Entanglement of Sepsis, Chronic Kidney Disease, and Other Comorbidities in

Patients Who Develop Acute Kidney Injury

Michael Heung, MD, MS,* and Jay L. Koyner, MD

Summary: Acute kidney injury (AKI) is a common and severe complication for patients in the intensive care
setting, often occurring in the setting of sepsis. Both sepsis and AKI are complex and heterogeneous
syndromes with overlapping risk factors. Comorbidities - such as chronic kidney disease, diabetes mellitus,
liver disease, cardiac disease and cancer may contribute to the development of these syndromes and
complicate their management. Recognition of the complex interplay between comorbid conditions, sepsis, and
AKI is key to the successful management of these syndromes.
Semin Nephrol 35:23-37 C 2015 Elsevier Inc. All rights reserved.
Keywords: Acute kidney injury, sepsis, risk factors, critical care

A
cute kidney injury (AKI) is a common and
severe complication for patients in the intensive
care setting, often occurring in the setting of
sepsis. Both sepsis and AKI are complex and heteroge-
neous syndromes with overlapping risk factors. Comor-
bidities - such as chronic kidney disease, diabetes mellitus,
liver disease, cardiac disease and cancer may contribute
to the development of these syndromes and complicate
their management. Recognition of the complex interplay
between comorbid conditions, sepsis and AKI is key to
the successful management of these syndromes.
In the intensive care unit (ICU) setting, sepsis
remains the leading cause of acute kidney injury
(AKI), accounting for upwards of 50% of cases.1
Neither sepsis nor AKI are single clear-cut entities.
Rather, both represent heterogeneous syndromes, with
many potential factors contributing to the risk of their
occurrence and/or to the risk of adverse outcomes. In
many cases, these two syndromes share comorbid
risk factors. In this review we explore the relationship
between sepsis, AKI, and some of the intertwining
comorbidities that may modify the risks and outcomes
from these two overlapping syndromes (Fig. 1).
CHRONIC KIDNEY DISEASE
Chronic Kidney Disease as a Risk Factor for AKI
Chronic kidney disease (CKD) and AKI share many risk
factors, including diabetes and aging, and some of these
*
Division of Nephrology, Department of Medicine, University of
Michigan, Ann Arbor, MI.
risk factors also are common to sepsis (Fig. 2). It therefore
can be challenging to distinguish between an association
resulting from common susceptibilities versus an inde-
pendent relationship when exploring CKD and AKI.
Nonetheless, CKD consistently has emerged as one of
the strongest independent risk factors for AKI even after
adjusting for known confounders. This relationship has
been shown across a variety of patient populations, and
the risk for AKI increases with worsening baseline renal
function.26 In an analysis of Kaiser Permanente Northern
California data, Hsu et al2 reported a marked increase in
risk for severe (dialysis-requiring) AKI with progressive
stages of CKD. Compared with patients with a baseline
estimated glomerular ltration rate (eGFR) greater than 60
mL/min, patients with eGFR ranges of 45 to 59 mL/min,
30 to 44 mL/min, 15 to 29 mL/min, and less than 15 mL/
min had adjusted odds ratios for severe AKI of 1.66, 4.75,
20.42, and 47.17, respectively. In addition to a lower
GFR, proteinuria also has emerged as an important risk
factor for AKI.2,4 In a population-based study from
Alberta, Canada, James et al4 observed increasing AKI
risk with worsening proteinuria; this relationship was seen
within each stage of CKD, providing further risk strat-
ication than when considering eGFR alone.
There is ample biologic plausibility to support the
role of CKD as a risk factor for AKI. Decreased renal
reserve is presumably one of the major reasons for
increased susceptibility to renal injury in patients with
CKD. Patients with CKD will have less ability to
compensate for injury through recruitment of uninjured
nephrons, as occurs in patients without renal impair-
ment. Decreased renal reserve also may explain the
increased susceptibility to AKI seen with advancing

Section of Nephrology, Department of Medicine, University of
Chicago, Chicago, IL.
Financial disclosure and conict of interest statements: none.
Address reprint requests to Michael Heung, MD, MS, 1500 E
Medical Center Dr, SPC 5364, Ann Arbor, MI 48103-5364.
E-mail: mheung@umich.edu
0270-9295/ - see front matter
& 2015 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.semnephrol.2015.01.004
age.7,8 Even in the setting of normal serum creatinine
levels, older patients will have lower renal functional
reserve, which may be unmasked by AKI. In this
sense, AKI is analogous to a failed renal stress test. In
addition, patients with CKD may experience a more
clinically obvious decrease in GFR with smaller
insults. For example, the Kidney Disease: Improving
Global Outcomes (KDIGO) denition for AKI

Seminars in Nephrology, Vol 35, No 1, January 2015, pp 2337 23

24
Figure 1. Tangled relationship between AKI, sepsis, and numerous intertwined risk factors and comorbidities.
Mech, mechanical.
(a minimum increase of 0.3 mg/dL greater than base-
line creatinine level within 48 hours) can be achieved
with a smaller injury/decrement in function in CKD
compared with normal renal function. In other words,
an increase from 1.0 to 1.3 mg/dL represents a far
larger decrease in renal function compared with an
increase from 3.0 to 3.3 mg/dL.
CKD as a Risk Factor for Sepsis
As with many chronic medical conditions, patients with
CKD are also at increased risk for sepsis, presumably
owing to a general increased risk for infection. CKD
represents a chronic inammatory state, while at the same
time being an immunodecient state. The development of
uremia is characterized by a disrupted regulation of the
immune system, leading to abnormal phagocytic function
of macrophages and polymorphonuclear leukocytes, as
Figure 2. Conceptual model of relationships between sepsis,
AKI, and CKD.
M. Heung and J.L. Koyner
well as reductions in both T-cell and B-cell function.911
Another potential mechanism by which CKD may worsen
sepsis is through reduced renal clearance of inammatory
mediators.12 These changes have been described primarily
in the end-stage renal disease (ESRD) patient population,
in whom infection remains the second-leading cause of
death.13,14 However, alterations to immune system
homeostasis are likely to begin occurring with advancing
CKD and clinicians should be aware of the heightened
risk for infection in this group.
Another proposed mechanism for increased infec-
tion risk and inammation in patients with CKD or
ESRD is disruption of the gastrointestinal barrier,
leading to introduction of bacteria or endotoxins into
the circulation. CKD patients are at risk for uid
retention, leading to uid overload and intestinal
edema, which may predispose to translocation of
bacteria.15 These factors may be particularly relevant
in the critical care setting where patients receive
signicant volume resuscitation, and may contribute
to delays in recovery or secondary infections. How-
ever, even in the absence of uid overload and
mechanical distention, it appears that uremia may
contribute to gastrointestinal barrier abnormalities
through molecular mechanisms. In animal models of
CKD, Vaziri et al16 described disruptions in colonic
tight junctions, which may account for increased
intestinal permeability. Finally, changes in gastrointes-
tinal microora have been observed in CKD and
implicated as another mechanism for gastrointestinal
barrier dysfunction.17 Studies currently are exploring
the potential clinical impact of interventions to restore
the gut microenvironment in patients with CKD.17
Sepsis, CKD, and comorbidities in AKI 25

Outcomes hypoxia from impaired renal blood ow, lowering the

threshold for free radical generation and ischemic
Hospital survival among patients with AKI superim-
injury.33 This can develop through microvascular and
posed on CKD actually may be better than in patients
macrovascular disease and/or through decreased
with de novo AKI.6 This perhaps is not surprising given
responsiveness to the vasodilatory effects of nitric
the lesser degree of injury required to cause AKI on
oxide seen in DM. Recent studies also have implicated
CKD compared with de novo AKI, and may reect
the chronic inammation associated with DM as
differences in the severity of acute illness. However,
contributing to the increased risk for AKI.34
studies consistently have shown that both short- and
Similar to CKD, DM is a condition characterized by
long-term renal outcomes, such as dialysis dependence,
immune system alterations, resulting in relative immu-
are worse with AKI superimposed on CKD compared
nodeciency and a predisposition to infection and
with AKI without pre-existing renal dysfunction.6,1820
sepsis.3537 In a cohort study using data from the
The poor renal prognosis in these patients presumably
National Health and Nutrition Examination Survey,
reects the lower renal functional reserve and further
Bertoni et al38 found that diabetic adults were twice as
underlines the importance of risk recognition and
likely to suffer an infection-related death compared with
preventative measures in this population.
nondiabetic adults. Immune system dysregulation result-
In recent years, a strong link between AKI and de
ing from hyperglycemia is seen in a variety of immuno-
novo CKD has been established.5,21,22 Whether this
logic pathways, including decreased activity of
relationship is associative or causal in nature has been
polymorphonuclear leukocytes and blunted response of
debated,23 but clearly the management of patients after
humoral immunity.39 Additional factors contributing to
AKI represents an important opportunity to improve
infection and sepsis include chronic complications of
secondary outcomes from this syndrome.24 Animal
DM such as vascular disease and neuropathy; an
models have elucidated potential mechanisms mediating
unfortunate example of the conuence of these risk
the transition from AKI to CKD, including persistent
factors is diabetic foot infection.
inammation and altered renal repair mechanisms.2527
Recently, clinical trials in animal models of AKI have
provided some optimism regarding the potential to Glycemic Control in Critically Ill Patients and AKI
mitigate the risk of CKD after an episode of AKI. Bao
Even in the absence of prior DM, patients with critical
et al28 examined the impact of lithium administration in
illness are at risk for developing hyperglycemia, and
2 mouse models of AKI (cisplatin-induced AKI and
glucose control has emerged as an important aspect of
ischemia-reperfusion injury). In both models, the mice
management in the ICU setting. Several physiologic
treated with lithium showed evidence of accelerated renal
factors contribute to hyperglycemia in the critically ill,
recovery compared with controls, as evidenced by renal
including increased levels of stress hormones,
tubular epithelial cell proliferation. The putative mecha-
increased gluconeogenesis, and insulin resistance.40
nism is lithium inhibition of glycogen synthase kinase 3,
In addition, clinical factors such as hyperalimentation,
a molecule that has been implicated in the pathogenesis
the use of corticosteroids, and administration of
of AKI. In another animal study, Barrera-Chimal et al29
dextrose-containing solutions are likely to play a role.
used spironolactone pretreatment to attenuate renal
As with DM, the acute hyperglycemia of critical
inammation and brosis after ischemia-reperfusion
illness contributes to immune system dysfunction and
injury. Compared with controls, treated animals were
can contribute to infection.41,42 Several clinical trials
signicantly less likely to develop CKD as dened by
also have explored the impact of glycemic control on
onset of proteinuria or a decrease in creatinine clearance.
outcomes among critically ill patients, including
These studies contributed further evidence of a causal
patients with sepsis (Table 1). In one of the rst large
relationship between AKI and subsequent CKD develop-
clinical trials examining the clinical impact of glycemic
ment while also providing hope for future therapeutic
control, van den Berghe et al43 randomized 1,548
options to diminish the risk of that transition.
primarily surgical ICU patients to intensive insulin
therapy (targeting blood glucose levels between 80
DIABETES MELLITUS AND HYPERGLYCEMIA and 110 mg/dL) versus standard therapy (targeting
blood glucose levels between 180 and 200 mg/dL).
Diabetes Mellitus, Sepsis, and AKI These investigators found an overall decreased mortal-
Diabetes mellitus (DM) remains the leading cause of ity rate in the intensive treatment group compared with
CKD and ESRD in the United States, accounting for controls (4.6% versus 8.0%; P o .04), a reduction in
nearly 45% of incident ESRD cases.14 DM is also well sepsis episodes (4.2% versus 7.8%; P .003), and a
established as an independent risk factor for AKI.3032 reduction in episodes of AKI requiring dialysis (4.8%
A key mechanism for increased susceptibility to renal versus 8.2%; P .007).43 Interestingly, these same
injury is the diabetic kidneys predisposition to investigators conducted a similar trial in medical ICU
26 M. Heung and J.L. Koyner

Table 1. Clinical Trials of Glycemic Control in Critically Ill Patients

Patient Population Comparison Groups Mortality Outcomes Renal Outcomes
Van den Berghe Single-center: 1,548 Blood glucose concentration 4.6% versus 8.0% ICU 4.8% versus 8.2% with AKI
et al,43 2001 primarily surgical ICU 80-110 versus 180-200 mortality; P o .04 requiring dialysis;
patients mg/dL P .007
Van den Berghe Single-center: 1,200 medical Blood glucose concentration 24.4% versus 26.8% 5.9% versus 8.9% with AKI
et al,44 2006 ICU patients 80-110 versus 180-200 ICU mortality; (doubling of admission
mg/dL P .31 creatinine concentration
or peak 42.5 mg/dL);
P .04
Brunkhorst Multicenter: 537 patients with Blood glucose concentration 39.7% versus 35.4% 27.5% versus 22.5% with
et al,47 2008 sepsis 80-110 versus 180-200 mortality at 90 days; AKI requiring dialysis;
mg/dL P .31 P .19
NICE- Multicenter: 6,104 mixed Blood glucose concentration 27.5% versus 24.9% 15.4% versus 14.5% AKI
SUGAR,45 medical and surgical ICU 81-108 versus o180 mortality at 90 days; requiring dialysis; P .34
2009 patients mg/dL P .02
Preiser et al,48 Multicenter: 1,101 mixed Blood glucose concentration 17.2% versus 15.3% No difference in total
2009 medical and surgical ICU 80-110 versus 140-180 ICU mortality; dialysis-requiring patient-
patients mg/dL P .41 days; P .753

Abbreviation: NICE-SUGAR, Normoglycemia in Intensive Care EvaluationSurvival Using Glucose Algorithm Regulation.

patients and failed to reproduce the same benets in this
population.44 In these studies and subsequent similar
trials, intensive glucose control is associated consis-
tently with a greater risk for hypoglycemia, which in
turn may be associated with increased mortality. The
Normoglycemia in Intensive Care EvaluationSurvival
Using Glucose Algorithm Regulation trial randomized
more than 6,000 mixed ICU patients to strict glucose
control (target glucose level, 81-108 mg/dL) versus
standard glucose control (target glucose level, o180
mg/dL). In this study, strict glucose control was
associated with higher mortality rates (27.5% versus
24.9%; P .02), and this appeared to be attributable to
hypoglycemia.45,46 The Normoglycemia in Intensive
Care EvaluationSurvival Using Glucose Algorithm
Regulation study also did not show any signicant
benet in renal outcomes, specically AKI requiring
renal replacement therapy, associated with strict glucose
control.45 Additional trials also have failed to show
survival or renal benets from strict glucose control
(goal, 80-110 mg/dL) compared with less-stringent
glucose control (goal, o180 mg/dL).47,48
Based on the earlier-described ndings, it is clear
that clinicians need to balance the risks of hypoglyce-
mia with any potential benets of glucose control.
Although theoretically there is a benet for AKI
prevention, the preponderance of evidence does not
support renal outcome benets from strict glucose
control (Table 1). Although there remains some con-
troversy as to optimal glucose targets, guidelines
currently recommend moderate glycemic control in
the ICU setting, targeting upper-limit glucose values
less than 180 mg/dL, with an emphasis on avoiding
hypoglycemia.49
LIVER DISEASE
Cirrhosis and Sepsis
Cirrhosis is one of the leading causes of death in
developed countries, and infections are a leading cause
of mortality in this population.50,51 Similar to CKD and
DM, mechanisms of increased infection risk in cir-
rhotic patients include alterations to the immune
system such as impaired neutrophil function.52,53
Furthermore, decreased intestinal motility can lead to
bacterial overgrowth that, along with portal hyper-
tension, predisposes to bacterial or endotoxin transloca-
tion.54 Spontaneous bacterial peritonitis (SBP) is thought
to develop in this manner, and both selective -blockers
(which increase bowel motility)55 and antibiotic decon-
tamination of intestinal bacteria56 have been shown to be
effective for SBP prophylaxis. Of some concern, and
perhaps in part owing to antibiotic prophylactic practices,
a recent study showed an increasing rate (up to 25% of
cases) of resistant organisms contributing to infections in
cirrhotic patients.50
Cirrhosis and AKI
Cirrhosis is an independent risk factor for AKI, and up
to 50% of cirrhotic patients hospitalized with infection
will develop AKI.57,58 This remarkably high incidence
may not be surprising when considering the abundance
of risk factors for AKI typically seen in this popula-
tion: hyperbilirubinemia, hypoalbuminemia, low intra-
vascular volume owing to third-spacing, and high
infection risk. One particular challenge is early recog-
nition of AKI because of overestimation of renal
Sepsis, CKD, and comorbidities in AKI 27

function based on creatinine values. Patients with
cirrhosis often suffer from malnutrition, decreased
muscle mass, uid retention, and decreased hepatic
creatine generation. These factors combine to result in
lower baseline serum creatinine values and thus
inated estimation of renal function in patients with
cirrhosis.59,60 In recognition of this, an international
working group recently suggested an updated deni-
tion for AKI in patients with cirrhosis61 that largely
parallels the KDIGO AKI denition and removes the
requirement of a creatinine increase greater than
1.5 mg/dL, which was part of the International Ascites
Club denition.62 Studies are ongoing to assess the role
of novel AKI biomarkers in patients with cirrhosis,63
and these may hold particular promise in differentiat-
ing between AKI involving structural injury versus
hepatorenal syndrome. Until such biomarkers become
established, clinicians need to be aware of the potential
for signicant renal dysfunction in the presence of
normal serum creatinine values in this population.
Hepatorenal syndrome (HRS) is a specic form of
AKI seen in the setting of cirrhosis, and frequently is
triggered by infection or sepsis. For example, up to
30% of cirrhotic patients with SBP will develop
HRS.64 The pathophysiology underlying the develop-
ment of HRS includes marked splanchnic vasodilata-
tion and decreased systemic vascular resistance leading
to renal hypoperfusion.64,65 Therefore, the mainstay of
management (outside of liver transplantation) is the
administration of vasoconstrictors such as terlipressin,
which may be effective in up to 50% of cases.64,66 In
the United States, where terlipressin remains unavail-
able, the combination of midodrine plus octreotide,
usually with albumin, is used in many centers as a
result of early studies showing efcacy with this
regimen.67 Still, medical management serves primarily
as a bridge, and liver transplantation remains the
optimal therapy for HRS: a recent study found that,
among patients who required acute dialysis and who
survived for 6 months after liver transplantation, less
than 10% failed to recover renal function to the point
of dialysis independence.68
AKI and Liver Injury
Although progression from liver failure to AKI is well
recognized, an emerging area of investigation is whether
(and how) AKI can contribute to liver injury. Studies
have shown that ischemic renal injury results in a release
of proinammatory mediators such as tumor necrosis
factor- and interleukin-6, which in turn can cause
hepatic damage.69,70 Other potential effects of AKI on
the liver include altered hepatic metabolism of drugs,
impaired lipid and protein metabolism, and exaggerated
immune response in the liver.71,72 Although the clinical
signicance of the hepatic injury seen in models of AKI
remains unclear, there clearly is mounting evidence of
bidirectional cross-talk between these organs.
PULMONARY-RENAL INTERACTIONS
Over the past several years, multiple reviews have
covered the link between lung injury and AKI.7375
Similar to AKI, lung injury recently underwent a
rebranding with the new consensus denitions of acute
respiratory distress syndrome (ARDS), entitled the
Berlin Denitions.76 These criteria (Table 2) classify
patients according to the PaO2/fraction of inspired
oxygen ratio and no longer include the term acute
lung injury. In addition, the new denition claries
issues relating to the time of onset (1 week of insult),
the role of chest imaging, and setting a minimum
positive end-expiratory pressure of 5 mm Hg. This
rebranding of ARDS comes on the heels of several
decades of lung injury work that not only has informed
and improved the care of critically ill patients, but also
has assisted in elucidating the interplay between the
lungs and kidneys in the setting of critical illness.
ARDS has been studied extensively, with more than
one third of ARDS patients developing some form of

Table 2. The Berlin Definition of Acute Respiratory Distress Syndrome76

Criteria Definition
Timing Within 1 week of a known clinical insult or new or worsening respiratory symptoms
Chest imaging (chest radiograph or Bilateral opacitiesnot fully explained by effusions, lobar/lung collapse, or nodules
computerized tomography scan)
Origin of edema Respiratory failure not fully explained by cardiac failure or fluid overload
Need objective assessment (eg, echocardiogram) to exclude hydrostatic edema if no
risk factors present
Mild oxygenation 200 mm Hg o PaO2/FiO2 r 300 mm Hg with positive end expiratory pressure or
continuous positive airway pressure Z 5 cm H2O
Moderate oxygenation 100 mm Hg oPaO2/FiO2 r 200 mm Hg with positive end expiratory pressure Z 5 cm
H2O
Severe oxygenation PaO2/FiO2 r 100 mm Hg with positive end expiratory pressure Z 5 cm H2O

Abbreviation: FiO2, fraction of inspired oxygen.

28
AKI, which in turn signicantly increases inpatient
morbidity and mortality.77 In a recent prospective
observational study of 8,029 ICU subjects, of whom
1,879 had ARDS, ARDS was associated independently
with AKI. AKI, dened by the Risk, Injury, Failure,
Loss, End-stage (RIFLE) criteria, occurred in 44.3% of
those with ARDS, but in only 27.4% of those without
ARDS (P o .001), and remained more common in
patients with ARDS after adjusting for AKI risk factors
in the setting of critical illness. In patients with ARDS,
AKI increased the mortality rate from 20.2% to
42.3%.78
The 20% mortality rate in the setting of non-AKI
ARDS was slightly less than in other recent ARDS
studies,79 but highlights the dramatic decrease in
ARDS-associated mortality that has occurred over the
past few decades.80,81 This improvement in patient
outcomes has been, in part, a direct result of systematic
randomized controlled trials and a well-established
network of investigators. It deserves noting that the
incidence of sepsis as the source of ARDS varies
across ARDS network studies, with some investiga-
tions being performed exclusively in patients with
sepsis-related ARDS79 whereas the majority have
sepsis rates that vary from 20% to 30%.8083 In the
recent randomized, double-blind, placebo-controlled
trial investigating the utility of rosuvastatin in the
setting of sepsis-associated ARDS, rosuvastatin did
not improve 60-day in-hospital mortality, with the trial
being stopped early (roughly 75% enrollment) because
it was deemed futile. However, it deserves noting that
patients receiving rosuvastatin were at increased risk of
developing persistent renal failure, dened as a serum
creatinine concentration greater than 2.0 mg/dL.79 This
atypical, nonconsensus denition of AKI has been
used consistently by the ARDS network over the past
decade.81,82
It is this same denition of renal failure (creatinine
level, 42.0 mg/dL) that was used when investigating
the role of a liberal versus conservative uid manage-
ment strategy in the setting of resuscitating patients
with early ARDS (Fluid and Catheters Treatment
Trial).82 Importantly, the liberal uid strategy
attempted to keep the central venous pressure at 10
to 14 or the pulmonary artery occlusion pressure at 14
to 18 mm Hg, while the uid-conservative arm aimed
for a central venous pressure of less than 4 and
a pulmonary artery occlusion pressure of less than 8.
Neither of these arms were able to achieve these
targets, with the uid-conservative arm achieving a
mean central venous pressure of approximately 8 to
9 mm Hg and the liberal uid arm decreasing slightly
from a baseline of 12 to 13 mm Hg to 11 to 12 mm Hg.
The mean starting pulmonary artery occlusion pressure
was 15 to 16 mm Hg for the cohort, with patients in the
M. Heung and J.L. Koyner
liberal uid arm nishing close to 16 mm Hg and
patients in the conservative arm at 12 to 14 mm Hg.
There was no difference in 60-day mortality rate
(P .30), incidence of serum creatinine concentration
higher than 2.0 within the rst 7 days of the study
(P .45), or the need for renal replacement therapy
(RRT) (uid conservative, 14%; versus liberal uid,
10%; P .06). There was a similar trend toward a
higher serum creatinine concentration in the uid-
conservative group (P .07), along with signicantly
higher blood urea nitrogen and serum bicarbonate
levels. When looking at the role of uid balance in
these ARDS patients, patients in the liberal uid arm
were, on average, 5.61 L net positive over the rst
4 days and 7.11 L net positive over the rst 7 days.
This was signicantly higher than the conservative
arm, which was 0.21 L positive at 4 days and 0.01 L
positive at 7 days.82
Given the dilutional impact of positive uid balance
on serum creatinine concentration and the inadequate
denition of AKI, Liu et al84 performed a secondary
analysis of the Fluid and Catheters Treatment Trial in
which they adjusted the serum creatinine concentration
for uid balance and dened AKI as a 0.3 mg/dL or
50% absolute increase over 48 hours. Patients rst
were classied by AKI status based on changes in
serum creatinine concentration and then reclassied for
the uid balanceadjusted serum creatinine concentra-
tion. Importantly, patients who were reclassied based
on uid status had outcomes that were more concord-
ant with the reclassied AKI status than their initial
designation. Thus, in the setting of ARDS, volume
overload is a signicant contributor to under-
recognized AKI (both mild and severe forms) and
can impact mortality rates.84 Similarly, in a recent
secondary analysis of the prospective observational
Italian multicenter Nefrologia e Cura Intensiva
(NEFROINT) study, Cruz et al85 showed that in 601
ICU patients, after adjusting for age, sex, DM, hyper-
tension, diuretic use, severity of illness, and sepsis,
every liter of positive uid balance increased the risk of
28-day mortality by 67% (P o .001). When studied
exclusively in the setting of septic shock, positive uid
balance has been associated with increased mortality
rates.86 In a secondary analysis of the Vasopressin in
Septic Shock Trial, 778 patients with septic shock were
divided into quartiles based on their net uid balance,
with the mean uid balance being 11 L positive over
the rst 4 days; a positive uid balance at 12 hours and
at 4 days was associated with a signicantly increased
risk of death.86 In the Randomized Evaluation of
Normal versus Augmented Level (RENAL) Renal
Replacement Therapy trial (n 1,453), in which all of
the patients received continuous RRT, the incidence of
severe sepsis was 49% and a positive uid balance was
Sepsis, CKD, and comorbidities in AKI
associated with an increased length of ICU stay and an
increased risk of 90-day mortality.87 Finally, in a smaller
single-center study of 170 hospitalized adults requiring
RRT uid overload at the time of RRT initiation was
associated with worse renal recovery at 1 year.88
POSTOPERATIVE AKI
Cardiac SurgeryAssociated AKI
The incidence of cardiac surgeryassociated (CSA)-
AKI varies with the denition of AKI. Milder forms of
AKI (eg, KDIGO stage 1 AKI: a 0.3-mg/dL absolute
increase or a 50% increase from preoperative baseline
values) occur in 15% to 30% of patients,8991 whereas
more severe forms (eg, KDIGO stage 3 AKI or the
need for RRT) are less common, occurring in less than
5% to 10% of patients.90,92,93 Importantly, sepsis is an
uncommon occurrence after cardiac surgery, with two
separate large database analyses showing that the
incidence of major postoperative infections, of which
sepsis is a subset, is less than 1.5%.94,95 However,
despite this low event rate, when looking at a 4-year
nationally representative sample of cardiac surgery
patients, Vogel et al94 showed that the presence of
sepsis after cardiac surgery, regardless of AKI, was
associated overwhelmingly with an increased risk of
mortality (30.8% versus 1.17%) in patients without
postoperative sepsis. Common factors that increase the
risk of CSA-AKI have been identied and can be
separated into preoperative and intraoperative catego-
ries.91,96,97 Factors such as female sex, older age,
insulin-requiring DM, congestive heart failure, and
chronic obstructive pulmonary disease all are associ-
ated with increased AKI risk. However, the presence of
preoperative CKD remains the most important deter-
minant of CSA-AKI risk.98100 Intraoperative risk
factors also are associated with postoperative CSA-
AKI, including the use of intra-aortic balloon pumps,
hypothermic circulatory arrest, the use of vasopressors,
and the number of blood transfusions needed.96,101,102
Based on these risk factors, a variety of clinical tools
have been developed and validated to improve the AKI
risk stratication of individual patients undergoing
cardiac surgery (Table 3). Importantly, the role of
cardiopulmonary bypass pump as a risk factor for
CSA has been investigated intensively. In a
propensity-matched cohort stratied by preoperative
renal function, Chawla et al103 showed that off-pump
procedures were associated with a lower risk of RRT
and inpatient mortality. Similarly, in the Coronary
Artery Bypass Grafting Surgery Off- or On-pump
Revascularization Study, which enrolled 4,752 patients
undergoing their rst isolated coronary artery bypass
graft surgery, the rates of AKI (dened by the AKI
29
Network criteria) were higher in patients receiving a
cardiopulmonary bypass pump (32.1% versus 28%;
P .01).104 However, based on the 1-year follow-up
data, there was no difference in the long-term loss of
renal function between on- and off-pump surgeries: at
1 year the on-pump patients saw a 15.3% decrease in
their eGFR compared with 17.1% for off-pump
patients (P .23).105
In addition to traditional on- and off-pump cardiac
surgery, ventricular assist device (VAD) implantation
represents a growing population of cardiac surgery
patients at high risk for the development of AKI.106
Despite the growing number of VAD implantations,
the impact of AKI during the perioperative period, its
etiology, predictors, and short- and long-term conse-
quences require further investigation; the limited liter-
ature has been difcult to interpret because many
studies have not used consensus denitions of
AKI.107112 Certainly sepsis and infection play a role
in the development of post-VAD implantation AKI,
with postoperative infection rates varying from 8% to
22%.113,114 Interestingly, in a prospective observatio-
nal multicenter study of 158 VAD patients, increased
pre-implantation serum creatinine concentration was an
independent risk factor for postoperative infections
complications.113 For the studies that used consensus
AKI denitions, the incidence of AKI, dened at its
simplest (RIFLE risk or AKI Network stage 1), varied
from 7% to 56%.114116 Although some of these
investigations have shown that postimplantation
AKI has similar risk factors to traditional cardiac
surgery (eg, preoperative eGFR,116,117 length of
cardiopulmonary bypass time,116 and the presence
of diabetes114), others have shown that preoperative
hematocrit level, the presence of cerebrovascular
disease, and preoperative hepatic function may be
risk factors for post-VAD AKI.114,116,117 Further
investigations are needed to tease out any potential
differences between the risks of AKI after traditional
cardiac surgery versus VAD implantations. It is well
documented that several months after VAD implanta-
tion, in the presence of improved renal perfusion, the
majority of patients have an improvement in renal
function.118 However, the impact of perioperative
AKI on this long-term improvement in renal function
remains unclear.
NonCSA AKI
As with cardiac surgery, the event rates for post-
operative sepsis are rather low, with Vogel et al94
reporting that 78,669 (1.21%) of 6.51 million elective
cases developed sepsis. Event rates were highest in
esophageal (3.8%), pancreatic (3.1%), and gastric
(2.8%) procedures.94 Compared with CSA-AKI, the
30 M. Heung and J.L. Koyner

Table 3. Selected Scoring Systems for Predicting Acute Kidney Injury After Adult Cardiac Surgery
Cleveland Clinic Score Society of Thoracic Wijeysundera AKICS Score
(Thakar et al96) Surgeons (Mehta et al100) et al98 (Palomba et al160)
Age N/A Variable (1-10) N/A 2.3 (465 y)
Non-white race N/A 2 N/A N/A
Female sex 1 N/A N/A N/A
Congestive heart failure 1 3 N/A 3.2
Left ventricular ejection fraction 1 (o35%) N/A 1 (o40%) N/A
Preoperative intra-aortic balloon 2 N/A 1 N/A
pump
Recent myocardial infarction N/A 3 N/A N/A
COPD 1 3 N/A N/A
Diabetes 1 (regardless of N/A
Noninsulin N/A 2 medication)
Insulin 1 5
Preoperative blood glucose N/A N/A N/A 1.7
concentration (4140 mg/dL)
Previous cardiac surgery 1 3 1 N/A
Emergency surgery 2 N/A 1 N/A
Surgery type
Valve only 1 2 or 4 1 N/A
CABG and valve 2 5 or 7 1 3.7
Preoperative creatinine
concentration
o1.2 mg/dL N/A 0-10 N/A 3.1
1.2-2.1 mg/dL 2 10-20 N/A N/A
42.1 mg/dL 5 25-40 N/A N/A
Preoperative eGFR concentration
31-60 mL/min N/A N/A 1 N/A
o30 mL/min N/A N/A 2 N/A
Cardiogenic shock N/A 7 N/A 2.5
Central venous pressure N/A N/A N/A 1.7 (414 cm H2O)
Cardiopulmonary bypass time N/A N/A N/A 1.8 (4120 min)

NOTE. The Cleveland Clinic Score96 was designed to predict RRT after adult surgery: a score of 0 carried an incidence of RRT of
0.13%, a score of 4 had an incidence of RRT of 2.3%, a score of 6 had an incidence of RRT of 8.0%, and a score of 10 had an
incidence of RRT of 19.6%. The Society of Thoracic Surgeons100 score was designed to predict RRT after adult surgery: a score of 10
carried a 0.2% incidence of RRT, a score of 20 carried a 1.1% risk of RRT, a score of 30 carried a 5.4% risk of RRT, a score of 40
carried a 16% risk of RRT, a score of 50 carried a 28% risk of RRT, and a score of 60 carried a 56% risk of RRT. The Wijeysundera
score98 was designed to predict RRT after adult cardiac surgery. For Palomba et al,160 five risk categories (scores 0-4, 4.1-8, 8.1-12,
12.1-16, and 16.1-20) were associated with an increased incidence of developing AKI (1.5%, 4.3%, 9.1%, 21.8%, and 62.5%,
respectively).
Abbreviations: CABG, coronary artery bypass graft; COPD, chronic obstructive pulmonary disease.

incidence of AKI (mild or severe) after other surgical
procedures was lower, however, event rates varied
depending on the surgical procedure.119122 These
studies have shown that procedures such as major
vascular surgery (eg, abdominal aortic aneurysm
repair), gastric bypass surgery, and liver transplanta-
tion all have their own unique AKI risk proles. By
using the American College of Surgeons National
Surgical Quality Improvement Program data, Kheter-
pal et al123 reviewed 75,952 general surgeries and
identied several predictors of postoperative AKI;
these included preoperative CKD, age older than 56
years, emergency surgery, and the presence of DM or
congestive heart failure. The development and vali-
dation of this risk assessment tool built on this
groups previous work that showed that intraoperative
factors such as the use of intraoperative vasopressors,
furosemide, or mannitol all increased the risk of
postoperative AKI.119
Outcomes of Postoperative AKI
Mortality rates in the setting of CSA-AKI and post-
operative AKI have improved over the past 10 to 15
years,124 but remain exceedingly high. Postoperative
AKI is associated with an increased risk of readmis-
sion, incidence, and progression of CKD, as well as
poor long-term survival.121,125128 Coca et al126
recently showed that urinary biomarkers of tubular
injury measured in the early postoperative period are
Sepsis, CKD, and comorbidities in AKI
associated with 3-year mortality in adults who have
undergone cardiac surgery. This association held true
for patients both with and without AKI and perhaps
offers a preview into the next generation of risk-
stratication tools that will incorporate novel bio-
markers, severity of AKI, and other factors to risk
stratify patients for long-term mortality after AKI.129 In
addition, uid overload has been shown to impact
patient outcomes after cardiac surgery. In a recent
secondary analysis of a prospective observational
study, uid overload (dened as a 5% gain greater
than admission body weight) was shown to impact
pediatric patients hospital course negatively after
cardiac surgery.130
AKI IN THE IMMUNOCOMPROMISED HOST
AKI in Cancer Patients
As the eld of onconephrology continues to grow, AKI
increasingly is recognized as a common and signicant
complication in patients with cancer; several reviews
on this topic have been published recently.131133 As in
other clinical settings, the incidence and severity of
AKI varies depending on the type and stage of cancer,
treatment course, and patient comorbidities.32,133136 In
addition, in the setting of cancer, AKI morbidity, and
mortality increase in the presence of critical illness or the
need for RRT.137139 The sources of AKI in the setting
of malignancy are similar to those in other clinical
settings. However, given the increasing number of novel
therapeutics and complexity of cancer treatment proto-
cols, nephrologists need to stay informed in the emerging
landscape of onconephrology.
Very few large investigations of AKI among cancer
patients have been performed, however, these types of
studies are increasing in number.32,134 Previous inves-
tigations have examined the etiologies of AKI in
cancer patients and, as in other clinical settings, they
have been categorized into prerenal, intrarenal, and
postrenal AKI. A recent, prospectively collected, cross-
sectional analysis of 3,558 subjects showed that DM,
hyponatremia, iodinated contrast, chemotherapy, and
antibiotics all increased the risk of AKI in patients
admitted to a comprehensive cancer center.32
Prerenal AKI is extremely common in cancer
patients and often is associated with intravascular
volume depletion from vomiting, diarrhea, and reduced
oral intake (eg, from chemotherapy-induced mucosi-
tis).140 Importantly, early stage and under-resuscitated
sepsis may present clinically as volume depletion
(hypotension, vasodilation, fevers, and so forth), and
separating this from other sources of AKI often proves
difcult. Finally, other sources of prerenal AKI
include medications (eg, diuretics, nonsteroidal anti-
inammatory drugs, angiotensin-converting enzyme
31
inhibitors/angiotensin-receptor blocker, calcineurin
inhibitors) and hypercalcemia, which can induce a
natural diuresis, further depleting intravascular volume.
Obstructive (postrenal) AKI is more common in
cancer patients compared with other AKI patients.131
Whether owing to bladder outlet or ureteral obstruc-
tion, obstructive AKI can result from cancer of the
bladder, prostate, uterus, or cervix, and also from
retroperitoneal brosis in the setting of malignancy.
The treatment for obstructive uropathy involves reliev-
ing the obstruction, and clinical recovery depends on
the duration and severity of the AKI.
The intrinsic causes of AKI in the cancer setting are
numerous and have been covered in several recent
reviews.131,132,141143 Acute tubular necrosis (ATN),
whether from ischemia or nephrotoxins, remains an
important and all too common source of AKI in
patients with cancer; however, other etiologies such
as acute glomerulonephritis, hematopoietic stem cell
transplantation, tumor lysis, and cast nephropathy
contribute to the AKI case load. Briey, nephrotoxins
such as bisphosphonates (ATN and collapsing focal
segmental glomerulosclerosis), cisplatin (tubulopathy
and cellular apoptosis), methotrexate (crystal-induced
tubulopathy), ifosfamide (ATN and Fanconi syn-
drome), gemcitabine (thrombotic microangiopathy),
and contrast nephropathy are some of the common
agents that induce cancer-associated AKI.131 Contrast
nephropathy is fairly common in the cancer patient
given the commonality of their risk factors including
older age, pre-existing CKD, exposure to other neph-
rotoxins, and generally poor hydration status.144
AKI after hematopoietic stem cell transplantation is
extremely common, with incidence rates of 50% to
80%, depending on the denition or transplant being
performed.136,145 Because of the increased exposure to
nephrotoxins as well as the complexity of the trans-
plants, the risk of AKI is greater in allogenic (versus
autologous) transplants and myeloablative (versus
nonmyeloablative) transplants.136,143,145 Importantly,
hematopoietic stem cell transplantation patients are at
risk from a variety of sources including the aforemen-
tioned prerenal azotemia and obstruction (eg, from
acyclovir-induced crystalline disease), but also from
tumor lysis syndrome (TLS) (discussed later), hepatic
veno-occlusive disease, sepsis/infections (bacterial,
fungal, and viral), and nephrotoxins (antibiotics, calci-
neurin inhibitors).143 Goldstein et al146 showed that in
the setting of pediatric stem cell transplantation, uid
overload, dened as either 5% or 10% uid overload
(calculated by subtracting the total uid output from
the total uid input over the course of admission
divided by the patients admission weight), was asso-
ciated with adverse patient outcomes.
TLS, an oncologic emergency, is most common in
the setting of hematologic malignancy, although the
32
incidence in the setting of solid tumors is increasing.
Although a classication schema has been published, it
is not used broadly because distinguishing clinically
relevant TLS from laboratory-dened TLS remains a
challenge for oncologists and nephrologists alike.147
Dened by increases in uric acid, potassium, and
phosphorus, with a concomitant decrease in calcium,
TLS is more common in patients with prechemother-
apy CKD. In a retrospective observational study of 772
adults with acute myeloid leukemia, 17% developed
TLS, and independent risk factors included baseline
creatinine concentrations greater than 1.4 mg/dL,
pretreatment uric acid concentrations greater than
7.5 mg/dL, white blood cell count greater than
25  109/L, and increased pretreatment lactate dehy-
drogenase levels.148 Newer treatments such as febuxo-
stat (a xanthine oxidase inhibitor) and rasburicase
(recombinant urate oxidase) are reshaping the treat-
ment of TLS; intravascular volume expansion,
increased alkalinized urinary ow, calcium supplemen-
tation, and RRT remain at the cornerstone of TLS
treatment.
Multiple myeloma (MM), a malignant plasma cell
disorder, is highly associated with AKI, with more than
one third of MM patients developing some form of
kidney injury and 10% to 15% requiring RRT.149
Multiple investigations have shown that MM-
associated AKI increases patient mortality, however,
interestingly, the mortality risk was reversible with the
restoration of renal function.150,151 AKI from hyper-
calcemia, higher pretreatment eGFR, and proteinuria
less than 1 g/d all were predictive of improved renal
and overall survival. However, these studies all pre-
date several of the modern treatments for MM, includ-
ing early removal of serum-free light chains with
hemodialysis.152 Regardless, AKI in the setting of
MM remains a complex clinical entity with multiple
clinical presentations including myeloma cast nephr-
opathy, amyloid light-chain amyloidosis, monoclonal
immunoglobulin deposition disease, and ATN.
AKI in Nonrenal Solid Organ Transplant Recipients
Although patients with nonrenal solid organ transplants
represent a small percentage of patients with AKI and
critical illness, nevertheless they are a complex
immune-compromised population with multiple
comorbidities. Among these comorbidities are an
increased incidence of CKD and ESRD resulting from
the nephrotoxicity of immunosuppressive agents, peri-
operative AKI, pretransplant CKD, and other tradi-
tional CKD risk factors (eg, DM, hypertension, and so
forth).121 Peritransplant AKI varies in its incidence
from 20% to 60%, depending on the organ being
transplanted, with RRT being used in 10% to 25% of
subjects.153,154 Sepsis remains a common risk factor
M. Heung and J.L. Koyner
for AKI in the solid organ transplant recipient and was
associated independently with risk of death in a recent
cohort study of solid-organ transplant recipients who
all had dialysis requiring AKI.153
AKI in the Human Immunodeciency Virus Patient
AKI in the setting of human immunodeciency virus
(HIV) carries a broad differential with sepsis and acute
tubular injury playing major roles; however, several
risk factors often are present.155157 HIV patients are at
high risk for AKI in large part owing to their predis-
position to CKD, predominantly through glomerular
disease. This CKD can manifest through a variety of
mechanisms including podocyte injury (eg, HIV-
associated nephropathy, focal segmental glomerular
sclerosis) or immune complex disease (eg, IgA nephr-
opathy, membranous, membranoproliferative glomer-
ulonephritis), which often is related to co-infection
with a hepatitis virus.157,158 Medications represent
another important source of AKI with highly active
antiretroviral therapy nephropathy (eg, tenofovir, indi-
navir), acute crystalluria nephropathy (eg, acyclovir,
indinavir), acute interstitial nephritis, and rhabdomyol-
ysis (eg, zidovudine and didanosine).157,159 A prospec-
tive cohort study of 56,823 HIV-infected patients in the
Veterans Affairs registry showed that the incidence rate
of AKI (dened as a 0.3-mg/dL absolute or 50%
relative increase in serum creatinine concentration)
decreased from 1996 to 2006. As expected, the
presence of an eGFR less than 60 mL/min, proteinuria,
hypoalbuminemia, a CD4 cell count less than 200 cell/
mm3, and a high viral load (4100,000 copies/mL) all
were shown to be strong risk factors for the develop-
ment of AKI.156 AKI in the setting of HIV has been
associated with an increased risk of long-term
mortality.155
CONCLUSIONS
AKI is a common and frequently deadly syndrome in
critically ill patients. AKI does not represent a single
entity, but rather is a complex syndrome that can be
inuenced by a variety of risk factors. This is most
evident in the setting of sepsis, in which a variety of
shared risk factors for both sepsis and AKI may co-
exist and contribute to both syndromes. Examples
include immunocompromised syndromes (DM, HIV,
cancer, cirrhosis) and inammatory states (postsurgi-
cal, CKD). Recognition of the risk from these shared
susceptibilities is critical to the early identication and
management of developing AKI and sepsis. In recent
years, research has yielded a great deal of insight into
the complicated interactions between AKI, sepsis, and
shared comorbidities. Finding opportunities to inter-
vene and reverse or attenuate the injury resulting from
Sepsis, CKD, and comorbidities in AKI
these entangled conditions remains a major focus for
clinical care and research.
REFERENCES
1. Singbartl K, Kellum JA. AKI in the ICU: denition, epidemi-
ology, risk stratication, and outcomes. Kidney Int. 2012;81:
819-25.
2. Hsu CY, Ordonez JD, Chertow GM, Fan D, McCulloch CE,
Go AS. The risk of acute renal failure in patients with chronic
kidney disease. Kidney Int. 2008;74:101-7.
3. Zeng X, McMahon GM, Brunelli SM, Bates DW, Waikar SS.
Incidence, outcomes, and comparisons across denitions of
AKI in hospitalized individuals. Clin J Am Soc Nephrol.
2014;9:12-20.
4. James MT, Hemmelgarn BR, Wiebe N, Pannu N, Manns BJ,
Klarenbach SW, et al. Glomerular ltration rate, proteinuria,
and the incidence and consequences of acute kidney injury: a
cohort study. Lancet. 2010;376:2096-103.
5. Chawla LS, Kimmel PL. Acute kidney injury and chronic
kidney disease: an integrated clinical syndrome. Kidney Int.
2012;82:516-24.
6. Khosla N, Soroko SB, Chertow GM, Himmelfarb J, Ikizler
TA, Paganini E, et al. Preexisting chronic kidney disease: a
potential for improved outcomes from acute kidney injury.
Clin J Am Soc Nephrol. 2009;4:1914-9.
7. Hsu CY, McCulloch CE, Fan D, Ordonez JD, Chertow GM,
Go AS. Community-based incidence of acute renal failure.
Kidney Int. 2007;72:208-12.
8. Hsu RK, McCulloch CE, Dudley RA, Lo LJ, Hsu CY.
Temporal changes in incidence of dialysis-requiring AKI.
J Am Soc Nephrol. 2013;24:37-42.
9. Vaziri ND, Pahl MV, Crum A, Norris K. Effect of uremia on
structure and function of immune system. J Ren Nutr.
2012;22:149-56.
10. Betjes MG. Immune cell dysfunction and inammation in
end-stage renal disease. Nat Rev Nephrol. 2013;9:255-65.
11. Girndt M, Sester U, Sester M, Kaul H, Kohler H. Impaired
cellular immune function in patients with end-stage renal
failure. Nephrol Dial Transplant. 1999;14:2807-10.
12. Leelahavanichkul A, Huang Y, Hu X, Zhou H, Tsuji T, Chen
R, et al. Chronic kidney disease worsens sepsis and sepsis-
induced acute kidney injury by releasing High Mobility Group
Box Protein-1. Kidney Int. 2011;80:1198-211.
13. Sarnak MJ, Jaber BL. Mortality caused by sepsis in patients
with end-stage renal disease compared with the general
population. Kidney Int. 2000;58:1758-64.
14. U.S. Renal Data System. USRDS 2013 Annual Data Report:
Atlas of Chronic Kidney Disease and End-Stage Renal
Disease in the United States. Bethesda, MD: National Insti-
tutes of Health, National Institute of Diabetes and Digestive
and Kidney Diseases, 2013.
15. Goncalves S, Pecoits-Filho R, Perreto S, Barberato SH,
Stinghen AE, Lima EG, et al. Associations between renal
function, volume status and endotoxaemia in chronic kidney
disease patients. Nephrol Dial Transplant. 2006;21:2788-94.
16. Vaziri ND, Yuan J, Rahimi A, Ni Z, Said H, Subramanian VS.
Disintegration of colonic epithelial tight junction in uremia: a
likely cause of CKD-associated inammation. Nephrol Dial
Transplant. 2012;27:2686-93.
17. Ramezani A, Raj DS. The gut microbiome, kidney disease,
and targeted interventions. J Am Soc Nephrol. 2014;25:
657-70.
18. Hsu CY, Chertow GM, McCulloch CE, Fan D, Ordonez JD,
Go AS. Nonrecovery of kidney function and death after acute
on chronic renal failure. Clin J Am Soc Nephrol.
2009;4:891-8.
33
19. Coca SG, Singanamala S, Parikh CR. Chronic kidney disease
after acute kidney injury: a systematic review and meta-
analysis. Kidney Int. 2012;81:442-8.
20. Wu VC, Huang TM, Lai CF, Shiao CC, Lin YF, Chu TS, et al.
Acute-on-chronic kidney injury at hospital discharge is asso-
ciated with long-term dialysis and mortality. Kidney Int.
2011;80:1222-30.
21. Heung M, Chawla LS. Predicting progression to chronic
kidney disease after recovery from acute kidney injury. Curr
Opin Nephrol Hypertens. 2012;21:628-34.
22. Chawla LS, Eggers PW, Star RA, Kimmel PL. Acute kidney
injury and chronic kidney disease as interconnected syn-
dromes. N Engl J Med. 2014;371:58-66.
23. Rifkin DE, Coca SG, Kalantar-Zadeh K. Does AKI truly lead
to CKD? J Am Soc Nephrol. 2012;23:979-84.
24. Goldstein SL, Jaber BL, Faubel S, Chawla LS. Acute Kidney
Injury Advisory Group of American Society of Nephrology.
AKI transition of care: a potential opportunity to detect and
prevent CKD. Clin J Am Soc Nephrol. 2013;8:476-83.
25. Basile DP, Leonard EC, Tonade D, Friedrich JL, Goenka S.
Distinct effects on long-term function of injured and contrala-
teral kidneys following unilateral renal ischemia-reperfusion.
Am J Physiol Renal Physiol. 2012;302:F625-35.
26. Zager RA, Johnson AC, Becker K. Acute unilateral ischemic
renal injury induces progressive renal inammation, lipid
accumulation, histone modication, and end-stage kidney
disease. Am J Physiol Renal Physiol. 2011;301:F1334-45.
27. Clements ME, Chaber CJ, Ledbetter SR, Zuk A. Increased
cellular senescence and vascular rarefaction exacerbate the
progression of kidney brosis in aged mice following transient
ischemic injury. PLoS One. 2013;8:e70464.
28. Bao H, Ge Y, Wang Z, Zhuang S, Dworkin L, Peng A, Gong
R. Delayed administration of a single dose of lithium
promotes recovery from AKI. J Am Soc Nephrol. 2014;25:
488-500.
29. Barrera-Chimal J, Perez-Villalva R, Rodriguez-Romo R,
Reyna J, Uribe N, Gamba G, Bobadilla NA. Spironolactone
prevents chronic kidney disease caused by ischemic acute
kidney injury. Kidney Int. 2013;83:93-103.
30. Forni LG, Dawes T, Sinclair H, Cheek E, Bewick V, Dennis
M, et al. Identifying the patient at risk of acute kidney injury: a
predictive scoring system for the development of acute kidney
injury in acute medical patients. Nephron Clin Pract.
2013;123:143-50.
31. Finlay S, Bray B, Lewington AJ, Hunter-Rowe CT, Banerjee
A, Atkinson JM, et al. Identication of risk factors associated
with acute kidney injury in patients admitted to acute medical
units. Clin Med. 2013;13:233-8.
32. Salahudeen AK, Doshi SM, Pawar T, Nowshad G, Lahoti A,
Shah P. Incidence rate, clinical correlates, and outcomes of
AKI in patients admitted to a comprehensive cancer center.
Clin J Am Soc Nephrol. 2013;8:347-54.
33. Heyman SN, Rosenberger C, Rosen S, Khamaisi M. Why is
diabetes mellitus a risk factor for contrast-induced nephrop-
athy? Biomed Res Int. 2013;2013:123589.
34. Gao G, Zhang B, Ramesh G, Betterly D, Tadagavadi RK,
Wang W, et al. TNF-alpha mediates increased susceptibility to
ischemic AKI in diabetes. Am J Physiol Renal Physiol.
2013;304:F515-21.
35. McMahon MM, Bistrian BR. Host defenses and susceptibility
to infection in patients with diabetes mellitus. Infect Dis Clin
North Am. 1995;9:1-9.
36. Joshi N, Caputo GM, Weitekamp MR, Karchmer AW.
Infections in patients with diabetes mellitus. N Engl J Med.
1999;341:1906-12.
37. Muller LM, Gorter KJ, Hak E, Goudzwaard WL, Schellevis
FG, Hoepelman AI, et al. Increased risk of common infections
34
in patients with type 1 and type 2 diabetes mellitus. Clin Infect
Dis. 2005;41:281-8.
38. Bertoni AG, Saydah S, Brancati FL. Diabetes and the risk of
infection-related mortality in the U.S. Diabetes Care.
2001;24:1044-9.
39. Casqueiro J, Casqueiro J, Alves C. Infections in patients with
diabetes mellitus: a review of pathogenesis. Indian J Endo-
crinol Metab. 2012;16(Suppl 1):S27-36.
40. McCowen KC, Malhotra A, Bistrian BR. Stress-induced
hyperglycemia. Crit Care Clin. 2001;17:107-24.
41. Turina M, Fry DE, Polk HC Jr. Acute hyperglycemia and the
innate immune system: clinical, cellular, and molecular
aspects. Crit Care Med. 2005;33:1624-33.
42. Andersen SK, Gjedsted J, Christiansen C, Tonnesen E. The
roles of insulin and hyperglycemia in sepsis pathogenesis.
J Leukoc Biol. 2004;75:413-21.
43. van den Berghe G, Wouters P, Weekers F, Verwaest C,
Bruyninckx F, Schetz M, et al. Intensive insulin therapy in
critically ill patients. N Engl J Med. 2001;345:1359-67.
44. Van den Berghe G, Wilmer A, Hermans G, Meersseman W,
Wouters PJ, Milants I, et al. Intensive insulin therapy in the
medical ICU. N Engl J Med. 2006;354:449-61.
45. NICE-SUGAR Study Investigators, Finfer S, Chittock DR, Su
SY, Blair D, Foster D, et al. Intensive versus conventional
glucose control in critically ill patients. N Engl J Med.
2009;360:1283-97.
46. NICE-SUGAR Study Investigators, Finfer S, Liu B, Chittock
DR, Norton R, Myburgh JA, et al. Hypoglycemia and risk of
death in critically ill patients. N Engl J Med. 2012;367:
1108-18.
47. Brunkhorst FM, Engel C, Bloos F, Meier-Hellmann A,
Ragaller M, Weiler N, et al. Intensive insulin therapy and
pentastarch resuscitation in severe sepsis. N Engl J Med.
2008;358:125-39.
48. Preiser JC, Devos P, Ruiz-Santana S, Melot C, Annane D,
Groeneveld J, et al. A prospective randomised multi-centre
controlled trial on tight glucose control by intensive insulin
therapy in adult intensive care units: the Glucontrol study.
Intensive Care Med. 2009;35:1738-48.
49. Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H,
Opal SM, et al. Surviving Sepsis Campaign Guidelines
Committee including the Pediatric Subgroup. Surviving sepsis
campaign: international guidelines for management of severe
sepsis and septic shock: 2012. Crit Care Med. 2013;41:
580-637.
50. Bartoletti M, Giannella M, Caraceni P, Domenicali M,
Ambretti S, Tedeschi S, et al. Epidemiology and outcomes
of bloodstream infection in patients with cirrhosis. J Hepatol.
2014;61:51-8.
51. Bruns T, Zimmermann HW, Stallmach A. Risk factors and
outcome of bacterial infections in cirrhosis. World J Gastro-
enterol. 2014;20:2542-54.
52. Tritto G, Bechlis Z, Stadlbauer V, Davies N, Frances R, Shah
N, et al. Evidence of neutrophil functional defect despite
inammation in stable cirrhosis. J Hepatol. 2011;55:574-81.
53. Bajaj JS, OLeary JG, Wong F, Reddy KR, Kamath PS.
Bacterial infections in end-stage liver disease: current chal-
lenges and future directions. Gut. 2012;61:1219-25.
54. Bellot P, Frances R, Such J. Pathological bacterial trans-
location in cirrhosis: pathophysiology, diagnosis and clinical
implications. Liver Int. 2013;33:31-9.
55. Senzolo M, Cholongitas E, Burra P, Leandro G, Thalheimer
U, Patch D, et al. beta-Blockers protect against spontaneous
bacterial peritonitis in cirrhotic patients: a meta-analysis. Liver
Int. 2009;29:1189-93.
56. Rasaratnam B, Kaye D, Jennings G, Dudley F, Chin-Dusting
J. The effect of selective intestinal decontamination on the
M. Heung and J.L. Koyner
hyperdynamic circulatory state in cirrhosis. A randomized
trial. Ann Intern Med. 2003;139:186-93.
57. Fagundes C, Barreto R, Guevara M, Garcia E, Sola E,
Rodriguez E, et al. A modied acute kidney injury classi-
cation for diagnosis and risk stratication of impairment of
kidney function in cirrhosis. J Hepatol. 2013;59:474-81.
58. Wong F, OLeary JG, Reddy KR, Patton H, Kamath PS,
Fallon MB, et al. North American Consortium for Study of
End-Stage Liver Disease. New consensus denition of acute
kidney injury accurately predicts 30-day mortality in patients
with cirrhosis and infection. Gastroenterology. 2013;145:
1280-8.e1
59. Takabatake T, Ohta H, Ishida Y, Hara H, Ushiogi Y, Hattori
N. Low serum creatinine levels in severe hepatic disease. Arch
Intern Med. 1988;148:1313-5.
60. Slack A, Yeoman A, Wendon J. Renal dysfunction in chronic
liver disease. Crit Care. 2010;14:214.
61. Wong F, Nadim MK, Kellum JA, Salerno F, Bellomo R,
Gerbes A, et al. Working Party proposal for a revised
classication system of renal dysfunction in patients with
cirrhosis. Gut. 2011;60:702-9.
62. Salerno F, Gerbes A, Gines P, Wong F, Arroyo V. Diagnosis,
prevention and treatment of hepatorenal syndrome in cirrhosis.
Gut. 2007;56:1310-8.
63. Vanmassenhove J, Vanholder R, Nagler E, Van Biesen W.
Urinary and serum biomarkers for the diagnosis of acute
kidney injury: an in-depth review of the literature. Nephrol
Dial Transplant. 2013;28:254-73.
64. Wadei HM, Mai ML, Ahsan N, Gonwa TA. Hepatorenal
syndrome: pathophysiology and management. Clin J Am Soc
Nephrol. 2006;1:1066-79.
65. Gines P, Schrier RW. Renal failure in cirrhosis. N Engl J Med.
2009;361:1279-90.
66. Gluud LL, Kjaer MS, Christensen E. Terlipressin for hep-
atorenal syndrome. Cochrane Database Syst Rev. 2006;4:
CD005162.
67. Angeli P, Volpin R, Gerunda G, Craighero R, Roner P,
Merenda R, et al. Reversal of type 1 hepatorenal syndrome
with the administration of midodrine and octreotide. Hepatol-
ogy. 1999;29:1690-7.
68. Sharma P, Goodrich NP, Zhang M, Guidinger MK, Schaubel
DE, Merion RM. Short-term pretransplant renal replacement
therapy and renal nonrecovery after liver transplantation
alone. Clin J Am Soc Nephrol. 2013;8:1135-42.
69. Park SW, Chen SW, Kim M, Brown KM, Kolls JK, DAgati
VD, et al. Cytokines induce small intestine and liver injury after
renal ischemia or nephrectomy. Lab Invest. 2011;91:63-84.
70. Golab F, Kadkhodaee M, Zahmatkesh M, Hedayati M, Arab
H, Schuster R, et al. Ischemic and non-ischemic acute kidney
injury cause hepatic damage. Kidney Int. 2009;75:783-92.
71. Lane K, Dixon JJ, MacPhee IA, Philips BJ. Renohepatic
crosstalk: does acute kidney injury cause liver dysfunction?
Nephrol Dial Transplant. 2013;28:1634-47.
72. Yap SC, Lee HT. Acute kidney injury and extrarenal organ
dysfunction: new concepts and experimental evidence. Anes-
thesiology. 2012;116:1139-48.
73. Seeley EJ. Updates in the management of acute lung injury: a
focus on the overlap between AKI and ARDS. Adv Chronic
Kidney Dis. 2013;20:14-20.
74. Koyner JL, Murray PT. Mechanical ventilation and the
kidney. Blood Purif. 2010;29:52-68.
75. Liu KD, Matthay MA. Advances in critical care for the
nephrologist: acute lung injury/ARDS. Clin J Am Soc
Nephrol. 2008;3:578-86.
76. Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND,
Caldwell E, Fan E, et al. Acute respiratory distress syndrome:
the Berlin Denition. JAMA. 2012;307:2526-33.
Sepsis, CKD, and comorbidities in AKI
77. Cooke CR, Kahn JM, Caldwell E, Okamoto VN, Heckbert
SR, Hudson LD, et al. Predictors of hospital mortality in a
population-based cohort of patients with acute lung injury.
Crit Care Med. 2008;36:1412-20.
78. Darmon M, Clech C, Adrie C, Argaud L, Allaouchiche B,
Azoulay E, et al. Acute respiratory distress syndrome and risk
of AKI among critically ill patients. Clin J Am Soc Nephrol.
2014;9:1347-53.
79. Truwit JD, Bernard GR, Steingrub J, Matthay MA, Liu KD,
Albertson TE, et al. Rosuvastatin for sepsis-associated acute
respiratory distress syndrome. N Engl J Med. 2014;370:
2191-200.
80. Bernard GR, Luce JM, Sprung CL, Rinaldo JE, Tate RM,
Sibbald WJ, et al. High-dose corticosteroids in patients with
the adult respiratory distress syndrome. N Engl J Med.
1987;317:1565-70.
81. Brower RG, Lanken PN, MacIntyre N, Matthay MA, Morris
A, Ancukiewicz M, et al. National Heart Lung, Blood Institute
ARDS Clinical Trial Network. Higher versus lower positive
end-expiratory pressures in patients with the acute respiratory
distress syndrome. N Engl J Med. 2004;351:327-36.
82. Wiedemann HP, Wheeler AP, Bernard GR, Thompson BT,
Hayden D, deBoisblanc B, et al. Comparison of two uid-
management strategies in acute lung injury. N Engl J Med.
2006;354:2564-75.
83. Young D, Lamb SE, Shah S, MacKenzie I, Tunnicliffe W,
Lall R, et al. High-frequency oscillation for acute respiratory
distress syndrome. N Engl J Med. 2013;368:806-13.
84. Liu KD, Thompson BT, Ancukiewicz M, Steingrub JS,
Douglas IS, Matthay MA, et al. Acute kidney injury in
patients with acute lung injury: impact of uid accumulation
on classication of acute kidney injury and associated out-
comes. Crit Care Med. 2011;39:2665-71.
85. Teixeira C, Garzotto F, Piccinni P, Brienza N, Iannuzzi M,
Gramaticopolo S, et al. Fluid balance and urine volume are
independent predictors of mortality in acute kidney injury. Crit
Care. 2013;17:R14.
86. Boyd JH, Forbes J, Nakada TA, Walley KR, Russell JA. Fluid
resuscitation in septic shock: a positive uid balance and
elevated central venous pressure are associated with increased
mortality. Crit Care Med. 2011;39:259-65.
87. Bellomo R, Cass A, Cole L, Finfer S, Gallagher M, Lee J,
et al. An observational study uid balance and patient
outcomes in the Randomized Evaluation of Normal vs.
Augmented Level of Replacement Therapy trial. Crit Care
Med. 2012;40:1753-60.
88. Heung M, Wolfgram DF, Kommareddi M, Hu Y, Song PX,
Ojo AO. Fluid overload at initiation of renal replacement
therapy is associated with lack of renal recovery in patients
with acute kidney injury. Nephrol Dial Transplant. 2012;27:
956-61.
89. Lassnigg A, Schmidlin D, Mouhieddine M, Bachmann L,
Druml W, Bauer P, et al. Minimal changes of serum creatinine
predict prognosis in patients after cardiothoracic surgery: a
prospective cohort study. J Am Soc Nephrol. 2004;15:
1597-605.
90. Parikh CR, Coca SG, Thiessen-Philbrook H, Shlipak MG,
Koyner JL, Wang Z, et al. Postoperative biomarkers predict
acute kidney injury and poor outcomes after adult cardiac
surgery. J Am Soc Nephrol. 2011;22:1748-57.
91. Thakar C, Liangos O, Yared J-P, Nelson D, Piedmonte MR,
Hariacher S, et al. ARF after open-heart surgery: inuence of
gender and race. Am J Kidney Dis. 2003;41:742-51.
92. MoraMangano C, Diamondstone L, Ramsey J, Aggarwal A,
Herskowitz A, Mangano D. Renal dysfunction after myocar-
dial revascularization: risk factors, adverse outcomes, and
35
hospital resource utilization. Ann Intern Med. 1998;128:
194-203.
93. Conlon P, Strafford-Smith M, White WD, Newman MF, King
S, Winn MP, et al. Acute renal failure following cardiac
surgery. Nephrol Dial Transplant. 1999;14:1158-62.
94. Vogel TR, Dombrovskiy VY, Carson JL, Graham AM, Lowry
SF. Postoperative sepsis in the United States. Ann Surg.
2010;252:1065-71.
95. Fowler VG Jr, OBrien SM, Muhlbaier LH, Corey GR,
Ferguson TB, Peterson ED. Clinical predictors of major
infections after cardiac surgery. Circulation. 2005;112:l358-65.
96. Thakar CV, Arrigain S, Worley S, Yared JP, Paganini EP.
A clinical score to predict acute renal failure after cardiac
surgery. J Am Soc Nephrol. 2005;16:162-8.
97. Chertow GM, Lazarus JM, Christiansen CL, Cook E, Ham-
mermeister K, Grover F, et al. Preoperative renal risk
stratication. Circulation. 1997;95:878-84.
98. Wijeysundera DN, Karkouti K, Dupuis JY, Rao V, Chan CT,
Granton JT, et al. Derivation and validation of a simplied
predictive index for renal replacement therapy after cardiac
surgery. JAMA. 2007;297:1801-9.
99. Roques F, Nashef SA, Michel P, Gauducheau E, de Vincentiis
C, Baudet E, et al. Risk factors and outcome in European
cardiac surgery: analysis of the EuroSCORE multinational
database of 19030 patients. Eur J Cardiothorac Surg.
1999;15:816-23.
100. Mehta RH, Grab JD, OBrien SM, Bridges CR, Gammie JS,
Haan CK, et al. Bedside tool for predicting the risk of
postoperative dialysis in patients undergoing cardiac surgery.
Circulation. 2006;114:2208-16.(quiz 2208)
101. Khan UA, Coca SG, Hong K, Koyner JL, Garg AX, Passik
CS, et al. Blood transfusions are associated with urinary
biomarkers of kidney injury in cardiac surgery. J Thorac
Cardiovasc Surg. 2014;148:726-32.
102. Slogoff S, Reul G, Keats A, Curry GR, Crum ME, Elmquist
BA, et al. Role of perfusion pressure and ow in major organ
dysfunction after cardiopulmonary bypass. Ann Thorac Surg.
1990;50:911-8.
103. Chawla LS, Zhao Y, Lough FC, Schroeder E, Seneff MG,
Brennan JM. Off-pump versus on-pump coronary artery
bypass grafting outcomes stratied by preoperative renal
function. J Am Soc Nephrol. 2012;23:1389-97.
104. Lamy A, Devereaux PJ, Prabhakaran D, Taggart DP, Hu S,
Paolasso E, et al. Off-pump or on-pump coronary-artery
bypass grafting at 30 days. N Engl J Med. 2012;366:1489-97.
105. Garg AX, Devereaux PJ, Yusuf S, et al. Kidney function after
off-pump or on-pump coronary artery bypass graft surgery: a
randomized clinical trial. JAMA. 2014;311:2191-8.
106. COIITSS Study Investigators, Annane D, Cariou A, Maxime
V, Azoulay E, DHonneur G, et al. Corticosteroid treatment
and intensive insulin therapy for septic shock in adults: a
randomized controlled trial. JAMA. 2010;303:341-8.
107. McCarthy PM, Smedira NO, Vargo RL, Goormastic M,
Hobbs RE, Starling RC, et al. One hundred patients with the
HeartMate left ventricular assist device: evolving concepts and
technology. J Thorac Cardiovasc Surg. 1998;115:904-12.
108. Kaltenmaier B, Pommer W, Kaufmann F, Hennig E, Molzahn
M, Hetzer R. Outcome of patients with ventricular assist
devices and acute renal failure requiring renal replacement
therapy. ASAIO J. 2000;46:330-3.
109. Haddad M, Hendry PJ, Masters RG, Mesana T, Haddad H,
Davies RA, et al. Ventricular assist devices as a bridge to
cardiac transplantation: the Ottawa experience. Artif Organs.
2004;28:136-41.
110. Feller ED, Sorensen EN, Haddad M, Pierson RN 3rd, Johnson
FL, Brown JM, et al. Clinical outcomes are similar in pulsatile
36
and nonpulsatile left ventricular assist device recipients. Ann
Thorac Surg. 2007;83:1082-8.
111. Demirozu ZT, Etheridge WB, Radovancevic R, Frazier OH.
Results of HeartMate II left ventricular assist device implan-
tation on renal function in patients requiring post-implant
renal replacement therapy. J Heart Lung Transplant. 2011;30:
182-7.
112. Yoshioka D, Sakaguchi T, Saito S, Miyagawa S, Nishi H,
Yoshikawa Y, et al. Predictor of early mortality for severe
heart failure patients with left ventricular assist device
implantation: signicance of INTERMACS level and renal
function. Circ J. 2012;76:1631-8.
113. Gordon RJ, Weinberg AD, Pagani FD, Slaughter MS, Pappas PS,
Naka Y, et al. Prospective, multicenter study of ventricular assist
device infections. Circulation. 2013;127:691-702.
114. Naik A, Akhter SA, Fedson S, Jeevanandam V, Rich JD,
Koyner JL. Acute kidney injury and mortality following
ventricular assist device implantation. Am J Nephrol.
2014;39:195-203.
115. Patel AM, Adeseun GA, Ahmed I, Mitter N, Rame JE,
Rudnick MR. Renal failure in patients with left ventricular
assist devices. Clin J Am Soc Nephrol. 2013;8:484-96.
116. Alba AC, Rao V, Ivanov J, Ross HJ, Delgado DH. Predictors
of acute renal dysfunction after ventricular assist device
placement. J Card Fail. 2009;15:874-81.
117. Sandner SE, Zimpfer D, Zrunek P, Rajek A, Schima H,
Dunkler D, et al. Renal function and outcome after continuous
ow left ventricular assist device implantation. Ann Thorac
Surg. 2009;87:1072-8.
118. Brisco MA, Kimmel SE, Coca SG, Putt ME, Jessup M, Tang
WW, et al. Prevalence and prognostic importance of changes
in renal function after mechanical circulatory support. Circ
Heart Fail. 2014;7:68-75.
119. Kheterpal S, Tremper KK, Englesbe MJ, OReilly M, Shanks
AM, Fetterman DM, et al. Predictors of postoperative acute
renal failure after noncardiac surgery in patients with previ-
ously normal renal function. Anesthesiology. 2007;107:
892-902.
120. Thakar CV, Kharat V, Blanck S, Leonard AC. Acute kidney
injury after gastric bypass surgery. Clin J Am Soc Nephrol.
2007;2:426-30.
121. Ojo AO, Held PJ, Port FK, Wolfe RA, Leichtman AB, Young
EW, et al. Chronic renal failure after transplantation of a
nonrenal organ. N Engl J Med. 2003;349:931-40.
122. Karapanagiotou A, Kydona C, Dimitriadis C, Sgourou K,
Giasnetsova T, Fouzas I, et al. Acute kidney injury after
orthotopic liver transplantation. Transplant Proc. 2012;44:
2727-9.
123. Kheterpal S, Tremper KK, Heung M, Rosenberg AL, Eng-
lesbe M, Shanks AM, et al. Development and validation of an
acute kidney injury risk index for patients undergoing general
surgery: results from a national data set. Anesthesiology.
2009;110:505-15.
124. Thakar CV, Worley S, Arrigain S, Yared JP, Paganini EP.
Improved survival in acute kidney injury after cardiac surgery.
Am J Kidney Dis. 2007;50:703-11.
125. Thakar CV, Parikh PJ, Liu Y. Acute kidney injury (AKI) and
risk of readmissions in patients with heart failure. Am J
Cardiol. 2012;109:1482-6.
126. Coca SG, Garg AX, Thiessen-Philbrook H, Koyner JL, Patel
UD, Krumholz HM, et al. Urinary biomarkers of AKI and
mortality 3 years after cardiac surgery. J Am Soc Nephrol.
2014;25:1063-71.
127. Ishani A, Nelson D, Clothier B, Schult T, Nugent S, Greer N,
et al. The magnitude of acute serum creatinine increase after
cardiac surgery and the risk of chronic kidney disease,
M. Heung and J.L. Koyner
progression of kidney disease, and death. Arch Intern Med.
2011;171:226-33.
128. Brown JR, Parikh CR, Ross CS, Kramer RS, Magnus PC,
Chaisson K, et al. Impact of perioperative acute kidney injury
as a severity index for thirty-day readmission after cardiac
surgery. Ann Thorac Surg. 2014;97:111-7.
129. Coca SG, Yusuf B, Shlipak MG, Garg AX, Parikh CR. Long-
term risk of mortality and other adverse outcomes after acute
kidney injury: a systematic review and meta-analysis. Am
J Kidney Dis. 2009;53:961-73.
130. Hassinger AB, Wald EL, Goodman DM. Early postoperative
uid overload precedes acute kidney injury and is associated
with higher morbidity in pediatric cardiac surgery patients.
Pediatr Crit Care Med. 2014;15:131-8.
131. Campbell GA, Hu D, Okusa MD. Acute kidney injury in the
cancer patient. Adv Chronic Kidney Dis. 2014;21:64-71.
132. Lam AQ, Humphreys BD. Onco-nephrology: AKI in the
cancer patient. Clin J Am Soc Nephrol. 2012;7:1692-700.
133. Benoit DD, Hoste EA. Acute kidney injury in critically ill
patients with cancer. Crit Care Clin. 2010;26:151-79.
134. Christiansen CF, Johansen MB, Langeberg WJ, Fryzek JP,
Sorensen HT. Incidence of acute kidney injury in cancer
patients: a Danish population-based cohort study. Eur J Intern
Med. 2011;22:399-406.
135. Canet E, Zafrani L, Lambert J, Thieblemont C, Galicier L,
Schnell D, et al. Acute kidney injury in patients with newly
diagnosed high-grade hematological malignancies: impact on
remission and survival. PLoS One. 2013;8:e55870.
136. Parikh CR, Schrier RW, Storer B, Diaconescu R, Sorror ML,
Maris MB, et al. Comparison of ARF after myeloablative and
nonmyeloablative hematopoietic cell transplantation. Am J
Kidney Dis. 2005;45:502-9.
137. Darmon M, Ciroldi M, Thiery G, Schlemmer B, Azoulay E.
Clinical review: specic aspects of acute renal failure in
cancer patients. Crit Care. 2006;10:211.
138. Benoit DD, Hoste EA, Depuydt PO, Offner FC, Lameire NH,
Vandewoude KH, et al. Outcome in critically ill medical
patients treated with renal replacement therapy for acute renal
failure: comparison between patients with and those without
haematological malignancies. Nephrol Dial Transplant.
2005;20:552-8.
139. Bagshaw SM, Laupland KB, Doig CJ, Mortis G, Fick GH,
Mucenski M, et al. Prognosis for long-term survival and renal
recovery in critically ill patients with severe acute renal
failure: a population-based study. Crit Care. 2005;9:R700-9.
140. Lameire N, Van Biesen W, Vanholder R. Acute renal
problems in the critically ill cancer patient. Curr Opin Crit
Care. 2008;14:635-46.
141. Leung N, Nasr SH. Myeloma-related kidney disease. Adv
Chronic Kidney Dis. 2014;21:36-47.
142. Wilson FP, Berns JS. Tumor lysis syndrome: new challenges
and recent advances. Adv Chronic Kidney Dis. 2014;21:18-26.
143. Sawinski D. The kidney effects of hematopoietic stem cell
transplantation. Adv Chronic Kidney Dis. 2014;21:96-105.
144. Heiken JP. Contrast safety in the cancer patient: preven-
ting contrast-induced nephropathy. Cancer Imaging. 2008;
8:S124-7.
145. Zager RA, OQuigley J, Zager BK, Alpers CE, Shulman HM,
Gamelin LM, et al. Acute renal failure following bone marrow
transplantation: a retrospective study of 272 patients. Am J
Kidney Dis. 1989;13:210-6.
146. Michael M, Kuehnle I, Goldstein SL. Fluid overload and acute
renal failure in pediatric stem cell transplant patients. Pediatr
Nephrol. 2004;19:91-5.
147. Cairo MS, Bishop M. Tumour lysis syndrome: new therapeu-
tic strategies and classication. Br J Haematol. 2004;127:3-11.
Sepsis, CKD, and comorbidities in AKI
148. Montesinos P, Lorenzo I, Martin G, Sanz J, Perez-Sirvent ML,
Martinez D, et al. Tumor lysis syndrome in patients with acute
myeloid leukemia: identication of risk factors and develop-
ment of a predictive model. Haematologica. 2008;93:67-74.
149. Dimopoulos MA, Terpos E, Chanan-Khan A, Leung N,
Ludwig H, Jagannath S, et al. Renal impairment in patients
with multiple myeloma: a consensus statement on behalf of
the International Myeloma Working Group. J Clin Oncol.
2010;28:4976-84.
150. Knudsen LM, Hjorth M, Hippe E. Renal failure in multiple
myeloma: reversibility and impact on the prognosis. Nordic
Myeloma Study Group. Eur J Haematol. 2000;65:175-81.
151. Blade J, Fernandez-Llama P, Bosch F, Montoliu J, Lens XM,
Montoto S, et al. Renal failure in multiple myeloma: present-
ing features and predictors of outcome in 94 patients from a
single institution. Arch Intern Med. 1998;158:1889-93.
152. Hutchison CA, Cockwell P, Stringer S, Bradwell A, Cook M,
Gertz MA, et al. Early reduction of serum-free light chains
associates with renal recovery in myeloma kidney. J Am Soc
Nephrol. 2011;22:1129-36.
153. Charbonney E, Saudan P, Triverio PA, Quinn K, Mentha G,
Martin PY. Prognosis of acute kidney injury requiring renal
37
replacement therapy in solid organ transplanted patients.
Transpl Int. 2009;22:1058-63.
154. Wyatt CM, Arons RR. The burden of acute renal failure in
nonrenal solid organ transplantation. Transplantation. 2004;78:
1351-5.
155. Lopes JA, Melo MJ, Raimundo M, Fragoso A, Antunes F.
Long-term risk of mortality for acute kidney injury in HIV-
infected patients: a cohort analysis. BMC Nephrol. 2013;14:32.
156. Li Y, Shlipak MG, Grunfeld C, Choi AI. Incidence and risk
factors for acute kidney injury in HIV Infection. Am J
Nephrol. 2012;35:327-34.
157. Cohen SD, Chawla LS, Kimmel PL. Acute kidney injury in
patients with human immunodeciency virus infection. Curr
Opin Crit Care. 2008;14:647-53.
158. Hartle PM, Carlo ME, Dwyer JP, Fogo AB. AKI in an HIV
patient. J Am Soc Nephrol. 2013;24:1204-8.
159. Wyatt CM. The kidney in HIV infection: beyond
HIV-associated nephropathy. Top Antivir Med. 2012;20:
106-10.
160. Palomba H, de Castro I, Neto AL, Lage S, Yu L. Acute kidney
injury prediction following elective cardiac surgery: AKICS
score. Kidney Int. 2007;72:624-31.