzw z0\s=m1101): improved
renal function and albuminuria (GmWauun 1019;139366)

QBESITYRELATED GLOMERULOPATHY (Nat Rev nepal 2016:11:453)

Glomerular hyperNkrarion -) glomerular hypertrophy > podocyte hypertrophy UASN

1011111254 - podocyte deuachmenr -» FSGS
Bx: glomerulomegaly, FSGS (perihilar common), segmental foot process effacement
Proteinuria: subnephrodc (52-9094). normal albumin, NS is uncommon (<6%)
Tx: we loss. RAASi induce proreinuria reduction >nonobese l;Asn 101112111211
Prognosis: 10-33% progressive renal failure and ESRD

G As Tnl c BY P AS S S unc s k v

Indications (Arcs Guideline Ohwlr 201111511

BMI 240 w/o excessive risk o( bariatric surgery
BMI 235 widl 21 severe obesity related comorbidities:T2DM. HTN. HLD. OSA. obesity
hypoventilation, NAFLD, NASH, pseudotumor cerebri, GERD. asthma, venous stasis.
severe urinary incontinence, debilitating ar thritis. considerably impaired QoL
BMI 30-34.9 with diabetes or metabolic syndrome may be offered
Types of Surgery
Malabsorptive: biliopancreatic diversion with or without duodenal switch
Restrictive: adiusrable gastric banding and sleeve gastrectomy
Malabsorptive + restrictive hybrid: rouxenY gastric bypass (RYGB)
General Effects of Bariatric Surgery
Lower mortality (1.3%) in 4.3 yr than matched cohort (2.3%) uAmn01ma 19;zm
T Remission of HTN. DM. HLD (;AMA 10189194911
Deficiencies of iron.vitamin Biz. D.and thiamine. Gallstone. sagging skin
T Additional GI op (x2.0), op for obstruction (x10.S), peptic ulcer (x3.4) (mAMA
101&319:291)
Renal Effects of Bariatric Surgery
Postoperative AKI 8.5% (T 50% Cr or dialysis requirement). Risk factors are higher
BMI. HLD, intraop hypotension and preoperative use of ACEilARB lCMSN z001:z41s1
Renal function predicts postpp complicaiion:4.6 (CKD1) .. 9.9% (CKD5) mm z01z=2Jaes)
1 Proteinuria, albuminuria (Pedau ~»pnfa z009;24=a51; cu- n¢w-i1 zuce.704941
27 kg weight reductions with RYGB: 1 absolute mGFR (1 glomerular hyperfiltration).
unchanged mGFR adjusted for BSA. T creatininebased eGFR (overestimation dlt
1 muscle mass), unchanged cyscatin Cbased eGFR (mc mur z0 i7;1s:s21
Q Improvement in KDIGO CKD risk categories 1/ASN 2018;1911B9)
g At median flu of 4 yr. 58% L eGFR decline 230%,S7% L ESRD or Cr doubling of 10149011641
6 C a l c i u m Ox a l a te N e p h r o p a th y
as
u Saponification of calcium/insoluble calcium oxalate complexes formation -» excessive
reabsorption of oxalate by the gut
Malabsorptive procedure T urine oxalate excretion. oxalate nephviopathy (KI 2007:moa
clAsn anceansvel kidney sine and CKD (x1.06] lx: zo1 s:s7.aa9)

CKD-MINERAL AND BONE DISORDER

Definition (KI Suppl ZOl0;7H $10)
Systemic disorder of mineral metabolism. bone. and vascular calciticaUons
Abnormalities of Ca. PO 4. PTH,vitamin D metabolism
Renal osteodystrophy refers to the bone component of CKDMineral and Bone
Disorder (CKDMBD) and is a spectrum of disorders in bone 8um9295 minerallation.
and volume in CKD
Background
Linked to vascular calcificauon: the leading cause of mortality in dialysis patients
Clinical outcomes in CKDMBD are increased risk of CV events and fractures
Risk of CKDMBD and (-) clinical outcomes T with severity of CKD (usually eGFR <40)
CKD: t risk of falls 2/2 frailty and sarcopenia,1 fragility fracture and related morality
(2.5x 1yr mortality rate after hip fracture) compared to general pop WKD z00013e2111s)
Renal osteodystrophy is a form of osteoporosis: osteoporosis is defined as a disorder
of bone that increases risk of fracture
Pathogenesis
Phosphonls retention with 1 ionized Ca and vitamin D -» 2 hyperparathyroidism
In early CKD.T fibroblast growth factor 23 (FGF23) peptide -» suppression of
1nihydroxylase 4 1 calcitriol producdcn -» T PTH -a phosphaturia with further GFR
decline -» hyperphosphatemia v oszeoblastlc transformation of vascular smooth
muscle 4 vascular calcification
Vascular calciGcatlon: media >intima -> vascular stiffness and LVH. FGF23 linked to
LVH and CV events (atherosclerotic and death) in CKD UAS~1014a5=3491

RENAL OSTEODYSTROPHY (xl Suppl z010.7&s10)

A d yn a mic B o n e Dise a se
Very low rate of bone formation (1 SD below normal mean,<20 yg'lum'/yr bone for
mauon) secondary to PTH suppression by inflammatory cytokines 4 low osteoblast
a ct ivit y a n d b o n e f o rma t io n ra ms
5 5 % o f HD p a u e n t s u m 1 0 1 1 1 2 6 2 1 3 6 8 1
In cre a se d in cid e n ce wh e n PTH <1 0 0 p g ./mL (PPV >9 0 %)
T Serum calcium secondary to reduced bone uptake; l alkaline phosphatase
Some evidence that it is associated with increased risk of arterial calcification
Ost eomalacia
Low bone turnover with abnormal mineralization
Previously from deposition of aluminum containing binders; now 4 incidence (3%)
(IBMR 1011;26:1 asa)

Hyperparathyroidisrn (34%)
High bone turnover disease" t rates Iormadon and resorption PTH >600 pglmL
Secondary to calcitriol deficiency, hyperphosphaternia. hypocalcemia. and excessive
FG F2 3 i n e a r l y CK D

Re la tive ly L o w P TH
Associated with T mortality (Ushaped mortality curve with T PTH) secondary to cal
dumbased binders. dialysate bath. assay differences. excessive active Vit D repletion
Vit a m ln D D e f icie n cy
1.25(OH)1D3 active metabolite secondary to worsening CKD. Supplementation
associated with improved survival in CKD and HD patients
.> 25(OH)D (<30 fig/mL) associated with T mortality in HD patients. supplementation
wick nutritional/inactive D2 (ergocalciferol) or D3 (cholecalciferol) results in reductions
in PTH that are more appreciable in patients with less severe CKD
Hyperphosphatemia and Hypophosphatemia
Phosphorus <3 and >6-7 associated with t mortality
Hypercalcemia and Hypocalcemia
Both associated with increased CV morality
Hypocalcemia ( PO» retention, i calcicriol. PTH resistance) -\ T PTH -i abnl bone
r e mo d e l i n g
Hyp e rca lce mia -» e xtra ske le ta l ca lcifica tio n

Increased Alkaline Phosphatase (Hyperphosphatasemia)

Linear ailw allcause and CV morality (pyrophosphate hydrolysis - vascular calcifica
don) and hip fracture risk in HD pts (nor z014;2*ms3z).¢ w/ vitamin D and calcimimetics

OSTEOPOROSIS
Definition
Disease of low bone mass. disrupted bone architecturee,and skeletal fragility
Osteoporosis: dual energy xray absorptiometry (DXA) Tscore 22.5 SD below young
adult mean OR fragility fracture
Low bone mass (previously osteopenia):Tscore 21-2.5 below young adult mean
Normal:within 1 SD of young adult mean
Background
US prevalence 9.9 million. 2 million fractures annually lomipalus on 2014415:23591
CKD: lower bone mineral density (BMD) and 2x the facture risk of age matched conuols
ESRD: up to 40% prevalence of fragility fractures
Screening
All postmenopausal women and men >50 should be evaluated for fracture risk
DXA recommended for all women 265 or <65 with equal or greater fracture risk on
Fracture Risk Assessment Tool (FRAX): 10yr risk 29.3% lusrsTF Ann IM 2011=1s4¢Jss1
FRAX is available at sheMeld.ac.uMFRAX
Clin ical Risk F act o rs f o r F ract u re
Advanced age. previous fracture. family hx of fracture. low body weight

Risk Factors for Osteoporosis-Related Fracture

(Office of the Surgeon General US 2004)
Lifestyle Alcohol abuse, immobilization. low calcium intake,vitamin D
deficiency. smoking. hypervitaminosis A
Genetic CE osteogenesis imperfects. porphyry. Marfan syndrome. Ehlers-
Danlos syndrome. hemochromatosis. homocysdnuria. Gaucher
disuse. glycogen storage disease
Hypogonadal states Anorexia nervosa. panhypopituilanism, premature maiopause (<40 yr).
hyperprolactinemia. androgen insensitivity.Tumer syndrome.
Klinefelter syndrome
Endocrine Cushing syndrome. DM. hyperparathyroidism, thyrotoxicosis. central
obesity
GI disorders Celiac disease. IBD. malabsorption. PBC. gastric bypass. pancreatic
disease
Hematologic Hemophilia, leukemia/lymphoma. multiple mydono. sidle cell disease.
thalassemia
Rheumatologic RA. SLE. ankylosing spondylitis
Neurologic and Epilepsy. MS. muscular dystrophy. Parkinson disease. spinal cord
musculoskeletal injury stroke
Medications Aluminum, anticoagulants. anticonvulsants. aromatase inhibitors.
barbimrates. chemodielapeutic rigs, depomedroxypnogesterone.
glucocorricoids (>2.5 mg/day prednisone for >3 mo). GnasH
agonist. methotrexate. PPls. SSRls.TZDs. dvyroid hormones.
P2lB1l\il nutrition
Miscellaneous HIVIAIDS, amyloidosis. COPD. CHE ESRD, sancoidosis. posttlansplant
bone disease

GlucocorticoidInduced Osteoporosis iAA Andrus Rhemalal 2017.s91sz11

Monitoring and prevention for patients taking >2.5 mg/d prednisone for >3 mo
Osteoprotegerin inhibition & T RANKL synthesis -» osteoclast proliferation
Inhibited gonadotropin secretion-» i androgens and estrogens 4 l bone resorption
T O st e o b la st a p o p t o sis + 1 b o n e f o rma t io n
High fracture risk during early rapid bone loss phase (first 3-6 mo) and subsequently
correlates to dose and duration of glucocorticoid treatment
Clin ica l Ma n if e st a t io n s
None until there is a fracture (often no preceding trauma)
Vertebral fracture most common (2/3 asymptomatic. usually incidentally found on
other imaging, signs: height loss and kyphosis)

Workup and Fracture Risk Assessment iOnwnawsis i! 2014:Z51159)

DXA for BMD of hip and spine:spine BMD has limited use in CKD to predict fracture
risk 2/2 extraosseous calcification and focal osteosclerosis
Vertebral imaging (lateral T and Lspine Xray or lateral assessment on DXA) in setting
of low bone densitylrisk factors to assess for vertebral fracture (indication for ueaunent)
FRAX: calculator to estimate 10yr probability of major osteoporotic or hip fracture for
untreated patients age 40-90. Can be used with or without BMD at the femolal neck
Bone turnover markers: not routinely used. possible role in monitoring response to D(
Evaluation for secondary etiologies if recent/multiple fractures or very low BMD

TREATMENT (Nut Rc n¢vl\mI 20119681; C]ASN 101849629

Conventional osteoporosis meds effective in mild CKD when CKDMBD excluded

(normal PTH, Ca. and FO 4)
Insufficient evidence for fracture reduction in stage 4-5 CKD
Initiate treatment if eGFR <30 with fragility fracture or osteoporosis (KDIGO HBO
2017)
 Exdude adynamic bone disease prior to bisphosphonaves (theoretical L In bone formation)
Exclude hypaparadvyroid hone disease in patients with CKD prior to anabolic treatment
Nonpharmacologlc Treatment
Die: (1,200 mud calcium. 800-1.000 IUld Vic D). lifestyle (exercise and fill prevention)
In CKD patients. lim: calcium intake w 500800 mg daily. replete 25OH it D to 30
and manage metabolic disturbances a/w CKDMBD (hyperparathyroidism. hypocalcemia.
hyperphosplutemia, vitamin D deficiency) prior to starting treatment for osteoporosis
E s t ro g e n
1 Fractures. initiate within 10 yr of menopause given CV risk. Dosereduce In CKD.
Avoid estrogenprogestin combo dltvTE. CVA. CAD,and breast CA risk
Selective Estrogen Receptor Modulators (SERMs)
Raloxifene L vertebral fractures in eGFR <45. t Lspine BMD in stage 4-5 CKD
TVTE risk and 1.4x higher serum levels in CKD (KI 1003;63:1169)

B isp h o sp h o n a t e s
1 Fracture rate by 50% In postmenopausal osteoporosis WM 2009;177;$14). effectiveness
cor r elates with degr ee of bonetumover
Fracture reduction comparable in mild CKD.but data lacking in stage 4-5 CKD (small
¢ BMD in ibandronateueated HD patients) iA-J n¢pnmI 2012;zs:23s)
Prevents resorption by binding mineralized bone surface-half bound with remaining
half excreted unchanged by the kidney Cleared by HD.
Teriparatide: Recombinant Human PTHI/4 Peptide
A n a b o lic e f f e ct wit h d a ily S Q in je ct io n s
T BMD and 4 fractures in mild CKD. T BMD in adynamic bone disease (lGdney alan4 pvus
Ne 2 0 1 0 :3 ]:7 .2 1 ). No e vid e n ce to su p p o rt u se in CKDMBD.

De n o su ma b
Monoclonal ab against RANKL (osteoclastdiflerentiation cytokine)
Antiresorptive. nonrenally excreted. no restriction with CrCI <35
i Vertebral fracture in mild CKD um 1011216518291
Risk of severe symptomatic hypocalcemia in late stage CKD (Jane 20n:z7147I).
No evidence [D suppor t use in CKDMBD.

Strontium Ranelate: Incorporated into Bone in the Place of Calcium

Used outside the US for postmenopausal osteoporosis
Renaliy cleared, no safety data to recommend use in CKDMBD
Osteoporosis Pharmacotherapy in CKD we no ~.ui,.l2.01as=ee1: KI zoiuwal
Dru g Co mme n t s F DA L a b e l

Alendronate No t re co mme n d e d fo r CrCI <3 5 2013

Risedronate No : re co mme n d e d fo r CrCI <3 0 2013
Ibandronale No r re co mme n d e d fo r CrCI <3 0 2013
Zoledronic acid No t re co mme n d e d fo r CrCI <3 5 2013
Teriparatide Caution in recent urolithiasis 2009
Be n e fit in CKD.lcw PTH a n d lo w BMD
Denosumab Risk of hypocalcemia in CrCI <30 2013
May be useful KO :neat hyperealcemia
Calciwnin No renal adjustment 2012
Probably safe,weak effects. no dm in CKD
Raloxifene No renal adjustment 2007
Pilot data with beneficial elfecls in HD patients
Estrogen Limited dam in CKD 4-S;appropriate in premenopausal 2011
women with CKD and amenorrhea

PROGNOSIS AND MONITORING

8-35% excess monaliry within 1 yr of hip fracture (osoapwus lm 1009;2¢1633)

Monitoring
eGFR >30: BMD testing 1-2 yr after initiation of therapy q2yr thereafter
eGFR <30:
quo mo serum calcium. phos.25(OH)D: calcium 10 d after sraning denosumab
Annual Cr monitoring on bisphosphonates
Repeat DXA may be useful for response to tx (not for assessing fracture risk)
. Markers of bone turnover not recommended
r' PRIMARY HYPERPARATHYROIDISM
Definition and Pathogenesis
1 Hyperparadryroidism (PHPT): one or more paradvyrold glar\d(s) secretes excessive
PTH with elevated or highnormal serum calcium and replete vitamin D
Adenoma (80-8595). hyperplasia (10-15%).carcinoma (<1%)
2 HPT: renal failure (impaired alckrlol production and hyperphosphatemia).vitamin D
deficiency (may be present in PHPT and lower serum raldum to normal range),meds
(lithium. thiazides). calcium malabsorpt.ion.renaI calcium loss. inhibited of bone resorption
3 HPT: aker longstanding 2 (glands remain llyperfunctioning despice correction of 2)
Normocalcemic PHPT: variant with normal total and ionized calclum.elevated PTH.
and no 2 causes. Progression to hypercalcemia (19%), renal stones. fracture. decline
in BMD.and hypercalciuria (40%) over 3 yr (ICE/* 1007;3S:123)
Familial hypccalciuric hypercalcemia (FHH): benign mild Ca elevation 2/2 AD inacti
vating mutation in the parathyroid and kidney calciumsensing leceptor (CaSR)
PTH inhibits NHE3 and bicarbonate reabsorpcion in PI Clinical pRTA is uncommon
(KI 198$;2&187)
Clinical Manifestations
Mos: commonly asymptomatic hypercalcerniaz asymptomatic nephrocalcinosis
Renal stones in 55%. osteoporosis in 63%. vertebral fractures in 35% UCEM 2015;100:1309)
Nonspecific SX related to hypercalcemia: weaknas.ano4exia. fatigue. polyurialpolydipsia.
cognitive/neuromuscular dysfunction
Parathyroid bone disease: osteitis ibrosa cysdca (<5%) excessive osteoclast activity
- subperiosteal bone resorption in middle phalanges, tapering of distal clavicles, bone
cysts, brown tumors (fibrous tissue and poorly mineralized bone) - bone pain.
Reduced cortical BMD and increased risk of fracture.
CV HTN, LVH, diastolic dysfunction, coronary atherosclerosis
Atypical: parathyroid crisis (1-296) symptomatic severe hypercakernia (man 17.5 mg/dL)
Workup
Serum calcium: repeat to confirm. Most <1.0 mg/dL above ULN
PTH: elevated in 80-90%.wn1 10-20%. No performance differences between 2nd gen
"intact" and 3rd gen"whole molecule" 1-84 assays UCEM 10 14:w3s10)
Creatinine: for calculation of CrCl; 60 is the threshold of parathyroidectomy
24hr urinary calcium: elevated (>200-300 mg/d) in 40%. correlates with risk of renal
complications. FEW < 0.01 senslspec of 85%/88%, PPV 85% (can Enaaawmi 1a0816917u1
25Hydroxyvitamin D (25OH vit D):<20 may lead to a falsepositive dx of PHFI
Repletion increases urinary calcium excretion.

Differential Diagnosis for PHPT

PTH Ca Vitamin D Urinary Ca
PHPT t or high nl T Nl.lownl.or L T or high nl
FHH NI, T (15-20%) T NI 1
PHPT wlVit D deficiency t nl 4 Low nl or '
Z HPT dlt Vit D deficiency T nl or 1 l 1
Normocalcemic PHPT t nl nl nl

Genetic testing (Ca$RAP2$1, GNA11) for FHH. Indications: positive family hx. young
age. multigland involvement, concern for multiple endocrine neoplasm (MEN 1)
Renal Imaging: u/s. Cli or plain film for stone and nephrocalcinosis detection
Bone mineral density (BMD): decreased particularly at cortical sites (forearm and
hip). not required for dx. Imaging for vertebral fracture recommended if DXA negative
for osteoporosis dlt increased risk
Neck imaging (ultrasound, technetium99m sestamibi scan. dynamic CI MRI) not
indicated for dx. used for surgical localization
SurglcalTreatment: Parathyroidectomy
Symptomatic hypercalcemia or nephrolithiasis
 Indlcadons for Parathyroldectomy in Asymptomatic PHPT up z0149&ass1)

Me <50
Renal CrCl <60. 24hr urine calcium >400 mg/d with increased stone risk.
nephrolithiasis or nephrocakinosis on imaging swdy
Bone DXA T score <2.5 as lumbar spine. total hip. femoral neck, or dislzl 113
radius OR
Venebrad fracture by xray, CT. MRI.or venehral fracture assessment on DXA
Serum Ca >1 mg/dL above the upper limit of normal

Medieal Treatment
For nonsurgical candidates or failure of cure after surgery
Dietary Ca 1.000-1.200 mold: dietary Ca & vit D def T PTH: should not be
restricted
Vit D repletion (goal >30 fig/mL) J, PTH (17%) and T Lspine BMD (2.5%) ()C£m
201439:1072)
Thiazide: 1 PTH. urinary Ca ()CEM z017;10231270). Monitor serum Ca level.
Cakimimetics: serum Ca >1 above ULN. Cinacalcet normalizes Ca in 75%. no
change in BMD. preferred in patients with nl BMD (SurfEnda¢Ilrlo12015;171527)
Bisphosphonates: osteoporosis and/or fracture risk Improves BMD without change
in senim calcium. Combo therapy with cinacalcet can be used to reduce serum Ca
levels but has not been studied in RCTs.
Estrogen-progestin: significant increases in BMD in postmenopausal PHPT. Not ret
ommended 1stline tx dlt breast cancel: stroke. and CHD risk.
Prognosis
Surgery as the only definitive therapy
Significant increases in BMD and reduced risk of renal stones (NEW I 999;34\:\249)
Comparable BMD improvements with bisphosphonates alone www 20109s16sJ1:
Reduced fracture risk observed but not demonstrated in RCTs
No change in postop renal function ucw z014.99:u4sl
Excess mor tality (RR 1.7 male. 1.8 female) 2/2 cardiovascular disease persists
after surgery. unclear relationship to severity of underlying disease (Eur 1 cl»n< Invest
1998:28:271)
Small nonspecific differences in postop neuropsychiatric sx that favor surgery

URIC ACID (UA)

Background
UA H Urate + H. pKa 5.75:po:en:iaI no crystallize in acidic milieu (pH <S.5)
UA is the result of metabolism of purine in the liver; diem can provide ~40% of orate
UA excretion via the GI tract (1/3) and the kidney (2/3)
<5% protein bound; most UA is littered as the glomerulus
PCT Handling of UA
Process (Proportion of UA, PCT Segment) Transporter
Reabsorption ( 99%, $1 ), pos secretory URAT1, OAT4 (apical)
reabsorprion (40%. $3) GLUT9 (basolateral)
Secretion (507é. 52) OAT1 . OAT3 (basolateral)
MRP4.ABCG2. NPT1, NPT4 (apical)

URAIZ rate anion exchanger; OAT. organic anion transporter: GLUT. glucose uansponer: MRR multidrug
resistanceassociated pro¢ein,ABCG.ATP banding cassette sbfamily G member: NPT. sodiumdependef!
phosphate rransponer

FEud 10%: >20% in ATN

Females have lower levels by 1-1,5 (estrogenmediated renal orate excretion) (Hum
neama zo13:2e1asal.Af¢er menopause level males level (Aland: Red ho 2GGB;10:R116)

Pathogenesis of Clinical Conditions Associated With Uric Acid

Hyperuricemia: 85-90% underexcretion; 10-15% overproduction (Aninus umm 2001447:6101
Hyperuricemia is risk factor for renal and cardiovascular diseases (potential mechanism:
activation of the RAAS, 1 NO. l glutathione formation an antioxidant and dysfunction
of intrahepatic fructose metabolism)
CKD progression: T oxidative soess. endodlelial dysfunction -> systems and glomemlar
HTN:alr.eration of RAAS-» T renal vascular resistance. l renal blood flow (nor zoinemn
 Autosomal dominant tubulointerstidal kidney disease (ADTKD). aka medullary cystic
kidney disease can be cause by munitions of UMOD. REN. and MUC 1 gene: familial
CKD/ESRD.chronic tubulointerscitial nephrirjs, CKD. and hyperuricemia/gout
Hypouricemia associated with uricosuria may be associated with recurrent exercise
induced AKI resulting from muiztions in URAT or GLUT9 uansporters
Factors Al¥ecting Uric Acid Level
Hyperuricemia Hypouricemia
Diet Alcohol, red meal. seafood. high Lowfat dairy products. coffee.
fructose die: plays proteins
Medication Thiazide. loop diuretics. niacin, lowdose Allopurinol. febuxcstac
ASA. CNI. pynzinamide. ethambutol. Losartan. fenofibrate
pancreatic extract (for CF)
Pathologic Volume depleLion.Wc Be def. pre Mutation of URAT1. GLUT9,
conditions eclampsia pRTA.SIADH.cerebralsak
wasting

HYPERURICEMIA

Clinical Manifestations and Management of Hyperuricemia

DiagnosislLabs Pathogenesis Prevention/Therapy
Acute Url: Acid Nephropathy
AKI + UA >15 UA overproduction:TLS. IV fluid (HCOi controversial)
Urine UAIcreat >1 seizure Lesch-Nyhan Sd XOI. rzsburkase
Chronic Urate Nephropathy
CKD » Deposition of sodium orate CKD management
UA >9 for Cr s1.5 crystals in the medullar UA lowering agents
UA >10 for Cr 1.5-2 interstitium - chronic
UA >12 for Cr >2 interstitial fibrosis
DDx: lead nephropathy
Uric Acid Nephrolithiasis
Cli stone analysis Low urine pH. high urine UA Urine alkalinization
UOP >2 Ud
XOI in hyperurkosuria
(no RCT)
Gout
UA can be nl within 2 wk of Deposition of orate crystal Acute attack :reared wl
an acute attack acute gouty arthritis (starts colchicine. steroid (intra
Urabe crystals on polarized mostly at night dlt low articular/po) or unSAIDs
light microscopy body temp) UA <6 (<5 stophi) w/ XOI
Chronic gouty arthropathy
Tophaceous gout (connective
tissue deposits)
Asymptomatic High Uric Acid
2/3 of T UA is asymptomatic The degree of T UA is alw T Consider of of male wl UA
UA >8 risk of gout and >13.female wl UA >10
nephrolithiasis up IM 1018;178;1516;
Uncertain role of UA in A]KD 2015.66945)
CKD progression

General Management
Goal: lower UA levels by s1-2lmo
Weight loss. purine restricted diet
Die: modifications: ' coral calories. refined carbohydrates.saturated far. meat and fish,
T lowfat dairy products. plant proteins
Cherries reduces recurrence of gout;Vit C (500 mild) reduce UA levels by 0.5
Xa n th i n e Oxi d a se In h i b i to rs (XOI)
Initiate w/ antiinfiamrnatory drugs to prevent acute iiareup
Do not use w/ 6mercaptopurine and azathioprine; metabolism is inhibited by XOI
Allopurinol: a/w lower incident renal disease than febuxostat (Ann Meum on 2017;76216691
Stan w/50 mg qd in CKD4-5: 100 mg qd othewvise: uptitrate dose monitoring toxicity
(can exceed 300 mild) (ACR Guiddmes Animas cm an 1012;64:143)
 Allopurinol hypersensidviry (dosedependent): high risk if +HLA8*5B01: / in Han
Chinese.Thai. Korean. African American ¢s¢~» Anhms Rheum 2011;4s=s94):AKI. fever. rash.
eosinophilia,T LFTs
Other s/e: vasculids.AIN. xanchine or oxypurinol crysralluria and urolirhiasis
Febuxostan star: wl 40 mg qd: No crossreactivity w/ allopurinol
s/e:T all cause and CV morality or ailopurinol in pts with coexisting CV conditions
(NE/M 201&17s:1100): T LFTs. myopachy and rhabdomyolysis in CKD \qAs~ 20174117441
AntiIn(Iammatory Drugs
Treatment of acute gout and initiation of XOI
Colchicine.cor:icosceroid unSAIDs U Rheumatol z01&4s12nl

HYPOURiCEMIA
Background
Low serum UA <2 mg/dL
Hypouricemia is pathological in conditions alw renal umm reabsorption defects
(je, hypouricemia due no hyperuricosuria)
Etiologies
Decreased UA production:
. XOI therapy, liver disease
Hereditary xanthinuria (deficiency In XO): xanthippe stones treated with hydration
and urine alkalinization. myopathy
Purine nucleoside phosphorylase (PNP) deficiency: recurrent infections
UA oxidation: rasburicase
Decreased UA tubular reabsorption
Fanconi syndrome. volume expansion, SIADH. Sal: wasting
Familial renal hypourlcemia: nonAshkenazi Jews and Japanese. mutation in URAT 1
or GLUT9 leading to decrease orate reabsorption. GLTU9 more severe symptom
atology than URAT1. recurient nephrolithiasis and exerciseinduced AKI
ExerciseInduced AKI in Familial Renal Hypouricemia
UA is an antioxidant and AKI is due to an oxidative stress induced by exercise: other
potential etiology could be due to the increase of uric acid excretion that is exacer
bated by exercise leading to intratubular UA pretipitadon
Some patients were successfully treated with allopurinol
Prognosis is good with recovery of renal function

RHEUMATOLOGY
Many autoimmune disease (AID) present wir.h renal manifestations. eg. SLE; conversely
lupus nephritis may develop w/o systemic manifestation of SLE
Rheumatologic Conditions and Kidney
Systemic diseases/conditions SLE, systemic sclerosis. IgA vasculitis (HSP).
associated with kidney Cryoglobulinemia. ankylosing spondylitjs (loAn)
involvement Allergic interstitial nephritis: SiOgren syndrome
Medicationassociated AID immune checkpoint inhibitor
(NEWZOl8;37B:1$8)
AID causing AA amyloidosis AID 3/w 60% ofAA amyloidosis. RA (33%) is mlc (NEW
2007;3$6:136Il
Treatment of rheumatologic unSAIDs: vasoconstriction. interstitial nephritis. papillary
conditions allw kidney necrosis
involvement Allopurind: interstitial nephritis. DRESS
Sulfasalazine interstitial nephritis
AntiTNF agents: lupus nephritis. pauciimmune crescentic.
ICmediated (nor z0os5n 14001
Renal disease affecting course Exacerbation of gout by diuretiWCKD
of rheumatologic conditions
 SvsTEmic ScLERosls (SSC)
An autoimmune disorder causing vasculopathy and fibrosis of skin and multiple organs
Skin: edema and redness -» :hickening sclerodacryly. fingertip pitting ulcer
ClassiNcadon of SS: Based on Skin Involvement
Limited cutaneous 5Sc (lcSSc) Diffuse Cutaneous SS: (dcSS:)
Skin imolvemem on extremities distal no Skin involvement on trunk. disvaLand
elbows and knees >face proximal extremities and face
CREST syndrome: calcinosis cuds (soft Scleroderma renal crisis: more common
Ussue calcification). Raynaud Restrictive cardiomyopathy
phenomenon. Esophageal dysmoziliry,
Sclerodactyly. and Telangieciasia
PAH >pulmonary fibrosis
Andcenuomere Ab Anniiopoisomerase1 (Sci70) Ah
AntiRNA polymerase ill Ab

Vascular involvement Raynaud phenomenon. telangiecizsia

Albuminuria (25%), intermediate MW proteinuria (31.3%) a/w GI involvement and
dcSSc (on Nepnra z00a:1rn110): MPOANCA crescentic GN (Gln r4¢pw 2W7;68:l8$)
Penicillaminez used as antifibrotic; a/w MN, MPOANCA GN (I Rheumami zuoe,J3:1 see)
Myeloablative autoHSCT improved eventfree and overall survival (nf,1M 201S;37&3$)
Scleroderma Renal Cnsis (SRC)
Prevalence: 5-10% of systemic sclerosis w»»~»»a=d»=w 1009;4&ii3zi
Risk factors diffuse SSc. CS 215 mg/d prednisone (Andris Rheum 19ss,41=1sn),an¢iRNA
polymerase Ill Ab (25% risk vs 2% if -) (Nheumambgy 1D09;48:1570), fine speckled ANA
Less common w/ anticentromere Ab (QW 2007:100485)
AKl not explained by other causes. malignant HTN: abrupt onset or worsening of
HTN, t PRA, retinal hemorrhage and exudates
TMA: MAHA (schistocytes.' relics. 1 hapto.t LDH.. indirect bill) + Lplt
Urinalysis: normal or mild proteinuria with few cells or casts
Kidney Bx:TMA. onion skin hypertrophy from intimal proliferation and thickening
vascular thrombosis. glomerular ischemic collapse,and peritubular C4d deposits a/w
poor renal outcome (Hum Panini 2009=40aaz)
Treatment indefinite ACEr (T patient and renal survival) (Ann ii 199e11a:351:2au0.133¢w0;.
ARB unproven: avoid glucocorticoidsal PLEX (nor 1011;1714398)
Prognosis ESRD (54%), death (41%) despite ACEi on 45.8 mo flu (Rnmmawlqy
101L5 114ao); Kidney may recover in up to 18 mo of dialysis on ACEi (Am IM zuaaiauooi
Transplantation: wait for 6-1B mo for recovery; patient survival is better than on
dialysis 90.1% (vs 81.1%), 79.5% (vs 54.6%) as 1 and 3 yr :Alf 1004;4:2017)C 2V0id CNI
in; llheinnalal 1 w4;aa90) and highdose cs

RHsunAToIo ARTHRITIS (RA) (umm Dis an Nadl Am 201B:44:57 1)

Background
eGFR <60 more common (25-34%) dun general population (A}XD 2014163:2062 On Rnwnalal
1017:36:2b73)I chronic inflammation mediated CVD and metabolic changes
Hydroxychloroquine use is a/w 1 CKD Ieyasu 201813:701)
Rheumatoid Factor: IgM antibody against IgG Fc portion; elevated in various conditions:
Rheumatologicz RA. type II & III cryoglobulinemia
Aging, infection (endocarditis. HBV. HCV.TB) sarcoidosis. silicosis. asbestosis. PBC
Me th o tre xa te (MTX)
MTX is excreted by glomerular Filtration and tubular secretion
Rheumatologic dose d MTX does not abuse crystal nephropathy as in oncology high dose
MTX cause bone marrow suppression in CKD imp: fal 1006:28;95)
CrCl 31-50: reduce dose by 50%; CrCI s3lk contraindicated (ACT Annnzluiw zouaiswszl
Glomerular Disease

AA amyioidosis (17.2 yr) and mesangial GN (129 yr) 2lB a/w longer disease duration d can
MN (3.8 yr) (Afdv-» NM 1ws;J&z4z); Fat pad aspiration can diagnose AA amyloidcsis
Drugs a/w MN, bucillamine. penicillamine. gold.and auranoGn are now rarely used

Sl6CNEN SYNDROME (SS)

Background and Extrarenal Manifestations
Lymphocytic inhltntion around epithelial dum d exocrine glands (salivary. lacrimal) gland
Sicca syndrome: keratoconjunctivitis sicca (dry eyes). xerostomia (dry mouth)
Secondary form (alw RA. SLE. scleroderma) has exuaglandular findings: ILD. cutaneous
vasculitis. peripheral neuropathy
t Lymphoma (NHL) x6.S, in primary and secondary form (tiu ad 10C8=111;40291
(+)AntiRolSSA.AntiLalSSB
Kidney biopsy:TlN (71%) >> MPGN (8%). cryoglobulinemic GN, FSGS (QASN 200~h4:1423)
Tubulointerstitial Nephritis (TIN) in Sjiigren Syndrome
CD4+T lymphocyte dominant; Granulomatous TIN is me (qAsn z009.414231
Tx: prednisone.AZA. rituximab, MMF iamc Mutallndrekt Damn 20ie17¢11
Other Renal Manifestations
No CKD4 progression to ESRD (qASN 100%4;1423).The other study showed 11% ESRD
(A/uvmi Rheum 201J;6$.1M5)
GN a/w T death. CKD. lymphoma (Artemis Nnfwn 2013;6$:z94s1
Cryoglobulinemit GN: 32.5% (m/c noninfectious cause):22.5% S16grens only: 10%
SlOgrens + hematologic malignancy (;ASN 2016217112131
S1Ogrens wl cryoglobulinemia has T mortality (x4.36) than wlo (kleumawligf 2016:§5:1443)
dRTA >> pRTA: absence of HATPase in CCT UASN 1s9zJ;ze4);Ab against CAII iAni}m¢4
inns.11&1a1); severe hypocitraturia -» CaP nephrocalcinosis; stone 4/24 (c/Asn 2009;4¢1413)
Hypokalemia dRTA. sodium wasting (QIM 199ms;s1zl; rarely Gitelman syndromelike
metabolic alkalosis with antiNCC Ab we z00e:s2:1163)
Nephrogenic DI: polydipsia can be attributed to xerostomia

VASCULITIS
Large Vessel Vasculitis
Takayasu arterials: renovascular HTN >50%
Gian: cell aneridsz rare renal in»olvemencANCA GN may present (~~=»~w¢u 2014:s3w)
Medium Vessel Vasculitis
Polyaneritis nodosa: alw HBV frequently; renal artery microaneurysm -» rupture. peri
renal hematoma, renal infarctions; mild proteinuria. CKD. HTN (dl: RAS activation)
Skin: redform (angulated) purpura 1 palpable purpura
Small Vessel Vasculitis
IgA vasculitis (HSP). staphassoclated IgA dominant lRGN.ANCAassociated GN.
cryoglobulinemia
Renal manifestation: GN with hematuria and proxeinuria
Skin: palpable purpura. telangiecusia. ulcer urticaria
Skln biopsy: Ieukocytoclastic vasculiziszdirecc IF should be performed
IgA deposition in IV. IgM deposition in cryoglobulinemia. pauciimmune in ANCA
 PAIN MEDICINE
ANALGESIC NEPHROPATHY
CKD due to years of consuming as leas: 2 analgesics. usually containing codeine or
caffeine (A;XD 1996:27:16112 can also occur with single agents
Most cases were due to phenace:in.rnuch less common since banned in 1983 by FDA
Phenacetin also linked to urochelial malignancies
Chronic acetaminophen: possible (NEW 2001:34S:1B01)I aspirin: unlikely UAMA 1001;186:315)
unSAIDs cause AKI and worsening of preexisting CKD. but unclear if uses incident
CKD (Ann :m 2004=\64:1s1t Am/ m¢4 2oo7;1zazs0)
Pathogenesis 1AIKO 19964n5s391
Phenacetin metabolized no acetaminophen and other metabolites.which concentrate
in renal papilla. causing damage by lipid peroxidation: most damage in renal medulla
Aspirin potentiates effect of acetaminophen by further depleting glutathione. which
n o rma lly d e to xifie s a ce ta min o p h e n

Clinical Manifestations,Workup, and Treatment

Renal papillary necrosis. chronic interstitial nephritis. 1 urinary concentrating capacity
(KI 1007:72:517)
Often clinical diagnosis based on history.bland urine. minimal proteinuria
Noncontrast CT: indented kidneys and papillary calcifications but low sensitivity,
especially in absence of phenacetin (5-26%) (MSN 2006;17:1472)
Sensitivity of ultrasound likely even lower sensitivity, but frequently firstline imaging
Urinalysis with spot proteinuria (usually <1.5 g) (KI Z007:72:517)
Tx: no specific treatment other than stopping offending analgesics
P rognos i s
If analgesics are stopped. eGFR can stabilize if there is not heavy proteinuria or CKD
is not advanced. heavy proteinuria can develop due to nephron loss
Monitor patients with a history of phenacetin use for transitional cell malignancy

N s r H noTox lc 1 Tv oF unSA ID s

Mostly associated with AKI but can worsen preexisting CKD and may muse incident
CKD: no established sale dose/duration in setting of CKD. risk higher with lower GFR
Topical unSAIDs with far less systemic absorption than oral.fewer side effects (See
Anhwx Rheum 1016;45:51911 case reports of renal failure after topical use. not well studied
in CKD.c a nnot routine ly re c omme nd c urre ntly
COX2 inhibitors: risk of AKI may be lower with celecoxib than naproxen
or other nonselective unSAIDs (RR 1.5 vs 2.4 and 2.3. respectively) rAm} £via¢mIaI
2006:164:881)
Pathophysiology and Risk Factors
Inhibit renal prostaglandin (PG) synthesis; PG -o renal afferent arteriolar vasodilation
and natriuresis. in normal circumstances. not very important
In setting of hypoperfusion. renal PG needed to counteract excessive renal vaso
constriccive effects ofAIl and SNS to preserve renal blood flow and GFR
. unSAIDs blodt PGs. leading no vasoconstriction. renal isclleinia.L GFR. and fluid retention
AKI risk factors CHE cirrhosis, nephrotic syndrome, hypercalcemia. volume depletion
(all conditions that lead to decreased effective arterial volume): also CKD. elderly
Concurrent ACEI/ARB + diuretic v unSAIDs combo increase risk (5m}101J;346 ¢8525>
Clin ica l Ma n if e st a t io n
Hemodynamically mediated AKl,ATN,AIN, MN. MCD. chronic tubulointemitial nephritis.
hypertension lNE;M 19B4:310:563)
Usually minimal proteinuria (<0.5-1 g).wlth acellular urine; heavier proteinurla suggests
MN or MCD. or from preexisting CKD; sterile pyuria suggests AIN
Electrolyte Derangements
Hyperkalemia: UNSAIDmediated decrease in aldosterone release. hyporenin state from
d e cre a se in P Gs.a n d a n y co n cu rre n t re n a l fa ilu re
Hyponatremia: increased ADH activity from decrease in PGs.and concurrent renal
f a ilu re wh ich limit s f re e wa t e r cle a ra n ce
Treatment
Supportive. volume replerlon. hokl UNSAIDs/ACEIIARB: may need biopsy if no improve
men: in few days. or if atypical labs such as >1 g proneinuria or cellular urine :had would
suggest a lesion other than ATN (eg, membranous.AIN)

PAIN CONTNOL IN CKD AND ESRD (ScmmOal2014;27:188)

Mo s: data in HD. prevalence 21-81%. similar in PD and nondialysis stage 5 CKD: narly
73% in one study of CKD 1-5 paciencs (cm n¢w-u1 z010;7:4:z94)
Adjunctive nonpharmacologic therapies (kg,exencise, behavioral Maw) should be tried
Pharmacokinetics of analgesics are different in CKD vs nonCKD
General Approach to Chronic Pain
Modified WHO Analgesia Ladder (1Asr4 z00s;w1:19s)
Step 1 Acetaminophen
Step 2 Hydrocodone. oxycodone. tramadol
Step 3 Hydromorphone. methadone. fentanyl. oxycodone

Avo ld u n SAIDs. me p e rid in e (ca u se s se izu re s)

If ineffective add tramadol, or switch to lowdose opioids with slow titration if
needed

Ne u ro p a t h ic P a in
Common in CKD given high prevalence of DM
Tac sun wl SNRI or gabapendn/pneigahalin; cautiously use TCA: open need combo dierapy
Lidocaine patches if localized; addon acetaminophen +I- opioids/tramadol if needed
C a r p a I T u n n e I S yn d r o m e
9-63% incidence in ESRD. increases with duration of time on dialysis: due to deposition of
B2microglobulin amyloid. extracellular calcification. and ischemia related toAV access
T>c usually splinting. cs injection, or surgical decompression for sevenelrefractory cases
ADPKD
Pain due to enlarging cysts. scones. cyst hemorrhagehnfection. polycystic liver disease
Tx: consider surgery if mediations/conservative therapy fail, cyst aspiration. sclerodierapy

Dialysis Removal and Renal Dosing of Analgesics isemi ouzo14a7;1sa;

Me d i ca t i o n Re mo va l C o mme n t s a n d Ma ximu m D o sin g
A ce t a mi n o p h e n HD: yes; PD: no No dose changesfrstline analgesic
Co d e i n e HD: no: PD: unlikely No t re co mme n d e d . Me t a b o lize d t o
mo r p h i n e d e r i va t i ve s; ca n ca u se CNS /
r e sp i r a t o r y d e p r e ssi o n . h yp o t e n si o n
Tramadol e G FR 1 0 - 3 0 : $ 0 - 1 0 0 mg B I D
eGFR <10 or HD: S0 mg BID: dose after HD
P
Morphine HD: yes (parendacrive No t re co mme n d e d . Me t a b o lit e s w
u
mefabolices); a ccu mu l a t e i n CK D ca u si n g se d a t i o n .
PD: no co n f u si o n . r e sp i r a t o r y d e p r e ssi o n .
myoclonus
Hydrcmorphone HD yes (active Better talented than morphine. fewer toxic
metabolite): PD: ! met abolit es
Fenranyl HD/ P D: n o Inactive metabolites, safe to use if monitored
Buprenorphine HD/PD: yes Generally saf e t o use
Oxycodone HD: yes; PD: ? Generally safe to use. case reports of toxicity
Methadone HD/PD: no Similar plasma levels as nonCKD, may help
wit h neuropat hic pain. generally saf e
Gabapenlin sle: CNS depression, myotlonus if overdosed
CrCl <1$:dose after HD: 300 mg QD:stzn
100 mg after HD or 100 mg QOD if not
ESRD; CrCl 15-29: 300 mg BID: CrCl 30-49:
3 0 0 mg Tl D; Cr Cl 5 0 - 7 9 : 6 0 0 mg T I D
Pregabalin HD/ PD: yes QGFR <15: dose af t er HD: 75 mg QD: st art 25
mg alter HD or 25 mg QOD if not ESRD
e G FR 1 5 - 3 0 : 1 5 0 mg Q D
eG FR >30: 150 ms B I D
 Duloxedne 30-60 mg daily: eGFR <30: do no: use
TCA Use cautiously esp, in cardiac patients, can
(amitripryiine, cause QT prolongation and arrhythmias.
nomipryline) start low (je. 10 mg QD): nortripcyllne may
be better tolerated with less sedation

Topical capsaicin Useful for local pain (eg. knee osteoarthritis)

PSYCHIATRY, SLEEP MEDICINE, AND NEUROLOGY

CHRO NIC L IT HIUM T O XICIT Y

Lithium (Li) commonly used to treat bipolar disorder. mania. and depression

Pathogenesis
Li freely filtered at glomerulus; absorbed as various points in nephron uAsr4 201s;21=1 San
In proximal tubule. small amount of transcellular and paracellular reabsorption
In thick ascending limb. paracellular movement due to favorable luminal gradient cre
ated by potassium efflux into tubule via RO MK channel
In distal tubule/collecting duct. reabsorbed by principal cells through ENaC.causes
nephrogenic Dl (NDI) by downiegulating aquaporin2: Dl also caused by increased
prostaglandins. which inhibit aquaporin2 expression
Hypercalcemia due to hyperparathyroidism. raising threshold for calcium sensing
receptor in paradiyroid gland (lame 2012;an721; Jam 1984:59:354)
C lin ica l M a n if e st a t io n s
Nephrogenic DI: polyuria/polydipsia.hypernatremia.dilute urine. nocturia
CKD: chronic cubulointerstitial disease. renal microcysi.s.can progress to ESRD
(15% in Li users. 68x higher than general population) UASN 1018;1731 ssn
Typioliy subnephrodc pnoieinuria (<1 old usually). but can develop FSGS and increased
proteinuria; also rarely nephrotic range proteinuria with MCD
Hyperparathyroidism with hypercalcemia-up to 25% (KI 2003;64:58S1
Wor kup
/ BMR UIA with spot proteinuria and osmolality. PTH. UIS: microcysts
Renal bx: proximal tubular atrophy and chronic interstitial fibrosis. FSGS. microcyszs
originating from distal tubule/collecting duce. distil tubular dilacadon In lB03:64:5B5)
8 N ephr ogenic D I ( N D I )
é First option always dlc Li if possible
NDI can improve if treatment begins prior to onset of severe concentrating defect
Preferred: if continuing Li. start amiloride 5-10 mg daily, competes with Li for ENaC.
blocking entry into principal cells and T urine osmolality, if concenuating defect not
severe 1NE/M 19a5=31z4asl; monitor Li level as can T due to amilorideinduced volume
depletion and increased proximal tubular reabsorption
Other options similar for any fuse of NDI: (1) unSAIDs which 1 prostaglandins and
concentrate urine, but contraindicated with CKD: (2) low salt diet/thiazides -» hypo
volemia,causes i proximal urinary reabsorption.and i urine output. monitor Li levels
closely: (3) Acetazolamide (experimental) <~2Jm z016:.7s.100el
CKD
Stopping Li can stabilize or modesdy improve renal function if CKD not advanced.
otherwise can still progress. may be a "point of no return" around eGFR <40 where
renal function continues to decline even if Li is stopped (KJ 2003;s4=sB$)
7/9 patients with Cr >2.5 progressed to ESRD despite stopping Li ()ASN 10t10.11:1439)
Greater proteinuria alw poorer prognosis and higher rates of ESRD. possibly due to
superimposed FSGS UAS~ 2000211:1419)
O ther T r eatments
Hypercalcemia treatment: if severe consider cinacalcet (App) 2006:48:8J 1)
Cautious use ofACEllARB and thiazides which T Li levels: monitor levels closely.
usually need empiric Li dose reduction

ANX IE TY in CKD (s - D°» ,=» » 1 0 1 5 :1 8 :4 1 7 )

SSRIs can be used for generalized anxiety disorder
Benzodiazepines can be used, most hepatically metabolized and no dose adjusunen:
needed: Chlordiazepoxide has active merabolices -» 50% dose reduction: other ben
zodiazepines would start lower than usual dose
 PsvcHosls in CKD (Semn n4¢vi=»= 2015:19:417)
Aripiprazole and quetiapine have similar pharmacokinetics in CKD and nonCKD
Risperidone should be dose reduced with CKD due to active metabolite
Haloperidol not well studied but unlikely to need dose adjustment
Monitor for side effects including prolonged QTc

D EA N £SSIO N IN C K D
Prevalence 22% in both dialysis and nondialysis CKD. and is associated with increased
mortality (Ki 2013:a4:17/: kw 1013:62:493)
Adverse outcomes in CKD patients with depression may be due to increased inflam
mation. nonadherence. autonomic/endocrine imbalances
Likely underdlagnosed; routine screening controversial. unclear if treatment improves
outcomes; depression scales should be adjusted with higher thresholds in ESRD (eg,
Beck Depression Inventory threshold t (rom >9 to 14-16) Lu 100616116629
T reat m en t
RCT data lacking. ideally should be combination meds/behavioral changes
Underrreaced (<50% on meds) in ESRD (xl zoos;sm 1se2)
Nonpharmacologic rreacmenc limited dm show bench: for CBT and exercise
Meds: SSRI generally firs: line; in generaI.any medication should be started at low
dose with slow cirrarion

Antidepressants In CKD 00201u1z47= Apu:1009:s¢741; Aw N 1) nynuevy 2014;40:510)

Medication Dose and Comments
SSRI
Ciulopram Ciulopnm: start 10 mild: active metabolites. cautious use if eGFR <20
although probably safe based on small studies lAM rea z001=29=e1n
Fluoxecine Fluonnedne: sur: 20 mg/d: no renal dose adjusunenl. use uudously because
long halfIife.smalI studies showed safety in ERD an my-uw m iv 1997a7:7\)
Sertraline Senralinez sun S0 mg/dzactive metzbolire bu: no renal dosing
Paroxedne Paroxedne (immediate release) accumulates with eGFR <30. Starr at
10 mold, increase slowly co max 40 mg/d
Class sle: nausea. hyponaznemia. sexual. HA. ? bleeding
Rdadve good safety record was cardiovascular disease
SNRI
Venlafaxine Venlafaxine: toxic metabolites. avoid if eGFR <10.l dose by 50% for eGFR
10-50;stan ER 37.5 mg/d;side effects: HTN. sexual
Duloxenine Duloxetinez in 30 mg/d: do not use if eGeR <30;side effects: nausea.
dry mouth. fatigue
Trazodone No dose adjustment but start low (150 mg immediate release) in divided
doses:can be used for insomnia (start 25-50 mg QHS); side effects:
sedation. priapism. dry mouth
Bupropion Toxic metabolites. can fuse cardiac dysrhythmia
Nor recommended for CKD
Mirtazaplne Antidepressanrlanxiolytic effects; sedating properties: accumulates in
ESRD. use with caution (Hum f»<~i#w~»°t=I 19ss4imxsn
TCA
Amitriptyline Can have cardiac side effects including QTc prolongation and anrhrythmias.
and anticholinergic effects; use with caution
Nortripqrline Stan with low dose (10 mild) and increase slowly
Desipramine Can be useful for neuropathic pain

SL EEP D l s o n o s n s : n C K D
Insomnia and Poor Sleep Quality (Semm ~¢l»v1 Z015:3$:]S9)
Prevalence 2040% and increases even in early CKD:a/w somorbid conditions
including fatigue. depression. and anxiety; may increase risk of mortality in ESRD
(NDT 1008;13:998)
Conuibutcrs: comorbld conditions (eg.CHE depression).mediations. pmrims. pain,
dialysis schedules. physical inactivity. nocturia. substance abuse
History: if heavy snoring. restless legs, parasomnias. refer to sleep specialist to rule out
more serious sleep conditions (et, OSA)
 Nonpharmacologic treatment preferred over medications
Start with trial of slip hygiene. treat comorbidities. modify any culprit meds
Cognitive behavioral therapy has efficacy in ESRD W 2011m¢41s)
Pharmacologic treatment; limited data in CKD, always start at low doses
No dose adjustment for nonbenzodiazepine benzodialepine receptor agonists such
as zolpidem. zaleplon. eszopiclone (hepatially metabolized)
Melatonin receptor agonist ramelteon not well studied in CKD. no dose
adjustment
Benzodiazepines and trazodone can be used as well (see above sections)
Restless Leg Syndrome (RLS)
Definition: an urge to move legs during periods of rest. usually worse at night,
accompanied by discomfort. and relieved by movement
Distinguish from periodic limb movement disorder. characterized by increased limb
movements in sleep
Prevalence: much higher in ESRD than general population (30%),significantly lowers
quality of life (KI 2013;85112751; nondialysis CKD similar to general population
Risk factors in ESRD: low iron/hemoglobin and diabetes :so mea zo\411s11sn)
Treaunent (xi 2013:B51275)
Improves with transplantation (Mor aims 2002:17:1072)
Fix iron stores/anemia. remove SSRIITCA (may exacerbate RLS). dopamine agonists
(firstline medications). gabapentin/benzodiazepines (secondline)
Sleep Apnea Syndrome in 200s;10 1sa7i
Definition: disturbed sleep from periods of apnea -» oxygen desaturation and arousal
Prevalence: >$0% in ESRD vs 2-4% in general populationzt risk of CVD
Different phenotype in general population. usually obstructive. in ESRD even distri
bution between centrallobsuuctive/mixed; possibly due to uremic toxins.volume
overload, altered chemoreceptor sensitivity affecting respiratory control
Treatment; CPAR nocturnal hemodialysis (NEW 1001;344:1021. transplantation Hanging
style

STROKE AND CEREBROVASCULAR DISEASE

CKD is an independent risk factor for stroke; T risk 41% with eGFR <60 raM/
1010341:c4149)
Dialysis patients have 10x T risk of CVA and carotid endanerectomy vs general popu
lation. ischemic stroke most common. embolic most common subtype; high mortality
and worse neurologic outcomes We 1009;54146a Neuinlqy 20iua1909)
Perfusion abnormalities, subclinical white matter disease. brain atrophy.and silent
infarcts more common in CKD. especially dialysis (Sunni Nepnid z01s;as:311)
Besides traditional stroke risk factors. nontraditional risk factors more common in
CKD (anemia, inflammation, oxidathre stress. uremic toxins. sleep dysregulation)
Stroke Prevention in Setting of Atrial Fibrillation (A fib)
A fib common in CKD. exact management unclear
Warfarin use appears to reduce stroke risk, but may increase bleeding risk in CKD.
particularly in dialysis patients. and anticoagulation risk needs to be individualized
(WI 201§;]50:h246: WM 1014131 l:919)
Warfarin may have other adverse effects in CKD;associated with T vascular calcifica
tion in animal models, by interfering with matrix gla protein. which is a potent inhibi
tor of vascular calcification: also T risk for calciphylaxis (Mai Dd z014;17=371
Novel anticoagulants require dose adjustment in CKD. none well studied in ESRD where
warfarin Is still drug of choice: in retrospective cdion study apixaban 5 mg BID reduced
risk of suoie. bleeding, death vs warfarin while apinahan 2.5 mg BID reduced risk of
bleeding but not deadilsuoke vs warfarin (cranium. zmaiaeiswi
Stroke Treatment
Therapies less likely so be utilized in CKD (Seam n2p"ml 2015,zs23111
No dose adlusunent for tPA. but outcomes less favorable in CKD (nnuulqy 101381:17a0>

COGNITIVE DECLINE AND DEMENTIA

Epidemiology: even mildtomoderate CKD is a risk factor for cognitive decline
Cognitive impairment in 30-60% of HD patients ()A$n 2013;24=3s3)
Manifests as a vasculamype dementia with impairment in memory and executive
function (m Rey Neural 1009:5:542)i may also raise risk of nonvascular dementia
 Pathophysiology:
Tradrdonal and nomradltional (anemia. Inflammation,oxidative stress. uremic toxins.
sleep dysregulation, endothelial dysfunction) risk factors clustered in CKD
L cerebral blood flow.t subclinical cerebrovascular disease on MRI
Potential improvement after transplantation (NOT 200s;21:327s)

NEUROPATHIES (Not Rev Neuld 20025:5421

Ure mic Ne u ro p a t h y
On ly in E S RD, p re va le n ce 6 0 -9 0 %.ch ro n ic p ro ce ss
Clinical Manifestations: symmetric lengthdependent polyneuropatlvy. starting with
sensory deficits. paresthesia. loss of ankle reilexesz can eventually involve motor nerves
mu scle a tro p h y a n d we a kn e ss
Differential: diabetes. paraprotein disease.vasculitis. inflammatory demyelinatlng
neuropathies (associated with FSGS and membranous. usually much more acute)
Dia g n o sis: n e rve co n d u ct io n st u d ie s
Treatment: ensure achieving adequate clearance on dialysis: transplantation may
re ve rse symp to ms. p a in ma n a g e me n t

Carpal Tunnel Syndrome isemm Op: 1014:171881

Common in ESRD: 9-63% prevalence. increases with duration of time on dialysis
Clinical manifestations: sensory symptoms initially (numbness. paresthesia) which
can progress to muscle atrophy in medial nerve territory; can worsen on dialysis
Pathophysiology: multifactorial; deposition of B2microglobulin amyloid. extracellu
la r ca lcifica tio n . isch e mia re la te d to AV a cce ss
Treatment: usually splinting. corticosteroid injection. or surgical decompression for
se ve re /re fra cto ry ca se s
Aut onomic N eur opat hy
6 0 % o f p a t ie n t s wit h CK D
Clinical manifestations: has been detected even in early CKD
Intradialytic hypotension. orthoslasis. erectile dysfunction, cardiac arrhythmias
Higher resting HR. lower HR variability predict ESRD and hospitalization UASN
1010.211s601
Treatment: may improve with transplantation (he et Oialruiupianmnac 1979:16:261)
Midodrine for intradialytic hypotension
S ild e n a fil fo r e re ctile d ysfu n ctio n . has most day for CKD: consider holding on
dialysis days if imradialytic hypotension

ACUTE UREMIC ENCEPHALOFATHY

Due m buildup of uremic toxins: result: in irritability. confusion, headache. nausea,
tremor. asterixis, myoclonus. coma (in severe cases). treatment is dialysis
Treaunent is dialysis. overly aggressive dialysis on initial treatment with high BUN can
precipitate dialysis disequilibrium syndrome

DIALYSIS DISEQUILIBRIUM SYNDROME (Semin D041 200822049J 1

Clinical manifestations: headache. nausea. fatigue, seizures/coma (severe cases)

Risk factors: old age,very high BUN. initial treatment, neurologic disease
Padlop physiology: cerebral edema due to osmotic shifts; rapid decline in plasma BUN
causes water to shift intracellularly: also possibly from paradoxical CSF acidosis induced
by rapid correction of serum bicarbonate levels with dialysis
Prevention: slow, gentle dialysis aiming for no more than 40% urea reduction during
first session: et. 2 hr, blood flow 200 mUm in. with small Winer: IV manniml/hypenonic
saline for prevention. but data limited; increases dialysate sodium 143-146 mEq/L may
b e h e lp f u l if h ig h risk
Treatmenc supportive. reduce dialysis blood flow: terminate dialysis if significant
symptoms; IV mannitol or hypertonic saline may be useful: key is prevention

UREMIC MYOPATHY
Up to 50% of dialysis patients; proximal muscle weakness/wasdng. especially legs
Pathophysiology unclean! role for hyperparathyroidism. vitamin D deficiency. uremic
toxins, malnutrition, muscle biopsy nonspecific
Trearmenc correct metabolic disarray. nutritional sums. anemia
 DRUGINDUCED ENCEPHALOPATHY IN CKD
Numerous common medications implicated. especially when incorrectly dosed
H2 antagonists: infrequently causes altered mental status and delirium. improves with
withdrawal (Am1 m¢a so zoosaaozal
Baclofen: presents wl altered mental status. respiratory depression. somnolence; avoid
with eGFR <60. no safe dosing guidelines in CKD; treatment is daily dialysis (Semn ons
101538: 525)
Gabapendn: entirely renally cleared: useful in CKD for neuropathic pain, uremic pruri
ms. restless legs: improper dosing can lead to accumulation causing myodonus,altered
mental status, coma (pm Med z009110.1901
Acyclovir We 1992;10:647) and valacyclovir in PD: celepime

CEREBRAL EDEMA AND RENAL REPLACEMENTTHERAPY (Semin Dal 2D09;22.16§)

Cerebral edema and elevated intracranial pressure can be seen with trauma, hemor
rhage. stroke. liver failure. tumor, infection
Pathophysiology intermittent HD (HD) can worsen cerebral edema by removing solutes
from plasma. causing an osmotic gradient favoring movement of water intracellular also
rapid correction of plasma bkalbor\ate,which cannot readily cross bloodbrain barrier
can combine with hydrogen ions - CON formation -» diffuses into CSF > inuacellular
acidosis -> generation of intracellular osmoles and water mo.~ement intracellularly
CRRT preferred over iHD. due to less osmotic shifts and greater cardiovascular and
intracranial pressure stabilit aim for lower clearance than usual
If HD must be used: start low blood flow (50 mUm in increasing to maximum
250 mUm in). short sessions (2 hr), daily treatments, cool dialysate (35C). higher dial
ysate sodium (up to 10 mE/L higher than plasma). lower bicarbonate dialysate
Hypertonic saline boluses an be used during HD or CRRT to maintain sodium 145-155

SODIUM DISORDERS

57% in one series. with 20% developing sodium <130; more commonly due to SIADH
than cerebral Sal: wasting (69% vs 75%) (an Eniiuainal 1006;s4¢1s0);although true incidence
unknown given diagnostic challenges
Cerebral salt wasting usually within 10 d. resolves by 3-4 wk (nor 1000:15:262)
Comparison of SIADH and Cerebral Salt Wasting
SI AD H Cer ebr al Salt Wasting

Urine sodium Elewcedz >40 Elevated: >40

Urine osmolalizy Elevared;>100, often higher Elevaced;>100,of:en higher

Serum uric acid Usually low Usually low

Volume scacus Euvolemic/slightly hypervolemic Hypovolemic
Physical exam/ Typically normal 1 Skin wrgor, hemoconcencrarion.
T BIJN/Cr ratio. ordiosrasis.
Other Lab
relative hypotension

Pathophysiology Inappropriate ADH secretion Unknownzl syrnpathelic

Response w IV Does not improve. may even
worsen if Um >300 as infused
normal saline
sodium is excreted bu: some
challenge
water is reiainedc Um does
no: change significantly
reducing FT Na absorption,
possible unidentified nacriureric
factor (nor zoa0.1s= 1s21
Should improve hyponanremia as
restoring volume :urns off
ADH, causing excretion of
dilute urine;of note. :his is no:
always the case as there may
be coexisting SIADH
Treatment Fluid restriction or vasopressin
antagonist; however if SAH,
cannot fluid restrict dk risk of
vasospasm. give hypertonic
saline to ensure volume and
sodium correct ($6 T R4 hr)
Volume expansion widl IV normal
saline; +I- fludrocorzisone:
given diagnostic difficulty with
SIADH, star: hypersonic saline
if sodium not improving

Transsphenoidal Pituitary Surgery (1 Nwmrug 2007:10666: Fiwwr 200/:9:93i

Both SIADH and DI can occur postoperatively though DI more common
Associated win\ classic triphasic pattern. although incidence of this parer is low
1. Polyuria and hypernatremia from CDI (19% Incidence: usually first
48 hr )
2. Hyponatremia from release of stored ADH (994 incidence: 4-7 d postop)
3. Hypernatremia from CDI when stored ADH depleted
TX: depends on phase: DDAVF during DI.fluid restriction or hypertonic saline during
SIADH
Monitor sodium 1 wk following surgery as outpatient to check for SIADH
80% of DI resolved at 3 mo at one center

OBSTETRICS
PREG NANCY AND KIDNEY

Weight gain: 1-1.5 kg during 1s¢ zrimesrer (12 wk).0.45 kglwk during 2nd (13-27 wk).
and 3rd ¢rimes¢er (28-40 wk) (nor 199e;1J:Jz4»6). Overweighdobese mothers gain
more weighs; underweight gain less weigh: (cam G/~<~2015:1zs:773)
1 SVR.t CO. l MAP (nadir as 18-24 wk);glomerular hyperfilr.rnion.t GFR by 37-4098;
7 Kidney size by 1 cm.dilaxation of the collecting duct R > L (qAsn 101271073)
Adverse pregnancy outcome is lower with eGFR 120-150 lcusu 2017,111048)
Effects of T Progesterone (LH Surge ~4 wk before Delivery) and its Binding
to Mineralocorticoid Receptor (MR)
Normal Anragonisdc; Potassium rexemion
1 Aldostemnism Antagonistic; Resolution of HTN and hypokalemia
Geller syndrome GOF murazion of MR: progesterone and spimnolactone become
agonist; HTN and hypokalemia (Saenze NU0.1a9=119)

. PT reabsorption: glycosuria. amino aciduria. tubular proteinuria w/o true pathology

Hypokalemia and metabolic alkalosis: dl: vomitingzl serum albumin
Gesradonal DI: vasopressinase produced by placenta: polyuria throughout pregnancy.
recurs w/ each pregnancy. responds to both DDAVP and AVP
Other DI: alw HELLR acute fatty lMr: 3rd trimester; decreased metabolism of vaso
pressinase; responds only to DDAVP
Preterm and early term birth is alw later CKD likely dlt i nephron (aw 201%3A5:I13461

MEDICATIO NS IN PREG NANCY

 Hyperiipidemia

Amkoaguhrion Warfarin

Dose requirement is increased dl: T volume of distribution, hepatic metabolism. GFR.

and l albumin and drug protein binding
Medicat ion during Breast f eeding
For a list of medication use in breastfeeding. please refer to the LactMed Database:
https:l/toxnet.nlm.nih.govlnevnoxnet/lactmed.htm
Era la. capto. and quinapril do not pass into breast milk: warfarin is safe for brezsdeeding
Most andhypertensives are present at breast milk; kbeizlol and nifedipine acceptable;
avoid atenolol

HYPERTENSIVE DISORDERS oF PREGNANCV (HDP)

Gestational Hypertension
New onset of HTN (SBP 2140 and/or DBP 290) at 220 wk of gestation in the absence
of proteinuria or new signs of endorgan dysfunction
HTN at <20 wk is chronic HTN. not gestational HTN
alw sustained HTN and CV disease later in life (j i4lp¢ne1¢ z010:zs:m)
Tre a tme n t
BP control may prevent maternal endorgan damage
BP control may l placental perfusion:a/w 1 birth weight (/canel Gynuea\lCan z00zz4:941)
Tight control (DBP goal 85) not alw 1 pregnancy loss. highlevel neonatal care. maternal
complication including preeclampsia (NE/M 10155:l721407)
Sak restriction close to delivery is not recommended to avoid volume depletion
Ca (>1 g/d): 35% HTN and 55% l preeclampsia (a<n~»e Daahase Syxrkev 2010¢cooo\os9)
Weight loss during pregnancy: not recommended; gain goal (kg): 11.2-15.9 in BMI <25;
6.8-11.2 in BMI 25-29.9; <6.8 kg in BMI 230 (be Cyan Gwen:20ae111701
Weight loss after deliveryt recommended lAM) 2017;35B113014)
BP conuol in mild-moderate HTN: unclear benefit (Cotluune Daiaiaase synnezoimooozzszl
Severe HTN: >150/95 lest; EurHeor]10\1:32:]147) 160/105 lncoc. onus G>~<~
1013;11211221 should be treated w/ antihypertensive
Avoid UNSAIDs:frequently used for peripartum analgesia
Folkrw up no later than 7-10 d postpartum; if severe wfl 72 hr (aeu¢¢Gyn¢¢al201B;1J1;e140)
Pr ognosis
HTN development wu 10 yr is 14% (vs, 4% in nonHDP) (BM) zowlaseiaon
Half of postpartum stroke occurs wu 10 d of discharge (own Cyndi z018:1:70)
Chronic HTN (x2.8).T2DM (x1.7). hypercholesterolemia (x1.4) (Ann IM 2018;1691141

PREECLAHPSIA
Pathogenesis
Placental hypoperfusion inducing soluble fins-like tyrosine kinase 1 (sFlt1. soluble VEGF
receptor 1. sVEGFr1): circulating antagonist toVEGF and placental growth factor (PIGF):
t sFLT1/PIGF (no 20162374¢131
Deficiency of Apela/ELABELA, placental angiogenesis mediator (Soenre 1017;387:7071
Endothelial dysfunction (1 NO.t endothelin); injury of multiple organs
Definition iAcoG Geaelme Cami Gynecol 201].122l122)
BP >140190 after 20 wk of gestation, previously normal BP AND one of following
Proteinuria >300 mg/24 hr or spot urine prodcreat 0.3 gig
Platelet <100K; Cr >1.1 or doubling in the absence of other renal disease
Liver transaminases >x2 the normal; pulmonary edema: cerebral or visual symptoms
Severe Features:Any of Following (Acoc Goaan Obslet Gynecol 1013.112:1IZ2)
BP >1601110 x2 >4 hr apart on bed rest
Platelet <100K; Cr >1.1 or doubling in the absence of other renal disease
Liver transaminases >x2 the normal or RUQ or epigastric pain not explained otherwise
Pulmonary edema. newonset cerebral or visual symptoms
Clinical Manifestations
AKI:TMA (endothelial injury)
Seizure (eclampsia). cerebral hemorrhage. hepatic rupture, pulmonary edema. bleeding
related to thrombocytopenia. abruptio placenta. or fetal growth restriction
10-20% HELLP (hemolysis, elevated liver enzymes and low platelet) syndrome
ml cause of prematurity
Diagnosis in ESRD is challenging: proteinuria and renal function cannot be evaluated
Uterine and umbilical artery Doppler U/S:t pulsatility index » fetal growth resuiction
Risk Factors and Prevention
Risk assessment is available: https:I/fetalmedicine.org/research/assess/preeclampsia
Recovered AKI ()<4,7) l;Asn 2017:2a1su61. fetal APOL1 risk allele Luc 201&103=3671

Aspirin Prophylaxis for Pneeclampsla lusvsrf An IM 1014:15um

High risk factors Renal disease. hlo preeclampsia. esp. accompanied by an adverse
outcome.mulr.ifetal gestatiomchronic HTN.Type 1 or 2 DM.
SLE.APS
Moderate risk factors Nulliparity. BMI >30 kg/m*. mother or sisters ho preedampsia.
African American race. low socioeconomic status. 235 ylo. low
birth weigh: or small for gestational age. previous adverse
pregnancy outcome. >10yr pregnancy interval
Aspirin 81 ml qd if 21 high risk factors or several moderate risk actors from 12 wk no 510 d befog
expected delivery

Aspirin 1 delivery w/ preeclampsia before 37 wk in high risk group (NEW 1011;377:6131

Ca supplementation (>1 old): 55% l preeclampsia (Cachmne O0mnm¢ Syn an 2010;cD0010591
Weigh: loss loam: Gym#2010:116667)I bariatric surgery UAMA zucasoimssl

Monitoring and Diagnosis

U/S w screen for feral gmwdw reslrictiomif present umbilical artery Doppler velocimetry
Kidney biopsy not always necessary

T reat m en t
CS for lung maturity if <34 wk with severe features
M8SO4 pre and postpartum for severe features to prevent seilure;/ DTR. J Mg in
mother and baby: half dose for ESRD mother
BP control:antihypertensives for severe HTN >1 $0/95 - 160/105
Delivery (placental removal): only definitive treatment; consider regardless of gesladon
age if uncontrollable severe HTN,eclampsia. pulmonary edema.abruption placentae.
DIC. nonreassuring feral srazus IACOG GudelneOhuxn com: 2013;127;1 ml
Prognosis
cm esp wu 5 y x3.9 (delivery < 34w) x2.8 (delivery 34-36w) usu z019;365:II51 q
T ESRD x5;x9.2 if preterm; X7.1 if preeclampsia in 2 pregnancies (PLuS Med 2019e1001A7$) |
415% had HTN 1 yr after severe preeclampsia uqpenenwi 1018271149\)
alw dementia, esp. vascular type fam;1018;363k4109)
Regarded as riskenhancing factor ofASCVD (ACC/AHA Cnmlmn 101213941049

A K I I N PR EG N A N C Y
Absence of 1 Cr during pregnancy is sign of renal dysfunction
AKI requiring dialysis: 1/10.000; 4.3 vs 0.01% died: T preterm birth. low birth weight.
small for geslzdonal age, 69% experienced complications (preedampsia.TMA. HF. sepsis.
or poszparwm hemorrhage) UASN 2015:Z6:J085).

Possible Causes of AKI In Pregnancy (KJ up zmuam

1st Septic abortion. hyperemesis gravidarum
2 nd-3rd Preeclampsia/HELLP (after 20 wk),TTE complementmediated HUS (aHUS).
acute fatty liver of pregnancy
Anyri me LN.APS

Acute fatty liver of pregnancy 1 anzkhrombin activity:AKI 14-90%. HTNlpreeclampsia

26-70% U Cone: Go¢=<»l Res 2014:4as41>
 GLOMERULAR DISEASES AND PREGNANCY
Background
Proreinuria, t BP and CKD are a/w adverse outcome
Pregnancy can potentially worsen proteinurla. HTN. edema In NS
In leAn w/ Cr 51.2. pregnancy was not alw difference in kidney function (Ajxo 1010:S6;sOe)
Infant Survival Rates (X) law zmvntauzl
leAn 70-100 FSGS 55-94
MN 67-76 MCD 71-76

NS during Pregnancy In 1017.91,1464)

Causes: FSGS > ION. MN > Fibrillary. PIPGN. C3G. MCD
T preterm,preeclampsia (27 vs 3.4%). Csection
Kidney Biopsy during Pregnancy
T complimion Zhan posrpanum (7 vs 1%); major bleeding as 23-26 wk laps 2011114411)
Bx after az wk gestation is nor. recommended (kw \9B7:94:932)

ATYPlCAL HUS (aHUS) AND PREGNANCY

Alternative complement activation. Pregnancy is frequent triggering event.
Not all patients have genetic muutions
Risk factors: hlo HUS. aHUS (26%) UASN 20199910201
Common between 36 wk to postpartum; similar severity wl nonpregnancy aHUS;
r ar e death: 27-57% ESRD l qAs~ 2017;1Z:1137; or z01s:93:4so; I As~ 1018:19:1020)
Overlapping features with preeclampsia including biopsy finding (TMA)
aHUS does not resolve with delivery vs preeclampsia resolve with delivery
Eculizumab: used in pregnancy safely; no ESRD out of the 22 cases (KA z018:9J<4$0)

SLE AND S16GREN Svnoaor4E AND Pos<snAncv

Background
Risk factors of active nephritis during pregnancy: active disease wu 6 mo before con
ceprion, hlo multiple flares, dlc of hydroxychloroquine (Rheum Of an Nom»Am 1007;33:137),
past kidney disease. low C4: low C3 or dsDNA Ab alone are NOT (c;Asn 2017:I 2:940)
Risk factors of adverse pregnancy outcome: (+) lupus anticoagulant. antihypertensive use.
thrombocytopenia. mammal severe Rare. disease activity. high BMI (Am :m 201s;16321531

Clinical Manifestation/Prognosis
Fed and Maternal Pregnancy Outcome In SLE (%): T premature Births
and Material HTN With LN and APIA (+) (QI*$N zowxznwy
Spontaneous abortion 16.0 SLEHare 25.6
IUGR 12.1 HTN 16.3
Stillbirth 3.6 Nephritis 16.1
Neonatal death 2.5 Preeclampsia 7.6
Premature births of all live binhs 39.4 Eclampsia 0.8

Neonatal lupus: heart block and rash caused by SSA and/or SS8 Ab transfer from
mother: all mother w/ SLE. Sjégren syndrome should be screened for fetal heart block
All mother of fetus with congenital heart block should be screened for SSA. SSB:
asymptomatic mother can progress to SLE and/or Sjégren (Ann Rheum Dis z0o9¢se;a2a)
Prevention and Treatment
Recommend against conception within 6 mo of active class Ill and IV LN
/antiphospholipid Abs in pregnant women with suggestive APS history
HCQ in SLE: ¢ flare (Am nam on 10 1s011a5s1
HCQ in refractory APS: alw T live births in refractory APS lmiiuannwn Ier 101s;14;49e)
Active LN class III or IV: treat with CS - azathioprine
 CKD AND PREGNANCY
Pregnancy Outcome in CKD
Preterm and early term birth is a/w later CKD likely dlt 1 nephron in: 2019;36s1113461
Infertility and sexual dysfunction are common in advanced CKD and ESRD
In CKD adverse maternal events happened in 11.5% (2% in nonCKD control).
Premature birth 13% (vs 6% in nonCKD) (qAsn z011:s:2sa7)
CKD alw preeclampsia (x10.36). premature delivery (x$.72). small for gestational
age/low birth weight. Csec. and failure of pregnancy (qA$N 2015;l019641
CKD stage shift or RRT start was: 7.6% (CKD1). 12.6% (CKD2). 16.2% (CKD3). 20%
(CKD45).Adverse outcome is a/w HTN and proteinuria UASN z01s:26:z011).
1 proteinuria in DN during pregnancy. Insulin is recommended during pregnancy.
in CKD wl Cr >1.4 pregnancy L GFR 6 mo postpartum in 3196; progression was
highest in Cr >2.0 and uncontrolled HTN (NEJM 1996;J35:116)
Laboratory Changes in CKD
HCG: 36.7 koa,degraded and excreted by kidneyzcan be elevated in CKD w/o preg
nancy Ultrasound should be used to diagnose pregnancy.
Elevated HCG level may lend to misdiagnosis of molar pregnancy (cwmuupuun z01ssn41
AFP: i level is used to screen fetal Down syndrome: can be falsely elevated in CKD
General Management
Delay conception until txp if <35 y/o. Risk discussion if >35 lo (jueplnul 1011:25:450).

ESRD AND PREGNANCY

Pregnancy Outcome in ESRD
Live birzh/1,000 personyr: dialysis (1.26) <Transplan:ed (16) < General population
(6017); PD (1.06) < HD (2.54);among pregnancies on dialysis 79% achieve live birth;
53.4% preterm.65% low birch weight i~4»,.*i!r z01 a:1a:z7s)
HD has lower incidence of small for gesmtional age than PD (nor 1016;31219151
High BUN in 2D09:75:1217) and shorter dialysis for 201s;31:191s) is a/w adverse outcome
General Management
Iron. Epoetin alfa (C).and darbepoetin (C) can be used: ESA requirement goes up
Cholecalciferol 4,000 lU is safe UCEM 201 J;9872337). May need PO Ca for hypocalcemia
POW binder is usually unnecessary d/t high intensity dialysis: use Cobased binder
Noncalcium binder and active vitamin D are no: well studied
Hemodialysis
Intensive HD with goal predialysis BUN <50 (18 mmoIIL):weekly KW 6-8: requires
daily HD ~36 hi/wk
May need Mg and POW supplement and 3 K, 3 Ca bath for low level d/c intensive HD
Assess DW weddy and T based on expected weigh: gain (1-1.5 kg during 1st trimester I
and by 0.5 kg/wk in 2nd and 3rd trimesters) and physical examination
Avoid hypotension to keep uterine blood flow
Heparin can be used
Peritoneal Dialysis
May need to 1 fill volume and T frequency: may need HD conversion for clearance

KIDNEY TRANSPLANTATION RECIPIENTS AND PREGNANCY

Delay conception to 1 yr after KI stable graft function, minimal proteinuria
Higher risk of preeclampsia (27.0 vs 3.8%). gestational diabetes (8.0 vs 3.9%).
Csection (56.9 vs 31.9%),and preterm delivery (45.6 vs 12.5%) w1201I.11¢2aesl
Pregnancy does not affect graft or patient survival (rfamplaluuuan 2006;B1:660)
CNI: relatively safe; need to dose. 20-40% for T hepatic metabolism
Tacrolimus " gestational DM
MMFIMFA: switch to AZA
 RADIOLOGY
CONTRASTINOUCEN NEPHNOrATHY (CIN)
CIN:20.5 rise m serum Cr or a 25% t in serum Cr occurring within the first 24 hr
after contrast exposure and peaking up to 5 d aker (n£,IM 1018:]78603)
2-5% in patients was no risk factors: 10-30% among diese as risk lsmai NePhml7.0\1:31:JM)

Ri sk Fa ct o r s
Patient factors: CKD. DM. CHE hypovolemia. concomitant nephrotoxic medication
u sa g e a n d mu l t i p l e mye l o ma
Procedurerelated factors: higher dose of contrast. multiple contrast studies
performed within shon period. ionic contrast. hyperosmolar contrast
IV contrast may have no or low risk (Am Mm m¢4201B;71:44: wider 2017;28S¢4141
Risk prediction tools for CIN from coronary angiography (;Acc 2004;44,1393: Am Hahn]
1008;155:2W) are available at QxMD° app

P a t h o g e n e si s
Renal vasoconstrktion -» medullary hypoxia -» ATN (mediated by efliects of viscosity
and by alterations in nitric oxide. endothelln. andlor adenosine)
Direct cytotoxic effects of contrast agents on tubular epithelial cell -v ATN (mediated
by reactive oxygen species partly) yAcc 1008;s1:1419)
Cellular events occurs within first 60 min after administration of the contrast agent
with greatest risk in the first 10 min (AJKD 1996 n1s4: Ain 1000:183:167])

Clin ica l Ma n if e st a t io n s
Rise in creatinine. generally within 24-48 hr after contrast exposure
The creatinine usually peaks and then starts to decline within 3-7 d
Severity range from nonoliguric transient fall in GFR to severe renal failure requiring
dialysis in generally 1% <A~1 cmu 200w0n06a1
Urine sediment -) muddy brown granular/renal tubular epithelial cell cast
Absent or mild proteinuria (contrast agents may induce false positive proteinuria)
FEn often <1% (as opposed to ischemic/toxininduced ATN)
A persistent nephrogvam on intravenous pyelogram or contrastenhanced CT scan may
be suggestive of CIN in man 1997;70:B97)

P r e ve n t i o n
Avo id vo lu me d e p le tio n a n d u n SAIDs
o No proven benefit of holding ACE inhibitors/ARBs who 10114915751
9 Avoid repeated studies that are closely spaced (within 48-72 hr)
° Contrast lowest effective dose (<30 mL if diagnostic. <100 mL if diagnostic + interven
tion); low or soosmolar (lodixanol is nonionic and isoosmolal) (KDIGO AKI 10121
Volume expansion with isotonic NaCl in pt at risk (KDIGOAKI 20111
Outpatient: 3 mUkg starting 1 hr preprocedure and 1-1.5 mUg/hr during and for
4 - 6 h r p o st p r o ce d u r e
Inpatient: 1 mUkglhr for 6-12 hr pre. intraprocedure,and for 6-12 hr postpmcedure
Preventive Interventions
Intervention R¢$ul¢§
LvEDpguided vs standard IVF LVEDP guidance 1 ClAKl and bereft sustained through
6 mo (FOSHDON lance: 1014:18J:I814)

0.9% NaCl vs 1.26% NIHCO3 Similar rate of AKI, dialysis ac 90 d or persistent kidney
impairment and death iraiseiwe new zomaruon
Nacetykysneine Conilicring or no beneNz we z004.4>1; lm Hed]1€0&151:140¢
fnfsenvs new }01B:37&603 )
Sxarins Support use of suers in statinnaive patients
Higher dose superior zo lower dose (}ACC Z0\4:\14:1195;
An IM 2016;1(>4.406)
RRT No beneii: l,4mim¢4 Z012:115:66)

NSPHROCENIC SvsTsmlc Flsnosls (NSF)

Mos: gadolinium containing agent: are excreted by kidneys. Low renal function prolongs
halflife of gadolinium.
 NSF is a iibrosing disorder seen exclusively In paniencs with CKD or ESRD due to
exposure to gadolinium containing conzrasr agents (NDT 2009;z4£s6)
Characterized by marked expansion and fibrosis of dermis leading to thickening and
hardening of skin overlying trunk and extremities
Incidence of NSF in patients with renal dysfunction may vary from 0.19-4% (1A$n
2006:17:235*k Curr Open Rheumaml Z003:\5:7B5)

ACR CIassl6cation of Gadoliniumbased Agents Relative no NSF

Group I The greatest number of NSF cases Gadodiamide (Omniscan°)
Gadopenreraze dimeglumine
(Magnevist°)
Gadoversezamide (op¢amAnK°l
Group II Few. in any, unfounded cases of NSF Gadobenate dimeglumine
(MuI:iHance°)
Gadobucrol load=vis¢°l
Gadoreraxe acid (Dourer)
Gadozeridol (ProHance°)
Group Ill Limited data. but for which few. if Gadoxerare disodium (Eovis\°)
any unconfounded cases of NSF
reported

Pathogenesi s
Inciting event is tissue deposition of gadolinium - direct stimulation of bone marrow
co produce CD34» fibrocytes -> aberrant activation of circulating fibrocytes ac c u
mulation of fibrocytes in the tissues and producion of collagen l oc al ti s s ue fi br os i s
A c t iv a t io n o f T G F b e t a 1 p a t h wa y
Associations: use of ESA. placement of dialysis cadieters, chronic liver disease. hepa
torenal syndrome. peritiarisplant period after liver transplant
Clin ica l Ma n if e st a t io n s
Skin manifestations: fibrotic. indoorated papules.plaques. or subcutaneous nodules.
Lesions are symmetrical, bilateral. and centrifugal in distribution. May give "cobblestone"
woody" or pear dorang¢ appearance umjbomniagama12001;2]:38J)
Systemic manifestations: muscle induration, joint conuacture. involvement of lungs.
diaphragm. myocardium. pericardium. pleura. sclera. and dura mater
A fulminant form w/ liexion contlacnures and immobility in 5% (CwOph Rixmaiul 2003:1$:7B5)
Course: death (28%), no improvement (28%), modest improvement (20%) (see Alumina
M um 1006; 35: 118)

Workup
Elevation in serum CRE serum femtin. ESR.and reduction in serum albumin
Skin lesions can be visualized by ["F1FDG wholebody PET
Skin biopsy: proliferation of dermal librocytes in early lesions. marked thickening of
the dermis. with a florid proliferation of fibrocytes and long dendrite processes in
fully developed cases
Immunohistochemistry: CD34 and procollagenIo spindle cell infiltration
Prevention
US FDA recommends avoidance of gadolinium in patients with eGFR <30. receiving
dialysis. or with AKI lu,s, FM s»4 Drug Adniininrnian s¢91¢mu¢. zo07l
If study has no be performed in atrisk paziencs.avoid Group 1 agents
Lowest dose of gadolinium char is needed should be used in asrisk patients
Elimination of gadolinium with PD is much lower than with HD (Mad Rudi! 1998:$:491)
Gadollnium is effectively cleared by HD (Ana And z001:41:m; now M44 z00e;24=44s)
HD soon after the procedure and a repeat HD wu 24 hr can be considered among
prs on HD but no proven benefit (Ace Ciimmme¢ on 9 fw MY Conrrasx Midi 2017>

Treatment
No proven therapy
lmatinib, oral and topical steroids. plasmapheresis. exuacorporeal photopheresis. UVA
phototherapy have been studied with inconsistent results
Intensive physical therapy to reverse disability from joint contractures
Restoration of renal function with kidney transplant can slow or stop disease pro
gression Renal transplantation may offer benefit in patients who are candidates for
transplantation We 2005;46:763: nor 2011;u;1099: Gnfiumpiani 200B:Z2;803)
Prognosis
NSF has a chronic and unremitting course in mos: patients
More severe and rapid progression of the skin disease is alw a poor prognosis

DERMATOLOGY

Pathogenesis
Oxidative suess. inflammation. recurrent skin trauma
Arteriolar blood flow. endothelial injury; PTHinduced ischemic skin necrosis
Inhibitor of vascular calcification: fetuinA (reduced in CUA pts) (nor 201733z11s1
Impaired Vit K dependent carboxylation of Matrx Gla Protein. inhibitor of vascular
alclNauon 4 dermal arteriolar calcification (pisu z0\7:za:17171
Clinical Manifestations
Dysesthesia only in early sage; pmritic surrounding area
Painful vidaceous. plaquelike subcutaneous nodules;sometimes Iivedo redcularis pattern
Ischemic. necrotic ulcers with eschars. can be infected
Site: frequently abdomen. buttock. and thigh: possibly acral and penile
1 yr survival SO% l;AAz> 2001;$6:569). Mortality >80% wl ulcer in 2002;61:2210).
Diagnosis
Skin biopsy: arteriolar medial alcilication (von Kossa stain).thrombosls of dermal vessels.
ischemk necrosis w/o vasculitis; biopsy may complicate wl ulceration. infection. bleeding
Xray using mammography technique WKD 100e48;659). bone scan
T reat m en t
dlc VKA; DOAC safe alternative (IMJ Dur anal 2011:56:106sI
Low Ca bath (2.25-2.5 mErelL) d/c calcium containing binder vitamin D analogues
Lower pos Mth noncalcium containing binder to keep phos <5.5 and CaxP <55
Cinacalcet PO to L PTH <300; L CUA x0.31 levon qAs~ 201s;\oa00).eteIcaIce¢ide IV
Sodium thiosulfate Nzandoxidant;25 g (diluted in 100 mL of NS).infused over 3060 min
during the last hr of each HD session: effective In 70% lmpniuiag 20185n6691
s/e:AG metabolic acidosis. NN bad taste w/ periorbiizl tingling
lmralesional sodium thiosulfate (}AMA Devmainl z01J:14n46)
Hyperbaric oxygen (nepnfmqy 2015;10.444). bisphosphonates (uefwlqia 2012:321329)
Surgical debridement. parathyroidecwmy alw L mortality (Man avi he 2016;91:1384)
Vitamin K 10 mg TlW clinical trial ongoing (NE/M 101&378:1704)

UREMIC PRURITUS

42% of prevalent HD pts alw 17% higher mortality (mm nor 2ooea 1=349sl
18% are very much or extremely bothered by itching (cows qAsn 2017;11:1000)
t Wim inadequate dialysis. anemia,T BUN. PTH, CaxR Mg. CRP. IL2, l albumin
Polyarylethersukone > polysulfone membrane dialyzer (ac Nephrnl Z01$;\6:184)
alw xerosis: dry skin from sweat gland atrophy
Affects quality of life and sleep; fatigue. agitation, depression
Pathogenesis: systemic inflammation, calciNcarion, opioid receptor imbalance
T reat m en t
Adequate dialysis. control CaxR PTH; topical capsaicin. topical tacrolimus
If occurs during HD only.consider changing heparin formula:ion.dialyzer
Glycerollparaflin emulsion esp. in xerosis (dry skin) (C1ASN 1011:6:748)
Gabapentin who 1017;70:638). pregabalin is boner than doxepin lnfmmulnz 201711.6a)
Nalfurafine (ac opioid agonist. unavailable in USA)
 ACQUIRED PERFORATING DERMATOSiS (5,}n¢¢m¢i¢l 1995:\3§:67I)
Similar to the primary perforating dermatosis. Kyrle disease
Common in CKD. DM. and African American; 11% of dialysis pts
Skin biopsy: ulcer craters showing perforation of both collagen and elastic fibers
Pruritic domeshaped papules w/ cenuul crusts on the drunk & extensor limb surfaces
Treatment: topical steroid. retinoid

DRUG REACTIONS WITH EOSINOPHILIA AND SYSTEMIC

Sv nr r ons (D R ESS)
Drugs Causing DRESS
Xamhine oxidase inhibitorszallopurinol >> febuxosrat (A/M 2017;13fxe67)
Antiepilepricsz phenytoin. carbamazepine. oxcarbazepine, lamotrigine
Sulfonamides. sulfasalazine; vancomycin. dapsone. minocycline. lenalidomide
Clinical Manifestation
2-8 wk air use of dIe culprit drug symptoms may persist after stopping offending drug
Renal involvement interstitial nephritis;40%; higher (68%) renal involvement with
allopurinol cases; baseline CKD ()<24) is risk factor (Ann Demuml 2010¢146113731
Maculopapular rash. purpura. exfoliative dermatitis, lymphadenopathy
Fever. facial edema. hepatitis. pneumonitis, myocardids. hemophagccytosis. shock. death
Eosinophilia. atypical lymphocytosis. elevated aminotransferase (ALT)
Differential Diagnosis: StevensJohnson Syndrome/Toxic Epidermal Necrolysis
Similar offending drugs: allopurinol, antiepilepdcs. sulfonamides
AKI from volume depletion/hemodynamic change: extensive mucosal involvement
• 4-28 d after use of the culprit drug: leucopenia instead of eosinophilia
Treatment
dlc offending drug: systemic corticosteroids for incersddal nephritis
El Fisgón Morboso et al.

OTHER SKIN CHANGES IN CKD

Xerosis: dry skin from sweat gland atrophy
Uremic frost crystallized urea from swear evaporation (NE}M 2018:)7%669)
Lindsays nails (halfandhalf nails): distil pink nail bed and proximal white band: found
in CKD (NEW 2015;372:1748)

Skin Changes and Associated Renal Pathology

Skin Manifestation Renal Pathology
Purpura: nonblanchable red-purple. 3-10 mm Small vessel vasculitis: lgAv. staphassociated
(<3 mm petechiae:>10 mm ecchymoses): IgA dominant IRGN (cm nipuiuzaixnsuzl.
RBC leakage; leukocyioclastic vasculitis ANCA GN, cryoglobulinemia (immune
(LcV) on skin biopsy thrombi in small blood vessel)
Skin ulcer TMA: APS,TTP, Crystalglobulinemia
Livedo neticularis: mottled. reticulated: Medium vessel vasculopathyc APS. SLE. PAN.
congested venules cholesterol emboli
alw Raynaud phenomenon
Pyoderma gangrennsum ANCA GN (Ammmn Re 101731e11138)
Maculopapular rash Acute Interstitial nephritis
'LCV: will fusel vasculitis wld\ neuuuphil influale;44% has real iwelvemen: lgAVlHSP (30%).ANCA (10),
cryogiobulinemic (4%) (Mayo Can Proc 2014;89:1515)

Genetic Conditions Affecting Skin and Kidney

Conditions Skin Manifestations
Tuberous sclerosis Hypopigmenied spots. molar
angioiibromas. periungual
fibromas. connective :issue
nae vi. cafeauIain spots
VHL disease Capillary malformations.
hemangioma
Renal Manifestations
Angiomyolipomasz hemaruria. RP
bleeding 59% CKD3-5 aim
z01s=6616381
Benign cysts, lymphangiomas.
RCC
Clear cell RCC
Fabry disease Telangiectasias and Proteinuria w/ lamellaced
angiokemomas at groin and lysosome membrane strucmvesz
hip; Hypo or anhidrosis myeloid (zebra) bodia
Nail-pardla Hypoplasmic nails. webbing. Proteinuria. CKD with type III
syndrome absence of dismal dorsal collagen deposivjon in lamina
phalangeal skin creases denser and/or FSGS

Renal Manifestation of Dermatologic Diseases

Psoriasis leAn ><4.75 in mod-seven disease (as w11;17613ss1

Mesangioproliferarive GN (in Uid n¢»m=i z01z441s091

Hidradenitis suppuraziva M amyloidosis. Can progress to ESRD.

Tx: Infliximab new umm ma 200e:\9:¢32)

OPHTHALMOLOGY
Ag e re l a te d Ma cu l a r D e g e n e ra ti o n (AMD )
mlc cause of blindness in the developed world; x3.2 in eGFR <60 (jA$N zaawrsoe;
Drusen: extracellular deposits between Bruch membrane and the retinal pigment
e p ith e liu m (RP E ). E a rly sig n o f A MD.
CFH, alternative complement pathway regulator variation.Y402H is alw AMD
VEGF produced by RPE - T CFH -» regulate alternative pathway Us 2017112721991
Dry AMD: geographic atrophy of the retinal pigment epithelium: degeneration of
lightsensitive cells and supporting tissue + vision loss
Wet AMD: choroidal neovascularization; rapid and severe visual loss and retinal edema
Clinical manifestations: loss of vision.visual distortion
lntraviueal antiVEGF Ab for wet AMD: rarely may be associated with TMA (HTN.
proteinuria.AKl) in native lA;xo 1011157:756) and txp kidney (Tamara-maui" zoissnaazi
Diabetic Retinopathy (DR)
mlc cause of visual loss worldwide; x2.0 in renal dysfunction (}ASN 2004;1 s;z469)
T1DM (+) DN almost always have microvascular disease, such as DR and neuropathy
T2DM (-) DR is a predictor of nondiabetic renal disease. (+) DR is a predictor of ESRD
(Diabetes No Chi Prey 2011314981: (+) DR does not necessarily predict DN
Nonproliferative DR: cotton wool spots. intraretinal hemorrhages. microaneurysms
P ro life ra tive DR: n e o va stu la riza tio n
Clinically significant macular edema: retinal thickening and macula edema
Treatment: photocoagulation for proliferative DR. severe nonproliferative DR; intra
vltreal antiVEGF for proliferative DR and clinically significant macular edema
H yp e r t e n sive R e t in o p a t h y
Grade 1: generalized arteriolar narrowing: 2: Focal narrowing and AV nicking/nipping
3: 2 + exudates. hemorrhages. and cotton wool spots; 4: 3 + optic disc swelling
Grades 3 and 4: alw malignant HTN, requiring urgent or to prevent irreversible damage
Retinopathy, microaneurysms. retinal hemorrhages. soft exudates. and AV nicking were
alw renal dysf unct ion UASN 1004: \ s: z4e9)

Uveitis with Tubulointerstitial Nephritis

Causes sarcoidosis. SiOgren syndrome.TlNU.ANCA vasculitis
Anterior uveitis: pain. photophobia, ciliary i1 us: more systemic involvement
Po ste rio r u ye itis: flo a te rs, re d u ce d visu a l a cu ity
Tubulointerstitial Nephritis and Uveitis (TINU)
1-5% of IN. common in adolescent (median 15 lo). 9: typically bilateral and anterior
uveitis: 58% developed uveitis aMrTlN dx: easily misdiagnosed iqAsr4 z0i491zn
Modified can target Ag Ieyasu z011:6m); predict late onset uveitis ic1As~2o1419.zn
Eosinophilia, pyuria. pRTAlFanconi:T Urine B2microgiobulin WMA apnu\ahia12015;133=140)
Prednisone 1 mglkg topical corticosteroidslcyclopleglcs for uveitis
May spontaneously resolve. CKD in many cases despite steroids (Norma z<Ma:1:111l.
Ocular Effects of Hydroxychloroquine (HCQ)
Corneal deposits: reversible w/ dlc of HCQ
Retinopathy: Bulls eye matulopathy with a central patchy deplgmentation surrounded
b y a co n ce n tric p ig me n ta tio n
Risk factors: HCQ dose >400 mud, cumulative dose >1.000 g, >5 yr use, renal or liver
dysfunction, concomitant tamoxifen. retinal disease. obesity (HCQ is lipophobic)
Pretreatment and annual fundus examination: dlc HCQ if there is retinal damage
 Ocular Mmliestadon of Renal Condldows
SLE Keratoconjunctiwitis sicca (2 Sjbgren), retinal vascukapathy w/ cotton
wool spot. optic neuropathy. scleritis. anterior uveitis
C3G Drusen. retinal pigment epithelium detachment, choroidal
neovascularimion
GPA Conjunctivitis. corneal ulceration. episderitis/scleritis. optic neuropathy
retinal vasculitis, and uveitis
Alport syndrome Anterior lenticonus (20-30% of Xlinked)
Subcapsular cataracts. perimacular granulations
Fabry disease Conceal opacity (corner veniclllata). subapsular cataracts
Cystinosis Corneal cystine crystals/photophobia
Nephronophdmisis Retinitis pigmentosa (tzpetoretinal degeneration)Iblindness
CKD Narrowed retinal microvasculature (qAsn 2011;61872)
Corticosteroid Glaucoma. carrack. central serous chorioretinopathy
Hemodialysis T Intraocular plessure;Tx: hypertonic sodium. mannitd (n:/M 19nisa0z1.
glucose W*D zo14;sa1so0)

GERIATRICS
Background
Adjusted ESRD incidence rate highest in population >75 ye,though declining since 2010
iusaospfgy
For age >65 yo risk of ESRD exceeds risk of death only once eGFR <15 UASN zo07:1&z7ssi
In the elderly.frail population dialysis may not provide survival advantage dt optimal
medical management and is a/w a functional decline (qAsn 20 n;7:1as; NEW 2009;361:153t
2009;361:1612)
Kidney Changes in Ageing (;ASN 201738407: 2017:28liB38)
Structural changes in healthy aging conical volume loss. increase in simple renal cysts.
T glomerulosderosis (upper limit vary with age; nor 2015:30z034, mlunie nz Q»mo'), T inter
stitial Fibrosis. T tubular arroplvy. i arreriosderosis.decrease in nephron number
Normal GFR decline with aging is 0.75 mUmin/yr
Tubular dysfunction: 1 sodium reabsorpzion and potassium excrexion.and 1 urine
concenuacing abilicy
Increasing susceptibility to AKI particularly ischemic and toxic ATN

LiFE EXPECTANCY AND PRoGnos»s

Prognosis by Modality
Modality Prognostic Information
HD Remaining life in yr age 75-79: ESRD 3.2 (male) md 3.5 (female) vs Gai
Population 9.8 (male) and 11.4 (female) usrds.org
Quartiles of life expectancy in yr:
Age 75-79: 0.5 yr (lowest). 3.7 yr (highest)
Age 80841 0.4 yr (lowest). 3 yr (highest) In 20I1n261)
Median survival >6S yo in yr -Vent + dialysis (HD):0.9; post
CPR + HD:0.8:feeding we 4 HD: 0.4 UASN 20141151431
Nursing home population, cumulative mortality: 24% (3 mo). 41% (6 mo).
58% (12 mo) we znos=ss11szol
5.7% of prevalent ESRD patients age 75 and older are on PD (usrds.org)
Retrospective study of French PD registry and patients >76 yo showed
median survival of 27 mo (NDT 2011125:1S$I
Mortality benefit of PD over HD modified by age. HD many be favored
alter 90 d in age >65 yo UASN 1010.z1:499I
No difference in 12mo survival and hospiulizadon rate and QOL at 6
and 12 mo between HD and PD patients age 70+ (mu oumx2oo2:1z4e:I
Medical Median unadj survival 37.8 mo KRT and 13.9 mo medial management
manzgemenr lCI*5N1N0%4¢16\11
Low comorbidity: median survival 36.8 mo RRT and 29.4 mo medical
management High comorbidity: no survival benefit RRT vs medical
management (NOT 2011:2s,160e)
Renal supportive care dink: men survival 20 mo. median survival 16 ma
RRT padencs: man suwinl 36 mo. median survival 46 mo (qAsr47015310u01
Transplantation Age 70+: adjusted nelazive risk d deadi 41% lower in nransplam vs wait
listed puma. Risk d deadi among transplant neeipiems higher than was
listed until 125 d after surgervTrar\splan: recipient survival worse than
waidisned until 1.8 yr after uansplant.Ai: 4 ynadjusted survival d iransplanr
recipients 66% compared wid 1 5196 for waiting list andidaza. Subgroup
analyses shamed a signiNcantuansplantsunrival benetitforaga 70 to 74 yr.
ages 75 and olden DM and HTN. ECD kidneys lrliiiplimuia zmw:iuss)

Gait speed & timed get up and go res: predictive of mortality in CKD UASN z01 aa4az2)
Other prognostic risk factors for morcaliry (see palliative care chapter)

FRAI LTY

A physiologic stare of increased vulnerability no stressors that results from decreased

physiologic reserves. High vulnerability for adverse healdl outcomes including disability.
dependency, falls. and mortalizy
Characterized by slowness/weakness. poor endurancelexhausdon. physical inaczivicy.
unincendonal weight loss
Sxarcs early in CKD and increases as eGFR declines. High prudence in CKD. Independent
RF for deadi. hospiulizacion. and need for dialysis lqaw 2013810911 .44l<o 1012409121

HE MO DI ALY S I S V AS CULAR ACCE S S

Fistula first may not be appropriate in the elderly with a limited life expectancy, Patient
centered approach that considers risk to develop ESRD. overall survival. risk of primary
access failure. patient preferences, and quality of life should be considered.

AV F
O lder age is risk factor for 1 failure (up zoo3;4z 1001= ;ASN 1006;171n04; qAs~ 200a:3:4a7)
Higher prevalence of CAD and pAD;both risk factors for 1 failure uAsr4 zc0e:17a204: x:
1005167:2461)
Lower cumulative survival ofAVF up=< so 2007;45:4204 [lia¢A<¢ess z009;101991
alw with repeat vascular access placement compared to AVG (QAM 2015:10:I791)
alw HD initiation mm a catheter compared to AVG (/ASN 201$:26:448)
Patient factors affecting AVF placement. even among pts wl AVF + catheter, may
explain 2 2/3 of the mortality benefit observed in pts w/ AVF ()ASN 2017118:645)
Timing placing anAVF >6-9 mo predial7sis is not alw greater success and is associated
with increased number of vascular procedures UASN 20\5;16:448)
AVG
AVG use has declined with a concomitant increase in AVF and catheters in this pop
ulation 1c;Asr4 1M7:21M3: Aim 2003;42:1013: la elnadal IM z01z16=2331
AVG survival superior to AVF survival. in the first 18 mo after iCC€SS placement. when
primary failure rates included (CJASN 1010:5:243Bl
Some studies show no morality benefit of AVF over AVG msn z01m4:1297: Semis Dial
zoomason. others have shown some small benefit to AVF (qAsr4 2015;I0:1791)

H e m o d ia lysis C a t h e t e r
Higher morality than AVF and AVG (p\sn 2013=z411 z971
Majority of patients start with a catheter UASN 10IJ;l4;1297:jASN 2017;21:645)

MEDICAL MANAG EMENT /CO NSERVAT IVE CARE

Defined as planned holistic patientcentered care that includes intervention to delay
the progression of CKD and minimize risk of adverse events and complications.as
well as shared decision making.advanced care planning. active symptom management.
and psychological and social support Does not include dialysis in the treatment plan
(KDIGO KI Z015:88447; C[ASN 2016;11:19091
Guidelines recommend Informing all patients of this treatment option in addition to
RRT. include toolkit up>A/Asn Revsed Guldulina.Shared Decision Making. we z010;s.2zao;
Palliative care can mn concurrently with curative treatment
 FLow SHEET For MANAGING ELDERLY PATIENTS
Wm 4 Ao vAn csD CKD
1. Assess goals of treatment, including

patient preferences
2. Estimate prognosis and outcomes
3. Shored decisionmaking process

N ona lo law mat wns a poor prognn- . Fuel prognosis or putnem

a good functional mama. or parent Dftivmncs low no dialysis
p d o an o a f o r d alyss

Pr oceed wi th r enal r epl acement Medical ITl&f\8g€M8fll/COI\5GfV8liV€

ther apy pl anni ng care

Transphm
canddah
w

Tr anspl ant r efer r al Dialysis planning:

PD vs HD
Ti mi ng of access Shoul d take i nto account
competi ng r i sk of ESFI D vs death
Calheief sparing approach may favor AVG in those
with a more Iimixe¢ prognosis

PALLIATIVE CARE
Ba c k gr ound
High health care utiliurion and low hospice use compared no other end organ failure
lA:<h IM 2011:171:661)
High symptom burden, high prevalence of uncontrolled pain, and low healthrelated
quality of life we 19852312255311As~ z00s¢1¢¢z4s7¢ Acxo 1007;14azi

De f i ni t i on
Palliative care is an approach to care focused on improving quality of life of patients
and their families facing a lifethreatening illness through prevention and relief of suf 1
fering by means of impeccable assessment and treatment of pain and other problems. ,E
physical. psychosocial. and spiritual (http:llwww.who.indcancer/palliative/definition/) ::
Ca n mn c onc urre nt with c ura tiv e ue a rme nr
8
Guidelines recommend palliative care services and advanced care planning to aIIAKl.
C K D , an d ESRD patients who suffer from their disease burden (CJASN 201lk&1300) Q
=
Identifying Patients Most Likely to Benoit (qAsn z01<xs¢114n:1Asn 1a0u=11:1>409 Q
4:
Identifying Factor Measurement w

High mortality risk Age 275 yr

Dementia
High comorbidity score charlscn comorbidity Index >8
lqisu z0\<xs:z3s0)
Marked functional impairment; Kamofsky performance score
<40. noriambulatory wow 1994:2):4631
Serum albumin <2.5
Frailty
Surprise question-No: provider would not be surprised if
patient died in 1 yr
Cohen score (CJ*5N 2010.591 Malibu at of<mD°l
Berger score (Cl*$N 1011;7110)9)
High symptom burden Dialysis symptom index
Edmonton symptom assessment sale
Palliative care outcome Scale-Renal (Qiailiuulihtiarie 199*kB:2191
Pain assessment
Difficulty with Advanced care planning
determining goals
of care
Nephrology Palliative Approach
Advanced Care Planning UAS~ 2000;11;1z4<z qAsn z01o.s:zaa0i
Purposezhelp :he patient understand their condition. identify GOC.and prepare for
future decisions needed as the condition progresses over time
SpecMc goals: written advanced directives including health care proxy or power of
attorney. DNR or POLST form when appropriate
When: when considering RRI with sentinel events,when question raised by patient
or families. no to the surprise questions. routine are plan
Treatment of Symptoms: pain assessment scale and distinguish nociceptive vs
neuropathic pain
-WHO Ladder for Analgesic Therapy UASN 10047131981
P a in S c ore (# ) Mi l d (1 -4 ) Mo d e r a te (5 -6 ) S e v e re (1 -1 0 )

Treazmem Acetaminophen Hydromorphone or Hydromorphone'

£Adiuvan: for Tramadol t'Adjuvanc for
neuropathic pain *°Adiuvanr for neuro "WM pa in
pain
Dose Acetaminophen: max Hydromorph: 0.5 mg 0.5 mg q4h standing
daily dose 3.2 Yd q4h pm
Tramadol: 25 mold
to 75 mg BID
Adminisxrarion route Oral Oral KO start and IV PO standing. IV PRN
PRN

Morphine s hould not be us e d in CKD a nd E S RD

A bowel regimen should be prescribed with opiates
Pmritus: gabapentin effective in CKD and ESRD. dose adiusz for GFR
Reference: . Mdnqs upponi 1 e um . or g. .who.int/cancerlpalIiadvelpainladder
 GENERAL CONCEPTS OF RRT
ULTNAFILTNATION (UF)
Hemodialysls (HD)IHemofiltration (HF)
Driving force: hydrostatic pressure gradient across the membrane.transmembrane
pressure (TMR mmHg)
UF coefficient (K.,. mUhr/mmHg): water permeability of dialyzer
HD pump applies TMP = desired UF (mUhr)/K.,l (mUhrlmmHg)
High flux dialyzer (K¢ >20) requires lower TMP to achieve desired UF
Peritoneal Dialysis (PD)
Driving force: osmotic gradient between dialysar.e and blood.cleated by glucose (1.5%.
25%. or 4.75% glucose),or a poorly absorbed wtohydrace polymer icodexuin in dialysane
UF rate is maximum at the beginning of dwell and decreases as glucose is absorbed

CLEARANCE
Types of Cleamce
Diffusion Convection
Concept Movement of solutes across a Movement of solutes across a
semipermeable membrane along a semipermeable membrane resulting
concentration gradient from "solvent drag" during UF
between the blood and dialysate of plasma solutes across a
compartment semipermeable membrane
Removal Small solute Middle and some large salutes
Modality HD (predominant). PD HE PD: hemodiafiluation (HDF)
Types of Solutes (MW)
Small solutes (<500 D): urea (60). Cr (113), Na. K', H.glc, HCO!. lactate
Middle solutes (500-5,000 D): insulin,Vit Biz (1355).aluminumldeferoxamine complex
(700), vancomycin. aminoglycosides
Large solutes (>5 kD): PTH (9 kD). 132 microglobulin (11.8 kD). rnyoglobin (17.8 kD).
in LC (22.5 kD). u1 microglobulin (33 kD). A LC (45 kD), albumin (68 kD)
Protein bound solutes: indoxyl sulfate. pcresyl sulfa¢e.pcresol glucuionide ipinimhnwraiiiry
;As~ 1013;z4:19a1>; homocysteine, indoles;only small portion of ironbound form can be
cleared by HD
Determinants of Convective Clearance
UF replacement fluid (RF) is infused to allow for increased total UF to achieve con
vective clearance.yet maintain desired net fluid balance
Sieving coefNcienr; the ratio of the concentration of the solute in the ultrafiltrate over
the plasma; important factor in middle MW solutes; 1 in small MW solutes
Determinants of Diffusive Clearance
Flux (J): the rate of solute movement is based on Fick principle
Flux (J) I Diffusivity x Area x Concentration Gradient
Diffusivity (D. permeability): dependent on membrane composition (pore size. pone
density. membrane thickness. membrane charge). solute. and solvent
Area (A): effective membrane surface area (typically 1.7-2.0 ml)
The mass transfer coefficient (K.A) = permeability (K,) x surface area (A)
K.,: membrane and solutespecific constant
KaA determines maximal clearance at infinite blood flow (Qb) and dialysate flow (Qd)
Actual diffusivity is affected by stagnant fluid layer Qb and Qd
. Concentration gradient: dependent on dialysate solute concentration, Qb. Qd. stagnant
fluid films. geometry of flow (parallel vs antiparallel)
Floor. small salutes clearance is dependent on Qb and Qd; higher flows help to maintain
the concaitration gradiait across which diffusion occurs. up to optimal flows which. in
turn, is determined by the K.A of the dialyzer
Time: large solutes clearance is dependent on length of treatment (ie.contact time
across the dialysis membrane) dlt slow diffusion and to a lesser extent by the K,A d die
dialyzer
High Flux Membrane
High rare of water transfer. the ultrafiltntion coefficient (KJ) >20 mUhr/mmHg
Removes 10-15 kD (middle and some large) solute: does not remove albumin
Backfiltration of bacterial endotoxin from dialysate into blood is possible
No A in mortality and hospitalization rate memo ne1I.4 200z;347120101
Survival benefits in DM or patients w/ albumin $4 IMPOJASN l 009;2(k645)
High flux membranes use is a/w 1 CV morralicy 0.93 lcuanw Damien syn in zoizcocosoul
and low CV event in pts with AVF and DM lacE;As~ 201312410141
OtherTerms Used forTypes of Membrane
High permeability: higher clearance of the middle solute (eg, 52microglobulln)
B2microglobulin clearance >20 mUm in: high flux membrane
High ellieiencyz high urea clearance >210 mUm in and urea KaA >600 mUm in
High cutof? (HCO): remove 100 kD solutes. et. Ig LC (C1ASN 100%4:745). rnyoglobin:
Cons: albumin loss
Medium cutol? (MCC): remove 15-45 kD solutes; less loss of albumin than HCO
Greater clearance of large solutes (eg, 2. LC) than high flux (nor 201713111651

Sua s TITuTion FLu lo

Dialysate
Electrolytes and buffer containing fluid used to generate concentration gradient
Produced by adding acid and base concentrate to treated water
Separated by dialyzer from blood
Replacement Fluid (RF)
Electrolytes and buffercontaining sterile fluid that is given to replace fluid removal
Administered into systemic circulation before or after hemoiiltration
Prefilter RF: less extracorporeal circuit (filter) clot: preUlter RF flow rate is added to
plasma water flow rate. lowering Valuation fraction
Postfilter RF: more efficient clearance

For m s oF R R T

Forms of RRT
Column Title Fluid Clearance Comment
Hemodialysis Dialysare Diffusive >> Cgnyecdye clearance
(HD) Convective proportional no UF
amount
Hemofikmion RF Convective Small solute clearance
(HF) correlaze wl UF rate
Hemodiafillradon Diama¢e and RF Diffusive and Nor used for maintenance of
(HDF) Convective RRT

HDF: online ultrapure substitution fluid (dialysate and RF) production the cost
No 1 mortality. CV events (vs low flux HD). High volume HDF lmorxalityz CV event
(CONTRAST ;Aw 2012;23:1087)
No 1 monaliry. CV events (vs high Hux HD). High volume HDF l overall and CV
mortality for zoizzamy
Mortality, hypotension. hospitalization (vs 92% high flux HD) when convective
volume 23-24 Usession (ssl1ot /ASN 20!3:24:487)
Feritoneal dialysis (PD): utilizes the peritoneal membrane to facilime fluid and solute
transfer between dialysate in the peritoneal cavity and the bloodstream
Modalities Available in Hospital Setting Only
Continuous venovenous HD (CWHD): slow form of HD
Continuous venovenous hemoNltration (CWH): slow form of HF
Continuous venovenous hemodiafiltradon (CWHDF): combined CWHD + CWH
Slow continuous ulzrafilcrarion (SCUF): UF only. No dialysatelRE
Minimal convective clearance
In decompensated HE T Cr, adverse events in SCUF group. dw diuretic group (NEW
1012;36712296)
 RRT INMATlON IN CKD
The IDEAL Study we/m 2010.a6316091
828 pts in Australia and New Zealand (mostly white patients) were randomized
based on BSAcorrected CrCl by Cockcroft-Gault equation to early (10-14) vs late
(5-7) initiation of dialysis. Clinicians were allowed to initiate dialysis based upon die
presence of ureinic symptoms and volume overload in addition to CrCLThe mean
CrCl was 12 in the early start group vs 9.8 in the late start group.
The median time to the initiation of dialysis was 1.8 and 7.4 mo after randomization
in the early and late start groups. respectively
At a median followup of 3.6 yr, there was no difference in survival between groups
or in cardiovascular events. infections. or dialysis complications
NKFKDOQI and KDIGO we z0\s;se:aa4.i(oico coo 20n1
Based primarily based on assessment d s/s alw uremia. progressive deterioration in
clinical status refractory to dietary intervention, inability to control blood pressure.
volume overload. or metabolic abnormalities with medical therapy
Not based on a specific level of kidney function in the absence of symptoms
Canadian Society of Nephrology (CMAI 1014218621121
Intenttodefer dialysis until a clinical indication is present or eGFR has declined to
6 mUm in or less (even in the absence of symptoms). whichever occurs first
European Renal Best Practice Advisory Board (nor zoinzezoszi
In patients with an eGFR <15 mUm in when a clinical indication arises
When close supervision is not feasible and in patients whose uremic symptoms may be
difficult to der.ect,a planned in of dialysis while still asymptomatic may be preened
General Indications of RRT Initiation in CKD
The optimal time of dialysis initiation in CKD is controversial
Most patients will develop uremic symptoms with eGFR 5-10 mUmin.Younger pts and
those without multiple comorbidides may remain asymptomatic at lower levels of eGFR.
Uremic pericarditis or pleuritis. uremic encephalopathy
Declining nutritional staws (anorexia. weight Ioss.evidenced by decrease in dry weight
and serum albumih level)
Persistent or difiicuktotreat volume overload. refractory HTN or recurrent admissions
for HF
Metabolic acidosis. hyperkalemia.and hyperphosplutemia refractory to medical therapy
Cognitive impairment (consider timelimited trial of dialysis to see if AMS improves)
Other uremic symptoms: nausea. vomiting.pruritu$. fatigue, pain, muscle cramps. sleep
disturbance. altered use, sexual dysfunction

RRT INITIATION IN AKI

The initiation of RRT in patients with AKI prevents uremia and immediate death from
the adverse complications of renal failure
Emergent indications: K 26.5. metabolic acidosis wl pH <7.1.fluid overload especially
with increasing oxygen requirements in patients who are oliguric or anuric; uremic
pericarditis or uremic encephalopathy; certain intoxications (eg. methanol, ethylene
glycol. lithium. medormin)
Elective indications: K >6.0 or metabolic acidosis w/ pH <7.2 despite optimal medical
therapy. repeated positive fluid balance despite aggressive attempts at diuresis
RCTs have compared strategies of early vs delayed Initiation of RRT (in the absence of
emergent indications) in critically ill patients with AKI wid\ the majority of them not
showing a difference in mortality at 60 or 90 d. the risk of dialysis dependence, length
of ICU Ol hospital stay. or recovery of renal function (AKu<l n£/m 1016237521223 A/Rcavl
1018198458: BMC *11l"l°=ly 2017;18:78)
However in the delayed inidadon groups (48-72 hr) a significant amount of patients
did not receive RRI the majority of them because they recovered renal function. but
a few of them died before RRT was initiated (low likelihood that this would have
been prevented with dialysis) w8/m 2018:379:1431:NE}M 2016:375:122)
In hemodynamic insrability.ACS. acute brain injury.or fulminant hepatic failure CRRT
may be a better option compared to intermittent hemodialysis
 RRT MODALITY DECISION
Kidney transplant when feasible is the best option for ESRD. However. if a decision
to star: dialysis is made. adequate patient education and shareddecision making are
key factors in determining what is most suitable for the patient.
Patient should be informed about pros and cons of incenter HD and home dialysis
modalities (peritoneal dialysis. conventional. shortdaily.or nocturnal home henodialysis)

Companson of InCenter Hemodialysls vs Peritoneal Dialysis

He mo d i a l ysi s ( HD) P e rit o n e a l Dia ly s is (P D)

Frequency 3 - 4 h r o n ma ch i n e i n a CA P D: 4 ma n u a l e xch a n g e sl d
d i a l ysi s u n : xi t i me s/ Wk CCP D: cycl i n g ma ch i n e a s n i g h :
Benefits IACKD Less pazienr responsibilit y L o we r co st . p a t i e n t a u t o n o my.
201 l;\8:4Z8) Opport unit y f or adapt ed t o lif eszyie
socializat ion Higher saiisf aczicn and qualit y of lif e
Mo r e f r e q u e n t mo n i t o r i n g Pref erred in young. high f unct ioning
Pref erred in bedbound p e o p l e wi t h r e si d u a l r e n a l f u n ct i o n
pat ient s. t hose wit h Maint enance of residual renal
mu l t i p l e co mo r b i d i t i e s f unct ion

Risks (Acre A cce ss co mp l i ca t i o n s I nf ect ion (perit onit is)

z0\ 1: ie4za) Ce i u a l i e n a u s md i e n e r s L o ss o f UF ( me mb r a n e f a i l u r e )
(CVC): iniect icn Pat ient and caregiver burnout
( l za cwe l n i a yt h I u mb o si s. Body image piiohlem wide PD at het ier
VUTOUS stenosis Higher dropout rate mostly due to
Fist ula: body image problem perit onit is or inadequat e dialysis

Access and dialysis A l l o w 2 - 3 mo f o r f i st u l a t O Ro u t i n e P D: st a r t 2 - 4 wk a f t e r

iniziazion mat ure bef ore use: ca t h e t e r i n sa n i o n t o a l l o w f o r
u su a l l y a r o u n d 2 wk f o r a b d o mi n a l wa l l t o h e a l b e f o r e u se
graf t bef ore use Ur g e n t P D: st a r t wi t h i n 2 wk
CVC an be used immediat ely

Training t ime No t r a i n i n g n e e d e d Usu a l l y 1 - 2 wk

CV co mp l i ca t i o n s
Other co mp l i ca t i o n s
Angina. MI , and st roke can
b e p r e ci p i t a t e d b y l o w B P
Marked K changes can lead
t o ca r d i a c a r r h yt h mi a s
A cce ss ma l f u n ct i o n
Di se q u i l i b r i u m syn d r o me
Mu scl e cr a mp s
S a f e r f o r p a wi t h l o w B P a n d CV
disease
Mo r e g e o d e f l u i d r e mo va l
A cce ss ma l f u n ct i o n
Hyp e r g l yce mi a a n d we i g h : g a i n
Encapsulat ing perit oneal sclerosis
wi t h l o n g : e r m P D ( > 5 yr )

Absolut e Lack of vascular access Absence of a f unct ional perit oneal

Concraindicarions I n t o l e r a n ce t o HD me mb r a n e ( e t . e xt e n si ve
um I n¢pmul p r o ce d u r e abdominal adhesions.
10113011 : p l e u r o p e r i t o n e a l co mmu n i ca r Jo n )
A ct i ve a b d o mi n a l wa l l i n f e ct i o n
|-
so
739794)
(cellulit is. abscess. perit onit is)
z Severe inrescinal disease (et . I BD.
ischemia)
S e ve r e me n t a l i mp a i r me n t
L a ck o f su i t a b l e h o me e n vi r o n me n t
A K l i n p r e g n a n cy

Relat ive S e ve r e h e a t f a i l u r e Ost omy. abdominal hernias. mult iple

Conzraindicarions Severe ischemic heart abdominal surgeries
(Inc } Nephvd disease Fr a i l t y o r p h ysi ca l i mp a i r me n t
zolI aownsml Th r o mb o se d ce n t r a l ve i n s Poor personal hygiene
Needle phobia S evere malnut rit ion
L o n g d i st a n ce t o cl o se r Mo r b i d o b e si t y
dialysis unit Me d i ca t i o n n o n a d h e n e n ce
G E RD o r i l e u s
 CONTINUOUS RENAL REPLACEMENT THERAPY
Introduction
A renal replacement therapy (RRT) modality for acutely ill or hernodynamically unstable
patients unable to tolerate intermittent hemodialysis (iHD)
Continuous renal replacement therapy (CRRT) offers the advantage of gradual correction
of fluid electrolyte abnormalities in renal failure due to slow flow rates. smaller dialysis
dialyzer surface areas, and extended duration of therapy used in dlis form of RRT As a
result. this is the preferred modality in unstable patients particularly in the ICU
Indications (Gun 101%15S:616)
Acute indications are the same as those for initiating any form of RRT
Severe acidosis (PH <7.15). diuretic resistant fluid overload. uremia and certain drug
intoxications. and poisoning cases
The role of early initiation of CRRT in AKI is not established,There is currendy no
strong evidence to support the early introduction of CRRT. the choice d one modality
over anodien or a specific clearance dose
CRRT has been used for the removal of toxins with large volumes of distribution
effectively with rebound: metformin 15w/0w mean Pharmaznlunn 201 z:i7:z49), lithium.
methotrexate. dabigatran

Tvrss or CRRT
Slow Continuous Ultraliltration (SCUF)
Primarily designed for volume removal with slow UF rates. SCUF does not provide
meaningful clearance of solutes and is used in volume overload states. eg.refractory CHF
Continuous Venovenous Hemohltration (CVVH)
A convective method of CRRT where hydraulic pressure across die dialyzer mem
brane ultraNlters plasma war.er.The clearance delivered is directly proportional to
ultrafiltration volume.
Replacement fluid (RF) can be added [O the circuit either before the blood enters the
dialyzer (predialyzer) or after it leaves the dialyzer (postdialyzer)
. Predialyzer RF dilutes die blood entering the circuit somewhat decreasing the
concentration and thus the clearance of solutes. Predilution is die primary cincuk
setting used in the United States.
Postdialyzer dilurjon maintains concentration and thus efficiency but the higher
hematocrit at the end of the dialyzer resulting in decreased plasma volume increases
risk of dialyzer clotting
Continuous Venovenous Hemodialysis (CVVHD)
Employs diffusive clearance where dialysate is circulated in a countercurrent fashion
to facilitate maximal diffusion from the blood side.The diffusive clearance delivered is
proportional to the dialysate Row rate. Diffusive clearance is less effective at removal
of larger molecules including so called "middle molecules."
Continuous Venovenous Hemodiafiltration (CVVHDF)
Uses both dialysis and RF which allows for both diffusion and convection clearance.
This modality limits the loss of clearance by limiting the volume of RF used by adding
dialysate fluid used to dilute die blood entering the dialyzer. Newer circuits allow for
the use of both pre and postdialyzer addition of RF allowing for considerable custom
ization of the circuit.

PRESCRIPTION
CRRT differs from intermittent RRT in several respects as below
. Blood flow rates: much slower. 100~300 mUm in
Dialysate flow rates: when dialysate is used, the flow rates are much lower at
20-25 mUkg/hr (eg. for a 70kg person. 1.5-2.0 Uhr with CRRT vs >24.0 Uhr
with HD).
Since fluid is continuously removed at a low rate with CRRT. :here is less chance
of hemodynamic instability
RF flow rate: when prescribed,this is done ac a rate similar co dialysate and
expressed as mUg/hr
Net ultrafiltration rate: race of goal her Huid removal from the patient expressed
as mUhr. Ne: ultrafiltration rate is determined by patients volume slams. CRRT pre
scriptions are writxen either to maintain net even balance or negative balance.
 Total UF volume is the sum of :he RF (including the volume of fluid used for
anticoagulation) and the net UF volume removed from the patient
Effluent volume is the sum total of the zonal ult-afiltrate and the dialysate fluid
(if used) that is discarded
Given the rehuVely low flow ralzes and assumed sieving coeflident of 1 (ie.dl=at the equal
concernation of solutes in do blood is equal to due effluent) Br low MW substances.
small molecular clearance is:
U oWE U: effluent concenr.ration.V: effluent volume. P: blood concentration
It is equal the total effluent volume (V) in mUkglhr as UIP = 1
Howevelz predialyzer RF decrease the U/P ratio by l the solute concentration entering
the dialyzer compared to the solute concentration in the patient.T RF races and
i blood flow rates lower dIe clearance delivered (wjmfcqans 1012;3sA\3).

Doss
Currently delivered dose of CRRT recommended is 20-25 mUg/hr (KDIGO AKI 2012)
When prescribing RRT as supportive therapy for AKI. a weekly KW of >3.6 is rea
sonable and translates co an approximate goal of 20-25 nUke/hr
The prescribed dose may need no be increased to ensure :had the urge: dose is acnnlly
delivered. Dose reductions may be required in die presence of severe metabolic alkalosis
(given die high concentration of bicarbonate in r.he dialysane solutions). or if time primary
indiadon was volume managemevi: in die absence of metabolic derangements.
Time off CRRT usually lowers delivered dose by 20-30% per day
Eflluen: volume underestimates die total dose especially when sieving coeflicien: is
<1 and in prefilter CWH and CWHDF
In these cases. :he X decrease in clearance is = 1 - [Q,/(Q, + QaF)] where Q, is
blood flow rate and die Qnr is die replacement flow rate
Delivered dose is effluent volume x [Q\J(Qb + Owl]
CWH is do preened mochliny to rerncfve large MW substances lnduding myoglobin in
cases of severe dubdomyolysis (WM 2ao°n61:16z7; Co-ae orwaae so an zowcooosssei

ANTICOAGULATION
Anticoagulation of the CRRT circuit is necessary to ensure viability of the circuit and
:void blood loss :had result when the circuit clots
Unfractionated heparin: low dose. 300 units/hr: traditional circuit anticoagulation
Regional citrate anticoagulation: pts ac high risk of bleeding or in postoperative seeing
The administration of citrate predialyzer to dielate all the calcium and repletion of
calcium before returning the blood to the patient
Citrate is metabolized to bicarbonate and an contribute to metabolic alkalosis
Failure to metabolize curate In liver failure or shock can result in metabolic acidosis
Hypocalcemia may occur when there is an imperfect balance between the amounts
of citrate administration and calcium repletion
Citrate anticoagulation is now the preferred method (cm Care Med 201s:43:16221

Anliooagulation Prefnlter replacement Hued

(citrate of heparin) (for CWH a nd CV V HDF)

Counterwrrent dialysate
(for CVVHD and CVVHDF)

Calcium Postfiner replacement fluid

(only with curate anllcoagulation) (for CV V H a nd CWHDF)
 PRACTICAL CONSIDERATIONS
Good vascular access with a double lumen catheter placed in a large blood vessel is
necessary to ensure adequate flow. Lower blood flow rates make recirculation an
infrequent concern. Patients with ESRD and a working fistula need a catheter as well
as long term cannulation of the fistula is considered unsafe (camnb ruphml 1007;15e17s)
Given the slow rare of removal, HD is the preferred treatment modality for the
management of acute hyperkalemia (cy co 2015;19:s9)
Large variance between the prescribed and delivered dose of dialysis is common for
ICU patients due to the device being turned oil for a variety of reasons.This should
be taken into consideration by checking the total effluent volume for the preceding
24 hr and taken into prescribing subsequent flow rates.AIternatively. increase the
prescribed dose by 20-25% (Cm cm 20152m91

COMPLICATIONS
EIectrolyteIAcid-Base Complications
Hypophosphanemia is common especially when feeds are held. Unlike HD, the gradual
rare of removal allows phosphate to move from the intracellular compartment Can
potentially delay ventilator weaning. Either PO and slow IV repletion of phosphate is
often necessary (Semi Did Z018;J 1;7.1])
Metabolic alkalosis results commonly from diffusion of bicarbonate from the dialysate
solution or from direct mixing of the bicarbonate in the RE Bicarbonate concentration
in most fluids is 32-35 mErelL and this may impact the prescribed flow rates.
Hypocalcemia and hypomagnesemia are uncommon occurrences given the presence
of calcium and magnesium in fluid solutions. Hypocalcemia when using citrate antico
agulation requires an increase in the calcium supplementation rate.
Sodium concentrations in most dialysate and replacement fluid is 140 mEq/LThis is
of concern when initiating a patient with either hyponatremia or hypernatremia on
CRRT which may result in a rapid change in concentration of serum sodium which
should be avoided In re 2019:4;$'h ~=v-=f- Ci" Ina 2014;1za.3941
Inadequate Drug Dosing
When possible.drug dosing should be donated either using clinical response or therapeutic
drug monitoring. Most d"»s= require at loin some dose adjusunents for patient on CRKT
and subtherapeutic drug concentrations are common [see Did 101*17:441)
Drugs with a small volume of distribudon.low protein binding, low mdecuhr weight are
impacted to a great extent but the amount of drug removed depends on the delivered
dose of clearance and whedier the clearance was convective (greater drug removal) or
diffusive. Dialyzer size and membrane may also impact d is (on Can ma z012;4a1s1J1
Circuit Clotting: A Frequent Complication and Can Result From
Inadequate anticoagulation
Inadequate vascular access -» frequent alarms -> cessation of flow in the circuit
High filtration fraction: the goal filtration fraction is <20%
Filtration fraction = ultrafiltration volume/plasma water flow rate
Plasma water flow rate = blood flow rate (1 - Hct) + predialyzer RF rate
This can be lowered by decreasing the rate of ultrafiltration or increasing the plasma |
water flow rate (by adding predialyzer RF or Increasing die blood flow rate)
Oth e r C o mp l i ca ti o n s
Catheterrelated complications include catheter infections. bleeding, and clotting
Anticoagulation of the circuit an T the risk of bleeding especially in susceptible patients
Given the ability of glucose to diffuse from the blood to the effluent. rare instance of
normoglycemic ketoacidosis have been reported
Hypothermia resulting from the use of fluids in large volumes at room temperature
is primarily a concern in pediatric and small adult patients. Fluid warmers should be
considered in these situations iAgo 1998:3 2:1023)
Thrombocytopenia has been reported; usually responds to cessation of therapy or the
use of a dialyzer with a different membrane type (AM pliarmmu\er 101B;52:1204)

DISCONTINUATION
The most important predictor of successful cessation of CRRT Is urine volume at
the time of cessation panicularty achieved without diuretics (ox Cane m¢4 z009;37:1s76)
Standardized protocols for initiation and discontinuation of CRRT have been associated
with lower morality lcpisn 2017:11:218)
 HD INITIATION AND PRESCRIPTION

Indications
AKI, CKD: for conuol and correction of fluid and electrolyte imbalance that cannot
or no longer be managed conservatively by diet and medications. for control and
correction of acidbase abnormalities. and for the uremic syndmfne
Early (eGFR 10-14) vs late (eGFR 5-7) HD scar: did not result in improved out
comes at 1 yr of followup (IDEAL new 20103616091
Intoxication: lithium, ethylene glycol. methanol, aspirin. phenytoin, barbkurates.
theophylline
FirstThree Hemodialysis Sessions
Low intensity to prevent dialysis disequilibrium: avoid UF >2 L for 1st session
Examples of FirstThree Sessions of HD Initiation
Time (hr) Qb (mUm in) Qd (mUm in) Needle, Dialyzer
1 s: 1.5-2 150200 400 17 G, Low K.,A dialyzer
2nd 2.5-3 250-300 500 16 G
3rd 3-4 300350 600 15 G. High K°A dialyzer

DIALYZER
Dialyzer K°A = permeability x surface area: dewmines maximal clearance
Currendy available dialyzers are hollowfiber (capillary)
DlalyzerType by Membrane Material
TYPE Biocompatibility Example Comment
Cellulose Low Cuprophane Lowflux
Substituted lnlermediare Cellulose accuse Hi8hflux
(modified) Cellulose diaceune
cellulose Cellulose niacecaze (Excel¢ra°)
Synnheric High Polysulfone (F. FX. OprJflux°) Highflux
Polyethersulfonem Protein adsorption
Polyarylethersulfone (Revaclear°) esp. PMMA
Polymethyl medlacrylate Reflect dialysate
(PMMA) impurities

Polyacrylonitrile membrane: ches: pain and dyspnea in pts on ACEI. Unavailable.

Sterilized by gamma irradiation. ethylene oxide. or electron beam

FLu lf REMOVAL AND ULTRAFiLTRATiON (UF)

Estimated Dry Weight (EDW):Various definitions
EDW is the optimal weight patients should reach after HD
The weight at which the pt is asymptomatic wlo signs of volume depletion or overload
The weight at which patient is norrnotensive without antihypertensive medications
Failure to achieve EDW is alw ED visit and hospitalization UASN 2018;2H1781
Methods to Assess EDW
Empiric (trialandenar"ItraditionaI method) lowest postHD weight tolerated with
out inoaduiyrlr hypotension (IDH) or symptoms (cramps. NN dizziness. near syncope)
Blood volume monitoring (BVM): monitoring of relative contraction of intravascular
volume due to hernoconcentration from UF of the blood to help determine the
maximal rate of UFtolerated and the lowest postHD weight achievable without the
development of IDH
Bioimpedance measurement measure d trial body water (TBW);not in muune clinical use
DW assessment protocol J mortality: orthostatic BP may help (qAsn 2019;14:3B$)
UF Amount and UF Rate (= UF amount/dialysis treatment time)
UF rate >10-13 nUke/hr We 2016:ss911:K1z011:79a$01 and IDWG >4 kg (annum
20011196711 are alw mortality
 Strategies to Lower UF Rate
Increase treatment time (duration of each session or frequency)
Decrease interdiaiytic weight gain (IDWG)
Restrict fluid intake (including IV fluid for inpatient) co <1 Ud
Restrict sodium intake
Loop diuretics: . intradialytic hypotension. hospitalization (c/Asn 201%14:95)
Lower dialysate sodium gradually to 135 as tolerated

HEmoolALvsls PRESCRIPTION

Prescription of Maintenance Hemodiadysis

arm flow (ob) 400450 mUm in
200 mUm in: initial. reswarc hyporensiorncerebral edema (CRRT pldlemd)
Dialysare flow 600800 mUm in for high flux dialyzer
(Qd) Should be 1.5-2 x Qb for optimal clearance
Length Initially <50 kg: 3 hr. 50-90 kg 3.5 hr. >90 kg 4 hr
Adjust based on adequacy, UF requirement, lab (K. PO4)
Frequency zx3Iwk for minimal residual renal function
Incremental HD based on RRF is an option who z0l4x>4:1e1)
Needle Max Qb:300 (17 G),400 (16 G).450 (15 G)
Ultrafiltration (UF)
UF amount: Commensurate with EDW
UF modeling Higher UF rate (when the patient is at a higher volume and capillary
rein is presumably more rapid) - Lower UF me
Various profiles available: stepwise. linear. or exponential decline
Rarely lower 9 higher UF rate for intradialyric HTN wons in late par:
Dialysate
Temperature 36.5C: Low temperature (35-35.5°C) promote perkaheral vasoconstritdon
and aid in hernodynamk stability during HD: sic cramps,d1iIIing
Sodium Low Na: 1 BR IDWG (HmM 7.007.29;14:3): may cause cramps. NN
(132-155 High Na: may stimulate dlirst and T IDWG
mEq/L) Rapid Na reduction may cause cerebral edema
Rapid Na rise may cause osmotic demyelinadon; safe correction limit is
unclear: 15-20 [Semis Owl2011:24r407)
In severe hyponatremia CRRT with customized substitution fluid or
postfilter hypotonic fluid may be considered (C/ASN 201&1J17871
Sodium prowling Higher dialysate Na (Lo allow for higher UF me) Lower dialysate Na
(modeling) Various profiles available: stepwise. linear or exponential decline
Stepwise prowling is eiieczive 4H¢m¢¢0il»»i 201742113121
s/ez potential Na loading -» T thirst and fluid intake with higher
IDWG; alw t allcause & CV mortality (QASN zoimwaasi
Potassium 4 rarely used in advanced CKD
(0-4 mErelL) 3:preHD K <42 2: PreHD K 4-6
0-1: preHD K >6: alw cardiac arrest lx/ 101 l;7%2l8: cIAs~ 2o1zwns5 1
Potassium Higher K initially -> lower K later in treatment allows for gradual fall in
prowling serum K UASN 1017;28:}441) with less K gradient (nor 1018:33:1107)
Calcium 2.5 typical
(2-3.5 mEq/L) 3.0-3.5: hypoalcernia in hungry bone syndrome after parath/midectomy
2.0: hypercalcemia; a/w low BR sudden cardiac death (qAs~ 10 I3:9197)
Bicarbonate 35: typical: adjust to have preHD HCOJ level 21-22 (Ayn:1004;44=s611
(3040H1541/L) High dialysate bicarbonate BP (nor z009:z4:97a1, t death (AP(D z01J:6z13a)

Heparin Anticoagulation
Prevents cloning within the dialysis circuit
AVF/AVG: 25-50 ulkg: 60% bolus at initiation then 40% as infusion over duration of
HD: held las: 60 min of therapy for hemostasis (eg. 1.000 u bolus + 500 u/hr)
TDC: 50-75 u/kg heparin; 60% initial bolus: 40% as maintenance infusion - held last
30 min before completion of HD (eg.2.000 u bolus + 1,000 uR\r)
Akernativelyn the entire dose given as a bolus at the in of HD
HeparinFree Dialysis
Indication: active or recent Gl bleed. hemorrhagic or ischemic stroke. surgery w/i the
past 24 hr or a known/suspected allergy to heparin, HIT
 Options
1. Periodic flushing of the dialyzer with 50-100 cc NS every 15-20 min
2. Citrate infusion into the arterial side of the dialyzer (to bind Ca and inhibit pro
coagulant factors) w/ Cafree dialysate and repletion d akium on the venous side
3. Citrate containing dialysate;./ ionized calcium (iCe) after HD in (2) and (3)
Dialysis CatheterThrombosis
Prevention: 4% sodium citrate or tPA lock
Tx: tPA (alteplase. tenecteplase) to each port for 3045 min: if it does not dissolve
thrombosis. catheter exchange

MBD AND HEHOGLOBiN IN DIALYSIS PATIENTS

Conslderadons In MBD and Hb Management in Dialysis Patients

Conditions Considerations
High POW (>5.5) Dietary restriction: 750-1.000 mg/d
r P04 binder dose;/ compliance and timing: right bdore or wl men
Readdress the need for active and inactive vitamin D
R/o rhabdomyoiysis.hemolysis.wmor isis syndrome
Pseudohyperphosphatemia high Is. ball. or lipid
Low PO 4 (<3.5) Lower or stop POW binder
If PTH is high. sun or increase act we vtamin D
If PTH is within goal. consider lowdose active vitamin D (but
maintain PTH within goal)
High PTH (>600-770) Control PO¢
If Ca x P >70, avoid active vitamin D and consider PO cinacalcet
or IV etelcalceNde if Ca is not low: consider parathyroidectorny
If Ca x P $5-70. start low dose or titrate up active vitamin D
If Ca x P < 55. start or titrate up active vitamin D
Low PTH (<150-170) Lower active vitamin D dose and dlc inactive vitamin D
If slp paradiyiioidectomyn do not dlc active vitamin D for low
PTH-tiuate active vitamin D to maintain serum Ca 28.4
If Alk pos is low. possible adynamic bone: stop act vitamin D
and convert Ca containing P04 binder so nonCa containing
one. consider low Ca bath
High Ca Convert Ca containing POW binder to nonCa confining binder
Readdress the need for vitamin D
Rlo: malignancy. granulomas. hypothyroidism. immobility
If PlH is above goal, consider :inacalcet or etelcalcedde
Low Ca Use albumin corrected Ca level; Control high P04
Stop calcimimetics (PO cinacalcex or IV etelcalcetide) if it is given
If P04 is controlled. consider active 2 nutrient vitamin D
High Hb Lower (Hb 11-12) or stop (Hb >12) ESA dose
Rio malignancy (RCC, HCC. hemangiohlasmma). polycythemia Vera
Low Hb (<10) Start of increase ESA dose to avoid transfusion
lnithl ESA dose: epoetin 100 ulkgTlw or darbqacetin 0.45 Was/wk
ESA resistance: requiring >7S u/kg epoetin 3 x/wk (225 Wk.;/wk)
or equivalent dose
rlo other causes of anemia including iron deficiency (could be
alw blood loss). inflammation. malignancy.folate or vitamin Bn
deficiency.TMA. inadequate solute clearance.
hyperparathyroidism (Aim 1cc9;sa¢ezai
Proactive iron sucrose high dose (400 mg monthly unless ferrite
>700 orTsat 24058) 1 ESA dose dt neactiwe low dose 0400 mg
monthly reactive to ferrite <200 or Tsat <20% wpm z0193a0444

Initial Active Vltamln D Dose (TIW for W) Based on PTH

PTH 300-600 600-900 >900
Parecakizol (IV) 0.04 ugly 0.07 vs/*G 0.1l18/l<8
Doxercalciferol (IV) 0,025 ug/kg 0.04 pkg 0.055 pglkg
Calcitriol (Iv) 0.015 pg/kg 0.025 kg/kg 0.035 pglkg
Calcizriol (Po) moral weekly IV dose and divide into a daily PO dose
 Examples of Dose Adjustment Based on Senal monthly PTH
Change in PTH PTH <1S0 PTH 300-600 PTH >600
Fall >60% 1 25% 1 25% 1 25%
Fall 40-60% 125% Mainzaln Maintain
Fall<40% 125% Maintain T25%

Examples of ESA Dose Adjustment

. Hb >0.5/wk l 25% Hb 11-11.5 J25%
. Hb <0.S over 2 wk t 25% Hb 11.5-12 1 50%
Hb >12 hold until <11.5 and then resume at a 1 dose ( 25%)

HD ADEQUACY
Adequate HD
Solute clearance. BR and volume status are considered

SOLUTE CLEARANCE
Urea Reduction Rate (URR, %)
URL = (pre HD BUN - post HD BUN) X 100
pre HD BUN
Limitations: does not consider urea volume change and generation. inability to incor
porate the patients residual kidney function; cannot compare ueatrnents widl different
frequency
Should be 265% (68% if no UF during HD); KDOQI not recommending the use
Normalized Urea Clearance, Kt/V
Dimensionless, urea clearance normalized co distribution volume of urea
K = Urea clearance: z = Dialysis time:v =Volume of distribution of urea
Single Pool Urea Clearance, spKtN
Per treatment normalized urea clearance based on the single pool variable volume urea
kinetic model estimated by Me Daugirdas II equation UASN 1993>1:\20s.»vailable a¢QxmD'p:
UF olu e L
*PK*=-Ln(R-0,0osxn+(4-3.s><alx v m <)
post.HD weight (kg)
R _ postHD BUN :::
r = dialysis time (in hr)
p re H D BU N 3
spKtN should be >1.2 with target 1.4 (KNOQ1A;KO 201s;ss=aa4) 9
o
Equilibrated Urea Clearance, eKt/V 5
Similar to spKt/V except uses a postHD BUN drawn 30 min after the completion of <
HD to allow for tl\e initial rapid rebound and transcellular reequilibration of urea
eKt/V should be >1.05: approximately - spKtN 1.25
Computed from the spKt/V and session length (t) using. for example. the Tattersall
equation (KI 199s;$02094):

r = session duration (min)

C = time constant. specific for type of access and type solute being removed. For urea.
C should be 35 min for arterial access (AVF/AVG) and 22 min for TDC
Standard Normalized Urea Clearance,stdKtlV
An estimation of geglgly urea clearance on continuous or intermittent therapy
On intermittent therapy, use the Leypoldt formula to calculate s:dKt/V (Semen Dial
2004.17:142,cakulator is available at www.h¢kn.<am)
Typically used for treatment prescriptions other than 3x/wk dlaiysls sessions
stdKtN should be 22.0 if residual renal function is not measured or negligible
A spKtN of 1.2 delivered 3 x/wk yields a stdKtN of 2.0
Normallzed Urea Clearance from Residual Renal Function, KtIV,,.,,l
K: urea clearance from 24hr urine prior to the first HD of the wk and the predialysk
BUN (can pu: urine volume in dL and multiply by 0.07 = 100/1.440)
Urine urea (mg/dL) x Urine volume (dUd ay) X 100 mL x day
predialysis BUN (mg/dL) dL 1M0 min
t:1 wk= 60x24x7- 10.080 min
V: the urea space. or :oral body water (TBW) as: (a) dry weight TBW 0.6 (in men)
or 0.5 (in women) (b) alternatively. use the WatsonV formula
KfJV.,.\l >2.0 indicates sufficient residual renal function to not require dialysis
No residual renal function (RRF) is alw mortality RR of 17.66 compared to KtN,,,.,l
>0.84 (dw C..,.. 3.5 mUm lf in 70 kg man) uAs~1oo4;1s=1os1l
Total Weekly Ktlv
stdKt/V + Kt/V,,,,.l should be >2.0:for PD total KdV >1.7 is considered sufficient
Example 50yrold man male produces 10 dL of urine/24 hr with a urea nitrogen of
405.7 mgldL. His EDW is 71 kg.Treat.menr.s are 3.5 hr with 2kg inzerdialytic weight
gain and preBUN is 75 mg/dL and a postBUN is 25 my dL.
Estimated TBW or urea space is 0.6 x 71 kg = 42.6 L = 42.600 mL
Residual urea clearance = (405.7 x 10175) x 0.07 = 3.79 mUm in
. Kt/V,\,1l = (3.79 mUm in x 10.080 min/wk)I42,600 mL = 0.90
Calculation ofTotaI Kt/V
Method x3Iwk x2/wk

spKn/V Daugirdas II formula* 1.27 1.27

s:dKcN Leypoldt formula* 2.07 1.37
Tool Kl:N,,,.l + $tdKt/v 2.97 2.27

Use online alcularor

Conclusion: this patient could Mac xlfwk as this point

Normalized Protein Catabolic Rate (nPCR,glkgld)

Estimate of dietary protein intake based on the assumption of a steady state equi
librium between dietary protein intake and protein catabolism
Can be estimated based on interdialytic (ID) BUN and interval (Nina n.»ef 1991=1s=1sn
nPCR= 0.22 + 0.036 X ID rise in BUN X 24 + Urine urea nitrogen (g) X 150
ID interval (hrs) ID interval (hrs) x weight (kg)
Can be esrimamed based on preHD BUN and spKtN if there is no significant renal urea
nitrogen excretion, C... <2 mUm in (1As~ 1996:7,700)
nPCR = pneHD BUNI[a + (b x spKtN) + (¢'§plWV)] + 0.168
>a1wk Ho x2Iwk HD
1st 2nd Jed 1st 2nd

a 36.3 25,8 16,3 48.0 33.0

b 5.48 1.15 4.30 5.14 3,60

c 53.5 56.4 56.6 79.0 83.2

nPCR at least 1.0-1.2 glkg/d: optimal nPCR is 1.2-1.4 glkgld

Inadequate dialysis is associated with poor oral intake and decreased nPCR
Renal urea clearance corrected nPCR and its changes are a/w high albumin and low
mortality (C]ASN 2017;11:1109)
Clinical implication of Solute Clearance
Weekly timeaveraged BUN (TAC..,.) 50 (vs 100) was alw less hospitalization in
nondiabetic ESRD wlo residual renal funetion.TAC.,,, is an imperfect measure of urea
clearance alone as confounded by and not separated from urea generation rare (nPCR)
(NCDS NE]M 19B1:30$1176)
spKtN >0.80.9 was a/w less hospitalization ¢ncos Vu 19es=1s.szq
spKt/V goal of 1.65 (vs 1.25) and high flux dialyzer did not improve mortality and
hospitalization rate (HEMO new 2002:347,2010)
High flux dialyzers (K.,¢ >20 mUhrlmmHg) did not improve overall mortality. lt produced
survival benefits in DM or patients w/ albumin 54. presumably related to better middle
molecule clearance (MPO )Asr4 2009;10.64S).
High flux dialysis alw low CV event in pts with AVF and DM leGs 1Asn z013.z4110141
 x6 vs x3/wk HD for 12 mo (srdKnN 3.54 vs 2,49) resulted in L death or 1 LV mass
progression (HR 0.61). t access intervention (xi .71) lrHn new z010;zea:nsn. 3.6yr
followup showed . mortality (x0.56) (FHN ;As~ 20163z7:-9:40)

CAUSES OF INADEQUATE DIALYSIS

Cau ses o f In ad eq u at e So lu t e Clearan ce
Lower Qb than prescribed: inappropriate needle position; small diameter needle
Inadequate treatment time: late arrival. early termination
Dialysis noncompliance
Access recirculation: inflow and oudlow stenosis
Causes of Inadequat e Fluid Removal
Overestimated DW: volume overload: large interdialytic volume gain
Inadequate treatment time
Dialysis noncompliance. excessive dietary sodium. and fluid intake
Dialysis associated symptoms: cramping. hypotension

HD WATER TREATMENT
Water for HD is pretreated through a series of purilicauon steps before it is used [O
dilute the dialysate concentrate to generate the final dialysate solution
Chlorine dioxide. chloramine: added in municipal water supply to prevent bacterial
(eg, Legionella) growth
Conventional HD requires 600-B00 mUm in (100-200 Usession) of dialysate flow
The process consists of having water pass through a series of membranes and filters

C omponents of Water T r eatment

Heating Warmed xo 25 C (77F) for optimal RO membrane performance
Multimedia filters Remove large particulate matterscaka sediment filter
aka sediment Glter
Water softener Remove Ca". Mg". iron. and manganese
lon exchange resin: exchange with Na
Prevents Ca" scaling on RO membrane
Carbon Glter Remove chorine, chloramines. organic contaminants
(activated Usually 2 in series. the lstworker" rank and the 2nd polisher" tank
carbon) Empty bed contact time (EBCT) should be 210 min
High pH of water [O . copper. lead and chlorine cause lefliciency of
carbon filter
J Chlorine. chloramine between 1st and 2nd carbon tank at each shift
Reverse osmosis Remove inorganic (aluminum. zinc. lluoride.copper).organic
(RO) membranes contaminants. bacteria, viruses. endotoxins
Uses high pressure. rapid filtration of the water across a 300Da
pore membrane to generate the deionized water
Chlorine can damage RO membranes
J Conductivity of product water continuously
Deionizers Remove ionized contaminants, do not remove bacteria. endotoxins
(optional: used Exchange cations for H and anions for OH
with RO Either 2 tanks (cation and anion exchanger) or combined in 1 tank
membrane) J Resistivity continuously
Ultramicron filter Remove any remaining bacteria and bacterial products (endotoxins)
Cartridges alters with pone size <1 um in diameter

Bact eria and Endot oxins

Pyrogenic reaction is esp. a/w dialyzer reuse and high flux dialyzers
The presence of low levels of bacteria and endotoxin are alw chronic inflammation
and potential i risk for accelerated atherosclerosis and CV morbidity/mortality
 Cytokineinducing substances: endotoxin. pepzidoglycans, bacterial DNA and its
fragments lead to chronic inflammation: T ESR. hsCRR IL6 which may contribute to
accelerated atherosclerosis. CV disease. ESA resistance
Ultrapure water is required for high flux HD or HDF to reduce risk of backfikrazicn
of bacterial products
Bacwerla and Endotoxin Limits in Wanr Used for HD
CMS (AAMI 2004) Europe, AAHI 2014 Ultrapure
Bacteria (CFUlmL) <200 <100 <0. 1
Endotoxin (EUImL) <2 <0.2S <0.03

Potential Water Contaminants

Water Contaminant
Contaminant Manifestation Potential Cause
Chloramines Hemolysis. medlemoglobinemia. Short EBCT
ESAresistant anemia Chlorine contamination -r carbon
Damage RO membrane fiber failure
Aluminum Dementia. myoclonus. seizures. Acid concentrate pumped via low
delirium. ESAresisnan: anemia, pH incompatible tubing
osreomalacia
Fluoride Pruriws. headache. nausea. Sawrared deionizer
hypo¢ension.Vflb
HzO2 Merhemoglobinemia Incomplete rinsing
Copper. Zinc Hemolysis Meal pipes
Lead Abdominal pain. myopazhy Pipes
Cyanozoxin Neuronoxiciry. hepawxoxiciry Contaminated water

HD COMPLICATION
DIALYSIS DISEQUILIBRIUM SYNDROME
Epidemiology
Risk Factors: high BUN. low bicarbonate. CKD (>AKl). brain injury (stroke. seizure.
trauma). eerebrai edema (hyponauemia. hepatic encephalopathy. malignant hypertension)
Rarely wl CRRT with high intensity (effluent flow 40 mUkg/hr) (NE/M 2009;361:1627) or
significant osmolality drop (cit 2013:67516)
Pathogenesis
Intracellular osmotic equilibration in ESRD or AKI of relatively long duration
- Rapid osmolytes and fluid shim at the initiation of dialectic therapy
-»Osmotic disequilibrium across cellular membranes and fluid shifts into cells
-»Acute cell swelling and, in die brain, cerebral edema
Clinical Manifestations
Range from mild (headache, nausea) to severe (confusion. restlessness. altered senso
Q rium, blurred vision. seizures, coma, brainstem herniation.and death)
:z MRI: demyelinating white matter injury
Prevention
Initial HD URR <]*09lS wadi low Qb (150-200 mUni\) and short ueaunem titles (15-2 hr)
based on body weight (and esdmaued :oral body water or urea space). UF <1 L
Followed by gradual updzrazion of dialysis time (usually 30 min increments) and
blood flow (50-100 mUm in) until HD adequacy is achieved
+I- mannltol 75 g IV during EM 1-3 HD session
Treatment
Mild L Qb; consider d/c of HD according to indication
Severe:dlc HD, IV fluid. consider mannirol 10-75 g. 23% hypertonic saline 5 mL
Seizure: airway protection. lorazepam 4 mg IV or diazepam 5 mg IV

TYPEA DIALYSIS MEMBRANE REACTION

Pathogenesis
IgEmediated type 1 hypersensitivity reaction (anaphylaxis) to ethylene oxide
NonIgE mediated anaphylactoid reaction to acrylonitrile membrane + ACEi use
Clinical Mahifestation
Typically.wichin :he hrs: few min of initiation of dialysis
Burning as d1 e access sire, chest pain. dyspnea. bronchospasm, urticaria. hypotension
Treatment
Stop dialysis immedianelyado not return the blood in the extracorporeal circuit
• Epinephrine. IV steroids. and H1blockers; proper sterilization for prevention

TYPE B DIALYSIS MEMBRANE REACTION

Pathogenesis
Akemate pathway complanent activation: PMN sequestration in the pulmonary vascular
bed and degranuladon with release of inflammatory cytokines
Clinical Manifestation
Typically.within the firs: 30-45 min of initiation of dialysis: Chest and back pain
More common with the modified cellulosic membranes Chan synthetic membranes
Neutropenia during the event and have a posrdialysis rebound necrophilia (common
occurrence not clinically significant in the absence of systemic symptoms)
Treatment
Symptomatic. supportive

CRAMPS
Frequent cause of HD early termination and inability to achieve dry weight
Causes: below DW. high interdialytic weigh: gain (dietary noncompliance). high UF rate.
hypotension, hyponatnemia, hypovolemia, carnitine deficiency
Tre a tme n t a n d Pre ve n ti o n
NS. 25% mannitol $0-100 mL. 50% dextrose 25-50 mL
Readdress DW dietary counseling to educate on weight gain <1 kgld
Higher sodium dialysate or Na modeling
If fluid removal is needed, * treatment time and/or frequency to .l UF rate
Vitamin E 400 IU HS lAm/nȢn010:17:4ss). Carnitine 300 mg PO bid we 2cae;sz;9e2l
Quinine: may cause severe allergic reaction and TMA: not recommended

INTNANIALVTIC HYrOTENSlON (IDH)

Background and Clinical Implication
Minimum SBP <90 a/w mortality UAS~ 201s:16;724)
lDH in >10% of HD t CV mortality 22% lqAs~ 2014 1124i
alw residual renal function loss (xi 2002;621046). cerebral ischemia (al 201$;B7:1109). access
thrombosis (}A$N 201 l:11:l516)
Myocardial stunning: recurrent myocardial ischemia, regional wall motion abnormalities
lqAsn 2ca83:i9> - fibrosis -> dysfunction ac/Asn 200924:914: xi 201994:6411
HD early termination, T EDW _. chronic hypervolemia -| LVH, HF (swan nm12016:z9;41s1
Causes
Contraction of the intravascular volume which occurs when the race of UF exceeds
the rate of capillary refill from the interstitial space reaching a critical point where die
patients CV system can no longer compensate to maintain systemic BP
UF rates >13 mUg/hr (H¢ma¢allnz2018;12:170); volume depletion below DW
Hlgh predialysis osmolality reno 101516614991
Paradoxical withdrawal of reflex vasoconstriction UC' 1992;9016$7)
Dialysate: acetate. low Na. low Ca, high Hco, vasodilation (nor z009=24397a1
Bleeding, distributive (sepsis. adrenal insufficiency). cardiogenic. obstructive shock
Clinical Planlfestation
Asymptomatic. lightheadedness. NN cramps. hoarseness (thinning of vocal cords). vagal
symptoms (yawning, Sighing) (qAs~2014:9:708)
Stroke. myocardial and bowel ischemia. shock
Treatment
Stop UF. headdown (Trendelenburg) position. 1 Qb If solute clearance is not an issue
Administer NS.hypertonic saline, albumin or mannitokaddress causes
 Prevention
Strategies to Prevent IDH
Ulrrahlxrariun L UF rare <13 mUg/hr: . dialysis Mme. additional HD session
(UF) LIDWG: restrict fluid (<1 Ud) and Na intake; lower dialysare Na may
. thirst: loop diuretics if UOP >200 mud rqasu 1019:144ls)
UF profiling/modeling: greater UF earlier when :he patient is more
volume overloaded and a lower UF rare laze in HD as die parien:
approaches the EDW and is more prone to lDH
Reassess volume status and EDW: may need to T EDW
Osmolalizy Na profiling/modeling: high Na dialysaze to prevent fluid shift into cells:
change stepwise profiling is effective (Hwan: Ml 2017;21:312)
sle: may cause () Na balance and izhirs: leading to lDWG:rou:ine
use is alw mormaliry ac;/isn zo1'zi4¢3as)
Sequential UF: UF wlo dialysis for 1-2 hr while BUN concenuavion
remains high;followed by HD with no or less fluid removal
Low Qb ieyasu 2018.1].1197)
Vasaconsuicrion dlc antihypertensive or dose after HD
L dialysate temperature (3535.5 C): promote vasoconstriction to
maintain BE . IDH mm 100s.z 1:1as3: qAs~ 10l6:ll:442), 1 regional wall
motion abnormalities lcusu 2(l06:1:1Z16)
High dialysate Ca for 1ca'n497n; may cause (+) Ca balance
Low dialysate bicarbonate (NDT zuatuany
Midodrine: a1 agonist: 2.5-10 mg 15-30 min before HD: removed by
HD; additional small dose can be given during HD: SBP of 12.4
Ivor 2U04:l9.1S53)1 no additional effect (O cool dialysate WM 1999=ns20).
s/e: urinary retention. supine HTN
Droxidopa; NE prodrug no benefit wl sle u=~=~I~=»~1 my 2015;111m)
Others Avoid food intake during HD; manage anemia
Blood Volume Monitor (BVP1): helps determine the maximum rate of
UF that a patient can tolerate before developing IDH: monitor for
the relative contraction of intravascular volume (goal <8%/hr or
16%/session). No clear benefit IC}ASN zoI 7;1zi031:201*xI4.ass).
Switch to PD
High predialysis BP does not prevent IDH (w-~=» at PM z00s;103:<un

INTRADlALYTlC HYPERTENSION
Background and Clinical implication
Common: z1.3/100 HD session (li[AmlOrluns 201113s10z11
alw Tambularory BP url/~$~ z011;6:14>e4>
- t Short:erm morzalicy. hospizalizadon (An-11#www 201813113291
3 t Longterm adverse CV events and death WKD 10091548B81. K11013;8479§)
Pathogenesis and Causes
Volume overload: inadequate dialysis (NOT 201tn15:3355)
u Acrivadon of the RAAS ;t SNS. removal of antihypertensives. high sodium dialysaze
D ESA T endothelin1 (ETLvasoconstrictor); endothelial dysfunction (C/ASN 101141016)
: Low SaO1 -o sympathetic activity. ET1 (nor z0maz;1o40)
Dietary Sal: and high [Na] no 2012:81.40n. Serum KO dialysate sodium gradient wi1 ~=¢~=l
2D13;3B:41J)

Management of Interdialytic Hypertension

Early Late
1 Target EDW J, Dialysaxe Na: 5 mEqIL below serum level IAlxL>201s¢es=4s4l
1 Dialysate Na If being used. dlc Na prohlinglmodeling
T Ancihypertensives Add or . nondialyzable RAAS inhibitor (ARB or fosinopril)
SNS blockade (¢x and Badnenergic blockade)
Carvedilol 50 mg bid: . EI1 release \qA$N 1012113001

Consider addition of RAAS blockade (ACEi/ARB) and/or SNS blockade (carvedilol)

 PERICARDIAL DISEASE
Causes
Inadequate dialysis solute clearance > volume overload
Clinical Manifestations
Dyspnea. pleuriric chest paimfever. pericardial rubs
Tachycardia (in ramponade: can be absent in uremia). cardiac ramponade.deach
Workup
rlo other causes: infection (Tb. fungal.vinl-Coxsackie. enteroviruses. adenovirus.
echoviruses. CMV). MI. hypothyroidism. malignancy. autoimmune (SLE. MCTD)
EKG: diffuse ST elevations. PR segment depression. lowvoltage QRS complexes
Echocardiography: pericardial effusion
Tamponade physiology respiratory variation in transvalvular velocities
Treatment
Pericardiocemesis: tamponade. large effusions (usually resistant co intensive dialysis)
u N4pnmI 101s;za91)
Intensive dialysis: wlo tamponade.daily heparin free HD or PD
. failure is alw admission temp >102F. rates, admission SBP <100.JVD, PD only
because of hemodynamic ins\zbilil:y.WBC >15K. large effusion <A~»J mea 19841763s1

PULMONARY HYPERTENSION
Cause: chronic volume overload or t venous return to the RV from a high flow AVF
or AVE typically in >2 Umin
Echocardiogram to evaluate for elevated RV pressures
Treatment
Auempr no reduce DW: banding of AVF to reduce flow through the access

Am EMBOLISM
Cause
Air leak within :he exuacorporeal circuit
Symptoms
Chest pain, dyspnea/wheezing, tachycardia. hypotension (can progress to overt shock)
Treatment
Terminate dialysis
Place patient in the left lateral decubitus position and in Trendelenburg (to trap air in
RA/RV)
Monitor oxygen saturation: supplemental high flow oxygen
Echocardiogram and/or Chest CT angiogram (if needed) to tonearm air embolism
Vasopressors for shock. mechanical ventilation for respiratory therapy

HYPERKALEMIA
Background
Hyperkalemia is more common in pts on HD (K > 6 5%) (KI 2003;64:254) than PD
High preHD K alw morality iqAs~ 2007:z:999: Aixo z011;s<n6s)
Low (<2) K dialysate use is a/w cardiac arrest In 2011:n:2\& QA$~ zo11:7ns)
HD diffusive clearance is decided by serumdialysis K gradient: reduced after 2 hr of
HD and after using hyperkalemia treatment for intracellular shift
HD pts have x2-3 colonic K secretion mediated by All/aldosterone (Senor DmlZ014;27:571):
~35% of daily intake is removed by colonic secretion (CJASN 201&13:155)
Each HD session removes $0-100 mEq K according to dialysate K, time, Qb
 Causes of Hy pe r k a l e m l a I n HD P a ti e nts (semi of z01+.11s71: qisn 2018:1J:155)
T Intake Dietary indiscretion. znnsfusion. IV or PO supplementation
`Transcellular shift Metabolic acidosis
Cell lysine: hemolysis, rhabdomyolysis, puma. minor lysine
Prolonged fasting DI: Linsulin secretion
High Na dialysare l;Asn zeoainzasn
Inadequate HD Recirculation: Missed, shortened, or low dose (Qb. Qd) HD
I Renal K excretion In pts with signihcanr residual renal Iunction: RAAS inhibitors, loss
of residual function
Colonic K secretion Constipation: 1 wet stool weight. RAAS inhibitors

P re ve n t io n
Prolonged fasting: D10W S0 mUm in + regular insulin 10 U/L if diabetic
Dietary K restriction: 2-3 g (51-77 mmol) diet; dlc RAAS inhibitors
Potassium exchange agents: sodium polystyrene sulfate. patiromer (NEW 2015:372:211).
sodium zirconium cyclosilicate (new Z015:371:2221

Tre a t me n t
Prior to HD: dextrose + insulin; NaHCO; only is not effective in HD pts; albuterol
1 0 -2 0 mg n e b ;Ca g lu co n a te 1 g IV if E K G ch a n g e s
HD: low K bath according to preHD potassium; long session
K profilingzlrom moderate (2 mEqIL) to low K (1 mE/L) less arrhydimogenic (NDT
209813114152 IASN 2017:2B:]441)

HE MO LY S I S

Ca u s e s
Contamination: chlorine/chloramine (inadequate removal by carbon membranes),
copper. nitrate, bleach. formaldehyde, peroxide
Mechanical trauma to RBCs due to a malfunction of the blood pump, kinked cube
Hig h Ro w t h ro u g h n a rro w n e e d le
Hypotonic dialysis from erroneous electrolytes mixing, overheated dlalysate
All other causes of hemolysis: mediation induced.TMA, autoimmune hemolysis
Clin ica l Ma n if e st a t io n
Chest pain, dyspnea. back pain. bradycardia due to severe hyperkalemia
Port wine appearance of blood in venous line, pink plasma in centrifuged specimen
Acute anemia

Tr e a tm e nt
If severe. dlc HD; do not remm hemolyzed blood to patient: J K. Hb.LDH. redo count
to
THRO MBO CY TO P E NI A
.é
s Ca us e s
Heparin induced rinsing of the circuit (Hensndailn 2017;21:E30). catheter lock
2 Election beam sterilization of membrane (MW 201113061679)

,§ Treatment of HeparinInduced Thrombocytopenia

Q d/c heparin: / heparinPF4 Ab by ELISA and confirm with serotonin release assay
I Consider nonheparin anticoagulation for 23-6 mo if (+) thrombosis
HD anticoagulacion heparin free HD. argatroban (KI Z004:66:2446)
Apixaban approved for Afib/ESRD (uanauan z01e;\1a:1s19) can be considered
Bivalirudin can be removed by HD
 HD VASCULAR ACCESS
Background
Vascular access patency is crucial for patients with ESRD.A significant amount of
hospitalizations in ESRD patients is related to vascular access problems.Also. diamis
catheter infections are associated with higher morbidity and mortality
In 2016, 80% of patients of ESRD in the US were using a catheter at hemodialysis (HD)
initiation.After 90 d, 69% of patients were still using catheters.The percentage of
patients with a functional or maturingAV fistula at time of HD initiation was increased
from 28.9% in 2005 to 33% in 2015 (USRDS 2018 Annual Data Report)
The US has higher rate of grafts and dialysis catheters compared to japan and many
European countries within 5 d of first dialysis treatment (al 100]:63:3Z3)
Optimal vascular access planning should begin when eGFR <20 mUm in
Vihdiout early planning patients often end up requiring placement of temporary dialysis
catheters with increased risk of infections and higher mortality
Types of Access
Types of HD Vascular Access
Access Time to Use
Arteriovenous fistula (AVF): connection Aldiaugh someAW may be ready for emulation
between native artery and vein. typically at 30d.alongerdme(upto6mo)maybe
constricted with endtoside vein to needed Mom they provide reliable HD
artery anastomosis access [KI 2005;67:2399)
Aneriovenous graft (AVG): a connection Can usually be cannulated within 2-3 wk
between an artery and a vein using a Immediate use AVG (widiin 24-72 hr of
prosthetic graft placement) is an option ()in¢Aam zoo 1;17¢14s)
Dialysis central venous catheter (CVC) Can be used immediateiyn but require verification
of pager positioning prior to use

Selection of the Appropriate Dialysis Access

The choice of optimal access for an individual patient depends on multiple factors:
timing of referral, personal preference. life expectancy. comorbidities. frailty, patient
anatomy, institutional resources. and surgeon experience
Factors that can Influence Vascular Access Selection
Repeated venipuncture. May lad to phlebitis.venous sclerosis.stenosis and
peripheral IV catheters, thrombosis which may interfere with Mum AVF placement
CVC. PICC lines (um 1/41 In CKD 3S.avoid PICC UASN 201z7:16s4¢qAs~ zn16:n:\4J41
201*r.pmlo 311s88461: Dorsal veins of the hand are the preierted location for
previous dialysis access; phlebotomy or peripheral access
history of neck/thoracic Internal jugular vein is :he preferred location for central
surgery or CABG access use lnzew Rural 200&I 141091
Cardiac devices (AICD. May lead to central vein stenosis
pacemakers. CRT) Create AVF in contralateral upper limb
Avoid central venous catheters
If possible. avoid transvenous leads
Consider leadless pacemakers. subcutaneous leDs, or
epicardial leads (lllaxktess 201s.19,sz11
Potential for early kidney Preemptive transplantation is alvnys preferred if feasible
transplant Adverse ellecrs of posttlansplant outcomes on dialysis dwerapy
are duration dependent
No mortality diilenence between HD or PD prior to
transplant lrmplun no 200<x41=11n
Estimated life expectancy For elderly patients with frailty, functional and cognitive
impairment or severe comorbidities always discuss
palliative care
If a trial of dialysis is desired. may benefit from a CVC.AVG
or assistedPD us niwisasy
 Use or AVF AND AVG
Background
An AVF is a direct surgical anastomosis between an artery and a vein
Advantages ofAVF: lowest morbidity and mortality. lowes: need for intervention. and it
has the best longterm patency WKD zo0¢4ais1; KI 200s;s7;2s9~x qAsn 2010§¢1 1s7). In most
patients k should be the initial hemodialysis (HD) access (Ajxb 2006=4s suppl 1:S116).
Disadvantages of AVF: longer maturation time. potential for vascular steal syndrome.
aneurysm formation
AVF are more likely to experience primary failure (access never usable or failed widiin
3 mo of use) than AVG
In order to be usable, several characteristics must be present in an AVEThese include
adequate blood flow. adequate maturation. reliable repeated cannuladon.and accessi
bility in sitting position.
In order to determine the best location to create an AVE evaluation should start dismally
in the forearm of the nondominant arm and then move proximallycA radiocephalic AVF
(1st choice. Figure 1) should be done it feasible.Alternative vessels may be used if
needed (Figures 2 and 3)
AVG or prosdxetic bridge grafts are surgically created artificial conduits that connect an
artery to a vein and are superficially tunneled under the skin to allow easy cannuladon
The conduit can be looped (Figure 4) or straight (Figure 5). Forearm looped grafts are
preferred (law SW 101§:62:l7.$B),
In older patients or those with poor vascular anatomy an AVG may be preferred.There
is no clear AVF patency advantage in pts >6S yo compared to AVG (see Dai 200742asosl.
AVF may be more difficult to cannulate than AVG. particularly during initial use.
Timing ofAVF Creation and Time to Use
Evaluation for vascular accts include clinical exam and vascular mapping by Doppler US
A number of events take place before a successful AVF is created: referral to surgery.
surgical evaluation. scheduling for surgery. a period of maturation. and the possibility
of a need for salvage procedure to achieve usability which may be followed by another
waiting period before the AVF is finally declared suitable for use
Although a minimum time for AVF maturation may be 1 mo, we generally try to place
AVF 6-12 mo prior to anticipated dialysis
When created at least 4 mo prior to starting HD there may be a lower risk of sepsis
and mortality (1As~ 2004:15:1936)
Minimum time for maturation in older pos should be longer (>3 mo) UASN 20151164481
Polyteuafluoroetlvyiene (PTFE) AVG can typically be cannulated in 2-3 wk Polyurethane
AVG can be cannulated in as little as 24-48 hr if needed U\'as<A:t:ss 1011:11.248).
Concepts ofAVF Maturation
Once an AVF is created. the blood vessels involved are subjected to marked changes
in hemodynamic forces and increases in wall shear stress that trigger vascular
remodeling, resulting in an increase in vessel diameter and wall thickness which are
needed for a successful cannulation (]lhs<A¢cess 2014:15:291)
Blood How through the AVF will increase providing adequate delivery to the dialysis
machine. In addition, appropriate AVF depth. length. and location. which contribute to
successful cannulation. are critically important.
Evaluation ofAVF Maturatlon
A thorough evaluation of a new AVF 4-6 wk after creation should be considered
mandatory to assess for AVF maturation and to detect problems as soon as possible
Physical exam by an experienced practitioner has >80% accuracy for predicting AVF
maturation (K 4¢l\1l°ly 2002:215:S9)

Rule of is: More Likely to Be Useable ifAVF Meets Following Criteria

at 6 wk A&¢r Creation n(DoQIA;xD 1n0e¢4a511s)
Depth <0.6 cm below skin surface
External diameter >0.6 cm
Blood flow >600mUm in
 Are line Venous line

I
x

Ax..ry
win

auic
CoD\lJic\!il B¢ld\i. vlerr vain
Bradlill angry
EndIOSian
lnaslorloin "

4
I
Figure 1. Bruhiocephak AVE (From Zdenock GB. ef. Figure J. Bradxiehasik AVE (From Zclenodc
Manny of vnsadar and endawscula surgery. 1 so ed. 2006) GB. ¢d..Maslely ofnscudav and enduvnswlar
surgery. in et 2006)

Endxo8169
Separate - :91 anwomow
indslan if!
Bladliil lfllly

Flgun 4. Brachialanlxuhiul forearm bop

AVG, PTFE. poly\nnlIuo1uedmenl. (From Figure S. Brulicaxilary soaighc AVG. (From Zehnock
Zelaneck GB. ed..Mouery of vuimlar and GB, ed..Masury ofvasmlar and udomuulal surgery.
endouwWaf swguy. 1so ed. 2006) he ed. 2006)
 Physical Exam of HD Vaxular Access liwxiees zornrxn
History Difficulty placing needles. low KtN low Inflow stenosis
blood flow
Prolonged bleeding after removal of needles. Oudlow stenosis
high venous pressure during HD. large
aneurysms
Inspection ipsilateral arm swelling Subdavian vein stenosis
ipsilateral arm and face swelling Brachiocephalic vein
stenosis
Bilateral arm and face swelling Superior vena an stenosis
Enlarged veins on chest Central vein stenosis
Long scar In forearm or arm Transposed or
superficialized AVF
No collapse of AVF with arm raise Outflow stenosis
Aneurysm with paimenlargemenf. skin erosion impending rupture
Cold and pairNul hand.gangrene of fingertips Steal syndrome
Palpation Compression of loop AVF Pulsation felt in arterial
p o rtio n
Hyperpulsatile access Outiiow stenosis
Compression of access with palpation Poor augmentation suggests
between arterial anastomosis and inflow stenosis
occluding Finger (Augmentation test)
Auscultation Highpitched predominantly systolic bruit Stenosis

If there are abnormalities in die routine exam of the new AVF do has failed co mature.
this should be further evaluated as soon as possible. usually using duplex US and/or
contrast angiography Some parameters such as AVF internal diameter and volume flow
are typically assessed by U/S (qAsn Z016;111817)

Surgical Procedures for AVF Maturation

Superficialization: used often in obese patients and those with deep veins
Transposition: used mainly in AVF using the basilic vein.since this vein is more medial
it re q u ire s la te ra liza tio n
Translocation: with a vein uansloation AVE a vein is removed from its normal anatomic
location to another location and thus requires the creation of aW anastomosis and aVA
anastnmosis.The construction of a vein translocation AVF is similar to the placement of
an AVG.The only difference is that a native vein is used instead of prosthetic material.
Ca n n u la t io n Te ch n iq u e
AVF: rotating site (rope~ladder) technique with sharp needle or constant site (but
tonhole) with blunt needle. Constant site cannulatjon offers some advantages: less
hematomas. less need for interventions. However. it may be associated with higher
infection rate and more difficult cannulation compared to rotating site technique
(NDT 101(k15:215; qAsn 1012;7:l6J2)
AVG: must use routing site technique with sharp needle

AVF FAILURE
Primary Failure
AVF that has never been usable for dialysis or that fails within the first 3 mo of use.
lr is essentially a failure of maturation lqAs~ zuasmm).
The primary failure rate for the brachialbasilic transposed AVF has been reported to
be the lowest. followed by the brachialcephalic,and then the radialcephalic with the
highest rate (C]ASN 1009;4:86)
Failure in :he first mo is often due to technical errors in fistula construction or vessel
selection UASN w91:3111

Late Failure
Mawre AVF that fails after at least 3 mo of normal usage. Usually caused by stenosis
(venous or artelial).flow stasis (excessive Rsuula compression after HD or due no §l¢°pi'\8
position). hypotension or hypovolemia. lrypercoagulabilityendodmelial injury we 199741)
Evaluation ofAyF
The best validated and mos: widely recommended method for access surveillance for
detecting hanodynamically signitiant stenosis is monthly access Bow (Qb) measurement
In one study access with >35% decrease in Qb had a 14fold increased risk d d1r ombosis
compared to those without change W 1998:S4i1714)
 Several techniques are available for Qb measurement ultrasound dilution, conductivity
dialysance, duplex UIS. Measurement of static and dynamic pressures is less effective
for access monitoring.
The mlc indications for AVF intervention are inadequate blood flow during dialysis,
thrombosis, and failure to mature. Specific endovascular interventions include angiog
raphyn thrombectomy. angioplasty. and stenting all of which are performed with fluo
roscopy in a dedicated facility by adequately trained sniff. Surgical interventions are
now rarely needed.
Signs and symptoms suggestive of access dysfunction are edema. decreased delivered
dialysis dose, excessive negative pressures. prolonged bleeding time after needle
withdrawal
Percutaneous Balloon Angioplasty
Angioplasty is indicated if the stenosis is >S0% and is associated with clinical or phys
iologic abnormalities u<l>OQI App: 2006;4B:Sl76)
in AVF the mlc stenosed site is the "swing point" or "iuxtaanastomotic area." the
portion of native vein mobilized during creation of the AV anastomosis (Can Nepluul
2003;6835)
Treatment of stenosis increases access blood ilow and longevity, reduces access
thrombosis and reduces vascularaccess related hospitalizations We zaastswz)
Successful angioplasty is defined as no more than 30% residual stenosis and resolution
of physical indicators of stenosis II(ooQI ~»<1> zu0s;4s;s17al
Stents
There is no clear access patency benefit of primary stem use versus angioplasty alone
within a stenotic access or cenual vein ac/Asn 1008:3:699)
Stalls should be considered in the setting ollailed balloon angiaphsxy (an elastic lesion).whe1
dveiealefewren1ainingacc5ssites.ifd\epadauisnotasuvgizzlandiclalneforanewaccess
or when an outflow vein ruptures after balloon angioplasty (nmluugy 1997304943)

CompucATlons oF AVF AND AVG

Local Complication
Easy bruising: hematomas may also result (rom improper cannulation technique
Skin rashes:allergic reactions no iodine, Betadine.anrJbiotic cream are not uncommon
Prolonged access bleeding should raise suspicion for elevated intraaccess pressure
and outflow stenosis
Infections
Bacteremia frequently occurs during cannulation without actual AV access infection
Dialysis pts with uncomplicated catheterrelated bacteremia are treated with systemic
antibiotics for 3 wk.Those with metastatic infection (eg, endocarditis or osteomyeli
tis) should receive 6 wk of antibiotic therapy We z0095s41.1
Venous Hypertension
Usually occurs in pts with central venous stenosis or valvular incompetence
May present as edema. skin discoloration.dilated collateral veins.
Although mild extremity swelling is common following access surgery it usually sub
sides. If the problem persists beyond 2 wk an underlying problem should be suspected |
Aneurysm and Pseudoaneurysm
True aneurysms: abnormally dilated focal regions of a blood vessel that contain all the |
layers of the vessel wall
Pseudoaneurysm: a focal disruption of the vessel widi a collection of blood outside the
vessel that is contained by fibrous tissue
Complications: rupture. infection, bleeding.erosion of the underlying skin, difficulty with
cannulation
Hand Ischemia (Vascular Steal Syndrome)
Placement of AVF can reduce perfusion of the more dis ml extremity as a result of
shunting of arterial blood flow into the AVF Ughs<Aaest 1011:12413>
More common after creation of a high flow upper arm AVF than a more distil AVF
(iurjllmr Endavmc Surg 2004;27:1)
lr on cause paresthesias, sense of coolness. loss of sensation. weakness. Symptoms
often worsen during HD.
Tx: if symptoms are severe and persistent pts may require MILLER banding. distal
revascularization, and AVF ligation
High Output Heart Failure and Pulmonary Hypertension
In addition to dyspnea on exertion and fluid retention. pts may have a hyperkinetic
precordium and wide pulse pressure in the high output state.Access should be
hypertrophied. located in the upper arm,with high (>2 Umin) access flow rates.
The Nicoladoni-Branham sign can be elicited by brief manual compression of the
AVE The response to this diagnostic maneuver is an immediate i in pulse rate and
an T in BE which occur as a result of the sudden restoration of normal blood flow to
the systemic circulation coincident with occlusion of the AVF
Definite diagnosis of high output Slllé requires right hun cadleterization. High cardiac
output. lownormal systemic vascular resistance and pulmonary HTN are character
istic (nemuaial in! 1011;15:104)
Evaluation of other etiologies of high output heart failure should be done
Tx: lAVF inflow by banding techniques or surgical ligation of the access
Coronary Steal
Symptomatic steal from an internal mammary artery CABG from an ipsilateral upper
extremity AVF can cause myocardial ischemia lA}KD 2002;40:B52)
Thrombosis Infections and Seromas
Occur more frequently with AVG than AVF

Advantage
Can be used immediately. Does not require cannulation.
Option if an AVF or AVG is contraindicated (eg. severe heart failure). or if die expected
duration of dialysis is less than 1 yr
Used temporarily with a failing AVG or AVF until these are repaired
Disadvantage
1 infection, sepsis, and mortality and die development of central venous stenosis or
thrombosis. which comprises further access in the upper limbs In 1ooz;a1¢3os>
The annual Medicare expenditures for pts with a CVC average approximately $20,000
more than for pts with an AVF (USRDS 2006 Annual Data Report)
Location of Catheter
The right internal jugular vein is the preferred vein for HD access because the vein
takes a straight path directly into the SVC (jiuxunuv aaau 2013:24:129§)
In cases of occlusion of all central veins. alternative sites for catheter insertion are the
IVC which can be accessed via a percutaneous translumbar approach (J!'°°< Inue new
2013;14=997) or the hepatic vein (A~l\i=< so; 2013:27:332)

Types of Catheter
Tunneled dialysis catheter (TDC) or nontunneled dialysis catheter (NTDC)
TDC dual lumen, composed of silicone.polyethylene. PU. PTFE and contain a subcu
taneous cuff for tissue ingrowth to immobilize the catheter below the skin surface
NTDC are preferred for pts who require emergent HD
TDC are associated with lower rates of infectious complications and greater blood
flow rates compared with NTDC.Tissue ingrovnh into the cuff seals off the catheter
tunnel and reduces risk of infection Irv nr 1008;23;977)
Realtime UIS guidance is recommended for venous access during the placement of
CVC. Once inserted, positioning of the up of the catheter open needs to be verified
by imaging.
Duration of Catheter
Due to the increased risk of infection over time. the duration of use of NTDC Is
limited. Usually <2 wk for IJV catheters and <3 d for femoral catheters.
If there is a longer anticipated duration of dialysis a cuffed TDC should be used
The overall survival ofT DC is variable when used as a permanent access. One study
showed 74% 1yr and 43% 2yr catheter survival (nor 1992;7;I 111)
Care and Maintenance of Catheter
Before and after each use dialysis CVC should be disinfected with chlorhexidine. flushed
with saline to evacuate residual blood and locked with antithrombotic prophylaxis to
prevent catheter malfunction
Common solutions to lock TDC are normal saline. heparin.4% sodium citrate.tPA
The available data do not support use of routine systemic antithrombotic prophylaxis
for HD catheters to prevent catheter dysfunction Ul'¢lscAccess 2016;17:S41)
Antibiotic coating appears to be effective in preventing intravascular catheter infections
in the short term. but no data is available in the long term (Car cmm¢4 2009.37.702)
Complications of Catheter Placement
Bleeding. usually due to arterial puncture or venous laceration
Pneumothorax, air embolism.cardiac dysrhythmias.atrial perforation. pericardial tam
ponade
Catheter Infection
Exp site infections: Ioallzed cdlulids confined to 1-2 on where the atlieter exits the skin
Tunnel track infections: involves space surrounding the catheter >2 cm from the exp site
Risk factors for catheterrelated bacteremia: poor personal hygiene. use of occlusive
transparent dressing, accumulation of moisture. nasal and skin colonization with Staph
aurous and bacterial colonization of HD catheters
mlc organisms of dialysis catheterrelated bacteremias are coagulase negative
Szaphyiococcus. s. aurous. Enierorocci and gramnegative rods we z004.4411s)
Patients often present with fever or chills. Patients with severe sepsis can develop
hemodynamic instability. altered mental status or acidosis.
The diagnosis of dialysis catheterrelated bacteremia requires one of the following:
Concurrent positive blood cultures of the same organism from catheter and
peripheral vein
Culture of the same organism from both the catheter tip and at least one percuta
neous blood culture
Cultures of the same organism from two peripherally drawn blood cultures and an
absence of an alternate focus of infection
Broad spectrum antibiotic coverage should consist of vancomydn plus either tobramycin
or cefepime.Antibiotic regimen should be modified based on sensitivity
Catheter Removal in Infection
NTDC removal: in all bacteremia
TDC removal: in severe sepsis. hemodynamic insiability.metastadc infection (eg, endo
carditis or venebral osteomyelitis). exitsite or tunnel infection. persistent fever or bac
teremia >72 hr after initiation of antibiotics. bacteremia used by S. aurous, Pseudomonas.
fungi or mycobacteria. or mukidrug resistant organisms (lon Gudeline an vnfea Du z(10m9;1)
In this setting. a temporary NTDC is placed for shortterm dialysis access until the
bacteremia resolves.Then.a new TDC can be inserted.
If there are absolutely no alternative sites for catheter insertion catheter exchange
Over a guidewire can be performed nu 1998;53117921
In pts without indications for immediate removal ofT DC the principal options are
guidewire catheter exchange or instillation of antibiotic lock solution as adjunctive
therapy to systemic antimicrobial treatment we 2007so:zs9)
CentralVenous Stenosls
Stenosis of superior vena cava (SVC) or brachiocephalidsubclavian vein
Risk factors: subclavian catheter (ASAIOJ Z00$;51;77), duration and number of prior cath
eter. pacemaker younger age at dialysis initiation lqAsr4 2019:PNID J0765534)
Often these are initially asymptomatic. but the stenosis may manifest after the creation
of a peripheral AVF in the ipsilateral exrnmiq
It may present as edema or elevated venous pressures on dialysis (KI IW;33:11%)
Severe extremity edema may lead to patient discomfort. skin ulceration, and infec
dion
SVC syndrome: SVC stenosis or obstruction or bilateral brachiocephalic vein occlusion
Presents with edema of bod: upper extlemides.face. neck along with multiple dilated
collateral veins over chest and neck
Prevention: avoid catheterization especially subclavian including FICC (<JAs~20141I:14341
C a th e te r H a l fu n cti o n
Adequate catheter function is the ability to sustain a Qb >300 mUm in
lt is often suspected when blood cannot be wid\dllwn from the catheter or saline cannot
be infused into icalso when during dialysis there are high prasures and low flow rates
The mechanism of the obsutiction may be mechanical (kinking or improper positioning
of the catheter tip) or thrombotic (catheterassociated thrombus or a fibrin sheath)
Exp o sed T DC Cu f f
A TDC with an exposed cull can be easily pulled out
The exposed cuff also suggests that the catheter tip is no longer at the proper location
and delivery of blood through the catheter may be inadequate
 PD CONCEPTS
PERITONEAL TRANSPORT
Peritoneal Membrane Anatomy
The peritoneal membrane is semipermeable
Mesothelial cells with microvilli cover the peritoneal cavity
Microvilli increase the surface of exchange
In females. the fallopian tubes and ovaries are connected to the pentoneaI cavity
(during menses PD fluid may turn red given the appearance of hemoperitoneum)
In PD. due perkoned membrane serves as d1e dialysis membrane; surface area of 1-2 my
The peritoneal cavity serves as the dialysate compartment
The lymphatic system drains the peritoneal cavity
TheThl*ee Pon Model In mu£§m
Pore: Size Comments
Large 100-250 A <10% of solute removal
Small 40-50 A >90% of solute removal + 60% of water transport
Ultrasmall 2.5 A Aquaporin1, transport water only
Large pores < Aquaporins << Small pores an number

Nearest capillary hypothesis (pun of run 19%:16:1z1)

Capillaries closer to the mesothelial cells have a greater contribution to transport
across the peritoneal membrane
Transport is dependent on surface area. distance from mesothelial cell layer and the
extent of perfusion of capillaries (increased capillary perfusion in peritonitis)

WATER TRANSPORT
Osmosis
Osmotic gradient is created by :he additives to the PD solution. glucose. or icodexmn
40% of water moves through aquaporin1 channels
60% of water moves through paracellular transport between cells. je. via small pores
Hydrostatic Pressure
Hydrostatic pressure gradient is the difference between intraperitoneal pressure and
peritoneal capillary pressure
Higher when patient is supine compared to standing

SOLUTE TRANSPORT
Diffusion
Based on Fick lava transfer rate of a solute is determined by
The diffusive permeability of the membrane to a solute
The surface area available for transport. je. the surface area of the peritoneal
membrane and capillaries
The concenuauon gradient; solute moves from high to low concentration
The concentration gradient: highest at the beginning of a dwell -» fastest removal
In PD.creatinine,urea. K. H. and phosphate are mainly moved by diffusion
Convection
Occurs wid\ ultrafiltration and is determined by:
The mean concentration of the solute. je. the dialysate fluid concentratlon.The
higher the dialysate concentration - the higher the gradient between the dialysate
and blood -» faster movement of water across pores.
Of note. dextrose from the dialysate fluid is absorbed during dialysis and therefore
the concentration gradient is reduced as dwell time is prolonged
Water flux: depends on the number of small pores and aquaporins which varies
among patients
The specific solute reflection coefficient of the membrane: ranges from 0 to 1.
Reflection coefficients closer to 0 indicate faster transport
Dwell time je. show and frequent dwell times are the most effective because longer
dwell times allow for equilibration of solutes between blood and dialysate
Barriers to Effective PD
Effective surface area of peritoneal membrane available. je. number of capillaries and
area In contact with dialysate
Intrinsic permeability of the peritoneal membrane that allows sduces to be uansported
je. number of pores
Peritoneal fluid is absorbed at a rare of 1-2 mUm in (WwW oiPerlmneaI Dhlyshln
Handbodr °fDI°*tl*1. 3rd ed. 20012B\)

PD PRESCRIPTION
Peritoneal Dialysis (PD) Solutions

Advantages of kodextrin over Dextrosebased Solutions

1/3 of icodextrin is absorbed through lymphatics over 12 hr ¢ can be used for longer
dwells because oncozic pressure is maintained for ulnraflltration
Greater UF in high transporters (AJKD Z002:3%861)
Improved glycemic control UASN 2018;141B89)

PD MODALITIES

PD modalities

Continuous Manual
or or
Intermittent Automated

Continuous Ambulatory Peritoneal Dialysis (CAPD)

Multiple exchanges during the day followed by a night dwell
Automated Peritoneal Dialysis (APD) Combined with Day Dwell

APD with Morning Day Dwell

CYCLER CYCLER

DRY

APD with Evening Day Dwell

CYCLER CYCLER

DRY
Continuous Cyclic Peritoneal Dialysis (CCPD)
A cycler performs multiple nigh: dwells followed by a day dwell

7 am 10 pm
(From Daugirdas JT. ed., Handbook of Dialysis. so et. 2015)

Nocturnal Intermittent Peritoneal Dialysis (NIPD)

A cyder performs multiple nigh: dwells: No day dwell is used

Day Dry" APD (n 1pD)

CYCLES CYCLER

DRY

PD PRESCRIPTION
Patients Choose the Modality that Fits Their Lifestyle
CAPD needs less training than APD
APD oRers more flexibility for maintaining a good lifestyle
Calculate the Required Total Dialysate Volume
Daily Kr/vw..
Kt = 24hr dialysate volume x D,.,.,lP.,,.
D: the urea concentration in 24 hr effluent dialysate collection
. P: the serum concentration of urea
V.,..: the volume of distribution of urea total body water = ideal body weight >< 0.6
in male. x 0.5 in young female
The target is weekly Kt/V...., 21.7 = daily Kt/V,,.. 20.24 in anuric patient
The initial prescription usually assumes that the patient has average membrane uaris
port and that the plasma and dialysate urea are in full equilibrium; D ,.,. Pm
Daily Kt 24hr dialysate volume
eg. in a man with ideal body weight 70 kgV,,,,, is 42 L
Required Kt is 0.24 < 42 L = 10 L of urea clearance per day. 10 L is the amount of
dialysate that should be drained per day to achieve the goal weekly KtN 1.7.
In a patient who has residual kidney function. residual renal KW should be calculated.
This is :hen subtracted from 1.7,The resultant number will be die target KW used
to calculate the dialysate amount.
Determine the Fill Volume per Exchanges and the Number of Exchanges
The initial fill volume is usually 30-35 mL of dialysate per kg per exchange. or
1.500 mum' of BSA per exchange. or 2.5 U1.73 m1 of BSA per exchange
The initial (ill volumes should not increase intraperitoneal pressure >1B cm H20
In patients with residual renal function.it is possible to avoid a daytime dwell
Determine Ultrafiltraticn Needs
The initial dialysate composition depends on die volume status of the patient and
their residual kidney function
Euvolemic patients with residual kidney iunttion can start with 1.5% dialysate
In hypervolemit patients. 2.5% dialysate can be initially used
UF can be increased by using diah/sar.e with higher dextrose concenuation. by decreasing
dwell time. increasing dwell volume. and increasing the number of exchanges
Adjust Prescription Based on:
The total UF (diaiysate and urine). changes in body weight. volume sums
Uremic symptoms and dialysis adequacy
4 wk following prescription,/ peritoneal transport rate

PERITONEAL TRANSPORT RATE MONITORING

Pentoneal MembraneVariablllty
Variability in peritoneal membrane transport between different individuals
Changes in efficiency of peritoneal membrane over time
Therefore. PD prescriptions should be individualized
Tests to Evaluate PD Transport Rate
Multiple tests have been advocated:
Peritoneal equilibration test (PET)
Standard permeability analysis (SPA)
Peritoneal dialysis capacity (PDC) measurement
Dialysis adequacy and transport test (DATT)
Peritoneal Equllibration Test (PET)
PET is the mos: commonly used rest
The PET is a 4hr standardized rest with several steps
It should be done no earlier :han 1 mo after initiating PD. PFT can also be performed
after bouts of peritonitis as well as with UF failure.
A dwell of 2 L (200 mUm in for 10 min) of 2.5% dextrose dialysare is used
Drain 200 cc at 0.0,5. 1. 2,and 4 hr: 10 cc are sampled and the rest is rein fused
The dwell is drained at 4 hr.and tonal volume of dialysate is calculated. Uluafiltrate is
then inferred.
use aeainlna
D/F DIP
1.1

0.9 0.9

0.7 0.7

0.5 0.5

0.1

ego glucose sodium

1.1 1.00

0.9

0.90

o.a0

0.1

hours

W high HA hlghavevage LA bwavungo L low

Peritoneal membrane lranspon types are based on 4.hr equilibration ratios low Una. creatinine.
glucose. and sodium. (From Daugirdas JI ed.. Hlndheck of Die}ysis. Sth QUO. 2015)
 4 hr after the dwell, sodium. potassium.urea.creatinine.glucose.and :oral protein are
measured in both d 1e serum and the dialysate
High transporters remove waste products fast but are not effective at UF
Tx: short dwells and frequent exchanges. je. CCPD
Low transporters remove waste products slowly but are effective at UF
Tx: longer dwells and less frequent exchanges, je. CAPD
Peritoneal Membrane Failure
The peritoneal membrane properties change over time.This is related to the exposure
to dialysate and to inflammation in the membrane. Peritonitis increases the risk of
membrane failure.
Peritoneal membrane failure is defined as a UF <400 mL after a dwell time of 4 hr using
4.25% dextrose solution in die absence of any catheter malfunction or fluid leaks
Type I membrane failure is characterized by high solute transport
Tx: shortening dwell time and doing more frequent exchanges
Type II membrane failure is characterized by decrease solute transport and water transport
. Tx: dlc of PD and switching r.o HD
Type Ill membrane failure is due to lymphatic absorption
Tx shorter dwell time and using 4.25% dextrose or icodextrin solution

PD ADEQUACY
Adequate Dialysis
Effective dose :had maintains fluid balance and prevents metabolic complications
Measurement ofAdequate Dialysis

Factors Affecting PD Adequacy

Residual Renal Function (RRF)
PD prescription should be adjusted as residual renal function decreases over time
Higher RRF is associated with decreased odds ratio for death (Ajxo 1999832523:
CANUSA,lASN 2001:11:2158)
ACEi (Ann :m z00::u9:10s) and ARB we 2004;4310sq may help to preserve RRF
Higher solution osmolaiity increases UF and can increase solute clearance by convection
Higher fill volume can increase solute clearance
Higher frequency of exchanges can t the concentration gradient between dial/sate
and blood which leads to better solute clearance
Peritoneal transport type (described below)
Patient position the supine position T the peritoneal surface area available for
exchange
Catheter malfunction
Fill and ExchangeVolume
Can be estimated using the following formula:V,,.. =V + ((18lAP)I2) x 1.000 mL
Vi: the maximum dwell volume tolerated by the patient
IAP: the lnuaperitoneal hydrostatic pressure which should be <18 cmH1O in the
supine position. lAP is lowest in the supine position. highest in the sitting position
and intermediate in the standing position.
V: the intraperitoneal volume
Daily dwell volume = [kl/v xV]lt x DlP.,.. (V = volume distribution of urea.t = time in d)
PentoneaI Transport Type
Fast Transporter: require short dwells.ie. PD regimens that include frequent exchanges
Slow Transporter: require long dwells and high fill volumes. je. CAPD or APD
 PD COMPLICATION
PERITONITIS
Background and Pathogenesis
Presentation: abdominal pain. cloudy effluent fluid
Bacterial peritonitis: effluent WBC >100 cell/pL with >50% neutrophils
Maiorlty Grampositive organisms: S. epidelmidis > S. aurous > Enterococcus
Fungal or mycobacterial peritonitis: lymphocytic predominance of the effluent WBC
Candida albicans is the most common organism in fungal peritonitis
. Recent antibiotic use is a risk factor
Mycobacterial peritonitis: lymphocytic predominance of the effluent WBC
PCR is more sensitive and can yield faster results than acidfast smears
Eosinophilic peritonitis:>10% eosinophils in effluent fluid
Related to allergic reaction. drug exposure,fungal and viral infections
lcodextrinassociated sterile peritonitis: (-) peritoneal cultures
Can occur any time after exposure to icodextrin
Cloudy effluent with macrophage and eosinophil predominance
Workup
PD fluid total cell count and differential. Gram skin and cultures
If the suspicion for peritonitis is high and cell counts are low. resend cell count and
culture alter a dwell time of at least 2 hr
Swab of the catheter exit site if there is purulence
Treatment
Stepwise Treatments of Bacterial Peritonitis
1 Empiric antibiotics while awaiting cultures:
Vancomycin (15-30 mg/kg every 7 d) or lstgeneration cephalosporin (1e.cefazolin
15-20 my/kg daily) for grampositiye organisms
Aminoglycoside (je, gentamicin 0.6 mg/kg daily) or 3rdgeneration cephalosporin
(je, cefotaxime 500-1.000 mild) for gramnegative organisms
2 Followup daily effluent counts
3 If clinical manifestations of peritonitis persist beyond 48-72 hr or if effluent cell
counts remain positive for >5 d 4 treatment failure and need for catheter removal
4 Antibiotics are narrowed when culture sensitivities are back

Antibiotic course usually 2 wk: Sxapn aurous and Pseudomonas are heated for 3 wk
IP administration of antibiotics is superior to IV administration in treating peritonitis.
No specific antibiotic appears to have superior efficacy for preventing treatment failure
or relapse of peritonitis (Cochrane Dunham So: Rv 2014;CD005284).
Oral antifungal prophylaxis (lluconazole or nystatin) with each antibiotic course may g
reduce the risk of fungal perinonicis (Coduune Database SW Rev 20\7:CD004679)
Relapsing peritonitis: 2 peritonitis episodes caused by the same organism or 2 sterile 8
peritonitis episodes within 4 wk of each other 3
Refractory peritonitis: peritonitis that persists for >5 d z
Indications of PD catheter removal: relapsing or persistent peritonitis (Cndlmne DemOns: e
Syn an z014;cD00s1s4). pseudomonal peritonitis,and fungal peritonitis (high risk of death)
Mycobacterial peritonitis: 6-9 mo of isoniazid. pyrazinamide. olloxacin.and IP riiimpin
followed by a maintenance antimycobacterial regimen

EXITSITE ANDTUNNEL INFECTION (ISFD Guidelines his Didlnl 1017:]7:141)

Exitsite infections purulent discharge at the catheter-epidermal interface
Tunnel Infection: :he presaice d inlhmmacion (erythema. edema. iendemess. or induration)
or collections along :he tunnel
Exitsite infections or tunnel infections can occur at dl! same time
Investigation includes sending any drainage from the site for gram stain and culture
Catheter care should be continued during treaunent of an exitsite Infection. Please
refer to catheter care in the PD Catheter" chapter
Empiric antibiotic therapy of exitsite and tunnel infections includes oral antibiotics
that cover S. aurous. Patients who have a history of MRSA or R aeruginosa should
receive oral antibiotics that cover those organisms.
 Consider nysutin (or prophylaxis against fungal peritonitis
If the culmres grow P. aemginosa, then patients should be given two antibiotics for
coverage. one of which being an oral fluoroqulnolone. Of note, quinolones should
no: be given at the same time as phosphorus binders.
Duration of therapy for exitsite and tunnel infections is typically 2 wk.except in cases
of P. aeruginosa where the duration of therapy is 3 wk
Exit sires should be observed closely to evaluate response to therapy
J U/S of :he tunnel to document clearance of any fluid collections
Remove the catheter if fail to respond to antibiotics after 3 wk of therapy and in
patients whose exitsite or tunnel infection progresses to peritonitis
A new catheter an be replaced immediately after removal of an infected catheter in
patients MM exitsite and tunnel infections only In those with concomitant peritonitis.
a new catheter should be placed no sooner than 2 wk after catheter removal.

MECHANICAL CompucATlons
Hernias
Can develop secondary no increased inu1abdominal pressure
Encapsulating Peritoneal Sclerosis
Sclerosis of the peritoneal membrane -n bowel encapsulation and intestinal obstruction
The causes are not well understood bu: longer duration on PD is a risk factor. Many
patients present after stopping PD.
Clinical manifestations: partial or complete bowel obstruction. hemopeiitoneum.
abdominal masses.abdominal pain. poor ultiaiiltration among others
CT is the imaging modality of choice: peritoneal thickening and calcifications. bowel
thickening. tethering. dilatation, obstruction, and loculated ascites
Tx: discontinuation of PD.supportive care in use of bowel obstruction, nutritional
support. Enterolysis an be considered for recurrent or severe symptoms.
PD Cadwetewrelated Mechanical Complkadons
Impaired dialysate flow Can be seen during inflow or drainage
Can be related to constipation -» laxative regimen
Can be related to catheter rip migration -»AbdominaI Xrays
can detect migration
Entrapment of the catheter by the omer tum
Fibrin - add heparin to the diaiysate
Pain From abdominal irritation of die catheter up
From the dialysate flow against the bowel
Leakage of dialysate Can be related to high dialysate volume -» 1 dialysate volume
Can be related to weak abdominal muscles » supine exchanges
Hydrothorax PD catheter migrates into the pleural space -> a communication
between die pleural space and die abdomen
Presents with respiratory distress and lung collapse. High
glucose in die pleural effusion is a clue to die diagnosis
TX: temporary discontinuation of PD or diaphragm patching

Hemoperltoneum
PD catheters may erode into mesenteric vessels or internal organs
Other causes of hemoperitoneum include: menstruation. ovarian cyst rupture. renal
cyst rupture.carcinoma in the abdomen. abdominal organ infections,splenic rupture,
and sclerosis peritonitis
. J effluent counts. culture. amylase and CBC. Ha >2% is suggestive of intraperimneal
bleeding and requires further workup of intraabdominal bleeding.
Oral contraceptives can stop bleeding related to menstruation
TX: rapid exchanges (2-3 hr) MM 500 units of heparin per liter of dialysate.This pre
vents clot formation that can result in catheter malfunction
 ME TABO LI C CO MP LI CATI O NS

Metabolic Derangements With PD and Causes

Hyperglycemia Absorption of glucose from the PD solutions
Hyperlipidemia Nor completely understood. possibly due to hypoalburnlnemia and
hyperglycemia
Hyponaznemia Fluid overload and low dialysate sodium
Hypokalemia Low dialysace potassium concencrazionlcontinuous diaiysisluse of
diuretics
Hypercalcemia High dialysace calcium concentration
Hypermagnesemia High dialysare magnesium concentration
Hypoalbuminemia 1-2 g losses/L of drained dialysace

PD CATHETER
Relative Contraindications to PD Catheter Placement
Previous abdominal surgeries: abdominal wall hernias

T y p e s o f C a th e te r s
Tenckhoff (mos: widely used). Missouri swan neck.Toron\:o wesr.ern catheter

P D Ca the te r S e gm e nts
Inrnperitoneal The section inside die peritoneal cavhiy widi side holes no drain due dialysare
No difference in function between srnight innapericoneal segments
compared to coiled
Double cuff Superficial curl is in the subcutaneous portion of die abdominal wall
Deep cuff is in the rectus abdominis muscle
Exuaperironeal The section within d1 e abdominal wall and outside :he body

Preplacement Recommendations
Laxatives to avoid postoperative constipation
Antibiotics prior to PD catheter insertion: cephalosporins iisro reno niiiiin 10173711411
Pre/perioperative intravenous vancomycin may reduce the risk of early peritonitis in
:he first few wk (<1 mo) following PD catheter insertion but has an uncertain effect
on the risk of exitsite/tunnel infection (Cotkrune Dawbose Sir Rev 20I 7:CD004679)
Periplacement Care (but before use)
PD adieus are flushed widi dialysate followed by immediate drainage to maintain patency
Heparin is flushed to avoid clots
Catheter is covered.Traurna and change of dressing should be avoided for at least 1 wk
PD is started at least 10-14 d after catheter insertion
Showers should be avoided until the exit site is healed
Urgent start PD is started 24-72 hr after PD catheter insertion.This is done in
patients who need dialysis urgently but want to avoid hemodialysis.
Early in PD is started 72-14 d after PD catheter insertion
Both urgent start and early start PD should be done by trained staff, using low volume
exchanges in the supine position
PD Catheter Maintenance
Wash PD exit site daily with antiseptic. either chlorhexidine or povldone iodine
Topical antimicrobial agent should be applied daily: Mupirocin. Gemamicin
Nonocclusive dressing should be used to cover the site
Catheter should be immobilized with tape to prevent injury to the site
If patients report trauma to their catheter site -v 3 d of cephalosporins
Patients should avoid baths and swimming
Pets should not be in the room when exchanges are being done. windows and doors
should be closed
Mechanical and infectious PD catheter malfunction causes 50-70% of patients to
switch to hemodialysis.
 RECIPIENT EVALUATION
Background
Kidney Txp l death and T survival compared to remaining on dialysis 1n£;M 1999;341:1725)
Preemptive txp: the optimal treatment for ESRD.Waiting time on dialysis is one of the
strongest independent modifiable risk factor for txp outcomes (Tuwgiainunn 200z74:um
Transplantation Evaluation Referral
Early referral is important to avoid the development of comorbldities associated with
dialysis and to increase chance for preemptive transplantation (nunxplanauan 100174 1377)
Refer all medically appropriate pts w/ CKD stage 4.5 (eGFR <30) (A/xo 2007:sos901
Patients can begin to accrue wait time on the waitlist once eGFR or CrCl 520 or when
they are receiving chronic dialysis therapy (http:/lo ptn.transplanLhrsa.gov)
Goal of Evaluation
To assess patients medical. surgical.social.and psychological suitability for transplant
To educate the patient about the risk vs benefit of transplant
To discuss donor options: living vs decased donor. Kidney Donor Profile Index (KDPI)
>85%. Public Health Service Increased Risk (PHS IR)
ISDEI combines a variety of donor factors (age. height. weight. edmicityt HTN, DM. cause
of death. Cr. HCV siams. donation after circulatory death status) into a single number
that summarizes the likelihood of graft failure after DDKT (eg.a kidney MM a KDPI of
85% is expected to have shorter longevity than 85% of recovered kidneys)
PH idendhes donors at increased risk of transmitting HBV. HCV. and HIV
Contraindications of Transplantation :Aim 2007sos90)
Chronic illness that shortens life expectancy significantly; Poor functional staws
Reversible renal failure. Chronic or active infection (needs treatment prior transplant).
Active malignancy: needs treaunent prior transplant and must be in remission
Uncontrolled psychosis; active substance abuse: ongoing noncompliance
Cardiac Disease
Cardiovascular disease is the leading cause of death after kidney transplantation
Se. Sp of noninvasive cardiac tests in CKDlESRD pts are very low (knpeniisan 2003147;1631
Immunosuppressive agents can worsen HTN, hyperglycemia.and dyslipidemia.and
thereby accelerate CAD (calcineurin inhibitors.sirolimus,steroid)
Asymptomatic for CAD:23 risk factors (age >60. DM. HTN. dyslipidemia. obesity. lo
angina pectoris. LVH. previous cardiac events. smoking history, (+) family history. HD
duration 22 Yf)9r 21 CAD risk equivalent (DM.ad\erosderosis in other vascular beds.
history of spoke) . noninvasive cardiac stress test (s¢t~i om:10101231598
Symptomatic for CAD.type 1 DM complicated with ESRD,ordiorrlyopad1y with reduced
EE (+) noninvasive cardiac stress test -» coronary angiogram
(.) Coronary angiogram -» If amenable. revascularization before txp (A/KO 2007;5&a901
Preuansplant LVH and elevated LA volume are associated with reduced survival after
kidney transplantation (Ymnspiam Ro 20141310) -| Echocardiogram should be obtained in
those with suspected valvular disease or CHF - Patients with severe inreyersible cardiac
dysfunction should not be listed for kidney transplantation alone (may be candidates for
combined heartkidney transplantation) (GMAJ 1005;17J:S1)
Infectious Disease
J HIV. HBV, HCV. tuberculosis. CMV (risk stratification). EBV. toxoplasmosis
J If from endemic areas foncoccidomycosis. histoplasmosis. strongyloidiasis
HIV
Not an absolute contraindication. Needs HIVspecialist consultation.
Should be on stable antiretroviral regimen. should have no detectable viral load. and
should have CD4 count >200 cellslmm'
Protease inhibitor can increase serum concentration of calcineurin inhibitors
Shortterm outcomes comparable to general kidney Dup patients. Higher acute rejec
tion rate. No increase in HIVassociated complications (u6/m 201(k3612004).
For H Ninfected ESRD patients. kidney transplantation is associated with a significant
surviral benefit compared with remaining on diadysis.Adlusted RR of mortality at 5 yr
is 79% lower after kidney transplantation compared widi dialysis win so; 1017Jts¢s04I.
Liver Cirrhosis
HBV, HCVpositive patients should undergo liver biopsy and hepatic venous pressure
gradient measurement (>10 mmHg clinically significant portal HTN)
Pts w/ cirrhosis and portal hypertension needs evaluation for combined liver-kidney
txp (AIKD 2007;50:B90l.A contraindication for KT alone due to increased mortality
HCV qua Rev ~.¢n~l 201 s:11:m): needs hepamlogy referral
HCVinfected patients have a lower mortality following KT c/w mortality on dialysis
HCVinfected renal transplant recipients have worse patient and allograft sunmral after
transplantation compared with noninfected recipients
An HCVpositive organ may reduce waiting time substantially -» Consider postponing
antiviral treatment until after transplantation co maintain eligibility for an HCVpositive
organ as long as disease severity does not warrant earlier treatment
HBV (www Hemi 10179 10541: needs hepatology referral
lmmunosuppression t HBV reactivation -a HBsAgpositiverecipients are at high risk
Both, patients with chronic HBV (HBsAgpositive) as well as resolved HBV (HBsAg
r\egative.antiHBcpositive) should be initiated on antiviral therapy around die time
of transplantation iGuw\=ev~wv1°ly 2015:148215)
The use of antiviral therapy to prevent reactivation has improved longterm patient
and graft outcomes -| Similar Syr patient and graft survival when compared to HBV
negative recipients (qA$N 2011:6:l481)
Ma l i gna nc y
Immunocompmmised padeuvs are at increased risk for recurrent and de now malignancy
All padems need ageappropriate screening. If malignancy is diagnosed.r.he cancer
should be :reared and cured before transplantation.

Mlnlmum Tumo»»Fr¢e Waiting Period (vi lU0$;173:§1; .quo zoouwol

Cancer Mi ni m a l Wa i t Ti m e Ca nc e r Mi ni m a l Wa i t Ti m e

Bladder In situ: none Breast Early in situ: 2 yr

Invasive: 2 yr Other : 5 yr
Cervix In situ: <2 yr Prostate At l a s t 2 y r
lnvasive:2-5 yr
Colorful Duk e s A or B1 : 2 - 5 y r Renal Smal l , i nci dental r umor s: none
Other : 5 yr O t he r : 2 - 5 y r
Lymphoma 2-5 yr Basal cell None
Lung At l east 2 yr Mel anoma 5 yr

He ma tol ogi c Di s e a s e WK0 2 0 0 7 :5 M9 0 )

-15-20% of ESRD pts have hypercoagulable scare (et, activated protein C resistance.
factory Leiden gene mumion, prothrombin gene mutation, and APLA)
History of thrombosis (DVD PE. recurrent dialysis access cloning), and/or recurrent
spontaneous abortion/preeclampsia -» J hypercoagulability workup
Plan pre. peri.and poswperanive anticoagulation: hematology referral for bleeding risk
G l om e r ul a r Di s e a s e
Transplant should be delayed until disease is quiescent. Not absolute connzindicazion.

Risk of Primary Kidney Disease Recurrence (qAsn 10ua=JB00)

Di s e a s e Ra t e Di s e a s e Ra t e

Pr i mar y FSGS 20-30% MP G N Type 1: 20-30%

Ty pe 2 ( DDD) : 5 0 - 1 0 0 %
MN 10-30% ANCA G N 17%
l g, 1n Z( ) 6 0 % AndG BM di s e a s e 15%

SLE 2-10% HUS I TTP Noni nfecti ous: 60%

Ne ur ol ogi c Di s e a s e
History of corwulsion: avoid andconvulsanls which an interfere with CNI metabolism
(carbamazepine.fosphenytoin. phenobarbital. and phenytoin may decrease serum
concentrations of calcineurin inhibitors) -> neurology referral
History of CV/*a needs neurology evaluation. Modiflable risk factors should be addressed.
P ul m ona r y Di s e a s e
Smoking cessation. CXR & PPD/IGRA (QuantileronTB Gol°"> -» isoniazid if indicated.
History of extensive smoking and/or any signs of obscrucnive or restrictive lung disease
-> PFTICT chest -a pulmonary referral
P s y c hi a t r y
Mild cogllimre impairment is not an absolute contraindication. esp wl good social support
Stable and controlled mental illness is nor a contrainditazion
Complia hte s hould be doc ume nte d prior tra ns pla nta tion
Substance abuse should be eliminated prior transplantation
Needs psychosocial evaluation In conjunction with a transplant social volker to
assess support network, determine suitability. and develop a plan to avoid adverse
nntnrnnlznrainn ntvrhnsnrial nutnnmes
 LIVING DONOR EVALUATION
Living donation: 25% of uansplancs performed in the US in 2016.The rate remains
stable. compared to rising deceased donation since 2011 (Air 201a21s suppl 1:18)
Racial disparities in donacio.: Junors: 12.3% black (36.4% waidisr pts) vs 65.1% white
(33.2% waitlist pa) WT 201a.is s-4w 1.1a)
Commercial donation, a common practice in some countries. comprises 10% of
uansplants. I: had fallen after d1 e Declaration of Istanbul on Organ Trafficking and
Transplant Tourism (Lancer zcweanfs; KI 2019;95757)
Superior outcomes compared to deceased donor transplant: 10yr graft failure 34.2%
vs 51.6% and 10yr deathcensored graft failure 18% vs 26.2% WT 2o1&is Suppl 1:18)

MEDICAL EVALUAT IO N
Informed consent mandated by UNOS: evaluation process: surgical procedure: alter
native treatment for recipient: medical and psychological risk; financial and insurance
factors; voluntarism and the right to opt out of donation at any time
J The operative cardiac. pulmonary. bleeding risks and anesthesiarelated complications
H&P. includes focus on kidney disease history and risk factors:AKIl CKD. DM. HTN.
gestational DMIgestational HTN. hemawria. proteinuria. kidney stones. UTI. congenital
genitourinary anomalies. medications review including unSAIDs. PPI. herbal supplements.
genetic or familial kidney disease. family history of HTNIDM
Social history including adequate support. psychiatric disease history and behaviors
meeting Public Health Service (PHS) highrisk criteria
Compatibility r.esting:ABO typing (x2) including groupA subtype: HLA typing for MHC
Class I (A, B. C), Class II (DR DQ. DR). Donor specific AntiHLA anubodies in recipients.
ID screening: HIV. HCV. HBV. CMV. EBV. Syphilis,TB testing w/in 28 d of surgery
Ageappropriate cancer screening

'UNOS requires mGFR or merCI

Hematuria (KDIGO Tiuiupianiarian 2017;101 as 9991 1s1)
Persistent x2-3 of 2-5 RBCJhpf. rlo infection (UA). malignancy (cystoscopy). nephro
Iithiasis (stone panel).glomemlar disease:TBMN, I N (kidney biopsy).
TBMN does not preclude from domdon (in absence of proteinuria and with normal BP)
HTN (numplanmuan 2017;101 as mapu \:$1)
J Office BP xl, If indeterminate. confirm w/ AB , Not an absolute conmindiudon
if controlled on 1-2 antihypenensives w/o endorgan damage (LVH. albuminuria)
Imaging MRI or CTA. In case of functional and anatomical disparities.the kidney with
smaller size and/or lower function kidney is to be procured
Additional considerations: dependent on each transplant center preference and based
on the individuals lifetime ESRD risk.
Obesity: BMI >40:absolute conuaindiadon, In the general population. BMI >30 alw
CKD msn 1006;17:169S; up zwasrwi AMD 2005:46:587). 3.57 fold T in ESRD (Ann :m
zm;1u=z1) and 1.16 we 201437414111 in otherwise healthy potential donon.albu
minuria, and glomerulopathy
Smoking relative contraindication at most centers despite association with renal
inluq.AWised w quit before donation Ifwwww 20172101 as 991 1:51)
DM is an absolute contnindiodon. Screening widl 2hr GTT orA1C.
 Role of APOLLO testing is unclear.Tes:ing is advisable among young donors ofAfrican
ancestry with ESRD family history although precise risk is not quantified.APOL1
highrisk genotype donors have lower eGFR pre and post donation compared to
lowrisk black donors w/ 0-1 risk variant (57 vs 67. 12 yr) UASN 201839 13091.
Surgical Technique: handassisted laparoscopic donor nephiecwmy (LDN) widely used
compared so open nephrectomy (ON). LDN is 51 min longer but has less blood loss.
shorer hospital sraya and time co rewrn to work compared to ON (rimpluni nu 2013;45:65)

OuTcomEs

S h o r tte r m Ou tc o m e s
90d mortality is 0.03% up 20109039591
Perioperative complications encountered in 6.8% of donors: 4.4% GI. 3% bleeding.
2.5% respiratory. 2.4% surgical/anesthesiarelated injuries. 6.6% other [A/y 1ol6ns1a4a).
Similar rates compared no patients undergoing cholecystectomies or appendectomies
bu: lower than nephrectomies for cancer (qAs~ 2013;B:17I3).
L o n g te r m Ou tc o m e s
Physiologic changes post donation:
50% immediate reduction in GFR with subsequent compensatory hypertiltration
by increased RBF and thus SNGFR ultimately leading to 30% GFR decrease
. Physiologic adaptationzat 36 mo post donation, 1.47 mUmin/yr increase in GFR
in donors vs 0.36 mUminlyr decrease in healthy controls WM 2015;s6114).And 0.20
mUmin/1.73 m'/yr at 12.2 t 9.2 yr (NEIM z0o9.aw4s9l,
No accelerated loss of kidney function of-~»v¢»~»»»~ z001;n;444)
At 12.2 e 9.2 yr after donation. among zss donors: 85.5% GFR 260 men zo0nso¢4s9}
Proteinuria: same estimate across studies: 12% (N = 4.793. 7 yr) lx: z00s;70 1a01); 12.7%
(11% >300 mold. N = 255, 12.2 1 9.2 yr) we/M zuo~r 3so.4s9l: 13% (3% with >1 old.
N = 331, 18 mo-16 yr) (A/xo z01s:66: 114). lt correlates to longer time since donation
[NgIVI z009.3s0.4s9> and HTN WM 201s;ss;1141.
HTN: developed in 321% (NS/M z009;:iw4s94491 to 38% (TusplanlaUol 200127z4441 of nor
mownsive donors. Risk similar to age matched nondonors in men but lower in
women rnantpunmuan z001:7z:444l. 85% of white HTN donors had BP <140/90 at 6 and
12 mo after donation but readings are higher d1 an normotensive donors. Cr. UACR
were similar (hongblantown 2W4;7B:276).
CV events: no difference in deatncvD events between donors and nondonors at 6.2 yr
after donation (Tl\l»1=1vIvrivw 1G0&B63399). In Norway, the risk increases among donors by x1.4
an 15.1 yr (K12014;86:1621.
Older donors: in the US. 5.717 donors with age >55 from 1996-2006. Compared to
agematched donors (mean age 59) with median followup 7.8 yr. no difference in
mortality or combined outcome death/CVD (As z014;14.1ss3l.
Pregnancy: gestational HTN/preeclampsia are more common among living kidney
donors (11%) than among nondonors (5%. OR 2.4): Preterm birth (8% vs 7%1 and
low birch weight rates (696 vs 494) are similar IN£/M z01 s1m2u41
Quality of life: donors physicalhealth summary score and mentalhealth summary
score are above the US population norms INE/M 2009;3w.4s9). In Canada. Scotland. and
Australia both scones are comparable WT 201l:l 1:46J).
ESRD rate
1.8/10.000/yr vs 2.68I10,000/yr in the general population (flu 22.5 yr) in white
dominant donors MM zucmasofassi
In another study. ESRD rates in donors 30.8110.000 vs 3.9110.000 in matched non
donors.Aldiough higher than :he controls. the risk remains low I/AMA 2014.111:s191
The 15yr risk in donors is x3.5-5.3 higher than the estimated projected risk of non
donors. Longterm ESRD risk varies by age at donation and race (NEW 101&374411)
Obesity: BMI >30 86% T risk of ESRD compared to nonobese donors no 2017991;699)
Life expectancy similar to nondonors (hansplaninuan 1997164876: NS/M 2009¢3s0459)
Other Considerations
Kidney paired donation: incompatible donor/recipient swap for matched kidneys. Chains
often initiated by nondirected donors.The National Kidney Registry facilitated 1,748
transplants,d\lough 344 chains. 78 loops from 2008-2015/2016 (4[rzo\7:17,z4sn
Financial impact from oval to 3 mo after donation: median outolpocket expenses
Can $1254 (5312589) and the median for lost donor productivity costs: can $0
(01908) (12 centers in Canada 2009-2014) lIAsn z01s.29¢2a47)
Potential donors are more willing to take potential health risk compared to potential
recipients and health care professionals (K12005;7311S9)
Kidney donors on the waidisc 56 donors were listed as of 2/2002 (Tiumpianianun
z00z74:1349), From 1993-2005. 102/8.889 donors were on the waidist Black donors
14 3% of donors but 44% of donors reaching the waitlist lfmnnlnzu 2007846471
IMMUNOLOGIC TESTING AND MONITORING
PRETRANSPLANT IMMUNOLOGIC EVALUATION
Background
ABO blood type antigens and the human leukocyte antigen (HLA) system provide
the major immunologic barriers to renal transplantation
Transplant across ABO barriers is generally contraindicated (an be done in experi
enced centers. bu: at increased cost and risk of rejection)
HLA Antigens
Class Expressed by: Control the Action of
Class l (A. B, C) All nudeared cells CD8+ cy:otoxicT lymphocytes
Class II (DR DQ. DR) Antigenpresenting cells CD4- helper" T lymphocytes
B cells

HLAA, B. and. DR are the primary antigens considered for HLA matching between
recipient and donor: 2 alleles at each locus I 6 antigens total.A recipient will there
fore have 0-6 HLA mismatches" with a particular donor
Significance of HLA Matching
Deceaseddonor KTR T #S of HLA mismatches are associated in a stepwise fashion
with decreased longterm graft survival lnunspianmusn
z016;10a1094)
Livingdonor KTR Aside from zeromismatch donorrecipient pairs (who have :he
best longterm graft survival). the number of mismatches has
little effect on graft survival

T h e Se n sit ize d Pa t ie n t
Patients may have preformed antibodies to HLA antigens as a result of prior transplants.
pregnancies. blood transfusions.and (rarely) viral/bacterial infections
Such patients are referred no as "sensitized," and comprise approx. 1/3 of patients
awaiting renal transplant in the US
Preformed donorspecific antibodies (DSA) is associated with T incidence of AMR
and 1 allograft survival compared to DSAnegative pts WT 2C0s;s324)
Cnossmatch (XM): tests reactivity of recipient serum against allogeneic cells or HLA
molecules (see table); can be performed against a specific donor or against "panels"
of cellslamigens representative of the general population
Antibody Detection Methods luqm zo1 eJ14s40l
Assay Components Readout Sensitivity

C o m p le m e n t Donor lymphocytes. 76 killing of donor Low (requires

dependent recipient serum. and cells high Ab levels
cytotoxic complement for positive
( CDC) XM result)
F l o w cyt o m e t r i t Donor lymphocytes. Binding of antibodies Intermediate
XM recipient serum. and to donor
lluoresteinlabeled lymphocytes
antibodies against (quantified as
human IgG mean fluorescence
intensity orMFI")
" Vir tual" XM ( via Recipient serum. beads Binding of antibodies High (can detect
solidphase assays. coated with purified to beads low Ab levels)
et. Luminex°) HLA molecules (quantized as
tagged with unique. MFI): allows
identifying precise definition
lmmunofluonescente of DSA specificity

Immunologic Testing Prior to Deceased DonorTransplantation

1. HLA typing of recipient
2. Use solidphase assay no detect and define andHLA andbodia present in recipient serum
3. Lis("unacceptable" HLA antigens based on centerspecific MFI threshold. Recipients
will not receive offers for donors who possess unaccepizble antigens.
 Calculate the calculated panelreactive antigen (CPRA): CPRA reflects the probability
of a CDC XM+ based on the listed unacceptable antigens and their frequency in the
general population (pts with CPRA >80% are considered "highly sensitized" and given
higher priority for HLAmatched kidneys)
5. Final crossmatch: CDC crossmatch performed just prior to transplant using fresh
serum from recipient
Immunologic Testing for Living Donor Transplantation
1. HLA Typing of recipient and donor
2. Solidphase assay co detect and define andHLA abs present In recipient serum
3. Perform CDC.flow,and virtual XMs
Crossmatch Test Interpretation
Crossmatch Interpretation (Nepluniig N11;16:17.5)
(4 CDC Tcell XM DSA to HLA class I, 4- class II
(+) CDC BceII XM High risk olAMR and Is a contraindication to transplant. unless
DSA an be reduced with desensitization protocols
() CDC Tcell XM DSA to HLA class II OR low level class l DSA OR nonHLAAbs
(+) CDC Bcell XM High risk of AMR and is a contraindication to transplant, unless
DSA can be reduced with desensitization protocols
(+) CDC Tcell XM Possible false (+);tes¢ should be repeated
() CDC Bcell XM
(*) flow XM Poses an intermediate risk of AMR-> may benefit from netxp
desensitization and require posttxp irrmunosuppression and/
or monitoring Wt 14104,4.10331
(+) DSA by solid T Risk of AMR and graft hilune compared with negative DSA UASN
phase assay zaizaaansn
( )flow and CDC
XM

Crossmatch Pitfalls and Limitations

Falsepositive flow XMs may be caused by nonspecific lg binding no Fc receptors on donor
lymphocytes. Riurxinmab dwerapy in redpienrs may also muse falseposiUle flow XM.
Antigens such as MHC class Irelated chain A (MICA) and angiotensin II type I receptor
(ATTAR) have been implicated in graft failure but are nor routinely detected by :radi
tional XM pladorms

POSTTRANSPLANT IMMUNE MONITORING

Presence of DSA. whether formed prior to or after txp. is alw inferior graft out
comes.
De novo DSA formation (after transplant) occurs in 13-30% of previously nonsense
sized pts.
De novo DSA formation associated with late acute AMR. chronic AMR, transplant
glomerulopadmy. and L graft survival or 2012:12:1157; qAs~ 101B:13:182)
Risk factors for de novo DSA: high HLA mismatches (especially DQ). inadequate
immunosuppression. and graft inflammation of any cause (QASN 201&1]:181)
Posttransplant DSA monitoring (using solid phase assays such as Luminexs). with
protocol biopsies for high immunologic risk patients. is recommended to guide
immunotherapy and permit early intervention (fonxplonuzrlun 2013:95:19)

PostTmsplant DSA Monitoring

Highrisk: pts with preexisting DSA
Lowrisk: nonsensitized. 1st top
Months 1. 3. 6. 12. annually thereafter
Protocol biopsies are recommended in the first yr
to screen for subclinical AMR.
At least once 3-12 mo posttxp. and/or whenever
a significant change in maintenance
immunosuppnession is considered. suspected
nonadherence. graft dysfunction. or before
transfer of care to another transplant center
 KIDNEY ALLOCATION
Deceased donor transplantation provides a significant survival advantage over dialysis
There are large regional variations in the median time no transplantation
While preemptive listing prior to starting dialysis is preferred given outcomes for
preemptive transplantation. only a minority of patients are preemptively waitlisted
Discards are higher on the weekend even after adjusting for organ quality (KI 1016:9m15n
Inappropriate unilateral kidney discards is common (qASN 201B;lJI 18)
Kidney Allocation System (KAS) (Tunxpbnrlle z 017,31 61)
The new KAS was implemented to imprtwe organ utilization. reduce racial disparities in
waitlisting, introduce longevity matching and prioritization for the most sensitized patients
Allocation time starts from start of dialysis or what added to the waitlist. whichever is
earlier: Can be preemptively listed if the measured or calculated GFR or CrCl $20
s Kidney Donor Risk Index (KDRI): estimate d the relative risk d postuanspWt graft failure
Variables: age. height, weight. ethnicity/race, HTN. DM, cause of death. Cr, HCV.
donation alter circulatory death (DCD)
Kidney Donor Profile Index (KDPI): simple mapping of the KDRI to a cumulative
% scale using all kidneys procured for op in the preceding calendar year in the US
eg, KDPI 85% has higher gray failure risk than 85% of all donated kidney
Estimated PostTransplant Survival (EPTS) score: assigned to all waidisted patients
Variables: age. dialysis vintage. DM. number of all previous transplant
0-10076; lower scores alw longer survival: pts wl $20% are prioritized to KDPI <20%
Calculated panel reactive antibody (CPRA) score: the percentage of antibodies in the
recipient serum to the donor pool.This is monitored on a monthly basis.

Allocation Points for Adult Transplantation Candidate

Characteristics Points Given
Allocation time 1ld
Prior living donor 4
Sensicimion (CPRA. %) 0.08 (220.<30). 0.21 (230.<40)....17.30 (297,<98).
24.40 (298,<99). 50.09 (>99.<100). 202.1 (100%)
Single HLA-DR mismatch 1
Zero HLA-DR mismatch 2

Priority was also established for blood group 8 candidates to accept blood group A2
Outcomes of KAS
KAS has resulted in a signiiant decrease in racial disparities in access to uansplanudon
t shipping times dl: more national sharing for high KDPI kidneys -» t cold ischemia
time, DGF
Despite prioritizadomandidates with CPRA 298% continue no have long wait list times
The discard rate continues to rise and is approximately 20% post KAS
Reference
https:l/opu1.rransplanLhrsa.gov/learn/professionaleducation/kidneyaIloca:ionsyst.em/
I Policy 8: allocation of Kidneys and Frequently asked questions

ALLOGRAFT DYSFUNCTION
Def init ion and Background
After excluding volume depletion: >25% rise in serum Cr and/or new proteinurla >1 g
Cr >1.5.0r ACr between 6 mo -a 1 yr aM graft failure regardless of cause (xi zoouzzn)
Improvement w/ empiric reduction in CNl is insufficient (unless extremely elevated)
since many patients have more dlan 1 diagnosis (ie.AMR + CNI toxicity)
Most surgical complications (je. subcapsular hematomas. lymphoceles) are only seen
early and can usually be detected on U/S

Causes and Workup

Differential Diagnosis of Allograft Dysfunction
Time After exp Possible Causes
0-3 mo Parenchymal: ATN. acute cellular rejection (ACR). antibody
mediated rejection (AMR), druginduced TMA.AlN. CNI toxicity
pyelonephrids. Recurrent FSGS. subcapsular hematoma
Urologic: bladder outlet obstruction (BPH, blood clot), uneteral
(ischemic stricture. blocked stem. blood dot. extrinsic compression
from Iymphocele). urine leak
Vascular: transplant renal artery stenosis (TRAS). anastomotic
eden\a.technical. fibrous contraction.vascular compression from
lymphocele. pseudoTRAs. iliac vascular disease. venous stenosis
3-12 mo Parenchymalz ACR.AMR. BK virus nephropathy. recurrent
glomerular disease. CNI toxicity (acute or chronk).TMA.
pyelonephrids.viral interstitial nephritis.AIN
Urologic: ureteral strictures (ischemic or BK virurla related). kidney
stones (frequently asymptomatic)
Vascular:TRAS or pseudoTRAS
>12 mo Parenchymal: chronic AMR. mixed ACR/AMR. recumnt glomerular
disease.chronic CNI toxicity BK virus nephropathy
Dominant role of noncompliance (Alf zoiznzaesi

Workup
CBC, BMR LFTs. IS levels, BKV DNA PCR. LDH. haptoglobin. donorspecihc antibody
(DSA) via Luminexs or Flow crossmar.ch.urine proteinlcreaUnine. UIA with urine cul
ture.and appropriate serologies if original disease was GN
Renal transplant UIS with dopplers of renal artery and vein
Renal bx: usually required unless UIS diagnostic; LM. IF +C4d staining (marker of C
activation in AMR). EM helpful for recurrent disease and some cases olAMR
Treatment and Prognosis
Depends in underlying cause of dysfunction (covered individually in dles e pages).
reversibility, and degree of interstitial fibrosis
Each 0.5 change in Cr a/w a 2.5 fold l RR of graft failure (KI 100161¢3\11
Later changes in Cr (>1 yr out) are less likely to be reversible than earlier changes
since degree of Fibrosis tends to be worse and the causes of dysfunction may be less
likely to respond to treatment

DELAYED GRAFT FuncTion (DGF)

Deilnition
DGF: need for dialysis within 7 d of zransplamation for any reason
Slow graft function: dysfunction do does not require dialysis. Has inconsistent defi
nition in swdies 1 25% in serum Cr between POD 1 and 2 or serum Cr >3 on d 5.
Similar mechanism to DGF but less severe.
Primary nonfuncrion: dialysis never stopped or eGFR <20 ac 3 mo
 Background
20-25% of deceased donor recipients
5-6% of live donor recipients.Associated with 25% graft failure at 1 yr. usually related
to severe event, je. allograft thrombosis
Associated with 40% increase in relative risk of allograk failure. increased rejection
risk and 6 fold increase in risk of Chronic Allograft Nephropathy W72011;11:1179)
Pathogenesis and Risk Factors
Donor factors: preexisting ATN-prehospital down time. hypotension/hypovolemia
alw brain death.donor DlC,1 terminal Cr. DCD,age
Ex vivo factors: prolonged cold ischemh time (CIT). perfusate soludan choke, pump versus
off pump uanspon (particularly if CIT >24 hr or DCD donor) (91 So; z013;\0<m1l
Recipient factors: age. DM. obesity. l PRA,African American. males Wf 1010;\0.19B1
Preexisting donor quality with ischemia reperfusion injury related to redox species.
followed by abnormal local C regulation. release of DAMPs -» activation of innate
immunity -» cellular infiltrates. tubular degeneration with apoptosis/necrosis
Clinical Manifestations
Oliguriaanuria. persistent elevation in Cr. fluid overload
T K:from l K excrerJon.absorbing blood in surgical bed.tissue destruction
Workup
Daily CBC. LFls. BMR and IS levels
Renal U/S q3-4 d initially, as UOP increases during recovery occasionally unmasks
ureteral or bladder outlet obstruction. evaluate renal arterial velocities for stenosis
Renal biopsy after 7-10 d (earlier in patients with DSA) for reiection.TMA due to IS.
early recurrence of FSGS
Treatment
Induction with thymoglobulin versus no induction or basiliximab may reduce risk slightly
bu: allows for delayed introduction of CNI uAs~ z009;2a 1:asi
Delayed adminisuauon of CNI has no impact on DGF rare. bu: may shorer duration
of HD dependence (T/ansglanluuan 2009s8n 1011
For persisteit DGE reasonable to attempt conversion to belatacept. avoid conversion
to rapamycin/mTOR inhibitor; prolongs recovery UASN 2003;14¢1031)
Preoperative dialysis ineffective at preventing DGF (Tiunspiamadun 2009:B8:1]77)
Prognosis
7 Graft failure 2.5 fold in standard donors or z00616.11 so)
t Both ACR and AMR. persists beyond duration ofATN. likely due to bodi allograft
factors and expansion of alloimmune response during what was initially nonspecific
innate immune activation (al 201Sa94:BS1)

RECURRENT GLOMERULAR DISEASE

Background
Nearly all glomerular diseases can recur in :he allograft. For most. the rate of recur
rence and allograft failure from recurrence is lower than allograft causes from other
q
:: Impact of GN recurrence increases over time: 1-3% of biopsies in the first 6 mo but
3 16% of all biopsies beyond first yr or zoiznfsaal
C Risk factors for recurrence: younger recipient age, DDRTx. steroidfree regimen (pie
dominanrly for IgA), more HLA mismatches reduces recurrence risk (Ki 1017;9z46\)
Recurrent Glomerular Disease AfterTransplantation (NDT 10141%5: KI 70179244611
Graft Failure 5-10 yr After
GN Type Clinical Recurrence Recurrence
leAn 10-15% (>50% hismlogically) 1040%
MN 5-30% 5-40%
FSGS 20-40% zo-40%
MPGN type 1 zmsox 30-70%
C3GN/DDD >80% 30-70%
Lupus 5-30x <10%
ANCA 20% 7%
AntiGBM Extremely rare Unknown
IgA Nephropathy (loAn)
Histologist recurrence is more common than clinical disease and early graft failure is
rare. However. recurrence leads to worse outcomes beyond 10-15 yr
Earlier age of onset and crescent are alw recurrence (AmjNeph¢ul 1017;45:99)
Steroid withdrawal a/w an t rate of recurrent disease in several studies. In USUNOS
data. maintenance steroid use alw 1 risk of allograft loss due to recurrent loAn (RR
0.66) but no difference in overall patient or graft survival (rruiapiInr zoleai nr51
Thymoglobulin induction alw L recurrence in single center studies rruupianirurri nueasnsos)
Membranous Nephropathy (MN)
Presence of antiPLA2RAb in serum preuansplant increases risk of recurrence 3-4 fold.
with 73% recurrence if positive. 33% if negative serologies (rraapinawan z016:i001710)
In those with recurrence,adding rituximab (with continued maintenance immunosup
pression) resulted in complete or partial remission in 75% WT 2009;9128001
Focal Segmental Glomerulosclerosis (FSGS)
Risk factors for recurrence: younger age. rapid time to progression to ESRD. white
race > nonwhite race. and prior recurrence in allograft >80% chance if first allograft
failed from recurrent disease (nor z010;2s=2s)
Recurrent cases suspected to be related to soluble factor. ~7J3 will have partial or
complete response to plasmapheresis and plasmapheresis use associated with better
longterm outcomes II Yranspfanr 201 §;201563961B)
Prophylactic PLEX or RTX did not reduce recurrence tfwnwltmtlitn 201B;10Z:e11S)
ApoLlo risk variants recipient do NOT predispose to recurrent disease.but deceased
donor carriers of risk alleles associated with increased risk of graft failure Wr zoiz\2m4)
De novo FSGS after transplantation: a/w viral infections (CMV. Parvovirus B19. HIV),
ischemia (ie.transplant renal artery stenosis).and CNI toxicity
ComplementMediated (Atypical) Hemolytic Uremic Syndrome (aHUS)
Unlike diarrheaHUS, aHUS associated with genetic abnormalities in alternate comple
ment cascade has a high recurrence and graft failure rate. depending on mutation.
Eculizumab prophylaxis may prevent recurrences in some cases (Air 1010:10:1517)
Recurrence and Graft Failure Rate of tHUS wrz01a1a1sm
Mutation CFH C3 CFI MCP
Recurrent disease 76% 57% 92% 20%
Graft failure 86% 80% 85% 17%

DE Novo THROMBOTIC MICROANGIOPATHY

Background
De novo TMA In patients whose original kidney disease was not related to TMA
0.B-3% of KTR. most commonly in the 1st several mo after transplant lA)KD 2003;42z105e)
Approximately 30% have renal limited disease which has a better prognosis but can
only be diagnosed by renal biopsy WND 2003:41:471)
Pathogenesis
Similar to native disease dough etiology of injury different: endodlelial inlury and
swelling with detachment from basement membrane leads to localized thrombosis.
hemolysis. and platelet consumption. Progresses to mucoid edema and onion skin
appearance of vessel walIs.Wid1 time.glomeruli develop thickened endothelium,
mesangial interposition.and double contours (nonimmunologic MPGN changes).
Calcineurin inhibitors (Cyclosporine >Tacrolimus) contribute to endothelial iniuiy.
roTOR inhibitor use associated with TMA as well but less frequently
Sirolimus have been rarely a/w TMA. particularly in combination with Cyclosporine
AMR. ischemiareperfusion injury. DCD also risk factors lAIr 2010. 10.1$17)
Infection: work as triggers: CMV. Parvo B19. HCM in addition to the diarrheal associated
HUS forms more common in native renal TMA (or vi urn" Transpiam 10\4;1naJ1
Clinical Manifestations
Systemic form: renal dysfunction. thrombocytopenia. anemia. low haptoglobin. elevated
LDH. fevers. hypertension
Renal limited form: renal dysfunction, hypertension. elevation in resistive index on UIS.
nominimal evidence of hemolysis on blood tests
Workup
AntiHLA ab screen. crossmatch with donor. anticardiolipin ab. lupus anticoagulant.
ADAMTS13 level, CMV PCR. Parvo B 19 PCR
 Renal biopsy is diagnostic. Presence of C4d staining in peritubular capillaries strongly
suggests AMR. presence of tubular vacuolization or arteriolar hyalinosis in nonafiected
vessels suggestive of CNImediated injury
T reat m en t
CNImediated TMA: controversial. Cessation of CNI adequate in mos: cases but places
patient as risk for neiection. FLEX has been used while excluding other causes. Switching
CNI no an roTOR inhibitor has been reported. Careful monitoring for renal toxicity is
recommended. Belatacep: has been used as a replacement for CNI WT 100m424)
AMR related: neat underlying rejection with steroids. PLEX. +I- rituximab.proteasome
inhibitor. Some refractory cases have responded Ra eculizumab (nam zuatnuosszi
Prognosis
Renal limited has better prognosis than systemic TMA (0% VS 38% graft failure)
From 1990s. de novo TMA has 50% graft failure rare at 3 yr we 2003;41:10$8). though
the advent of belatacept has increased therapeutic options
In contrast. recurrent TMA has graft survival rare of only 20% at 1 yr

SURG ICAL AND URO LO G IC CO MFLiCATiO N

Background
6% of renal uansplants, mos: occur within first 6 mo after surgery
Ureteral scents reduce incidence of urine leaks and obstruction bu: may increase
cost of transplant and require cystoscopy for removal 3-6 wk posttransplant
UrinomalUrine Leaks: 1-3% olTransplants
Pathogenesis Mos( common sire of leak is ureter-bladder anastomosis. though leaks
from midureter and renal pelvis also seen
Renal failure accompanied by enlarging fluid collection (usually adjacent to allograft and
bladder). chemical peritonitis and ileus are frequent. occasionally leakage from wound.
May only manifest as delayed graft function or immediately after ureteral spent removal
Diagnosis: (1) sample fluid collection for electrolytes and creatinine. If urine leak. then
creatinine and K will be higher than serum. (2) nuclear medicine renal scan can also
be diagnostic in cases where fluid inaccessible
Treatment: the majority of urinary leaks require surgical correction, Dlstal leaks with
minimal extravasation and clinical stability may respond to Foley insertion for 5-7 d.
Lymphocele: 1-16% of Transplants
Pathogenesis: inadequate ligation of lymph vessels near iliac vessels or hilum -o lymph
collection accumulates between :he transplanted kidney and bladder
Small Iymphoceles are frequent but usually asymptomatic. larger collections present
few wk to mo after transplantation.A bulge near the surgical wound sometimes with
extravasation of lymph and edema of lower limb ipsilateral to the graft may be seen.
Rarely. compressive symptoms such as urinary urgency or hydronephrosis and
allograft dysfunction may occur
Diagnosis: renal ultrasound showing the colleWon with associated compressive effects.
Fluid sampling to rule out urinoma (serum creatinine/potassium are similar to serum).
T>c expectant treatment for small lymphoceles. Drainage or laparoscopidopen surgery
(marsupialization) for larger and recurrent collections.
Llreteral Stricture: 3-6% ofTransplants
Pathogenesis: usually ischemia due to inadequate distal blood flow in ureter. though
fibrosis from local BK virus replication and rejection is also suggested or z00d63a521
Risk factors: donor age. DGE abnormal vasculature
Renal insufficiency with hydronephrosis on UIS despite decompressed bladder
Diagnosis: renal U/S or CT urogram usually suffice. If the diagnosis is uncertain, and
antegrade pyelogram needs to be performed
Tx: decompress collecting system with nephrostomy lo reverse AKI and perform
pyelogram. Stem placement can temporize. dilaiztion with stenos or balloons frequently
ineffective: success 28-80%. Most need surgical reimplantation (a. Twsplai 201519161
Allograft Pyelonephrltis: 10-15% of Transplants in FirstYear
Pathogenesis: reflux from surgical bladder anastomosis. RF: Female sex. diabetes. UTls
prior to transplant. immunosuppression, ureteral stent
AKI. fever. pain over allograft. frequently h/o UTI symptoms preceding allograft pain.
Occasionally asymptomatic and found on biopsy done for graft dysfunction
Diagnosis: usually made clinically,eonfirmed with urine cukure. blood cultures frequently
positive as well. CT AIP can suggest diagnosis but not specific as perinephric suanding
is common after all renal transplant surgeries.
 Tic broad spectrum IV Abx pending sensitivkles. continued treaunwt for 2-3 wk Patients
with 2 episodes in 6 mo or 3 episodes in 1 yr should be investigated funder by urology
Many benefit from suppressive andbacwials.such as methenamine 1 g BID plus vitamin C
Prognosis: single episode of pyelonephritis does not impact longterm allograft function
1nw$p Infect of 2016;18:647). Pyelonephrids may predispose (O subsequent rejection and
recurrent episodes can lead to allograft failure.

Asymptomatic Bacteriuria: 35-40% of Transplants

UTls and episodes o( pyelonephrizis frequently preceded by periods of asymptomatic
bacteriuria but most do no: progress xo symptomatic disease
Randomized trial of creating asymptomatic bacteriuria NOT associated with reductioh
in UTIs. hospizalizacions.or pyelonephritis or zo1e;1 s:z94zl

T NANSPL ANT RENAL ART ERY ST sn o sls

Background
Different etiologies than native RAS and more likely to respond no treatment with
improvement in renal function and BP conuol
Incidence 2% in US transplant population by 3 yr (reported range 1-20%) with risk
factors: donor age, recipient age. hlo DM, ischemic heart disease (Am 1 rhphmi 2ua~u04s9l
PseudoTRAS: similar presentation to TRAS but location of vascular obstruction is in
vasculature proximal to anastomosis. common iliac or early external iliac artery
Ecology by London of Stencils wr 7M4;l4:\J3)
RAS Type Location of stenosis Mechanism

A Anastomosis Surgical emote--sewn coo :ightba fibrous conuacdon

B
Bend/kink in artery as Malposiiioning of kidney leads no a kink (like a bent
any point straw) causing reduction in blood flow. may be
missed if only do Huoioscopvy in one orienmion

P Pos:Anaslomosis Adierosclerozic disease. compression from fluid

colIecdon.twisr in artery related to orientation
during sewing. weak association widl rejection
PseudoTRAS Proximal w arterial iliac artery atherosclerotic disease.clamp injury
anastomosis

Pathogenesis
Goldblan 1 Kidney 1 clip model of hypertension
Reduction in lumen size by >S0% (usually >70%)WlTH a mean arterial pressure gradient
>10 mmHg across lesion. Renal hypoperfusion -» L GFR and sodium retentlonlvolume
expansion - HTN. Renin, angiotensirtaldosterone levels usually in normal range
C lin ica l M a n if e st a t io n s
Graft dysfunction our of proportion to biopsy findings: delayed graft function
Hypataision requiring multiple fuss m control; Edema wlo protdnuria/liypoalaurnlnemia
Audible bruit over allograft (low sensitivity and specificity)
Wor kup
Renal UIS with Doppler: operator dependent. sensitivity/speciUcity -85%
Anastomosis >200 cm/s, acceleration time >0.1 s. iliac to renal artery gradient >1.8
Nuclear medicine: sensitivitylspecificity -70-80%
. Separation in rate of appearance of tracer in allograft vs artery (Hilson Index)
CTA and MRA sensitivitylspecificity 95% but require contrast
Angiography: gold standard

T r eatment
Angioplasty alone-patency rate 3069% at 10 yr ()Vas< Sw:2013;57216211
Angioplasty with stent-patency rate >80%. DES = BMS
Vascular reconstruction-best ueatment if within Erst 1-2 wk of operation when
stent placement could rupture anastomosis and cannot wait. Late attempts at surgical
convection associated with graft loss

Prognosis
Untreated TRAS associated with high rates of graft failure WT 2014;1411331
Creatinine decreased 2.9> 1.6 when angioplasty done for graft dysfunction
Angioplasty for HTN without graft dysfunction and/or fluid retention unlikely to lead
to clinical improvement (je, if no graft dysfunction. it is unlikely that stenosis is physi
ologic) gwiu SungZ013;§7:1621)
 ACUTE CELLULAR RE]ECTION (ACR)
As immunosuppression has intensifled.cellular rejection rates have been decreasing
for pas: 30 yr. now consistently below 15% for living donor recipients (Air 1004:4:37B)
Early detection and treatment are crucial, as complete reversal of rejection can
improve prognosis to level of nonnejectors
Pathogenesis
Migration of passenger dendrltlc cells (or native immune cells having processed
alloantigens) migrate to 2 lymphoid organs. stimulating immune cells via direct
(or indirect) allorecognition. Many become circulating efYectorT cells that infil
:rate the allograft -» interstitial inflammation/tubulitis/rejection (NEW 2010;363114s11
Innate immunity respond to tissue "damage associated molecular patterns (DAMPs)"
including redox species. nucleic acids. extracellular matrix components among others
leading to macrophage and dendrite cell activation as well as upregulation of adhesion
molecules -» attraction of adaptive immune cells and milieu for cell activation rather
than energy W12016;16:3338)
BiopsyBased Definition
Recommended adequacy: 2 separate cores (-90% concordance among samples).
210 glomeruli.and 22 arteries
- Minimal adequacy. 7-9 gfomeruli and 1 artery
Acute Tcell Mediated Relecdon Inna Com-in Afr 201m1wa)
Grade Histologist Cnteria
Borderline Fool of wbulkis (Bo) + minor interstitial inflammation (60-1).0r
moderatesevere interstitial inflammation (i2-3) + mild tubulids (11 )
IA Intersddal inflammation involving >2S% of nonscarred cortex (82) v
moderate zubulitis (12)
IB Interstitial inflammation involving >25% of nonscaned cortex (ii 2) +
severe wbulixis (G)
IIA mild w moderate intimal aneritis (vi) 1 any Vt
IIB Severe intimal aneritis (v2) : any ill
III Transmural aneritis and/or fibrinoid necrosis (y3)1 any ill

Addltlonal Notes
Gene expression profiles suggest that not all borderline inflammation is alloimmune
in nature (no Rev ~w»~=/ z01a:1zs34l
Arterials lesions may also be related to antibodymediated rejection
Tre a tme n t
Borderline it is no: clear that all patients need [O be treated. though most centers
will treat borderline rejection associated with allograft dysfunction using methylpred
nisolone 500 mg IV x 3. followed by corticosteroid taper
IA methylprednisolone 500 mg IV x 3, 250 mg IV x 1. then oral CS taper
IB: center dependent-many use Thymoglobulin at 10.5 mg/kg total dose In addition
to CS. However, in select patients. IV corticosteroids as above may be adequate
depending on comorbidities and infectious risk
IIAIIIB: thymoglobulin 10.5 mg/kg in divided doses with IV CS
Ill: thymoglobulin 10.5 mg/kg in divided doses with IV CS
Prophylaxis
Mucosal candidiasis: nystadn SS TID-QID. clotrimazole troches 10 mg TID (N.B. drug
interaction with alcineurin inhibitors) for 1-3 mo
Pneumocystis: uimethoprim-sulfamethoxazole 1 SS QD or 1 DS TIW for 1-3 mo.or
dapsone 100 mg QD for 1-3 mo or atovaquone 1.500 mg QD for 1-3 mo
CMV: valganciclovir adjusted for renal function for 1-3 mo in intermediate and highrisk
Prognosis
Severity direct correlation between the severity of rejection and long term graft sur
vival at 8 yr (control = 97.676, borderline = 93.396, IAlB - 79.696, IINB + Ill = 73.690
lfrunsplmvluOon 1014974146)
Reversibility: if creatinine returns to baseline after treatment, longterm outcomes
equal those without rejection (though more severe rejections less likely to reach
baseline) (Tuns9laMlun 1997;63:1739)
Time: late rejections have a worse prognosis than early rejections. Usually have more
advanced Fibrosis and less likely to be reversible if,°»w»11vl¢»1¢iv» 201437111461
Repeat rejection is common. particularly when associated wid\ noncompliance
 ANTIBODY-MEDIATED REIECTI0N (AMR)
&rlyA!1R (<3 mo): 10% door fuse biopsies done in dIe First 6 wk after surgery almost
:Mays in sensitized patients. If donor spediic ab (DSA) at time of uansplant. risk is 2040%
depending on strength. If no hlo sensitizing events. risk is <5% (A]r 2012;12;JS8)
Late AMR (>3 mo): usually from de novo DSA fonnation.frequendy presents as chronic
active AMR (CAAPIR) with slowly progressive rise in creatinine. and progressive pro
teinuria from transplant glornerulopazhylgiomerulitis, CAAMR make up majority of renal
biopsy results beyond first yr after uansplanr.
Pathogenesis
Circulating antibodies bind no target on endothelial cells.The mos: frequent targets
of antibodies are HLA molecules (MHC classes I and II),though antiangiotensin
receptors. antiMICA Ab. endodlelial Ab.and others have been described (nm Rev Nfpluul
20ts;12:4e4l.Antibody then cause lnlury through changing intracellular signaling, local
activation of complement,and attraction of inflammatory cells.
Endothelial injury can be sufficient to lead co local thrombus generation (TMA) though
chronic activation leading to increase matrix deposition and muldlayering of peritubular
capillaries is more common
Concomitant cellular rejection is common (304014): alw rapid 1 renal function
Definition
Recommended adequacy: 2 separate cores of tissue. 210 glorneruli, and 22 anerles
Minimal adequacy: 7-9 glomeruli and 1 artery
AntibodyMedlated Rejection: all 3 criteria must be met for diagnosis
(Banff cewe Arr 10\l:18:Z7J)
Active AntibodyMediated Rejection
1. Histologist evidence of acute tissue injury (21)
Micnovascular inflammation: glomerulitis (g>0) and/or peritubular capillaritis (ptc>4))
Aneritis (v>0)
Acute thrombotic microangiopathy without other apparent cause
Acute tubular injury without other apparent fuse
2. Evidence of antibody interaction with endothelium (21 )
Linear C4d shining in periwbular capillaries (C4d22 by IF. C4d20 by IHC)
At least moderate microvascular inflammation (g + ptc 22;g must be 21 ifTCMR)
3. Serologic evidence of donorspecihc antibodies
Chronic AntibodyMediated Rejection
1. Histologist evidence of chronic tissue injury (21 )
Transplant glomerulopathy (cg>0)
Severe peritubular capillary BM multilayering (EM)
Arterial intimal Fibrosis wlo other apparent cause
2. Evidence of antibody interaction with endodtelium (21)
Linear C4d staining in peritubular capillaries (C4d22 by IE C4d20 by IHC)
At least moderate microvascular inliammation (g + ptc 22:5 must be 21 ifTCMR)
3. Serologic evidence of donorspeciNc antibodies

Cllnlcal Manifestations
Acct AMK rapid decline in kidney function (or lack of recovery from DGF) with fluid |
retention and J, UOR occasionally ahv thrombocytopenia/anemia and features ofT MA
Chronic AMR: slow progressive decline in kidney function associated with proteinuria

Measuring DSA
ComplementDependent Cytotoxicity Crossmatch (CDCXM): recipient
sera + donor lymphocytes + complement 4 antihuman IgG Ab.Technician uses a vital
dye to determine if cell death has occurred.With +CDCXM, >90% risk of hyperacute
rejection and precludes transplantation
Flow Crossmatch (FXM): recipient sera + donor lymphocytes. run through a How
cyclometer with fluorescent marker antibodies against human IgG.T cells (usually
antiCD3). and B cells (usually antiCD19) to assess presenceabsence of binding as
well as cell type. Strength of antibody can be assessed by dilution or expressed at
mean channel shift"-a measure of brightness compared to background. +FXM at
time of transplant predicts a higher risk of AMR (20-50%) and ACR (20-50%) as well
as higher risk of graft failure at s yr ¢A;rz014:14;1s73)
 Limitation: does not :ell target specificity (which HLA antigen is target) and many
false posidws. Requires donor cells which may no: be available during posttransplant
phase. particularly if deceased donor
Beadbased Multiplex (eg, Luminex° Assay): recipient sera + polystyrene beads coated
with HLA peptides.place in flow cyclometer widl iiuorescent andIgG antibodies. Read
our is expressed as mean fluorescence intensity-"MFI" that is semiquanzitacive
assessment of Ab concen:radon.AIlows identification of Ab but may detect levels that
are not clinically significant. Modification of assay co include complement C1q bind
ing or generation of C4d may lead to better discrimination of high risk Ab (NEW
1013;369:1215)
Tre a tme n t
Reverse inflammation: highdose intravenous corticosteroids +I- Thymoglobulin
Antibody reduction strategies:
Plasmapheresis daily or every other day is effective, many centers replace with Ivlg
after treatments to prevent hypogammaglobulinemia. Duration is determined by level
of antibody assessed through FXM or Luminex° testing
High~.1ose Ivlg (2 g/kg in divided doses) has been used with some success
Rituximab: antiCD20 Ab to depletes Bcells in hopes of reducing DSA-random
ized trial showed no difference in graft survival as 1 yr compared to control but
did low DSA (fumplatntwn 2016;100:391)
Proteasome inhibition (bortezomib x 2 cycles of 4 doses) was no different from
placebo in a European trial uAs~ 2018:Z9:591)
Limit complementmediated injury:
Terminal complement blockade with Eculizumab prevents membrane attack complex
formation. Many case reports suggest utility for treating refractory AMR, and reduced
AMR rates when given prophylactitally to highrisk patients but 1 yr outcomes show
significant chronic Abmediated injury (A/r 2011;I1:z40s)
C1 esterase inhibition has also been successful or 201621631s961
Anticytokine therapy: tocilizumab blocks IL6,a key component in maturation ofT.
B.and plasmacells.dl of which are involved in progression of AMR. Use in transplant
patients has led to increased transplantation rates in sensitized waitlisted patients as
well as patients with AMR posttransplant Wr 1017;17:23B1)
Prognosis
Overall 1yr graft survival: 80-96%. 5yr graft survival: 65-75%
C 1q binding: antiHLA Ab :had bind to C1q (thus activating complement locally) are
associated with a worse 5yr graft survival 54% vs 93% (NEW zoimmzusi
Time (O rejection: early AMR (<3 mo) has a better prognosis than late AMR (>3 mo).
4yr graft survival of 75% vs 40% (Tunsplomauon 201J;96:791
Proteinuria, transplant glomerulopathy.and presence of interstitial inflammation/
concomitant cellular rejection have all been associated with more rapid disease pro
gression lTI=»=¢rl°m lmmunolqy 2014;31:l40)
 INFECTION AFTER KT
Background
Infectious complications occur in >1/3 of patients in the 1st yr with UTls and viial
infections are the most common causes
Infections are the 2nd leading cause of death in KTR (USRDS Annual Report 2010)
Risk factors for infection after transplant: donor exposures. prior and recent recipi
ent exposures. prior and current immunosuppression (IS) regimens, recent treatment
for rejection (A/r 2017;17:556)
Timeline of Common Infections After Kidney Transplantation (KT)
<1 mo 1-17. mo >12 mo
Wound infection. UTI. BK poiyoma virus Communityacquired
Dialysisaccess infection, Herpes viruses: CMV.EBV. pneumonia
C. drfiidk colics HSV,VZV UTI
MulUdrugresistant organisms: P]P Fungal infections
MRSA.VRE.ESBL Cryptococcus Late reactivation of herpes
Donordenived infections viruses
(uncommon)

DONORDERIVED INFECTiON$

Unexpected transmission of infections from donor is rare. and may be alw signiiunt
morbidity and mortality. May occur with living or deceased donors (AlT 2013213 Sup9i 4=22)
Kidneys from deceased donors with premorbid bacteremia can be used for trans
plantation with minimal risk for disease transmission if prophylactic antibiotics are
used. Kidneys from bacteremic donors have an increased risk of DGF but similar
patient and graft survival (rimaplainawi 1999;sa:1 Io7: Cui ruiapum Z0l6;30:415)
Kidneys from donors wl bacterial meningitis may be used or 2011;\1:1123)
Rabies, parasites, lymphomas.and leukemias (via lymphotropic viruses) when donors
w/ encephalitis w/o a proven cause were accepted as organ donors
Possible Transmission from Donors
Slnungyloides s!ercaIulis from donors who lived in endemic areas (je, Cenual and Soudi
America). Serologic screening of donors atrisk and prophylaxis with ivermectin in
recipients when donors test (+) can prevent transmission lA}r 1015;1S:1369)
Trypanosoma cruz from donors who lived in endemic areas (je. Central and South
America). In donors who test (+). regular resting of recipient by PCR. hemoculture.
and serology can identify disease transmission early (reported in 13%).and prompt
treatment with benznidazole can L morbidity alw Chagas disease or z013;13z4181

CYTOMEGALOV1RUS (CMV) INFeCTlON

Risk of CMV disease is related to donor/recipient serologic match:
Highrisk: D+/R-, intermediate rislc D+lR+,and D-/R+, lowrisk: DlR-
A/w T acute/chronic rejectiomgraft failure. EBVassociated PTLD. other opportunistic |
infections (fiuneplanlauan 2013:96333)
Clinical Manifestations
CMV syndrome: fevers. malaise. weight loss. diarrhea. arthralgias. leukopenia.
thrombocytopenia, transaminitis
Tissueinvasive disease: GI (mlc tissueinvasive disease in KTR;colitis > gastritis:
CMV viral load may be negative; in clinical suspicion is high. need biopsy with staining
for CMV), pneumonitis. nephritis. hepatitis. retinitis (can 1:ifm on z00e;44ȣ40)
Prophylaxis
Valganciclovir (900 mg QD, adjusted for CrCI) significantly reduces risk of CMV
posttransplant. Also a/w i in other viral (HSV.VZV) and bacterial infections
Duration: minimum 6 mo if highrisk; 3 mo if intermediate risk.consider 3 mo if Iow
risk (funiplunlnman 2013;96333)
Longer duration (200 d vs 100 d) alw 1 CMV infection in highrisk WT z010210x1zza1
Risk of infection air stopping prophylaxis.esp in 1st 3 mo and high risk:/ CMV titer
Treatment
PO val@ndclo»rir (900 mg BID adjusted for CrCl) and N gancidovir (5 mglkg qlladiusted
for CrCl) equivalent: consider IV if tissueinvasive disease or significant GI symptoms.
Treat until viral load undetectable x 2 wk.then start secondary prophylaxis. Consider
dosereduction of antimetabolite during/after treatment of CMV W1 z007:7110s)
Resistant CMV Infection IT1uvuplonmuan 2011.91.217: can Infer o» 2017;6$:571
Occurs in 1-2% of kidney transplant recipients
° Risk favors:for resistant CMV include D+lR. longer duration of antiviral exposure
Treatment: cidofovir and foscarnet; mortality rate up to 11% in resistant CMV

VAMCSLLA ZosTsn Virus (VZV) INFECTlON Wr 1009t9$108)

Disseninazed infection: vesicles and crusts not limited no a dermatome: 2/3 had visceral
involvement; morizliry (alw AZA and visceral involvement) 17% inunspiani he: 2011:44:1B14)
Visceral involvement; DIC. hepadris, pneumonitis, pancreatitis. meningoencephalitis.
vasculopazhy; may develop wlo skin lesion (nbr 2011:16:365)
Antivirals for CMV prophylaxis reduce risk ofVZV reactivation
Tx: acyclovir N if disseminat.ed,visceral or facial involvement: valacydovir PO if limited to
single dermatome; Consider decreasing or holding anzimetabolite until all lesions healed

EPSTEIN-BARR Virus (EBV) In=scTlon

EBV mismatched (D+/R-) recipients have higher risk of EBV uremia. up to SM in
1st yn It may be asymptomatic. may be alw mononucleosislike symptoms, or may
progress to PTLD. Late persistent EBV uremia may be a/w T risk of solid cancers
I*/T 20 un3165e Tinnsplamnuan 2017;10.l473)
Risk of PTLD 24x higher in EBVseronegative recipients Jan we on 1995520r13461
Monitoring in EBV D+lR-: J viral replication at least monthly for 3-6 mo. then every
3 mo until the end of die 1st yr. Resume after acute rejection tx (KolGo Afr 2009.9 sw¢lJ,S1)
EBV D~lR- recipients with increasing EBV viral load should have immunosuppression
reduced. which is aw i risk of developing PTLD WT 2013;13 suppl3:41)
Use of rituximab in EBV D+/R recipients with asymptomatic increasing EBV viral
load may reduce risk of developing PTLD WT 2011;1110581
Antiviral prophylaxis for CMV does not reduce the risk of developing PTLD We 2017;\7710)

BK POLYOMAVIRUS INFECTION
Lbiquitous poiyomavims; establishes latency in GU tract and an reactivate in semng d IS
BK viruria occurs in -30%. BK uremia in 15-20%. and BK nephropathy in 1-10%. BK
viruria can cause hemorrhagic cystitis (more common air HSCT) or irritative voiding
symptoms. Only sign of BK vireinia/nephropathy typically t crmtinine (new 2o0z 347:4aa.
Trasplnnlnhun 2013:9s94k BMT 2008;41:363)
Viral replication in urine and blood is most common in 1st yr posttransplant
Risk factors: T IS (most imponant).1 age. male gender: diabetes. Caucasian. ureteral
stent. donor/recipient serologic mismatch
BK nephropathy is an early complication that adversely affects allograft survival
up 10064691653 new 200z=14714ss1
Kidney Bx: intranuclear viral inclusions. interstitial infiltrates. and lymphocytic tubulitis
(may be difficult to distinguish from acute rejection): immune staining +SV40.7 Severity
of BK nephropathy by Banff criteria alw worse graft survival l;As~ 2018t296801
Screening for BK viremia.wi¢h L in IS if persistent uremia. can i risk of nephropathy.
Screening minimum q3mo in 1st 2 yr, then annually through 5th yr. Screening should
be resumed after treatment for rejection (Arr 2013.13 iu¢914:i79)
Despite L in IS if viremic, development of BK uremia alw T risk of allograft failure
(framplanlalian 2013:15:949)
Tx:firstline treatment is l in Is.Typlcally..L /eliminate antlmetabollte.then 4 CNI
trough if uremia persists. Other therapies include switch from tacrolimus to cyclo
sporine,switch from CNI to mTORi.switch MMF to Ieflunomide.add cidofovir
W12013:13 wppM:1 WE qAsn 20143932 As 2015;15:1014)
 HsrATms c IN=ECTION Virus (HCV)
Hepatitis C infected patients who remains on dialysis are as higher risk of death than
:hose who receive a kidney transplant (T'°I=VI\"l11¢\°'\ 20 u;9519431
AntiHCV antibody positive KTR have lower allograft survival rates and T risk of dash
compared co antiHCV antibody negative recipients (*)T 2005:5:1452)

Management of HCV (4) KTR: Live r Biopsy and Porn! Pressure Help Guide
No significant fibrosis (stage 0-2), no live DDRT w/ HCV+ or HCV-. then DAA post
donor transplant
No significant Fibrosis. has live donor DM then transplant with HCV- kidney
Significant fibrosis (stage 3-4). portal HTN SLK. Not a candidate for KT alone.
Significant fibrosis. no portal HTN DM and KT w/ HCV kidney vs SLK UASN
2016:272238)
In patients w/ compensated HCV cirrhosis and
hepauopord venous gradient <10 mmHg. KT
alone may be performed with similar patient
and gray survival dw HCV4 recipient wlo
cinriiosis (Tmwiuniaun zonnsasol
Historically. the use of interferonbased regimen to neat hepatitis C in KT patients
was alw increased risk of acute humeral rejection and should be avoided WT 20031374)
Posttransplant treatment with DAA for 12 or 24 wk achieves sustained virology
response at 12 wk in most HCV+ KTR and is well tolerated. with an acceptable safety
pro6le (Ann :m 2017;166:109)
Transplantation of kidneys from HC\Lposhlve deceased donors into HCVnegative
recipients. followed by the use of DAA. has been peiiormed as a way to address the
organ shomge. Showterm results show 100% sustained vimlogic response widl excel
lent allograft function we 2017;376123943 AM :m 1018;168:$33)

HIV INFeCTlON
In selected HIV+ pts wl ESRD (CD4 >200ImL'.viral load undetectable on stable and
retroviral regimen). pt and graft survival are high at 3yr (88% and 74%), although
slightly lower Chan among all US recipients. HIV infection remained well convolled and
where were few HIVassociated complications (NUM z01o.u>a:z0o4l.The slightly lower sur
vival in HIV+ recipients may be due to HCV coinfection. as HIV+ and HCV- recipients
have similar patient and allograft survival compared with HIV recipients (KJ 20158&3411
Protease inhibitors: interaction with Tac and CSA. and dose and frequency of antirejec
tion medications may need to be reduced. T allograft loss. especially during the 1st yr
postuansplanL and are a/w t death.A nonproteaseinhibitorbased ART regimen is
preferred in potential KTR if feasible (Arr z017;171:m4l
KT from HlVpositive deceased donors may be an acceptable treatment option for
HlVinfected patients, with patient survival of 84% at 1 yr. 84% at 3 yr. and 74% at 5 yn
and allograft survival of 93%, 84%. and 84% INEJM z015;s716131

PNEUMOCYSTIS HROYECII Pnsur4onlA (P]P)

Can occur anytime post transplantation. though it is rare in patients Mo remain on P]P
prophylaxis. Low eGFR and lymphopenia are risk factors (Anil #ma cmmul 201 a;4441s).
PJP transmission posttransplant an be nosocomhl. Standardized prophylaxis protocol
and airborne droplet precautions on uanspdant unks and clinics may help decrease
nosocomial transmission In 2013;B4:240)
Unexplained PTHindependent hypercakemia in a renal transplant patient who presents
wiM subacute respiratory complaints should raise concern for P1P (m zoisnanon

FUNGAL INFECTIONS
Invasive fungal infections: occur in -1.3% of KTR in the 1st yr posttransplant Invasive
candidiasis and aspergillosis are the mos: lirequent cause (cm MM of 201tnsa1101)
Candiduria in KTR is alw reduced patient survival race. However; treatment of asymp
tomalic candiduria does not appear to improve outcomes (an uuia no 2005;4Q 1413)
 U R IN A R Y Ta A C T infe c tion (U TI)

m/c infectious complication.all UTls in transplant recipients are complicated UTIs

Risk factors:female.T age, ESRD due to reflux. DDRT. T immunosuppression
For patients with allograft pyelonephridmfeverslallograft tenderness may persist for
several days despite appropriate antibiotic choice
Recurrent UTls defined as >3 in 12 mo or >2 in 6 mo. can occur in up to 32% of
patients. Recurrent UTls typically nested with longer course of antibiotics and
require evaluation for stru aural/functional abnormalities WT 2015:1S11021)
High prevalence of ESBL organisms. especially if recurrent UTls (rmmpl 1pn Do 2012;14¢5951
No RCTs to guide duration of therapy: 7-10 d for first UTI (longer if ureteral stent
in place). 14-21 d for allograft pyelonephritis or UTI with bacteremia
Asymptomatic bacteriuria develops in 50% of transplant recipients (XI z010.e7=77/1
Treatment does not 1 rate of UTI, nor improve renal function WT 2016116:2943)

INFECTiOU$ DIARRHEA

Diarrhea is a frequent posttransplantTwo mlc etiologies are medications (mycophe

nolate > tacrolimus) and infections. Evaluate for infection before L mycophenolate dose
as 1 mycophenolate dose -» T risk of reiectionlgraft failure lriulnplarlauai zooeaziuzl
Common causes of infectious diarrhea: viral (CMV. EBV. adenovirus. Norovirus). bac
terial (C. difficile). parasitic. Infectious etiology identified up to 70% of cases with
molecular testing (runugiiluiuan 2014:9s:a0sl
C. diffkilez 3.5-16% of hospitalized KTRs.8-33% will have as least 1 relapse. Initial Rx
10-14 d: if on Abx for coinfection with other organism, continue for 1 wk after other
antibiotic stopped. Consider longer duration with relapses/vanco taper. Consider pro
phydaxis if hlo C. diff and requiring new course of antibiotics lffaieplanaiaan 2014;9s¢sos1
Norovirus: 17-26% of severe diarrhea. may have significant weight loss. Main treatment
if transient . in IS. Nimzoxanide may be effective in some uses. If viral shedding and
symptoms persist. mycophenolate may need to be dIced lnnmplimiuan 1014:98:B06)

METABOLIC COMPLICATION AFTER KT

Newonss1 DiAaETES AFTER TNANSPLANT (NODAT)
Epidemiology and Clinical Implication
20-30% in the 1st yr after kidney transplantation (KT): Risk attributable to KT alone
is highest in the 1st 6 mo after txp
i Patient and longterm allograft survival. T risk of major CV events. inlection.and sepsis
Diagnosis and PostTransplant Screening
Symptoms of diabetes plus random plasma glucose 2200
Fasting glucose 2126 x2. weekly )< 4. at 3 mo. 6 mo. then annually posttxp
A1c 26.5% (test only valid after 3 mo posttxp;Alc cannot be used in conditions that
change RBC turnover), J at 3 mo.q3mo for 1st ynand at least annually thereafter
Risk Factors and Pathogenesis
Traditional: age >40. BMl z30.AA. Latino, Fllx of DM, personal he gestational DM. IGT
Transplantspecitic: infection (CMV. HCV), poswp hyperglycemia (fasting glucose >200).
. Mg. decased donor. increased HLAmismatch. PCKD. immunosuppressive agents
Immunosuppressive Drugs and Risk of NODAT
NODAT Risk Mechanism
Corticosteroids tT Reduce peripheral insulin sensitivity

Curls Ta c t t Cs A t Direct toxicity to pancreatic Bcells

Si . Ii us T Reduce ripheral insulin sensitivity

Treatment
Lifestyle modificationzfirstline therapy
2ndgen sulfonylureas. repaglinide,and DPP4 inhibitors have proven efficacy in KTRs
SGLT2 inhibitor: appears safe and LA1: and weight (Dobelei cm 20\9;4z10en
Metformin: limited data: appears to be safe in stable KTRs with eGFR >4S
Insulin as needed to attain A1 c <7%
Prednisolone reduction to 5 mg/d alw improved glycemia (nor 2001;16;s19)
Mixed data re: benefit of complete/early steroid withdrawal on risk of NODAT
Belazacentbased regimens aw a lower incidence of NODAT (Tlw\=pl¢\w¢i¢H z0\1;91.976>
 Lmn ABNORMALITIES AFTSN KT

Treatment
Spins L MACE by 21% and cardiac death or nonfatal MI by 29% (Al.£kT Air zo0s5:m9)
Siadns for all adult KTR. If <30 w/o DM. CVD. individualized decision (KDOGO Lipid 10131
CsA (bu: not tacrolimus) inhibits hepatic metabolism of stairs. raising levels
Goal is to attain a large: statin dose rather than a specific LDL value (see table)
Ezetimibe is probably effective in statinintolerant KTRs. but data is limited
Avoid librates T adverse events. a/w graft dysfunction (A/xo 2004244:s431

.2011 FDA: concomitanc use of CsA and simvasutin :s contraindicated; howaven if satin cannot be changed
dl: cost and patient is stable. may monitor CPK and LFTs q612mo

C K D -MB D A s nonr 4 A Lm s s A FTER K T

Pathophysiology
Regression of structural changes in the parathyroid gland (hyperplasia. adenoma) an
rake mo to yr; resolution of uremia improves endorgan resistance to PTH
Persistently T PTH + PTH responsiveness/healthy allograft 4 .1 R T Ca: similar to 1
hyperparathyroidism (HPT)
. FGF23 levels in the early posttxp period also promotes phosphaturia
CS: .L bone formation of osteoblasts. T bone resorption of osteoclasts. t RANKL
EidemioIo*sTand Clinical Implication
ersistent is common after KT >80% of patients have PTH > 65 and >40% have
PTH >130 at 1 yr posttxp. despite good renal function (TIunsphniauvn zols; 10c»1a4>
High prelransplant PTH level is a/w graft failure (T/amplamauan 200s=01:352)
L PO¢:40-90% of pts during the first 3 mo.gradually improves thereafter (NDT 2004;1r1za11
T PO4A/w top failure and mortality we 2017:1aJ17)
T Ca: approx 1/3 of patients during 1st yr. usually within the 1st 3 mo
1 25OH vit D is alw interstitial Fibrosis pro ression
x and low raft
s function UASN
ZOlJ:24:B31)
Posttxp CKDMBD abnormalities are alw T fracture. allograft dysfunction/loss. pro
gression of vascular calcification. and mortality
Monitoring
J Ca, Phos w/ routine labs;/ PTH. 25vit D q3mo for 1st yn diet q6-12 mo Mereafter
(more frequently if abnormality or if receiving vitamin Dlcalcimimetic therapies)
T reat m en t
Consider paradryroidectomy before txp if iPTH 2800 despite adequate medical therapy
Avoid POW supplementation unless severe (<1.0. or symptomatic <1.5). as it may T PTH
. PTH wlo T Ca: replete 25OH vit D no >20 no zuom7s:s4s1
If PTH remains elevated, :rear with activated vit D
T PTH w/ T Ca
Cinacalcec may 1 iac level (our zoca;23:104s)
Pararhyroidecromyz superior Ca and PTH reduction no cinacalcer UASN 1016427124871
 HYPERTENSION AFTER KT
Backgr ound
>90% d CNIoated transplant recipients have HTN (<5% normotensive wlo medications)
Risk factors: male. recipient age. donor age. DM. obesity. presence of native kidneys.
delayed graft function. previous acute rejection. Curls and steroids, CKD in transplant
Complications: increased risk of CVD. graft failure, and death
Risk of graft loss t by -15% with each 10 t in SBP at 1 yr postTx loewi 2000.1s36:m
Lowering SBP to $140 by 3 yr is a/w significantly improved 10yr graft survival (RR 0.79)
and L risk of CV death (RR 0.73) (A/r 200s:s:zns)

Pathogenesi s
Immediate postTx period: volume overload, graft dysfunction. ischemia, CNI toxicity
CrIs (CsA >Tac) a activate SNS. upregulate endothelin, inhibit NO oxide -o systemic
and renal (afferent arteriolar) vasoconstriction, t NCC activity (Nat M44 z011;17:1304)
Glucocorticoids (je. prednisone >10 mold); sodium and water retention due to partial
activation of mineralocorticoid receptors
Activation of the RAS in the native kidneys and/or a failing allograft
Evaluation
J graft dysfunction. CNI toxlckyc recurrence of primary disease. postbx AVF
Transplant Renal Artery Stenosls (TRAS): important to Identify
Presencationzworsening or refractory HTN and/or unexplained graft dysfunction. HE
f l a sh p u l mo n a r y e d e ma
Risk factors: operathle trauma. athevosclerosls of transplant renal artery or iliac artery.
CMV in fe ctio n . d e la ye d g ra ft fu n ctio n
Diagnosis: PRA may be relatively low due to volume expansion and high PRA is non
specific; Doppler U/S has 87-94% sensitivity and 86-100% specificity; spiral CT: MRA:
arteriography (risk of AKI due to contrast or thromboembolism)
Treatment: conservative therapy w/ ACEi; PTA +I stenting (can restore perfusion in

gzip
70-90% but may recur in up co 1076); surgery if PTA unsuccessful or stenosis inac
cessible to PTA (successful in 63-92% but recurrence rate up to 12% and high risk
of complications. should be reserved for refractory HTN) UASN 2004;15:134)

T r eatm ent
TalgetBP is basedcn presencedproleinuriaand addidanal comorlaidides (DPLCVDLHF)
Guidelines for Target BP
Guideline Recommendation
KDOQI <130180. if prouinuria. l goal may be appropriate we zc04:4351)
KDIGO s130Is80. irrespective of the level of urine albumin (KI 20I!:BJ:377)

EBPG
<130I85 lo prozeinuria, <125/75 w/ promeinuria (NDT 100Z17125)

Choice of drug class should be based on time air Txp.use of CrIs. presence/absence
of persistent albuminuria. and comorbidizies
D r ug Tr eatm ent

D H P C C Bs
May ameliorate vasoconstriction induced by Curls
( am l odi pi ne. CCB alw i graft loss (RR 0.75) and T GFR (man A 4.45) dw placebo
ni f edl pi ne) no R x uw i ugl m i i auun N 09:8877)
Nifedipine t GFR at 1 and 2 yr dw lisinopril ¢f~.»»=~w~~~ 2001;mnn

N onD H P C C Bs
Pot ent I nhibit ors of CYPJA4. cause p l a sma l e ve l s o l Ta c. CsA a n d
sirolimus; effect occurs in 48-72 hr; close monitoring of CNI or
( di l ti az em .
v enpam i l ) r o TO R i n h i b i t o r l e ve l s i s r e q u i r e d
Cause As in GFR whkh may interfere with do of acute rejection (esp. in
AC Ei , AR Bs
first 6 mo postTx);can exacerbate hyperkalemia (RR 3.76 for
incidence of hyperkalemia w/ACEi dw CCB). esp. in Pts on CrIs:an
exacerbat e anemia (Tunsplanlnnnn news 7)
Losarun an lower plasma uric acid levels in Pts widl gout
Despite beneficial effects on proteinuria and HTN. no longterm benefit
on graft, patient survival has been shown in RCTs
Wa it 3 -6 mo p o stTx b e fo re sta rtin g ACEi o r ARB. if in d ica te d
 MALIGNANCY AFTER KT
Ba c k gr ound
Overall cancer risk rare is elevated in solid organ transplant (SOT) patients
Standardized incidence Ratio (SIR) cl: general population is 2.1 (JAMA z011:30s:1s91I

SIR of Mallgnancles in Transplant Recipients UMM 1011;30s:1a9\)

I nf e c t i on Re l a t e d Noni nf e c t i on Re l a t e d

Kaposi sarcoma 61. 46 Nonmel anoma ski n 13. 85

Liver 11. 56 Ki dney 4.65
Vulva 7.6 Thyroid 2.95
NonHodgk i n l y m phom a 7.54 Mel anoma 2. 38
Anus 5.84 Lung 1.97
Hodgki n l ymphoma 5.84 Urinary bl adder 1.52
Penis 4. 13 Pancreas 1.46
Or ophar ynx i ncl udi ng tonsi l 2.01 Col or ect um 1.24
Stomach 1.67 Prostate 0.92
Cer vi x 1.03 Breast 0.85

Cancer (20%) is 2nd leading cause of death after CVD (24%) UAMA am 201614611
Cancers may occur de novo (eg. NMSC and Kaposi sarcoma).donorrelated (eg. RCC.
melanoma. or choriocarcinoma). and recurrent cancers
Impaired immune surveillance Is thought to be :he major underlying pathogenesis
coupled with higher rates of oncoviral infections

Risk Factors and Pathogenesis

Smoking Historic cancerrelated death T 1.4x if quit before op. T 2.6x if continued
smoking (ruepiwnaaan 20\e10fm7)
History of prior cancer
Kidney and thyroid cancers alw kidney allograft failure uAsr4 201s:z 7149s)
General Screening and Prevention Strategies
Smoking cessation
Updating pressansplant recipient malignancy screening
Screening postvransplant for skin. breast. colorectal. cervical cancer per USPSTF
EBV IgG seronegative recipients of seropositive organ should have protocol EBV PCR
monitoring throughout first year and beyond
G e ne r a l Tr e a t m e nt
1 IS;Chemorherapy; Radiation: Removal of affected organ as indicated
Pembrolizumab (amiPD1 Ab) caused cellmediated rejection l~glm 20laJ74¢s9s); CTlA4
i nhi bi tor . i pi l i mumab. di d not U an once 2014;32:c69)

NONMSLANOr4A SKIN CAncers (NMSC)

Ba c k gr ound g
Basal cell carcinoma (BCC) and squamous cell canzinoma (SCC) are the most common 4;
malignancies in solid organ transplant recipients lemma Sre 2012384622-1630)
Aldiough mortality risk is low, it has die highest incremental risk of death compared
;2
to general population (><29.8) UAMA ann:1016224631
Risk Factors 3N
Cumulaui»e ultraviolet radladon exposure.Age at txp (>50 yr lx T risk). Dungeon of top.
Immunosuppression: type (llA has 1.Sx risk of SCC) and Dose: high accumulated
dose ofAZA. CNl.and steroids T risk of SCC 4.6x (Amjannemaiafwll 2018)
Type of organ transplanted: higher risk of NMSC if utilize more intense immunosup
pression such as combined heart and kidney transplant compared to kidney alone
History of previous NMSC increases risk for subsequent NMSC
Screening and Prevention
Selfexam AND Heakh care provider skin exam annually (KDIGO Tmnglviuuon 2009)
Sun protection education (Use of highspF sunscreen decreases SCC. BCC)
Sirolimus L 56% risk NMSC vs CNI (Ami 2D14;349296s79). But a/w higher mortality (qAsn
2016:11:lB4§)
Treatment
In aggressive SCC. reduction of immunosuppression
Consider change to MMF from AZA. or roTOR inhibitor from CNI. systemic retinolds
(Am I an o¢-mmlA¢lil 2018)

POSTTRANSPLANT LYre PHOPNOLIFEaATIVe Dlsonosn (PTLD)

Background
Incidence 1% at 10 yr posttransplant with majority (>80%) occurring in first yr post
transplant (mau n¢Iniu 2014:29(91151n
Cumulative incidence over S yr is 1-3% in kidney transplants
The maioriry are EBVdrivenaup to 30% are EBV negative
Risk Factors
IS after SOT is a/w marked T risk of malignancy UAMA 1004294113211
Negative EBV serostatus of the recipient at the time of kidney transplant
Prior malignancy
Time PostTransplant, EBV naive occur early.whereas EBV IgG seropositive recipients
develop -10 yr pos:transplant (T/aiisglniuallon 2013;5:470)
Clinical Presentation
Nonspecific constitutional symptoms: B symptoms (fever. weight loss. night sweat)
Lymphadenopadiy and organ dysfunction: extranodal masses (>1/2). CNS disease
(20-2538), infiltrative lesions of the allograft (20-25%)
1 Hb. Plt.WBC. i LDH. Ca.uric acid. monoclonal protein in urine or serum
Allograft dysfunction: hydronephrosis. renal vessel stenosis, graft infiltration
Prevention
No role of antiviral prophylaxis or z011:17:1701
Workup and Management of EBV Reactivation (AIT 2013;13¢41)
Initial reactivation with elevated EBV PCR over 2 wk
Reduce immunosuppression. monitor EBV PCR once weekly until negative
In the following settings of EBV uremia. r/o PTLD via CT imaging or PET scan, and
pursue excisional biopsy when appropriate:
Persistent EBV uremia, or high asymptomatic EBV uremia w/wo I IS
Any EBV uremia with associated symptoms
Treatment (MH 10101496932 National Comprehensive Cancer Network Guidelines)
Goals: endication of PTLD and preservation of graft function
Tumor histology staging with WHO criteria
EBV status of tumor established (EBV+ tumor may respond best to reduction of IS.
EBVnegative lymphomas unlikely to respond)
Reduction of IS (where alterative organ supports possible. eg.dialysis)
Immunotherapy with CD20 monoclonal antibody rituximab (Effective in CD20+ PTLD)
Chemotherapy:
Anthracyclinebased: CHOP (cyclophosphamide. doxorubicin. vintristine. prednisone)
Care must be taken in patients with impaired cardiac function
Platinum drugs are nephrotoxic and even in normal renal function. care should be
taken
Fludarabine is renally excrend. monitor renal function
Radiotherapy
Surgical management
CNS Involvement; radiation therapy.surgical removal.and methotrexate (if renal
function preserved)
Prognosis Ly ca 0rWI}013:1Dt1N1)
Patients with PTLD had 5yr survival race of 53%. 10yr survival rate of 45%
Multivariable analyses revealed than age >55 yr.semm creatinine >1.5 mg/dL. LDH,
disseminated Iymphoma.brain localization, invasion of serous membranes. monomor
phic PTLD. and Tcell PTLD were independent prognostic indicators of poor survival
RENAL COMPLICATION IN OTHER ORGAN TRANSPLANTATION

CKD AFTER NONNeNAL Soup ORGAN TRANSPLAnTATION (NRSOT)

CKD is a known complication pos: NRSOT
CKD prevalence reported as 5 yr after transplantation was 21.3% for intestine
recipients. 18.1% for liver recipients, 15.8% for lung recipients. 10.9% for hear recip
ienv.s. and 6.9% for heartlung recipients
ESRD occurred as a rate of 1-1.5%/yr among NRSOT recipients (NUM z003:349931)

Risk Factors for CKD Post NRSOT mew 1W3:349:9J1: ;ASN z001:1e¢a031:
Tnmnglant Rev 2N 1$:2%17§)

Pretransplanr factors Older age. 9, preexisting CKD. DM. HTN. HCV

Perkransplam factors
Pos:transplant factors
Renal hypoperfusion: LV dysfunction. hepatorenal syndrome
Perioperadve AKI: hypotension. hypovolemia, iodine contrast.
nephrotoxic medications,atheroembolic disease
Calcineurin inhibitor toxicity
Acute: vasoconstriction of afferent arterioles.
Chronic: interstitial fibrosis. nodular arteriolar hyalinosis.
glomerulosclerosis. thrombotic microangiopathy
Nephrotoxic antibiotics. ongoing transplant organ dysfunction.
BK nephropathy (rare)

Treatment
NRSOT recipients with eGFR <30. protelnurla >500 mg/d or rapidly declining GFR
should be referred for renal evaluation. Management of complications of CKD (eg.
anemia. metabolic acidosis. bone and mineral disease) should follow guidelines for
nontransplant pts U Halt u", Tmmplam 201D:29:914; Lnerfnmspl 2013:19:3).
BP iargers and management should follow those for the general population. CCBs are
most commonly used. but ACEIIARB should be used if proteinuria and may be pre
ferred in DM. In patients on mTORi.ARB may be preferred to ACEI due to lower
risk of angioedema u Hear! hmlTnmsplani z01<z2~r914; iierfonspl 2013:1n: ClASN 2010:5:703).
C o n ve rsi o n fro m C N I to mTOR i
alw T GFR. However. conversion to mTORi also a/w T acute rejection in liver trans
plant and high discontinuation rate due to side effects.
mTORi conversion associated with improved GFR in heart and lung transplant recip
ienrs. mTORi may slow progression of cardiac allograft vasculopathy lrmmplaluiuon
101611006111 1016;10041558)
P a t ie n t s wit h p re e xist in g p ro t e in u ria o r CKD ma y h a ve wo rse n in g re n a l fu n ctio n
after conversion to an mTORi law aauwmi 101711735811 Heon lung Trasplant 1009;7.81564)

DiALvsis AFTER NRSOT

HD is the mos: common RRT modality in NRSOT patients who develop ESRD
PD has been used in heart and lung transplant recipients. who might be very sensitive
KO volume changes and fluid shifts associated with hemodialysis
In thoracic transplant recipients showed higher rate of hospitalization with HD vs
PD (231.4 vs 72.7/100 patient yr), higher rate of dialysisrelated infections with PD
(0.36 vs 0.08lpatien¢ yr), and no difference in mortality (he MM z01s;Js9sl

Kl1:>n£v TRANSPLANTATION (KT) AFTER NRSOT

Early referral for KT evaluation is essential given high mortality rare while on dialysis
KT is alw small T mortality peritransplant in NRSOT However the mortality rate is
i significantly after 141 d and remains sustained for 5 yr postrenal transplant (NE/M
1W];3491931)
5yr overall graft survival for KT in hear or lung recipients is lower than with primary
KT However deathcensored gray survival is comparable and KT i risk of death com
pared with dialysis by 43% in heart and 54% in lung recipients. Liver transplant recipi.
e n ts with ESRD have a 44-60% reduction in morality compared witll remaining on
dialysis (Air 2009;9$784 um Tmnspl 2011;19:3)
 URINF SEDIMENT IMAGES

Dysmorphlc RBCs. RBCs of diflenenz size, RBC cast. Typically seen in giomerulone
shape. hemoglobin content. with fraglnenndon phrids or vasculitis.
and budding. Seen in gkamerular bleeding.
Hansel shin.

Renal epithelial cell in AKI. Multiple vac

WBC cast (KI 1008;73:980). Frequently seen
uolazed renal epithelial cells in fosamet
in inzersririal nephritis. presence of eosino
nephrotoxicicy (ATN). Hansel szain.
phils suggests allergic origin. May also be
seen in glomemlonephriris. Hansel stain.
 »

Triple phosphate (stluvite) crystals (KJ

zoIs;ua:20sl. Coffinlid shaped Triple (ammoni
ummagnesium) phosphate crysnls (stru
vile) seen in infected alkaline urine with
uneaseproducing bacteria.

Urabe crysnls In 201181:118Il, Rosenes

and rhomboidshaped crystals M uric acid in
pink urine after recurrent seizure. after pro
pofol anesthesia.Also seen in hear stress-
relaxed Mesoamerkan nephlupazhy.

_ -
Sulla drug crystals (re 20 1s;a1sss; "Shock
of wheat" appearance of Suifamthoxazole
crymls seen in acute kidney injury following
high dose Sulfamthoxazole-Trimedroprim
therapy.
 RENAL PATHOLOGY IMAGES

Wir9-
A

Mesangial prolilerulve GN, H&E

924:

-5
.auf
Crescentic GN widl fibrinoid necrosis MPGN. H&E
(ormw).JMS

Immune thrombi in cryc\d¢bulinemk GN. PAS

FSGS. rip lesion variant, H&E

Nodular mesangid sclerosis. PAS Acute thrombotic microangiopathy in giom
erulus. H&E

Acute tubular necrosis, PAS Acute interstitial nephritis. PAS

H14
Strongly bireiringenr cadmium oxalate crystals.
H&E. polarized Iigh:
Arypkzl asks of myeloma/light chain as!
nephropathy. PAS

II T

Granulomatous interstitial nephritis. PAS Mucoid Intimal edema of a mediumcaliber

artery; scleroderma renal crisis H&E
Cholesterol emboli (arrow) in a large artery. Granular mesangial staining (loAN)
H&E

.4 S

Linear GCW shaming landGBM dIsease)

MIDD
 ., . . *w
"";`.4 Subepidmdial electron dense deposits
Suhaldomhelial electron dense deposit

= ~ Mac

°e~'=»=».».=.
Armed fibrils (8-10 nm)

'1.. n
} 13" I.
Fibrillary deposits (16-20 nm)

Annularuibular suhszniaure in cryoglohuli

nemk GN
 UNITS AND MOLECULAR WEIGHTS

Unit Conversion
Unit Conveniomx Factor Below
Conventional Conventional SI to
Substance (MW) Unit SI Unit to Sl Conventional
BUN (14 x 2 : 28) mg/dL mmolIL 0.357 2.8
Urea (60) mgldL mmol/L 0.167 6
Creatinine (113) mg/dL umollL 88.4 0,0113
Calcium (40) mg/aL mmol/L 0.25 4
Phosphorous (31) mg/dL mmollL 0.3229 3.1
Magnesium (24.3) mg/aL mmollL 0.41 2.43
Glucose (180) mgldL mmol/L 0.055 18
Uric acid (168) mgldL u mol/L 59.485 0.0168
PTH pg./mL pmoVL 0.106 9.4
Total cholesterol mgldL mmol/L 0.026 38.67
25OH vit D nglmL nmolIL 2.496 0.4
1.25(OH)1 vit D pg./mL pmoIIL 2.6 0.38
UPCR g/g Cr mg/mmol 113.6 0.0088
UACR gig Cr mglmmol 113.6 0.0088
'Urea 1 mmollL = run 1 mmol/L; BUN 1 mg/dL= Urea 2.14 meat
Sodium Chloride 58.44 glmoI: Na 22.99 glycol + CI 35.45 glycol
NaCl 3% = 30 g/L = 513 mErelL: 3% 100 mL = 3 g = 51.3 mEq Na + 51.3 mEq CI
NaCl 2% = 20 g/L = 342 mErelL: 2% 100 mL = 2 g = 34.2 mEq Na + 34.2 mEq CI
NaCl 5.1 g = 87 mEq (2 g) Na + 87 mEq (3.1 8) CI
NaCl 5.8 g (1 teaspoon) I 100 mEq (2.3 g) Na + 100 mEq (3.5 g) CI
NaCl 1 g= 17.1 mEq (393 mg) Na + 17.1 mEq (606 mg) Cl
Sodium Bicarbonate 84.01 g/mol: Na 22.99 glycol + HCO;
61.02 glycol
NaHCO; 8.4% = 84 mg/mL = 1 mEq/mL: 23 mg Na + 61 mg HCO; per mL
50 mL = 50 mEq Na + 50 mEq HCO3: almost same Na contents with 3% 100 mL
NaHCO; 650 mg = 7.7 mEq Na + 7.7 mEq HCO;
NaHCO; 4.8 g (1 teaspoon) = 57 mEq (1.3 g) Na + 57 mEq (3.5 g) HCOg
Potassium Chloride 74.55 glmolz K 39.10 g/mol + Cl 35.45 g/mol
KCI 1 g = 13.6 mEq (530 mg) K + 13.6 mEq (470 mg) Cl
Protein Size
Proton Size (kDa)
Abumin 68 192 microglobulin 11.a
Myoglobin 17.8 Cystatin C 13.3
Hemoglobin 68.8 or light chain 22.5
ISG 150 1 light chain 45
 ABBREVIATIONS
AlloHSCT allogenic hematopoietic
primary stem cell
secondary transplantation
betablocker ALT alanine aminotransfense
change in mental status AME apparent mineralocorti
1 betahydroxysteroid coid excess
dehydrogenase type 2 AML acute myelogenous
18FFDG fludeoxyglucose F 18 leukemia
6MP 6mercaptopurine AMR antibody mediated
alw associated with rejection
AA amino acid ANA annnuclear antibody
AAMI Association (Cr the ANCA ancineutrophilic
Adyancement cytoplasmic antibody
of Medical Ann IM Annals of internal
lnstrumentadon Medicine
Ab antibody APC antigenpresenting cell
ABG arterial blood gas APD automated peritoneal
ABMR antibodymediated dialysis
rejection APLA antiphospholipid
abnl abnormal antibody
ABFM ambulatory blood APOLLO apolipoprotein LE
pressure monitoring APS antiphospholipid
abx antibiotics syndrome
ACCP American College 01 AR autosomal recessive
Chest Physicians ARB angiotensin receptor
ACE angiotensin convening blocker
enzyme ARDS acute respiratory
ACEi angiotensin convening distress syndrome
enzyme inhibitor ARNa angiotensin Receptor
ACL anticardiolipin antibody Neprilysin Inhibitor
ACR acute cellular rejection ARV antiretrunral
ACS acute wwiiary synditume ASA aspirin
ACTH adrenocorticouophic ASCVD atherosclerotic cardio
hormone vascular disease
AD autosomal dominant AST aspartate
ADAMTS13 a disintegnin and metal aminotransferase
loprozeinase with a asx asymptomatic
thrombospondin type ATI acute tubular injury
1 motif.memb¢f 13 ATN acute tubular necrosis
ADH antidiuretic hormone AuwHSCT autologous
ADTKD autosomal dominant hematopoietic stem
tubulointerstitial cell transplantation
kidney disease aneriovenous. aortic
acidfast bacilli valve
atrial Fibrillation AVB atnioventricular block
anion gap AVF arteriovenous liswla
antigen AYG arteriovenous graft
anion gap metabolic AVM arteriovenous
acidosis malformation
AHUS atypical hemolytic AZA alathioprine
uremic syndrome
A¢ alkaline phosphatase
AIDS acquired bl: because
immunodeficiency BCx blood culture
syndrome B)P Bence lofts protein
AIHA autoimmune hemolytic BK maxiK channel
anemia BKV BK virus
All angiotensin II BM bone marrow
AIN acute interstitial BMD bone miuenl density
nephritis BMI body mass index
AlT American journal of BMP basic metabolic panel
Transplantation BNP MIPS naxriuledc pqmae
AKI acute kidney injury BP blood pressure
AKID dialysis requiring acute BPH benign prostatic
kidney injury hypertrophy
alb albumin BT bleeding dmc
aldo aldosterone BUN blood urea niungen
ALI acute lung lnlury
 biopsy carbon monoxide/
compared w cardiac Output
compared with/ chronic obstructive
consistent with pulmonary disease
complement COX cyderoxygenase
C3 glomerulopathy CPPD calcium pyrophosphate
C3 glomerulonephritis crystal deposition
carbonic anhydrase calculated panel reactive
coronary artery bypass antibody
grafting COI1\PIEl¢ remission.
CAD coronary artery disease complete response
CAI carbonic anhydrase Cr creatinine
inhibitor CrCI creatinine clearance
CAKUT congenital anomalies of CRP Creactive protein
the kidney and urinary CRRT continuous renal
tract replacement therapy
CaOx calcium oxalate C RT cardiac resynchronization
CaP calcium phosphate therapy
CAPD continuous ambulatory CS corticosteroids
peritoneal dialysis CsA Cyclosporine A
CaSR calciumsensing receptor Csection cesarean section
CBC complete blood count CSF cerebrospinal iluid
CCB calcium channel blocker CT computed tomogram
CCD cortical collecting duct CTA computed tomography
CD collecting duct angiogram
CDC complementdependent CTD connective tissue disease
cytotoxicity CTLA4 cytotoxic Tlymphocyte
CDI central diabetes insipidus associated antigen4
ceph. Cephalosporin cv cardiovascular
CF cystic fibrosis CVA cerebrovascular accideit
CFB complement factor B CVD cardiovascular disease
CFH complement factor H CVP central venous pressure
CFTR cystic Fibrosis transmem CVS cardiovascular system
brane conductance CVVH continuous V¢l10V€I1OU§
regulator hemofiltration
CFU colony forming units CVVHD continuous venavenous
CH50 total complement hemodialysis
activity CVVHDF continuous venavenous
CHF congestive heart failure hemodiaNltration
CHO carbohydrate cx culture
Cl cardiac index CXR chest radiograph
CIAKI contrastinduced AKI CyBorD cyclophosphamide.
CIN contrast induced bortezomib.
nephropathy dexamethasone
cold ischemia time CYC cyclophosphamide
creatine kinase CYP Cytochromes P450
chronic kidney disease cys cysraun C
dialysisdependent d day
chronic kidney disease dlc discontinue.
CKD ND nondialysis dependent discontinuation
chronic kidney disease due to
CKDT nondialysis dependent dopamine
chronic kidney disease directact.ing antiviral
wid\ a kidney disuse alveolar
transplant hemorrhage
CKDEFI Chronic Kidney Disease DAM Ps damageassociated
Epidemiology molecular patterns
Collaboration DBP diastolic blood pressure
CLL chronic lymphocytic DCD donation aker
leukemia circulatory death
CML chronic myelogenous dcSS¢ diffuse cutaneous
leukemia systemic sclerosis
CMP cardiomyopathy DCT dlscal convoluted tubule
CMS Centers for Medicare & DDAVP tdesamino8Darginine
Medicaid Services vasopressin
CMV cytomegalovirus dense deposition disease
CNI calcineurin inhibitors deceased donor kidney
CNT connecting tubule transplantation
Ddx differential diagnosis enzymelinked
def deficiency immunoassay
DES drugeluting stent enzymelinked
dFLC difference between immunosorbent assay
:he involved and electron microscopy
uninvolved light epithelial sodium channel
chain electrophysiology
DGF delayed graft function Epo erythropoietin
DHP dihydropyridine EPS encapsulating peritoneal
dHUS diarrhea associated sclerosis
hemolytic uremic EPTS Estimated Posttransplant
syndrome Survival
diabetes insipidus ERBP European Renal Best
disseminated inuavascular Practice
coagulation ESA erythropoiesis
diabetic ketoacidosis stimulating agen:
diffusion capacity of die ESR erythrocyte
lung ggdimgnggign rate
diabetes mellitus ESRD endstage renal disease
diseasemodifying anti ESRDHD hemodialysis dependent
rheumatic drug endstage renal
diabetic nephropathy disease
direct oral anticoagulant ET1 endothelin1
dyspnea on exertion EKOH alcohol
diffuse proliferative EU endotoxin units
glomerulonephrids EULAR the European League
drug racdon widi Against Rheumatism
eoslnophilia a systemic flu followup
symptoms F DA U.S. Food and Drug
DRI direct renin inhibitor Administration
dRTA distal renal tubular FFP fresh frozen plasma
acidosis FGF23 fibroblast growth factor
disease 23
donor specific antibody FGN iibrillary glomerulone
deep vein thrombosis phritis
dry weight FHx family history
diagnosis FLC free light chain
dual energy xray FMD fibromuscular dysplasia
absorptiometry FMF familial Mediterranean
elo evidence of fever
EAV eRecdv»e arterial volume lluoroquinolone
EBPG European Best Practice fracture risk assessnnent
Guidelines tool
EBV EpsteinBarr virus FRC functional residual apadty
ECF extracellular fluid FSG fasting serum glucose
ECG electrocardiogram FSGS focal segmental glomeru
ECHO extracorporeal mem losdemsis
brane oxygenation FTT failure to thrive
EDD electron dense deposit G6PD glc6phosphate dehy
EDTA ethylenediaminetet dragenase
raacetic acid GBM glomerular basement
EDW estimated dry weight membrane
EF ejection fraction GCA giant cell aneritis
EGD esophagogastroduode GCSF granulocyte colony
noscopy stimulating fatter
EGFR epidermal growdt factor GCW glomerular capillary wall
receptor GERD gastroesophageal reflux
eGFR estimated glomerular disease
filtration rate GFR glomerular ikration rate
eGFRcreat estimated glomerular GGT ygluumyl uanspq:d¢se
cys filtration rate using GI gastrointestinal
creatinine and as gastrointestinal bleed
cystatin C gk glucose
eGFRcys estimated glomerular glom glomeruli
filtration rate using GLP1 glucagonlikepeptide1
cystadn C GMCSF granulocytemacrophage
EGPA eosinophilic granuloma colonysumulating
tosis with polyangiitis facwr
GN giomerulonephritis l&D incision at drainage
GNR gramnegative rods IABP intraaortic balloon pump
GnRH gonadotlopinreleasing IBD inflammatory bowel
hormone disease
GOF gain of function IBW ideal body weigh:
GP glomerulopathy lCa ionized calcium
GPA granulomatosis with ICD implantable cardiac
polyangiitis defibrillator
GPC giamposiuve cocci ICP intracranial pressure
GRA ICU intensive care unit
aldosteronism IDA iron deficiency anemia
global sclerosis IDWG interdialytic weight gain
genitourinary IE infective endocardltls
graftversushost disease IF Immunofluorescence
hour IFITA interstitial fibrosis and
headache tubular atrophy
haptoglobin IFN interferon
hematoxylin & eosin is Immunoglobulin
stain IgAN Immunoglobulin A
history and physical nephropathy
examination IgAV Immunoglobulin A
hlo history of vasculitis
HZRA H2receptor antagonist IGF1 Insulinlike growth
Hb hemoglobin factor 1
HBcAb hepatitis B virus cone lgG4RD Immunoglobulin
antibody G4related disease
HBeAg hepatitis B virus envelope IGRA interferon1 release =35=1
antigen IGT impaired glucose
HBsAb hepatitis B virus surface tolerance
antibody HD intermittent
HBsAg hepatitis B virus surface hemodialysis
antigen IIFT indirect immunofluores
HBV hepauiis B virus cence testing
HC Heavy chain IKMG the International Kidney
HCC hepatocellular carcinoma and Monoclonal
HCDD heavy chain deposition Gammopathy
disease Research Group
hCG human chorionic gonad ILZRA interleukin2 receptor
ouopin antagonist
HCQ hydroxychloroquine ILD interstitial lung disease
Hot hematocrit IMCD inner medullary collect
HCV hepatitis C virus ing duct
HD hemodialysis IMI inferior myocardial
HDL highdensity lipoprotein infarction
HELLP hemolysis. abnl LFTs. low intlanasal
pIn idiopathic nodular
heat failure. hemohltra glomerulosclerosis
:ion INH isoniazid
hyperosmolar hypergly INR international normalized
cemic state ratio
HIF hypoxia induced factor IP intraperitoneal
HIT heparininduced throm IRGN Infectionrelated
bocytopenia glomerulonephritis
HLH hemophagocytic immunosuppression
lymphohistiocytosis International Society for
hypotension Peritoneal Dialysis
high power held ITGN immunotactoid glomeru
hyperparathyroidism Ionephritis
heart rate ITP idiopathic thrombocyto
hematopoietic stem cell penic purpura
transplantation IUGR intrauterine growth
HSP Henoch-SchOnlein restriction
purpura IV intravenous
HSV herpes simplex virus IVC inferior vena cava
HTN hypertension IVD U intravenous drug use(r)
HUS hemolytic uremic IVF Intravenous fluids
syndrome l vIg lntrannous immuno
history globulin
 luxtaglomerular MAHA microangiopathlc hemo
ones medienamine silver lytic anemia
jugular venous distention MAOI monoamine oxidase
jugular venous pulse inhibitor
potassium MAP mean arterial pressure
Kidney Allocation MATE multidrug and toxic
System compound exclusion
KDIGO Kidney Disease: MBL monoclonal B cell
Improving Global lymphocytosis
Outcomes MC mineralocorticoid
(Guidelines) MCD minimal change disease
KDOQI Kidney Disease mCrCl measured creatinine
Outcomes Quality clearance
Initiative (Guidelines) MCTD mixed connective tissue
KDPI Kidney Donor Profile disease
Index MCV mean corpuscular
KDRI Kidney Donor Risk volume
Index MDMA 3.4methylenedioxy
Kidney lntemational methamphetamine
Kidney International (Ecstasy)
Reports HDRD Modification of Diet in
kidney transplantation Renal Disease
kidney transplant MDS myelodysplastic
recipients syndrome
kidney-ureter-bladder mes mesangial
xray MG monoclonal pmmopadvy
left atriumllongacting/ mGFR measured glomerular
lupus anticoagulant filtration rate
light chain MGUS monoclonal gammopadvy
light chain proximal of uncertain signifi
tubulopathy cance
IcSSc limited cutaneous MHC major histocompatibility
systemic sclerosis complex
LCV leukocytodastic ml myocardial infarction
vasculitis MIDD monoclonal immuno
LCDD light chain deposition globulin deposition
disease disease
LDH lactate dehydrogenase min minute
LDKT living donor kidney multiple myelonna
transplantation mycophenolate mofetil
LDL lowdensity lipoprotein measles. mumps and
LE lower extremity rubella
LFTs liver function tests membranous
LHC light and heavy chain nephropathy
LHCDD light and heavy chain mo month
deposition disease MOA mechanism of action
LM light microscopy MPA microscopic polyangiitis.
LMW low molercular weight mycophenolic acid
LMWH lowmolecularweight MPGN membranoproliferative
heparin glomemlonephrius
LN lupus nephritis MR mineralocorticoid
Loc loss of consciousness receptor
LOS length of stay MRA mineralocorticoid recep
lpf low power Edd tor antagonist, magnetic
LPL lymphoplasmacytic iuonance angiography
lymphoma MRI magnetic resonance
lactated Ringers imaging
left ventricle MRSA mezhicillinresistant
LV enddiastolic pressure s. aureus
left ventricular MTb Mycobacterium tuberculosis
hypertrophy roTOR mammalian (mechanistic)
most common. most target of rapamycin
commonly MTX methotrexate
mAb monoclonal antibody MVP mitral valve prolapse
MAC membrane attack MW molecular weight
complex N/V nausea and/or vomiting
MACE malor adverse cardiac NAFLD nonalcoholic fatty liver
event disease
NAGMA nonanion gap metabolic PCOS polycystic ovary
acidosis syndrome
NaPi sodium phosphate PCP Pneumocystis jimved
cotnnsporter pneumonia
NASH nonalcoholic steatohep PCR protein catabolic rate.
atitis polymerase chain
NCC sodium chloride cotrans reaction
poner PCSK9I proprotein conyerase
NCX sodium calcium exchanger subtilisin/kexin type 9
NDI nephrogenlc diabetes inhibitor
insipidus PCT proximal computed
nuclear factor d activated tubule
T cells PCV13 13valent pneumococcal
NGT nasogastric tube conjugate vaccine
NHANES the National Health and PCWP pulmonary capillary
Nutrition Examination wedge pressure
Survey PD peritoneal dialysis
NHE sodium hydrogen PE pulmonary embolism
exchange PET positron emission
NHL nonHodgkin lymphoma tomography
NKCC sodium potassium chlo PE: physical examination
ride cotransporter PFO patent foramen ovate
normal FFT pulmonary function
nonmelanoma skin test
cancer PG prostaglandin
NNRTI nonnucleoside reverse PGNMID proliferative glomerulo
transcriptase inhibitor nephritis with MOI\O
NODAT newonset diabetes after clonal immunoglobulin
transplant G deposits
NPO nothing by mouth PHPT primary hyperparathy
Np! NaPi cotransporters roidism
NPV negative predictive value PHS Public Health Service
NR no response PI protease inhibitor
NRSOT nonrenal solid organ PICC peripherally inserted
transplantation central catheter
NRTI nucleosidelnucleotide PiT inorganic phosphate
reverse transcriptase transporter
inhibitor P]P Pneumocystis yimved
NS normal saline: nephrotic pneumonia
syndrome FKD polycystic kidney disease
NSAID nonsteroidal antllnllam PLEX plasma exchange
matory drug plt platelet
NSF nephrogenic systemic PMHx past medical history
fibrosis PML progressive multifocal
NYHA New York Heart Ieukoencephalopathy
Association PMN polymorphonuclear
OAT organic anion zranspona leukocyte
OCT organic cation PNA pneumonia
transporter PND paroxysmal nocturnal
osmolal gap ¢ly=pn=a
Organ Procurement and PNH paroxysmal nocturnal
Transplantation hemoglobinuria
Network pn5 peripheral nervous
OSA obstructive sleep apnea system
OTC overthecounter PO onl intake. by mouth
plw present(s) with POD postoperative day
PA primary aldosteronism PPD pufifigd protein
PAC plasma aldosterone derivative
concentration PPI proton pump inhibitor
PAD peripheral artery disease PPSV23 23valent pneumococcal
PAH pulmonary arterial polysaccharide vaccine
hypertension PPV positive predictive value
PAN polyarteritis nodosa Ppx prophylaxis
PAS periodic acid-Schiff stain PR partial remission. partial
PASF PA systolic pressure response
PCI percutaneous coronary PRA plasma renin activity
intervention panel reactive
PCN penicillin antibody
PR8Cs packed ned blood cells RZV recombinant zoster
PRES posterior reversible vaccine
encephalopathy sle side effect
syndrome slp status post
pRTA proximal renal tubular mis symptoms and signs
acidosis SAH subeladinoid l~e~°~h=s=
PSGN post streptococcal SBP spontaneous bacterial
glomerulonephritis peritonitis/systolic
pr patient blood pressure
PT proximal tubule. SC SUb(UCZl\€OUS
pro thrombin time see squamous cell carcinoma
PTA percutaneous translumi SCD sickle cell diseasdsudden
nal angioplasty cardiac death
PTH parathyroid hormone SCLC small cell lung cancer
P TH r P parathyroid hormone SCT stem cell toansdanmion
related protein Se sensitivity
PTLD posnransplant lymphop sFLC senim free light chain
roliferative disease SGLT sodium glucose cotrans
PTT partial thromboplastin poner
time syndrome of inappropri
PVR pulmonary vascular ate ADH
resistance serum immunoelectro
every phonesis
before every meal serum immunofixation
daily electrophoresis
every bedtime standardized incidence
e4ery odle r day ratio
quality of life StevensJohnson
rule in syndrome
rule out systemic lupus
rheumatoid arthritis. erythematosus
right atrium slow low efficiency
nenin-angiotensin- dialysis
aldosterone system simultaneous liver kidney
renin-angiotensin- transplantation
aldosterone system superior mesenteric
inhibition artery
RANKL receptor activator of soluble membrane attack
nuclear factor complex
kappa[s ligand smoldering multiple
RAS renal artery stenosis myeloma
RBC red blood cell SMX sulfamethoxazole
RBF renal blood flow SNGFR single nephron gfomeru
RCT randomized controlled lar filtration rate
trial SNRI serotoninnorepinephrine
RF rheumatoid factor. risk reuptake inhibitors
factor SNS sympathetic nervous
RI resistive index. renal system
insufficiency sos sinusoidal obstruction
RO MK renal outer medullary syndrome
potassium channel specificity
ROS reactive oxygen species. serum protein electro
review of systems phoresis
RP retroperitoneal scleroderma renal crisis
RPG N rapidly progressive supersaturation
glomerulonephritis Sjogren syndrome
RR relative risk. respiratory systemic sclerosis
rare selective serotonin
RRF residual renal function reuptake inhibitor
RRT renal replacement svc superior vena cava
therapy SVO; mixed venous oxygen
RT radiation therapy saturation
RTA renal tubular acidosis SVT supraventricular
RTE renal tubular epithelial tachycardia
RTX rituximab symptom(s).
RVT renal vein thrombosis symptomatic
Rx therapy syndrome
RYGB RouxenY gastric bypass type 1 diabetes mellitus
 UCI urine chloride
T2DM type 2 diabetes mellitus
Tacrolimus UCx urine culture
Tac
TAL Thick ascending limb of UF ultrahltration
the loop of Henle UFH unlractionated heparin
tuberculosis UGIB upper gastrointestinal
tubular basement bleed
membrane UIFE urine immunohxatjon
TBMN dtii hasemait membrane electrophoresis
nephlopadly UK urine potassium
TCA tricycle antidepressant ULN upper limit of normal
TCC uansltional cell UN: urine sodium
carcinoma UNOS United Network for
Organ Sharing
Tdap tetanus. diphtheria.
pertussis UOP urine OLIIPUL
TEE transesophagol echo UPCR urine protein to
temp temperature creatinine ratio
TG triglycerides UPEP urine protein
tiubuloglomerular electrophoresis
TGF
feedback Uprot urine protein
transient ischemic aback URI upper respiratory tract
TIA
TIBC total iron binding capacity infxn
tubulointerstitial nephritis USPSTF U.S. Preventive Services
TIN
TINU tubulointerstitial nephri Task Force
ds and uveitis USRDS United States Renal Dam
TIW three times a week System
UTI urinary tract infection
TKV total kidney volume
TLS tumor lysine syndrome UTO urinary tract obstruction
TMA thrombotic VBG venous blood gas
microangiopathy Vd volume of distribution
TMP trimethoprim VDRL venereal disease
TNF wmor necrosis factor research laboratory
TP total protein (test for syphilis)
total parenteral nutrition VEGF vascular endothelial
TPN
TRALI transfusionrelated acute growth factor
lung injury VF ventricular fibrillation
VHL Von Hippel-Lindau
TRAS transplant renal artery
stenosis vit vitamin
TRI wbuloreticular inclusion VKA vitamin K antagonist
TRP transient receptor VOD venaocclusive disease
potential VT ventricular tachycardia
Tsar tnnslerrin saturation VTE venous thromboembolus
TSH thyroid stimulating VUR vesicoureteral reflux
hormone vWF von Willebrand factor
TTE transthoracic echo vzv varicella zoster virus
TTKG transtubular pqgggium wl with
gradient wlo without
TTP thrombotic dirombocy wlu workup
topenic purpura WBC white blood cell (count)
TURP trinsurediral resection WH O World Health
of the prostate Organization
treatment week
transplantation Waldenstriim
rhiazolidinediones macroglobulinemia
urinalysis worsening renal function
ultrasound water restriction
uric acid test
urine albumin to weight
creatinine ratio Xlinked
urine anion gap xanthippe oxidase
urine albumin xanthippe oxidase
urine albumin to protein inhibitor
ratio Y
year
ulcerative colitis ylo year old
urine calcium zeaL zoster vaccine live
 Note: Page numbers followed by f and c denote figure and :able respectively.

Allele, 217
AA amyloidosis. 722, 912, 9S3 Allograft pyelonephrids. 1111-1112
Abdominal compartment syndrome. Allopurinol, 5 14. 951
914-915 Alltrans retinoic acid (ATRA). 932
A[}2M amyloidosis, 723 ix1 microglobulin. 11
Acetaminophen. 955 Alphaglucoside inhibitors. 941
Acetaminopheninduced nephrotoxicitya Alport syndrome, 122. 221. 710
915 Aluminum. 331
Acetazolamide. 413. 432 Aluminum hydroxide.432
Acetoacetic acid. 46 Ambulatory blood pressure monitoring
Acid-base balance. 43 (ABPM). 8 1. 84
in alcoholuse disorders. 915-916 Amikacin, 936
in GI diseases. 913 Amiloride. 434
Acquired cystic kidney disease (ACKD). for nephrogenic DI. 17
5.11 Amitriptyline. 957
Acquired perforatihg dermatosls. 969 Amyloid. 721
Activated charcoal, 334 Amyloidosis. 721-723
Acute cellular rejection (ACR). 1113 Anabolic steroid. 331
Acute decompensated heart failure Analgesic nephropathy. 954
(ADHF), 315. 91 ANCAassociated vasculitis. 122
Acute fatty liver of pregnancy 964 Anemia. 920
Acute interstitial nephritis (AIN). 58-59. Angiography. 29
937 Angiotensinconverting enzyme
Acute kidney injury (AKI). 1.24-128 inhibitors (ACEr). 39-311
Acute lung injury (ALI). 96 for hypertension. 85
Acute mesenteric ischemia. 911 Angiotensin receptor blocker (ARB).
Acute phosphate nephropathy. 431 39-311
Acute tubular necrosis (ATN). 215. 51. Angiotensin receptor neprilysin
9.14 inhibitor (ARNI). 311
cardiac surgery and, 51 Anion gap metabolic acidosis (AGMA),
Acute uremic encephalopathy. 9S9 45
Acyclovir. 960 Antibiotics
ADAMTS13 deficiency. 728 for UTI, 63
Adefovir. 938 Antibody agents. 323
Adenine phosphoribosyltranslerase Antibodymediated rejection (AMR).
(APRT) deficiency. 55 1114-11 15
Adolescents and young adults (AYA). Anticoagulation
transition of care for. 1.33 in membranous nephropathy. 925
Adrenalectomy. 814 nephropathy related to. 925
Adrenal insufficiency. 317-318. 425 for NVAE 924-925
Adrenal vein sampling (AvS). 8.14 Antidepressants. in CKD. 957
Adrenocorticotropic hormone (ACTH). Antidiuretic hormone (ADH). 16. 112.
318, 812 113. 25
Adynamic bone disease. 9.45 in hyponatremia. 422
AFib amyloidosis. 723 AntiGBM disease. 122. 710
Allibercept. 933 Antihypergiycemic agents, 941
Agalsidase B. 725 Antihypertensives. 87
Agerelated macular degeneration Antiinflammatory drugs. for gout.
(AMD). 970 951-952
Air embolism. 1017 Antimicrobial prophylaxis. 3.29
AKIN criteria,AKl, 18 Antineutrophil cytoplasmic antibodies
AL amyloidosis. 215, 722 (ANCA). 77. 78. See also
Albumin. 11 Pauciimmune
Albuminuria. 939 glomerulonephritis
i Albuterol. in hyperkalemia. 418 Antiphospholipid antibody (APLA). 727
Alcohol dehydrogenase inhibitors.48 Antiphospholipid syndrome (APS).
Alcoholic ketoacidosis. 47. 916 727
Aldosterone. 812 Antiproteinuric therapy. 76
ALECT2 amyloidosis. 723 Antithymocyte globulin (ATG). 324
Alemtuzumab, 324-325 Anuria. 19
Anxiety. 956
Apheresis. 333
Apixaban. 95. 925
Apneahypopnea index (AHI), 810
Apolipoprotein 1 (APOL1).72
Apolipoprotein L1 (APOL1).83
Aristolochic acid, 330
ART. adverse renal effects of, 938-939
Arterial pH. 43
Arterioyenous 6 stula (AVF). 973. 1020
Arterioyenous graft (AVG). 973. 1020
Aspirin. 335. 954
for preeclampsia, 963
Asymptomatic bacteriuria. 1112
Atrial fibrillation (AFib), 95. 958
ATTR amyloidosis. 723
Automated implantable cardioverter
dehbrillator (AICD). 96
Autonomic neuropathy. 959
Autosomal dominant polycystic kidney
disease (ADPKD). 512-513,
956
Autosomal dominant tubulointerstitial
kidney disease (ADTKD). 59.
514. 950
Autosomal recessive polycystic kidney
disease (ARPKD). 513
Axitinib, 933
Azathioprine (AZA). 321. 79
B Carbonic anhydrase (CA) inhibitors.
Baclofen. 960
Bacterial peritonitis. 1031-1032
Bariatric surgery. 944-94S
Bartter syndrome, 41-42
Basiliximab. 325
Bath sales. 331
Beer potomania, 916
Belatacept. 325
Belimumab. 325
Benign familial hematuria. 726
Benign variant. 219
IIBlocker. for hypertension. 85
[3hydroxybutyric acid. 46
[32 microglobulin, 11
Bevacizumab. 932
Bicarbonate therapy. for AGMA, 45
Biguanides. 941
Bile cas: nephropathy. 914
Bilirubin, in urine. 23
Biochemical tests, 217
Biologic agents. 932
Birt-Hogg-Dube syndrome. 515
Bisphosphonates
for glucocorticoidinduced fracture.
318
for hypercalcemia. 429
for osteoporosis, 948
BK polyomavirus injection, 1117
Bladder pain syndrome. 110
Blood gas analysis, 43
Blood transfusion. 35. 922
Blood urea nitrogen (BUN). 21
Blood volume estimation. 116
Body fluid comparunenrs. 111
Bone mineral density (BMD),949
Borcezomib. 729. 928
Bosniak classification 511. 515
Bosutinib. 933
Breastfeeding. medications during. 962
Bumeranide. 313
Buprenorphine, 955
Bupropion. 957
C
Cabazitaxel. 932
Cadmium, 331
CAKUT. 221
Calcify uremic arteriolopathy (CUA).
968
Calcineurin inhibitors (CNI). 31 B-320
Calcitonin, in hypercalcemia. 429
Calcium. 428
Calciumbased binders. 432
Calcium kidney stones. 511
Calcium oxalate nephropathy. 945
Calcium phosphate crystals. S4
Calcium supplementation. 431
Canakinumab. 722
Cannabinoid hyperemesis syndrome.
331
Cannabis. 331
Caplacizumab. 729
Captopril renal scan, 29
Captopril stenography. B11
Carbon Hker. 1013
312. 411
Carboplatin, 932
Cardiac catheterizations, 93-95
Cardiorenal syndrome (CRS). 91-92
Carpal tunnel syndrome. 955
Catastrophic antiphospholipid
syndrome (CAPS). 727-728
diagnostic criteria. 727
treatment. 728
Catheterrelated bacteremia. 1025
Cefepime. 936
Ceftaroline. 936
CefazidimeAvibactam. 936
Central diabetes insipidus (CDI), 15.
16-17. 112
Central venous stenosis, 1025
Cerebral edema. 960
and renal replacement therapy, 960
Cerebral salt wasting, 425. 960
C3 glomerulopathy (C3G). 718-720
C3 nephritic factor 71B
Checkpoint inhibitors. 933
Chlorothiazide. 313
Chlorthalidone. 313
Cholesterol emboli syndrome. 94
Chromosomal microarray (CMA). 218
Chronic kidney disease (CKD). 129-131
Chronic lymphocytic leukemia (CLL).925 |
Chronic tubulointerstitial disease. 59
Chvostek sign, 430
Cigarette smoking. 331
Ciliopathies. 221
Cinacalcet
in hypercalcemia. 430
in hyperphosphatemia, 432
Ciprofloxacin, 936 CREST syndrome. 952
Cirrhosis. 913-914 Cryocrit. 721
Cisplatin. 930-931 Cryoglobulinemia. 720-721
Citalopram. 957 Cryoglobulinemic glomerulonephritis,
Citrate supplementations. 57 122. 215
CKDMBD abnormalities. after kidney Cryoglobulinemic vasculitis. 720
transplantation, 1120 Cryoglobulins. 720
CKDmineral and bone disorder. Crystalglobulinemia. 927
944-945 Crystalloids. 32
Clearance in septic shock. 117
convective, 101 Crystalluria. 938
diffusive. 101 Crystal nephropathy. 53-55
Clevidipine. 87 CT scan. renal, 29
Cocaine. 331 Cyclophosphamide (CYC). 322-323.
Cockcroft-Gault equation. 22 78. 79. 928. 932
Codeine. 955 in antiGBM disease. 710
Cognitive decline. 958 in loAn, 712
COL4Aassociated nephropathy. 726 in MN. 76
Colistin. 936 in thrombotic dirombocytopenic
Collagenofibrotic GR 724 purpura. 729
Collapsing glomerulopathy, in SLE, 715 Cyclosporine (CM). 318
Collecting duct in MN. 76
Colloids. 32 Cystatin C-based eGFR, 2 1
Compensation assessment. 43 Cysteamine. 41
Complementdependent cytotoxicity Cystic diseases
crossmatch (CDCXM). hereditary. 512-514
11 1 S sporadic. 511
Complementmediated HUS. 729-730 Cystic fibrosis (CF). 97-98
Congenital chloridorrhea. 913 Cystinosin. 12
Conivaptzn, 314. 423 Cystinosis. 12. 41. 59
Constipation. 910 Cystinuria. 55
Continuous ambulatory peritoneal Cytomegalovirus (CMV) Infection.
dialysis (CAPD). 1027 1116-11 17
Continuous cyclic peritoneal dialysis
(CCPD), 1028 D
Continuous renal replacement therapy Dabigatran. 335. 924
(CRRT), 128. 105-107 Dabrafenib. 933
and drug therapy. 38-39 Daclizumab. 325
Continuous venovenous Daily nitrogen balance. 25
hemodiahltration (CWHDF). Damage associated molecular patterns
102, 105 (DAMPs). 1113
Continuous venovenous hemodialysis Dapromycin. 936
(CWHD). 102. 105 Daracumumab. 722
Continuous venovenous hemofiltratlon DASH died. 82
(CWH). 102. 105 Deferasirox. 923
Contrastinduced nephropathy (CIN). Deferiprone. 923
966 Deferoxamine. 923
Convection. 101. 1026 Dehydration. 111-1 13
Convective clearance. 101 Deionizers. 1014
COPD. 96-97 Delayed graft function (DGF), 119
Copeptin. 16. 425 Deleteriousness prediction. 219
Coronary artery bypass graft surgery Dementia. 958-959
(CABG). 93 Denosumab. 947
Coronary artery disease (CAD), in hypercalcemia,430
92-93 De novo :hrombodc microangiopazhy.
Corticosteroids (CS). 317-318 11 10-1111
in antiGBM disease. 710 Den: disease. 12
in cryoglobulinemia. 721 Depression. in CKD. 9S7
in idiopathic FSGS. 74 Dermatologic diseases, renal
in loAn. 712 manifestation of. 970
in MPGN. 718 Desipramine. 957
Cramps. 1015 Desmopressin
Creatine. 21 for central DI, 17. 112
changes in serum level of. 21 challenge, 15
estimated GFR (eGFR), 21 for nephrogenic DI, 17
Crescentic glomerulonephrids. 213 Dexamethasone. 929
Diabetes insipidus (DI) Druginduced encephalopathy. in CKD.
central. 15. 16-17. 112 960
nephrogenic, 15. 17. 113 Drug reactions with eosinophilia and
Diabetic glomerulosclerosis (DGS). systemic symptoms (DRESS).
214 969
Diabetic ketoacidosis. 47, 941 Drugs of abuse. 331
Diabetic kidney disease (DKD). Drusen. 971
9 3 9 -9 4 1 Dry weight (DW). 115
Diabetic nephropathy 940 Dual energy xray absorpdometry
Diabetic retinopathy (DR). 970 (DXA) Tscore. 946
Dialysate. 102 Duloxetine. 956
Dialysis catheter thrombosis. 1010 Duplex Doppler ultrasound. 28. 811
Dialysis central venous catheter (CVC). DSW 427
1019 Dysproneinemiarelated renal diseases.
Dialysis disequilibrium syndrome. 959. 2.1 s
1 0 1 4 -1 0 1 5 Dysuria. 110
Dialysis. in hyperkalemia. 418
Dialysis membrane reaction, E
10 14-101 S Early goalOirected therapy (EGDT).
Diarrheainduced NAGMA. 49 1 17
Diarrhea. in transplant recipients. EASTISeSAME syndrome, 42
1119 ECG abnormalities. in hyperkalemia.
Diethylene glycol. 336. 337 417
Diffuse alveolar hemorrhage (DAH). Ecstasy. 331
710. 99 Eculizumab. 327
Diffuse infiltrative Iymphocytosis for C3 glomerulopathy. 720
syndrome (DILS). 938 for complementmediated HUS. 729
Disusion. 101. 1026 for hemolytic uremic syndrome.
Dihydropyridine (DHP). 85 728
Dimercaptosuccinic acid (DMSA), 62 Edema. 120
Dipstick test, 11 Electrolytefree water clearance. 26.
Dipyridamole. 433 427
Directacting antiviral therapies (DAAs). Electron microscopy (EM). 212
918 Emphysematous pyelonephritis. 63
Direct renin inhibitor (DRI). 311 ENaC antagonists. 314
Direct sequencing. 512 Encapsulating peritoneal sclerosis. 911.
Directtoconsumer (DTC) genetic 1032
testing. 219 Endocapillary proliferative
Distal renal tubular acidosis (dRTA). glomerulonephritis. 213
49-410. 54 Endothelial tubuloreticular inclusion.
Distal tubule 215
EAST/$e$AME syndrome. 42 Endstage renal disease (ESRD),
Gitelman syndrome. 42 131-132
Gordon syndrome.42 Enteric hyperoxaluria. 53
physiology of. 42 Environmental substance. 332
Diuretics. 312 Epacadostat. 933
resistance. 314-315 Epinephrine. 118
syndrome. 3 15 Epstein-Barr virus (EBV) infection.
Diureticsinduced hyponatremia. 425 1117
Dlacdc acidosis, 46. 937 Equilibrated urea clearance. 1011
Dnaj heat shock protein family B Erythrocytosis. 923
member 9 (DNA]B9). 724 posttransplantation. 923
DNA sequencing. 217 Erythropoiesis, 920
Dobutamine. 118 Erythropoiesis stimulating agents (ESA).
Dolutegravin 938 921-922
DonnaiBarrow/faciooculoacoustico Erythropoietin (EPO), 920
renal syndromes. 12 excess production. 924
Dopamine, 118 Estimated dry weight (EDW). 108
DPP4 inhibitors. 941 Ethacrynic acid. 313
Droxidopa. 119
D~s(5)
dosage adjustments. 38
Ethanol. 48
Ethylene glycol ingestion. 336. 337.
47-48
;
o
Q
metabolizing mechanisms. 37 Euvolemic hypematremia, 112
pharmacokinetics. 36-38 Everolimus, 320. 513
proximal tubule drug transporters. Exerciseassociated hyponatremia
37-38 (EAH). 332
 Exerciseinduced AKl. in familial renal Gastroparesis. 910
hypouricemia. 951 Gemcitabine. 932
Exerciseinduced hematuria. 14 Genetic counseling, 217
Extracapillary proliferative Generic diagnosis. 217
glomerulonephrinis. 213 Generic diseases. features of. 217
Extracellular fluid (ECF). 111, 113 Genetic hypophosphatemk rickets. 433
Extracorporeal membrane oxygenazion Genetic research, 219
(ECMO). 99-910 Generic testing. 217-218
Extracorporeal therapy of inroxicatian. Genomic rearrangements, 218
3 3 4 -3 3 5 Gentamicin. 936
Geriatrics. 971-973
F Gestational diabetes insipidus. 15. 17
Fabry disease. 725-726. 970 Gestational hypertension. 962
Familial dysautonomia. 119 Giant cell arteritis. 953
Familial hypocalciuric hypercalcemia GI cations exchangers. in hyperkalemia.
(FHH). 949 41a
Familial renal hypouricemia. 952 Gitelman syndrome, 42
Fanconi syndrome, 433. 938. 952 Globotriaosylceramide (Gb3). 72S.
Fasting ketoacidosis, 47 728
Far pad aspiration. 953 Glomerular basement membrane
Febuxostac S14. 951 (GBM). 710
Fenoldopam. 87 Glomerular disease.914
Fentanyl, 9,55 with organized deposits. 2 15
Ferric carboxymaltose. 921 Glornerular injury. 212
Ferric citrate.432 Glomerular proteinuria. 12
Ferric pyrophosphate citrate. 921 Glomerulonephrids (GN). 122-123.
Ferumoxytol. 921 911
Fibrillary glomerulonephritis. 215. 724 GLP1 agonists,941
Fibromuscular dysplasia (FMD).810. Glucocorticoidinduced fracture risks.
812 318
Fibronectin GR 724 GIucocorticoidinduced osteoporosis.
Fibrosis of skin. 952 947
Flow crossmatch (FXM). 1115 Glucocorticoid remediable
Fludrocortisone. 119 aldosteronism (GRA). 814
Fluid imbalance. 111-116 Glucocorticoids
Fluid theapy. 32-36 in acute interstitial nephritis, 58
Fluoxetine. 957 in lgG4RD. 510
Flux. 101 in minimal change disease. 71
Focal segmental glomerulosclerosis in MN. 76
(FSGS), 213-2 14. 72-74 Glucose disarray. in patients on dialysis,
Fomepizole. 336. 48 941
Fractional excretion (FE), 25 Glucose. in urine. 23
Fractional excretion of sodium (FEM). Glue sniffing. 48
25 Goodpasture disease. 710
Fractional excretion of uric acid (FEud). Goodpasture syndrome. 710
25, 422 Gordon syndrome. 42
Fracture Risk Assessment Tool (FRAX). Gout. 951
946 Grasbeck-lmerslund disease. 12
Free water clearance (Ciao). 26. 427
Free water deficit. 427 H
Fungal injections. in transplant Hand ischemia. 1023
recipients. 1118 Hansel stain. 23
Furosemide. 313 H2 antagonists. 960
renal scan, 29 HBV prophylaxis. 329
stress test. 128 HCTZ. 313
Hernaropoietic stem cell zransplanurion
(HSCT). 92B-929
Gabapenzin. 955 Hemazuria, 13-1S. 121
Gadoliniumbased contrast agents Hemodiafiltradon (HDF). 102
(GBCA). 29 Hemodialysis (HD). 334-335, 965.
Gadoliniuminduced nephrogenic 101
systemic fibrosis (NSF), 29 adequate. 1011~1013
Galaccosedeficient IgA1 . 711 cathecen 1024
Gallium nitrate. in hypercalcemia, 430 complication. 1 0 1 4 -1 0 1 8
Gastric bypass surgery. 944 dialysis catheter thrombosis, 1010
I Gascroincescinal bleeding. 910-911 dialyzers. 108
 Hemodlalysis (HD) (continued)
and drug therapy, 38
estimated dry weight, 108
heparin anticoagulation, 109
heparinfree dialysis. 109-1010
inadequate. 1013
indications. 108
initiation. 108
prescription. 109
solute clearance. 1011-1013
in toxic alcohol ingestion. 336-337.
48
vascular access, 1019-1025
water treatment, 1013-1014
Hemodialysis catheter. 972
Hemofiltration (HF). 10 1
Hemoglobin (Hb). 919-920
Hemoglobinuria, 13
Hemoiysis. 1018
Hemolytic transfusion reaction. 922
Hemolytic uremic syndrome (HUS). 728
Hemoperitoneum. 1032
Hemosiderinuria, 13
Henderson-Hasselbalch equation. 43
Henoch-Schénlein Purpura (HSP), 712
Heparininduced thrombocytopenia.
1018
Hepatitis B virus (HBV). 916-917
Hepatitis C virus (HCV), 917-918
Hepatorenal syndrome (HRS). 913
Heptidin, 920
Herbal and dietary supplementary
agents. 330
Hereditary glomerular diseases,
7 2 5 -7 2 6
Hereditary cubuloinrersricial diseases.
59
Hereditary xanrhinuria, 952
Heroinassociated nephropathy, 331
Hidradenids suppurariva. 970
High bone turnover disease, 946
High flux membrane. 102
High output hear: failure. 1023-1024
HIVassociated nephropathy (HIVAN).
937. 938
HIVassociated tubulointersrjtial disease.
938
HIV infection. in uansplanr lecipienls.
11 18
Home BP monitoring (HBPPI), 81. 84
Human immunodeficiency virus (HIV).
9 3 7 -9 3 9
Hungry bone syndrome,430
Hydralazine, 87
Hydromorphone. 955
Hydronephrosis, 28
Hydrostatic pressure. 1026
Hydroxychloroquine
for lupus nephritis, 714
ocular effects of. 971
Hyperaldosteronism, 8 12-8 14
Hyperczlcemia. 47.9-430. 98. 934.
946
urine laboratory tests in, 27
Hypercalciuria. 98
Hyperchloremic metabolic acidosis. 49
Hyperchloremic normalgap metabolic
acidosis. 9 16
Hyperkalemia. 416418. 1017-1018
urine laboratory tests in. 27
Hyperlactatemia, 46
Hyperlipidemia. 121, 943
Hypermagnesemia, 433-434
Hypemazremia. 112. 426427
euvolemic. 112
hypervolemic. 112
hypovolemic. 112
Sal: and water balance and
mechanisms in. 112
urine laboratory tests in, 27
Hyperparathyroidism. 945
Hyperphosphatasemia, 946
Hyperphosphatemia. 432. 930
urine laboratory tests in. 27
Hypertension (HTN). 81
ADPKD and. 512
after kidney transplantation.
1121-1122
in ESRD. 8485
evaluation of, in CKD. 82
secondary causes of, 82
Hypertensive disorders of pregnancy
(HDP). 963-964
Hypertensive emergencies. 86-87
Hypertensive nephrosclerosis. 83-84
Hypertensive retinopathy, 970
Hypertensive urgency, 86
Hypertonic saline. for hyponatremla
induced cerebral edema. 425
Hyperuricemia, 951-952
Hypervolemic hyponatremia, 423. 425
Hypoalbuminemia. 115. 121
Hypoaldosteronism. 411
Hypocalcemia. 430431. 946. 107
in alcoholrelated disorder.
915-916
Hypokalemia. 418-420. 933
in alcoholrelated disorder. 916
urine laboratory cesns in. 27
Hypokalemiarelated cystic kidney
disease. 5 11
Hypokalemic nephropathy. 420
Hypomagnesemia. 434. 934
in alcoholrelated disorder. 915
urine laboratory rests in, 27
Hyponatremia. 115. 421-425. 933
in alcoholrelated disorder, 916
in cirrhosis. 916
urine laboratory cescs in. 27
Hypopararhyroidism. 430
Hypophosphatasemia. 946
Hypophosphatemia. 433. 934. 107
in alcoholrelated disorder, 915
urine laboratory rests in. 27
Hyporeninemic hypoaldosreronism. in
DM, 942
Hypotension
and AKI. 116
definition of. 116
orthostatic, 119
and shock. 116-118
Hypouricemia. 950. 952
Hypovolemic hypernarremia. 112
Hypovolemic shock, 113
Hypoxia induced factor (HIF).910
I Iron sucrose, 921
lauogenic cerebral edema. 112
Ibrutinib. 933
idiopathic erythmcytosis,924
Idiopathic nodular glomerulosclerosis
(ING), 214. 97
smoking and. 97
ifosfamide. 931 . 932
IgA nephropathy. liver disease and. 914
IgA vasculitis (IgAV). 122. 712-713
Ileal conduit. 49
IIeaI loop. 49
lleostomy drainage. 913
Imaging. renal, 28-210
Immune complexmediated GN. 938
Immune complex~mediated MPGN.
717-718
Immune reconstitution inflammatory
syndrome (IRIS). 938
immunofluorescence (IF). 212
Immunoglobulin A nephropathy (IgAN).
711-713
Immunoglobulin G4related disease
(lgG4RD), 510
Immunosuppressive therapy, 316-327
Imrnunotactoid glomerulonephritis
(ITGN). 215. 724
Infection. after kidney transplantation.
1116-1119
Infectionrelated giomerulonephritis
infectious endocarditisrelated GN.
116-717
postinfectious glornerulonephritis,
71 S-716
shunt nephritis. 7 17
staphylococcal associated GNIIgA
dominant IRGN. 716
Infectious endocarditisrelated GN.
716-717
Inflammatory bowel disease (IBD).
911-912
Inflammatory diarrhea. 913
Informed consent, 217
lnotropes. 118
Insomnia. 957-958
Intermittent HD (HD). 128
Interstitial cystitis. 110
Interstitial diseases. 58-59
TINU. 59, 971
lnr.erstiual f1 uid. 111
Interstitial lung disease (ILD). 98-99
lntersutial nephritis. 216, 58. 970
intoxication. 334
Intraabdominal pressure (lAP).915
Intracellular fluid (ICF), 111
Intradialytic hypertension. 1016-1017
lntradialytic hypotension. 1015-1016
Intravascular fluid, 111
intravascular hemolysis. 922
Intravenous IIuid (IVF). 32
Intravenous immune globulin (MG).
324
Intravenous pyelogram.210
Iron deficiency. 920-921
Iron dextran. 921
Iron overload. 923
Ischemic nephropathy, 810. 811
lsoprcpanol. 336. 337. 48
Karyolype. 218
Kerawconiunctivizis sicca, 953
Keroacidosis. 4647
Kidney biopsy (renal biopsy). 210. in
diabetes mellitus, 940
Kidney transplantation. See also
Transplantation
in endstage liver disease. 915
and proteinuria. 13
Kinetic GFR estimate (KeGFR), 22
L
Labetalol, 87
Laboratory tests, urine. 2-4-27
Lactic acidosis. 46. 916
Lanthanum carbonate, 432
Lead. 332
Leflunomide. 321-322
Left renal vein (LRV) entrapment. 1S
Lenalidomide. 928. 932
Leucovorin, 932
Leukocytereduced blood. 922
Liddle syndrome. 42. 814
Light chain cast nephropathy (LCCN).
215. 927
Light chain proximal tubulopathy
(LCPT). 215, 927
Light microscopy (LM). 212
Lindsays nails. 969
Linezolid. 936
Lipid abnormalities. after kidney
transplantation. 1120
Lipoprotein GR 724
Lithium. 335
Lithium toxicity. 956
Livedo reticularis. 969
Loin pain hematuria syndrome. 15
Loop diuretics. 312
cardiorenal syndrome. 92
in hypercalcemia. 429
Loop of Henle. 41-42
Lower urinary tract symptoms (LUTS).
1 10-1 11
Low-molecularweight (LMVV) proteins.
urinary. 11
Luminex assay. 1115
Lung function. in CKD. 96
Lupus nephritis. 713-715
Lupus podocytopachies. 713. 715
Lymphocele. 1111-1112
Lysozymeinduced nephropathy. 12
Maculopapular rash, 969
Magnesium. 433-434
Malignancy. after kidney transplantation.
1 1 2 2 -1 1 2 4
 Malignancyassociated MN. 77
Marijuana. 331
Massive blood transfusion,
complications of. 35
Mass transfer coefficient, 101
Matuzumab. 933
Measured glomerular filtration rate
(mGFR). 21
Medium vessel vasculopathy. 969
Medullary cystic kidney disease
(MCKD). See Autosomal
dominant tubulointerstidal
kidney disease (ADTKD)
Medullary renal cell carcinoma. 923
Medullary sponge kidney 54. 511
Melphalan. 929
Membranopnoliferadve glomerulcnephrids
(MPGN). 213
Membranouslike giomerulopazhy with
masked IgG kappa deposits
(MGMID). 77
Membranous nephropathy (MN). 214.
74-77
andcoagularion in. 924-925
Meropenem. 936
Mesangial proliferative
glomerulonephrids, 213
Mesoamerican nephropathy. 332
Metabolic acidosis. 4-4411, 934
Metabolic alkalosis. 43. 412-414, 107
Metabolic complicarion.af¢er kidney
rransplanrazion. 1119-1121
Metals. and renal toxicity: 331-332
Metformin, 335
Medormin associated Iacdc acidosis.
941-942
Methadone. 955
Methanol ingestion. 336. 337. 47-48
Methotrexare (MTX). 335, 931-932.
952
Methylenedioxymethamphezamine. 331
Mezolazone. 313
Plicroangiopadlic hemolytic anemia
(HAHA), 122
Midodrine. 959
for ordmosratic hypotension. 119
Migalaszat, 725
Milrinone. 118
Mineralocorticoid blockers. 413
Mineralocorticoid receptor antagonists
(MRA). 3 11
Mineralocorricoidreceptor blockers
(MRB). 314
Minimal change disease (MCD). 71
Minor allele frequency (MAF). 219
Mirtazapine. 957
Miromycin C. 932
Mixed cryoglobulinemia syndrome
(MCS). 918
Mixed renal tubular acidosis (type 3
RTA), 411
Monoclonal Ab agents. 323
Monoclonal B cell lymphocycosis (MBL),
925
Monoclonal gammoparhy (MG).
9 2 5 -9 2 8
Monoclonal immunoglobulin deposition
disease ( MIDD) . 215. 927
Monoclonal protein. 925
Morphine. 955
MR angiography. 811
MR antagonist (MRA). 85
MRI, renal, 29
roTOR inhibitors. 320
Mucin1. 5.14
Mucosal eandidiasis. 1114
Multimedia filters, 1013
Mult iple myeloma ( MM) . 925- 926
Multiplex ligationdependent probe
amplification (MLPA). 218
Mycophenolate mofetil (MMF),
320-321, 79
Mycophenolate sodium (MPA).
320-321
Myeloperoxidase (MPO) disease. 78
Nail-patella syndrome. 724, 970
Necitumumab. 933
Neonatal lupus. 964
Nephrectomyn 516
Nephrocalcinosis. 221. 53. 54. 97
Nephrogenic diabetes insipidus (NDI).
15. 17. 113
Nephrogenic systemic fibrosis (NSF).
966
Nephrolithiasis. 221. 53. 61. 97. 911
Nephronophthisis (NPHP). 59. 513
Nephropathic cystinosis, 4 1
Nephrotic syndrome (NS). 121. 221
Nesiritide. 314
Neuropathic pain. 955
Newonset diabetes after transplant
(NODAT). 1119
Nextgeneration sequencing (NGS).
218
NextGen sequencing, 512
Nicardipine. 87
Nicoladoni-Branham sign, 1023
Nicotinamide, 432
Nitrofurantoin. 63
Nitroglycerin. 87
Nitrosoureas. 932
Nocturia. 19-110
Nocturnal intermittent peritoneal
dialysis (NIPD). 1028
Nocturnal polyuria. 19
Nodular mesangial sclerosing
glomerulopathyn 214
Nonamyloid deposition diseases. 724
Nonanion gap metabolic acidosis
(NAGMA), 49
Noncaseating granulomatous interstitial
nephritis. 98
Nonmelanoma skin cancers (NMSC),
1122-1123
Nonrenal solid organ transplantation
(NRSOT). 1124
Nonsteroidal andinflammatory drugs
(unSAIDs). 311-312
Nontunneled dialysis catheter (NTDC).
1024
Norepinephrine. 118. 914 Percutaneous balloon angioplasty. 1023
Normalized protein parabolic me Percutaneous coronary intervention
(nPCR). 1012 (PCI). 93
Normalized urea clearance. 1011 Pericardial disease. 1017
from residual renal function. 1012 Perinephric abscess. 63
Nortripcyline. 957 Peritoneal dialysis (PD). 966. 101.
Novel oral annicoagulancs (NOACs). 95 102, 1026
Nuclear reprogram. 22 adequacy. 1030
Nucleoside/:ide reverse :ranscriprase catheters. 1033
inhibitors (NRTls). 938 complication, 1031-1033
Nutcracker syndrome, 14 modalities. 1027
Nucridon. 31 peritoneal membrane. 1026
Nuzricional phosphate deficiency. 433 peritoneal membrane failure. 1030
prescription. 1028
o solute transport. 1026-1027
Obesity, 943-944 solutions. 1027
Obstructive nephropathy. 61 transport rate monitoring.
Obstructive sleep apnea (OSA). 1029-1030
89-810. 97 urea clearance in. 1030
Octreotide. S 13. 914 water transport. 1026
Ocular manifestation. of renal Peritoneal equilibration test (PET),
conditions. 971 1029
Officebased BP measurements (OBPM), Peritonitis. 1031-1032
82 PGNMID. 215. 928
Oliguria. 18 Pharmacokinetics. 36
Oncogenic osteomalacia. 433 Phenylephrine. 118
Oral rehydration solution (ORS). 36 Pheochromocytomas. 815
Organic cation transporter2 (OCT2). pH. of urine. 22
931 Phosphate. 431-432
Orthostatic hypotension (OH). 119 Phosphate binders, 432
Orthostatic proteinuria. 12 Phosphate nephropathy. 54
Osmolal clearance (C.,,,,.), 26 Pigment nephropathy. 52
Osmolal gap (oG). 335-336 Piperacillintalobactam, 936
Osmolality. 111 Plain abdominal radiography. 210
Osmosis. 1026 Plasma exchange (PLEX). 333
Osmotic agents. 314 in antiGBM disease. 710
Osmotic demyelination syndrome for complementmediated HUS.
(ODS), 424425 729
Osteitis fibrosis cystica. 949 Plasmapheresls. In cryoglobulinemia.
Osteomalacia. 945 721
Osteoporosis. 945-947 Plasma renin activity (PRA), 811
and fracture, 317-318. 946 Pleural effusion. 99
Overflow incontinence. 111 Pneumocystis jiravecii pneumonia (PJP).
Overflow proteinuria. 12 1118
Oxalate nephropathy. 53-54 prophylaxis. 1114
Oxaliplatin. 932 Pneumonitis. 98
Oxycodone. 956 Polyarteritis nodosa. 953
Oxymorphone. 331 Polycythemia Vera. 924
Polymyxin B, 936
P Polysomnography. 810
Pain control, in CKD and ESRD. 955 Polyuria. 15-1 7
Palliative care. 973-974 Positron emission tomography (PET).
Pamidronate. in hypercalcemia. 429 2.10
Pancreatitis. 911 Postembolization syndrome. 2 12
Panitumumab. 933 Posthypercapnic metabolic alkalosis.
Parathyroid bone disease. 949 413
Parathyroidectomy. 430. 432. 949 Postinfectious glomerulonephritis.
Paroxetine. 957 716-716
Partial nephrecromy (PN), 516 Postprandial hypotension. 119
Passive leg raising, 114 Poststreptococcal GN (PSGN). 716
Pathogenic (P). 219 Posttransplantadon erythrocytosis.
I Pathogenic variants. criteria for. 219 924
. Pauciimmune glomerulonephricis. Posttransplant lymphoproliferadve
77-79 disorder (FTLD). 1123
Pazopanib. 933 Postural tachycardia syndrome (POTS).
Pendred syndrome, 42 119
 Potassium, 415-420
changes in hanatologic conditions. 920
Preeclampsia. 963
Pregabalin, 9SS
Pregnancy. 962-965
Primary hyperaldosteronism (PA). 812.
See also Hyperaldosteronism
Primary hyperoxaluria. 53
Primary hyperparathyroidism. S4.
948-949
Propylene glycol, 336. 337
Prostaglandin (PG). 954
Protease inhibitors. 939
Proteinase 3 (PR3) disease. 78
Protein bound solutes. 101
Protein catabolic rare (PCR). 25. 31
Proteinenergy wasting. 3 1
Protein size. 121
Proteinuria. 11-12. 121
Proton pump inhibitors. 912
Proximal renal tubular acidosis (pRTA).
410-411
Proximal tubule (PT).41
cysdnosis. 41
physiology of. 41
Pseudoaneurysm. 1023
Pseudohyperkalemia. 417
Pseudohypoaldosteronism. 42. 411
Pseudohypocalcemia. 428
Pseudohyponatremia. 916. 933
Pseudoresistant HTN.85
Psoriasis. 970
Psychosis, 957
Pulmonary hypertension (PHTN), 97.
1017
Pulse pressure variation (PPV). 1.14
Purine nucleoside phosphorylase (PNP)
deficiency. 952
Purpura, 969
Pyelography. 29-2 10
Pyelonephritis, 63
Pyoderma gangrenosum, 969
R Sarcoidosis. 9B
RAAS inhibitors. 39-311. 7.18
Radical nephrectomy (RN). 516
Radionuclide renal scan. 29
Random albumin to creatinine ratio
(UACR). 11
Random protein to creatinine ratio
(UPCR), 11
Random spot urine collection. 24
Rapidly progressive glomerulonephritis
(RPGN). 122-123
Reflection coefficient. 1026
Reflux nephropathy, 62
Refractory HTN, 85
Renal ammoniagenesis, 44
Renal arteriovenous malformation
(AVM), 15
Renal artery stenosis (RAS). 810812
transplant. 1112
Renal biopsy. 210-212
Renal cell carcinoma (RCC). 5.15-S17
Renal cortical abscess/carbunde. 6.3
Renal corticomedullary abscess. 63
Renal cysts. simple. S11
Renal function. 21-22
Renal generic diseases. 220-221
Renallimited lupuslike nephritis, 715
Renal osteodystrophy. 945
Renal replacement therapy (RRT). 22.
101-102
acute kidney injury and. 128. 103
in shock. 119
Renal resistive index (RI). B12
Renal tissue. processing of. 212
Renal ultrasound. 28
Reninangiotensinaldosterone system
(RAAS>. 113, 39
Replacement fluid (RF). 102
Reported pathogenic variant. 2.19
Reset osmostat syndrome. 916
Residual renal function (RRF). 1030
Resistant hypertension. 858.6
Resistive index (Rl). 28
Respiratory acidosis. 43. 415. 1415
Respiratory alkalosis. 43. 414-14.15
Restless leg syndrome (RLS). 958
Retinolbinding protein (RBP), 11t
Reverse osmosis (RO) membranes.
1013
Reversible posterior
leukoencephalopathy
syndrome (RPLS). 86
Rhabdomyolysis. 52
Rheumatoid arthritis (RA). 952-953
Rheumatoid factor, 952
RIFLE criteria.AKl. 18
Rituximab. 326-327. 79, 7.29. 933
in cryoglobulinemia. 721
in loAn. 7.12
in MN. 76
in pautiimmune GN, 78. 79
Rivaroxaban. 728. 925
s
Sacubitril, 314
Sanger sequencing. 218. 5 12
Scleroderma renal crisis (SRC). 9.52
Secretory diarrhea. 913
SediStain, 23
Selective estrogen receptor modulators
(SERMs). for osteoporosis. 947
Sepsisassociated AKI. 934-937
Senraline, 957
Sevelamer carbonate. 432
Sevelamer hydrochloride. 432
SGLT2 inhibitors. 314. 941
Shalhoub hypothesis. 71
Shiva toxin. 728
Shock. 116-118
Short bowel syndrome. 912
Shunt nephritis. 717
SIADH. 422
and cerebral salt wasting. 960
neuropsychiatric drugs causing. 960
Slcca syndrome. 953
Sickle cell disease (SCD). 922-923
Sickle cell trait (SCT). 922-923
Sieving coefficient. 101
 Sildenafil. 959
Singlenucleotide variants (SNVs). 218
Single pool urea clearance. 1011
Sinusoidal obstruction syndrome (SOS).
929
Sirolimus. 320
SiOgren syndrome (SS).953
Sleep apnea syndrome. 9S8
Sleep disorders. in CKD. 957-958
Slow continuous ultrafilcradon (SCUF).
102. 105
Slow low efficiency dialysis (SLED).
128
Small vessel vasculitis. 712. 969
Smokingrelated glomerulopadvy, 214
Smoldering MM (SMM).926
Sodium, 421-427
Sodium bicarbonate. in hyperkalernia,
418
Sodium ferric gluconate. 921
Sodium Glucose cotransporter2
(SGLT2) inhibitors, 314. 9-41
Sodium nitnoprusside. 87
Sodium phosphate bowel prep. 912
Sodium polystyrene (SPS), 912
Sofosbuvir, 918, 919
Solute clearance. 1012-1013
Solutefree water clearance (Cup).
26
Soluzes.types of. 101
Sorafenib. 933
Specific gravity (SG). urine. 22
Spironolactone. 434
Split radionuclide renal scan, 29
Spot urine albumin/protein ratio. 11
SSRIs. 957
Standard normalized urea clearance.
1 0 1 1 -1 0 1 2
Staphylococcal associated GN.716
Satin, 943
Scents. 1023
Steroids. in septic shock. 117
STOPBang questionnaire. 810
Streptozocin, 932
Stress incontinence. 110-111
Stroke. 958
Stroke volume variation (SVV). 114
Strontium ranelate. 947
Subarachnoid hemorrhage. 960
Substitution fluid, 102
Sucroferric oxyhydroxide. 432
Sudan III srain.23
Sudden cardiac death (SCD). 95-96
Sulfonyluneas. 941
Sulfosalicylic acid (SSA). 11
Sunidnib, 933
Superior vena cava (SVC) syndrome,
1025
y Syndrome of apparent
minenlocordcoid excess
(AME). B14
l Syndrome of inappropriate anzidiuresis
(SIAD). 423. 4ZS
Systemic lupus erythematosus (SLE).
122
Systemic sclerosis (SSc). 952
T
Tacrolimus, 3 18
in MN, 76
Takayasu arteritis. 953
Tamm-Horsfall protein (THP). 11.
514, 927
TCA. 9S6
Tenofovir alafenamide (TAF). 939
Tenofovir disoproxil fumarate (TDF).
938
Teriparatide. 948
Terlipressin. 9 14
Theophylline. 335
Thiazideinduced hyponanremia (TIH).
3 13. 425
Thiazides diuretics.for nephrogenic DI.
11, 113
Thiazolidinediones. 941
Thin basement membrane nephropathy.
726
Thrombocytopenia. 1018
Thrombotic microangiopathy (TMA).
123-1 24, 214, 713, 937,
938
Thrombotic thrombocytopenic purpura
(TTP). 728-729
Tigecydine. 936
Timed Cr clearance (CW), 2 2
Timed urine collection, 24
Tobramycin. 936
Tocilizumab. 722
Toluene inhalation. 48
Tolvaplan. 3 14. 423. 513
Tonicity. 112
Tonsillectomy. 7 12
Topical capsaicin. 956
Torsemide. 313. 92
Total body water (TBW). 111. 4-27
Total weekly KIN 1012
Toxic alcohols. 335-337
Tramadol. 955
Transarterial embolizazion. 212
Transfusionassociated cirtzulatory
overload. 922
Transient proteinuria. 12
Transition of care for young adults.
133
Transplantassociated thrombotic
microangiopazhy (TATMA).
929-930
Transplant renal artery stenosis (TRAS).
1121
Transsphenoidal pituitary surgery. 961
Transwbular K gradient (TTKG).417
Trazodone. 957
Triamcerene. 434
Trimechoprim-Sulfamethoxazole
(TMPSMX). 79
Trousseau sign, 430
Tuberculosis. 98
Tuberous sclerosis. 515. 969
Tubular proteinuria. 12
Tubular reabsorption of phosphate
(TRP). 431
Tubulointerstitial kidney disease
(ADTKD). 221