Assessment and Diagnosis of Renal

Dysfunction in the ICU

Jay L. Koyner

Chest 2012;141;1584-1594
DOI 10.1378/chest.11-1513
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 CHEST Recent Advances in Chest Medicine

Assessment and Diagnosis of Renal

Dysfunction in the ICU
Jay L. Koyner, MD

Identifying patients with impaired renal function is crucial in the setting of critical illness.
Serum creatinine serves as the gold standard for assessing steady-state renal function,
helping to define those with chronic kidney disease (CKD). Although these baseline creati-
nine values are often not available in the setting of critical illness, CKD, whether defined
by serum creatinine or proteinuria, increases the risk of developing acute kidney injury
(AKI). Despite delays in elevations following renal insults, serum creatinine remains the
standard for assessing acute changes in renal function. Standardized definitions of AKI,
using changes in serum creatinine and urine output, have informed the epidemiology of
ICU-acquired AKI and have helped define the long-term outcomes in patients who experience
AKI. A complex cyclical interplay exists between AKI and CKD, in which CKD predisposes
patients to an increased risk of AKI, whereas those with AKI, regardless of baseline renal
function, are more likely to suffer from post-AKI CKD. The clarification of the AKI-CKD
dynamic remains a work in progress and will be aided by the implementation of novel mea-
sures of renal function. Several novel biomarkers of renal function have been proposed to
augment serum creatinine in the diagnosis of AKI and CKD. These biomarkers, taken with
recent clinical investigations, have laid the groundwork for the impending paradigm shift in
risk stratifying and in diagnosing changes in renal function in the ICU.
CHEST 2012; 141(6):1584–1594

Abbreviations: AKI 5 acute kidney injury; AKIN 5 Acute Kidney Injury Network; ATN 5 acute tubular necrosis;
CKD 5 chronic kidney disease; CVD 5 cardiovascular disease; eGFR 5 estimated glomerular filtration rate; ESRD 5 end-
stage renal disease; GFR 5 glomerular filtration rate; MDRD 5 Modification of Diet in Renal Disease; NGAL 5 neutrophil
gelatinase-associated lipocalin; RIFLE 5 risk, injury, failure, loss, and end-stage renal disease; RRT 5 renal replacement
therapy; SCyC 5 serum cystatin C

Physicians and scientists have been measuring cre-

atinine concentrations in the blood for well over a
filtration and, thus, a proxy for renal function. How-
ever, physicians are no longer solely reliant on imper-
century, and this simple and aged clinical test remains fect creatinine as their only method of assessing renal
firmly entrenched in modern-day patient care.1 Cre- function, because other markers of renal function
atinine has long served as a biomarker of glomerular have been developed and validated. In this review,
I outline the current methods for assessing renal func-
Manuscript received June 16, 2011; revision accepted December 14, tion, in both steady state and during acute kidney
2011.
Affiliations: From the Section of Nephrology, Department of injury (AKI), and discuss their usefulness in caring
Internal Medicine, University of Chicago, Chicago, IL. for the critically ill.
Funding/Support: Dr Koyner is supported by the National
Institutes of Health-National Institute of Diabetes and Diges-
tive and Kidney Diseases [Grant K23 DK081616].
Correspondence to: Jay L. Koyner, MD, Section of Nephrology, Steady State: Defining Chronic
University of Chicago, 5841 S Maryland Ave, Ste S-506, MC 5100, Kidney Disease
Chicago, IL 60637; e-mail: [email protected]
© 2012 American College of Chest Physicians. Reproduction Estimating the glomerular filtration rate (GFR) via
of this article is prohibited without written permission from the
American College of Chest Physicians. See online for more details. serum creatinine allows us to assess the degree of kid-
DOI: 10.1378/chest.11-1513 ney impairment and track the course of chronic kidney

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disease (CKD). CKD has been defined by the National Proteinuria
Kidney Foundation Kidney Disease Outcomes Quality
Abnormal protein excretion is often present in the
Initiative (NKF-K/DOQI) work group as either2
setting of CKD, with urine protein being measured
(1) the presence of markers of kidney damage semiquantitatively with a dipstick or quantitatively
for ⱖ 3 months, as defined by structural or through urine protein to creatinine ratios. Dipsticks
functional abnormalities of the kidney with or are flawed in that they detect protein concentration
without decreased GFR, manifest by either as a function of urine volume. Urine protein (or urine
pathologic abnormalities or other markers of albumin) to creatinine ratios are the preferred method
kidney damage, including abnormalities in the of quantification but are predicated on the assump-
composition of blood or urine or abnormalities tion that an individual excretes 1 g of creatinine
in imaging tests or per day and that creatinine excretion is in steady state.
For adults , 50 years of age, creatinine excretion
(2) GFR , 60 mL/min/1.73 m2 for ⱖ 3 months, should be 20 to 25 mg/kg of lean body weight for
with or without other signs of kidney damage men and 15 to 20 mg/kg for women, with estimates
as described previously. decreasing with age.8 Persistent albumin excretion
between 30 and 300 mg/dL is considered to be micro-
The classification of CKD is described in Table 1. albuminuria (1-21 on dipstick). Values . 300 mg/dL
Despite providing no information on the source are considered to be macroalbuminuria (3-41 on
of the kidney disease, estimates of GFR remain dipstick). There are limited standards for 24-h protein
ubiquitous, with creatinine-based equations being excretion, but values , 150 mg/d are considered nor-
the preferred method. The Cockcroft and Gault and mal, whereas values between 150 and 3,500 mg are
the Modification of Diet in Renal Disease (MDRD) labeled “subnephrotic,” and values . 3,500 mg are
equations are flawed in that they do not accurately considered to be in the nephrotic range. Individuals
estimate renal function in those with normal GFRs, with subnephrotic- and nephrotic-range proteinuria
the obese, or older adults (. 70 years).3,4 In 2009, the will invariably have underlying renal disease, which
Chronic Kidney Disease Epidemiology Collaboration places them at increased risk of AKI (as discussed
(CKD-EPI) equation was developed and is as accu- following). Because 24-h collections are cumbersome
rate as the MDRD in those with preexisting CKD and difficult to carry out in hospitalized patients, 8- or
(estimated GFR [eGFR] , 60 mL/min) and more 12-h collections with extrapolation and random (spot)
accurate in those without CKD (ⱖ 60 mL/min).5 Com- ratios have become an accepted alternative.
pared with other equations, the CKD-EPI equation
results in a lower prevalence estimate of CKD and a Novel Biomarkers of GFR/CKD
more accurate risk prediction for adverse patient out-
comes.6 As such, we anticipate increased reporting of Increasingly, investigators have sought novel markers
the CKD-EPI eGFR in the near future. Finally, the of renal function that will provide an accurate estima-
US Food and Drug Administration recommends the tion of renal function without the foibles of serum
use of the Cockcroft and Gault equation when look- creatinine (variation with muscle mass/age and tubu-
ing to estimate GFR for drug dosing; however, recent lar secretion). Serum cystatin C (SCyC) may be more
studies have demonstrated excellent concordance sensitive than serum creatinine in detecting mild
rates with the MDRD equation.7 reductions in GFR.9 Additionally, SCyC is associated
with cardiovascular disease (CVD) outcomes and patient
mortality.10-12 After a mean of 10 years of follow-up, in
Table 1— National Kidney Foundation Kidney Disease nondiabetic subjects (eGFR, 15-60 mL/min), base-
Outcomes Quality Initiative Definitions of CKD
line SCyC was strongly associated with both all-cause
CKD Stage Definition and CVD mortality. In multivariate-adjusted models,
both creatinine and SCyC were associated with
1 Normal GFR (. 90 mL/min/1.73 m2) with
persistent kidney damage (eg, albuminuria) increased risks of all-cause mortality (1.27 [95% CI,
2 GFR between 60 and 89 mL/min/1.73 m2 with 1.06-1.49] and 1.41 [95% CI, 1.18 -1.67]), respectively.
persistent kidney damage (eg, albuminuria) For CVD mortality, the risks were 1.32 (95% CI,
3 GFR between 30 and 59 mL/min/1.73 m2 1.05-1.64) and 1.64 (95% CI, 1.28-2.08), respectively.12
4 GFR between 15 and 29 mL/min/1.73 m2
Despite this, the mainstream use of SCyC has been
5 GFR , 15 mL/min/1.73 m2 or end-stage
renal disease hindered by data demonstrating that SCyC is affected
by non-GFR factors, including diabetes, thyroid dys-
The table displays the consensus classification of CKD, in which
CKD is defined by either a decrease in GFR or the presence of function, corticosteroids, sex, and age.13,14 Addition-
kidney damage typically quantified as abnormal protein excretion. ally, the acceptance of SCyC has been limited by the
CKD 5 chronic kidney disease; GFR 5 glomerular filtration rate. lack of standardized reference material and by the

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assay drift that impacts interlaboratory extrapolation.15 oping AKI displayed a stepwise increase according
As such, no single eGFR-SCyC equation has been to the albumin to creatinine ratio. Individuals with
uniformly validated or accepted. microalbuminuria (30-299 mg/g) and macroalbumin-
Several other biomarkers of CKD are under inves- uria (. 300 mg/g) were 2.2 times (95% CI, 1.6-3.0)
tigation, including urinary neutrophil gelatinase- and 4.8 times (95% CI, 3.2.-7.2) as likely to be hos-
associated lipocalin (NGAL), cystatin C, and pitalized for AKI compared with those with a normal
N-acetyl-b-D-glucosaminidase. Many of these candi- albumin to creatinine ratio (, 10 mg/g).30 Similarly,
dates function as biomarkers of tubular function and in a cohort of 920,985 Canadian adults who had at
are being studied as biomarkers of AKI (see “Novel least one measurement of serum creatinine and pro-
Biomarkers of AKI” section).16-18 Promising prelimi- teinuria over a 5-year period, there was a stepwise
nary data display the importance of quantifying renal increase in the risk of AKI and need for RRT across
tubular function and reinforce the notion that renal proteinuria strata.31 Over the median 35-month
function is more than just glomerular filtration. follow-up, . 6,500 adults were admitted with AKI and
516 (, 0.01%) required RRT. Subjects with normal
CKD as a Risk Factor for AKI eGFR (. 60 m/min) and mild proteinuria (dipstick,
trace and 11) were hospitalized with AKI 2.5 times
The importance of estimating renal function goes more often than were individuals without protein-
beyond a more precise assessment of GFR. CKD has uria. These odds increased to 4.4 times (95% CI,
been increasingly validated as an important risk factor 3.7-5.2) in those with similar GFR and ⱖ 21 protein-
for the development of AKI. In the past, absolute uria. The adjusted rates of death were higher in
elevations in baseline serum creatinine have been participants admitted with AKI, although the rise asso-
included in AKI-specific risk stratification systems; ciated with this injury was attenuated in those with
however, recent systems have used standard CKD low baseline eGFR and heavy proteinuria. Despite
definitions.19-23 relying on laboratory tests that were drawn up as part
In a nested case-controlled study of . 600,000 hos- of clinical care and administrative codes, these studies
pitalized adults, those who developed AKI (n 5 1,764), still demonstrate that proteinuria is an emerging risk
defined as the need for renal replacement therapy factor for AKI.
(RRT), were more likely to have baseline CKD, com-
pared with those without AKI.24 There was a dose Other Risk Factors for AKI
response, with increasing risk of AKI with decreasing
eGFR (MDRD), which persisted after controlling The 2010 United States Renal Data System dem-
for clinical risk (diabetes, sepsis, cardiac surgery, onstrated that over the past decade, the incidence
and so forth). Individuals with a baseline GFR of of AKI has been increasing and that AKI is associ-
30 to 45 mL/min were nearly five times as likely to ated with older age and black race.32 Several scoring
develop AKI compared with those without CKD systems have been constructed to reliably forecast AKI
(GFR . 60 mL/min), whereas those with a baseline and the need for RRT following cardiac surgery.20-22
of 15 to 29 mL/min were 20 times as likely to be hos- Although there are several similarities among these
pitalized with AKI. This International Classification risk-assessment models (baseline renal function, pres-
of Diseases, Ninth Revision code-reliant retrospective ence of diabetes, and type of surgery), there are also
study has been corroborated by other investigations25,26 differences. Similarly, in the setting of radiocontrast
and supports the role of baseline GFR as a major risk administration, several risk factors have been shown to
factor for AKI. increase the risk of AKI, including preexisting CKD,
Proteinuria is also recognized increasingly as an diabetes, congestive heart failure, anemia, hypoten-
important risk factor for the development of AKI.27-29 sion, and contrast-load volume.33 In the setting of the
In a study of 1,051 subjects undergoing cardiac sur- critically ill, AKI-specific risk-stratification systems
gery, heavy proteinuria (21 to 41) was associated have been proposed but they remain underused in
with a sevenfold-increased risk of postoperative RRT clinical practice.19,23 Finally, it deserves noting that
compared with those without proteinuria (OR, 7.29; the avoidance of nephrotoxins (radiocontrast, amino-
95% CI, 3.0-17.7).27 This study did not attempt to glycosides, nonsteroidal antiinflammatory drugs, and
quantify the proteinuria beyond the dipstick but so forth) is of the utmost importance in vulnerable
demonstrates the importance of AKI risk stratifica- patient populations.
tion via proteinuria.
In 11,200 subjects from the Atherosclerosis Risk AKI as a Risk Factor for CKD
in Communities (ARIC) study, proteinuria correlated
with an increased future risk of AKI. Excluding patients CKD is a risk factor for AKI; however, there is a
with an eGFR , 15 mL/min, the hazard of devel- growing body of evidence to support the bidirectionality

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of this dynamic. Studies of the long-term outcomes subjects without preexisting CKD who were hospital-
of AKI suggest that episodes of AKI, regardless of ized with AKI (n 5 5,058) and its most severe form,
severity, are associated with adverse CKD-related acute tubular necrosis (ATN) (n 5 346), were compared
outcomes. with 63,491 subjects who were hospitalized with
In a large, community-based, retrospective, matched- pneumonia and acute myocardial infarction without
cohort analysis (N 5 556,090), the impact of AKI AKI. Subjects with AKI and ATN were more likely
requiring RRT was assessed in those with baseline to develop CKD of any stage compared with control
eGFRs . 45 mL/min who did not initially develop subjects, and their progression to stage IV CKD was
end-stage renal disease (ESRD). After controlling for similar to that of individuals from a separate cohort
potential confounders, AKI was independently asso- with known preexisting CKD.37 These studies cement
ciated with a 28.1-fold increased risk of developing the role of AKI as a risk factor for the development of
stage IV or V CKD (95% CI, 21.1-37.6) and a 2.3-fold CKD.
increased risk of death (95% CI, 1.8-30).34 This recent literature supports the bidirectional
In a population-based cohort study investigating relationship of the AKI and CKD, but it also demon-
the long-tem risk of an episode of AKI requiring strates that the development of post-AKI CKD is
RRT, 3,769 individuals who were RRT independent perhaps malleable. Not all subjects with AKI go on
at the time of discharge, following a hospitalization to develop CKD, just as not all hospitalized CKD
that required transient RRT, were compared with patients develop AKI. Although large numbers of
13,598 matched control subjects who did not have patients with AKI do not return to normal renal func-
AKI.35 Over a median follow-up period of 3 years, the tion, our ability to forecast who will recover and who
incidence of ESRD was 2.63 per 100 person-years in will develop CKD and progress to ESRD is limited.38-43
patients with AKI and 0.91 per 100 person-years in
control subjects (hazard ratio, 3.23; 95% CI, 2.70-3.86). AKI: Diagnostic Criteria
Surprisingly, there was no difference in mortality,
which may have been because of the inability to match For decades, clinical investigation into AKI was
a cohort of the 297 sickest patients with AKI, the hampered by the lack of a consensus definition of AKI,
exclusion of those still dependent on RRT at the time with studies using nonstandardized medical coding
of hospital discharge, and the exclusion of those who or arbitrary serum creatinine cutoffs.44 Consensus crite-
died within the first 30 postdischarge days. Regard- ria for AKI have been established through the collab-
less, a hospital-limited episode of AKI requiring RRT oration of intensivists and nephrologists, and these
increases the long-term risk of ESRD. projects have led to the concomitant shift in nomen-
Increasingly, investigators have sought long-term clature from acute renal failure to AKI. The Acute
outcomes of AKI that have not required RRT. Using Dialysis Quality Initiative (ADQI) created a graded
a multivariable model in a cohort of 233,803 Medicare definition of AKI called the RIFLE criteria, where
recipients (7,197 who had AKI), ESRD was found to RIFLE stands for risk, injury, failure, loss, and end-
be associated with the presence of both CKD and stage renal disease (Table 2).45
AKI. The hazard ratio for developing ESRD was 41.2 Recognizing the potential limitations of RIFLE,
(95% CI, 34.6-49.1) for patients who had both CKD and the Acute Kidney Injury Network (AKIN) pub-
AKI compared with those without kidney disease. Sim- lished their own criteria (Table 3).46 Included in these
ilarly, those with AKI (HR, 13.0; 95% CI, 10.6-16.0) RIFLE criticisms were the use of eGFR (eg, an indi-
and those with CKD (HR, 8.4; 95% CI, 7.4-9.6) were vidual with severe nonoliguric AKI may have a GFR
at increased risk of developing ESRD compared with of , 15 mL/min upon arrival to the ICU but it may
those without kidney disease.36 In an analysis of 5 years take days for him/her to progress through the criteria
of data from the US Department of Veterans Affairs, before getting to “failure”). This critique displays the

Table 2—RIFLE Criteria for AKI

Category GFR Criteria Urine Output Criteria

Risk 1.5-fold increase in serum creatinine or . 25% decrease in GFR , 0.5 mL/kg/h for 6 h
Injury 2-fold increase in serum creatinine or . 50% decrease in GFR , 0.5 mL/kg/h for 12 h
Failure 3-fold increase in serum creatinine or . 75% decrease in GFR or serum , 0.3 mL/kg/h for 24 h or anuria for 12 h
creatinine . 4.0 mg/dL in the setting of an absolute increase of 0.5 mg/dL
Loss Persistent AKI (on RRT . 4 w)
ESRD ESRD (on RRT . 3 mo)
This was the first consensus classification schema and accounted for changes in both creatinine and GFR, as well as changes in urine output.
AKI 5 acute kidney injury; ESRD 5 end-stage renal disease; RIFLE 5 risk, injury, failure, loss, and end-stage renal disease; RRT 5 renal
replacement therapy. See Table 1 for expansion of other abbreviations.

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 Table 3—AKIN Criteria for AKI

Stage Serum Creatinine Criteria Urine Output Criteria

1 Increase in serum creatinine ⱖ 0.3 mg/dL or . 1.5- to 2-fold increase from , 0.5 mL/kg/h for . 6 h
baseline serum creatinine
2 . 2- to 3-fold increase from baseline serum creatinine , 0.5 mL/kg/h for . 12 h
3 . 3-fold increase from baseline serum creatinine or an absolute , 0.3 mL/kg for 24 h or anuria for 12 h
increase of ⱖ 0.5 mg/dL in serum creatinine or the need for RRT
This classification schema, which followed the RIFLE system, is to be applied over a discrete 48-h period and accounts for an absolute change in
serum creatinine rather than relying solely on percentage change. The AKIN criteria also permit the evaluation of urine output but do not include
GFR in their definitions. AKIN 5 Acute Kidney Injury Network. See Table 1 and 2 legends for expansion of other abbreviations.

pitfalls of diagnosing AKI via serum creatinine. The In two recent large randomized trials of RRT dose
latter two stages of AKIN are similar to RIFLE, whereas (ATN trial [N 5 1,124] and RENAL study [N 5 1,465]),
AKIN stage 1 accounts for the absolute change in the in-hospital mortality rates were 49.6% and 44.3%,
serum creatinine. This departure from RIFLE is based respectively.38,41 These data are limited in that RRT is
on the evidence that small changes in serum creatinine often reserved for the most severely ill patients and
over discrete time periods (, 48 h) are associated that the initiation RRT, which automatically constitutes
with adverse patient outcomes in a variety of settings AKIN stage 3, is highly variable across physicians.
of critical illness.39,47,48 In the setting of CKD, the traditional teaching had
Both of these AKI classification schemas have been always been to initiate RRT when the GFR reached
shown to be associated with length of ICU and hos- 10-15 mL/min because this is when patients began to
pital stay, as well as mortality.49-51 However, the use of experience complications related to abnormal elec-
AKIN and RIFLE as diagnostic tools remain limited trolytes, acidosis, uremia, and fluid overload (CKD
given their reliance on serum creatinine and the stage V, Table 1). However, a recent randomized
absence of effective therapeutic interventions for the controlled trial demonstrated that the proactive initia-
treatment of AKI. Creatinine kinetics are such that tion of RRT at higher eGFRs (10-14 mL/min) pro-
serum creatinine often does not increase until 24 or vided no benefit in terms of long-term mortality or other
48 h after a renal injury; thus, by the time a patient adverse patient outcomes compared with waiting for
reaches AKIN stage 1 or RIFLE “risk,” the “window” a definitive indication at lower GFRs, (5-7 mL/min).54
for a potential therapeutic intervention may be closed
(Fig 1). Future iterations of AKI diagnostic schema
will include biomarkers of renal tubular injury/AKI
(discussed later), which increase within minutes to
hours of renal injury, thus obviating the need to rely
on creatinine, an imperfect, time-delayed marker of
filtration.
Regardless of these limitations, the current diagnos-
tic criteria have informed and advanced the epide-
miology of AKI and permit consistent AKI definitions
in clinical investigations. Studies that have specifically
compared RIFLE and AKIN have demonstrated that
neither criteria offer a clear advantage and both remain
hindered by the need to establish a “baseline,” which
is often impossible in the ICU.52
These criteria have furthered our understanding of
the link between AKI and mortality.39 In 71,486 vet-
erans with AKI (22% of a large ICU cohort), after
Figure 1. AKI timing and changes in creatinine/glomerular filtra-
adjusting for severity of illness, the odds of death tion. The figure demonstrates the timing among severe renal
were 2.2 (95% CI, 2.17-2.3) for AKIN stage 1, 6.1 injury, the drop in glomerular filtration rate, and the time-delayed
(95% CI, 5.74-6.44) for stage 2, and 8.6 (95% CI, rise in serum creatinine and other traditional markers of renal
function. Several novel biomarker are able to forecast AKI
8.07-9.15) for stage 3.53 The recent focus on small prior to changes in traditional markers (creatinine and urine out-
changes in serum creatinine (AKIN stage 1 or RIFLE put). This early diagnosis could potentially provide a window to
“risk”) impacting adverse patient outcomes should treat/intervene with RRT or other novel therapeutics and possibly
improve outcomes in the setting of AKI. AKI 5 acute kidney
not take away from the extremely high mortality rate injury; eGFR 5 estimated glomerular filtration rate; RRT 5 renal
in patients with AKI requiring RRT.48 replacement therapy.

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 In the setting of AKI, the established “indications” porary drops in urine output, which may be overcome
for RRT (Table 4) are severely limited and are reac- with fluid administration or diuretics, may not corre-
tive in nature. These criteria aim only to prevent late with eventual rises in serum creatinine.
the complications of acute renal dysfunction just Although further investigation of the urine output
prior to the point where they become life threatening. criteria seems needed, the AKIN and RIFLE criteria
Although some of the indications are objective and have reshaped how clinicians and investigators have
readily apparent (ie, hyperkalemia with ECG changes defined and studied AKI. Despite international accep-
or pulmonary edema requiring maximum ventilatory tance, these schemas remain, on some level, imper-
support), others are subjective and nonspecific (the fect, given their reliance on serum creatinine and the
clinical diagnosis of uremia). Levels of certain serum need for an established baseline value. These schemas
chemistries (eg, potassium, phosphorus, bicarbonate) will continue to be validated and may some day evolve
are affected by issues not directly related to the severity to include biomarkers of AKI besides serum creati-
of AKI, including dietary intake, choice of fluid admin- nine and urine output.
istration, and medication use; thus, the use of elec-
trolyte concentrations as thresholds for initiation of
RRT is not always appropriate. Diagnostics of AKI: Traditional
Trials investigating the timing of RRT initiation have and Novel Methods
failed to provide definitive clinical answers. Data sup- Urine Microscopy
porting the early initiation of RRT come from retro-
The development of RIFLE and AKIN has led to
spective, observational studies examining the use of
a more rigorous examination of the diagnostic capa-
RRT in a variety of clinical settings (sepsis, cardiac
bilities of urine microscopy, with several recent arti-
surgery, and liver failure).55-58 However, the retro-
cles investigating the ability of microscopy to reliably
spective nature of these studies, the variable criteria
detect the presence and severity of AKI.60-63 Uri-
used to define “early” vs “late,” and the diversity of
nary sediment analysis can detect glomerulonephritis
patient populations make it impossible to craft strong,
(erythrocyte casts), pyelonephritis and acute intersti-
evidence-based recommendations for the early initia-
tial nephritis (leukocyte casts), and crystal- and renal-
tion of RRT. Although the early initiation of RRT
stone-induced disease. Additionally, urinalysis can
may be associated with improved survival and out-
demonstrate the pathognomonic muddy brown casts
come, an adequately powered randomized controlled
and renal tubule epithelial cells in the sediment asso-
trial to address this question is needed.
ciated with the most severe form of AKI, ATN. In the
Urine output can be measured inexpensively and
critically ill, the most common use of microscopy is
easily, and is an important and equally weighted por-
to differentiate the featureless sediment of prerenal
tion of AKIN and RIFLE. However, it is also
azotemia from that of ATN. Recently, two distinct
impacted by a variety of clinical factors, including a
scoring systems that rely on counting renal tubule
patient’s intravascular volume status and diuretics.
epithelial cells and granular casts for the diagnosis of
The accuracy of the urine output criteria has not been
ATN have been validated in a formal and rigorous
as widely studied as that of creatinine. In studies that
evaluation which was long overdue.60,63 Despite strides
included both creatinine- and urine-output-based
to formalize and modernize urinalysis, investigations
definitions, AKI rates were higher with lower overall
of the interobserver reliability of microscopy demon-
mortality compared with creatinine-based AKI.49,59
strate that nephrologists achieve only slight to mod-
This finding suggests that urine output may overesti-
erate agreement and, as such, urine microscopy
mate the severity of AKI, compared with creatinine
remains a good but imperfect diagnostic tool for AKI.61
alone. Relative oliguria is often an appropriate clin-
ical response in the setting of hypovolemia, and tem-
Novel Biomarkers of AKI
The past several years have seen a flurry, nay bliz-
Table 4—Five Most Commonly Cited Indications
for Acute Initiation of RRT
zard, of investigations of novel biomarkers of AKI
and several in-depth reviews have been published
Severe acidemia (pH , 7.1) secondary to metabolic acidosis recently.64,65 Table 5, which is by no means exhaus-
refractory to medical care tive, represents a selected summary of the character-
Severe hyperkalemia (K . 6.5 mM) or rapidly rising K refractory
istics and the clinical settings in which the top four
to medical care
Ingestion of dialyzable toxins most widely investigated biomarkers have been stud-
Volume overload impairing cardiopulmonary function refractory ied: NGAL, kidney injury molecule-1, IL-18, and
to medical care cystatin C. The majority of articles cited in Table 5 are
Uremic complications of renal dysfunction limited in that they are predominantly single-center
See Table 2 legend for expansion of abbreviations. prospective investigations with low numbers of severe

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 Table 5—Novel Biomarkers of AKI: Clinical Settings of Investigation

Clinical Settings in Which Clinical Settings in Which

Biomarker Biologic Function and Link to AKI Source Biomarkers Detected AKI Biomarkers Detected CKD
NGAL Protein expressed in neutrophils and Blood Adult cardiac surgery66,67 Adult CKD17,68
proximal, distal renal tubule cells; Pediatric cardiac surgery69 Pediatric CKD70
binds and traffics free iron and is Contrast nephropathy71
upregulated in the setting of renal General ICU72
tubular ischemia Urine Adult cardiac surgery67,73-75 Adult CKD17
Pediatric cardiac surgery69
Liver transplant76
General ICU77
ED78
Pediatric ICU79
Contrast nephropathy71
Distinguishes prerenal from ATN80
Delayed graft function following
renal transplant81,82
IL-18 Inflammatory cytokine found in Urine Adult cardiac surgery75,83,84
macrophages and proximal tubule General ICU85
cells that is upregulated in the Sepsis-AKI86
setting of renal ischemic injury ARDS87
Contrast nephropathy88
Delayed graft function following
renal transplant81,82
Cystatin C Cysteine protease inhibitor freely Blood Adult cardiac surgery66,67,89 Adult CKD10-12
filtered at glomerulus (serum marker Pediatric cardiac surgery90 Pediatric CKD70
of GFR) that is normally reabsorbed General ICU91
by proximal tubule cells and appears ED92
in the urine in the setting of Contrast nephropathy93
tubular injury Urine Adult cardiac surgery73,75 Adult CKD18
General ICU85
Sepsis-AKI86,94
ED92
Delayed graft function following
renal transplant95
KIM-1 Type 1 cell membrane glycoprotein Urine Adult cardiac surgery73,75 Adult CKD96
that is shed into the urine following Pediatric cardiac surgery97
proximal tubule injury General ICU85
Contrast nephropathy88
Delayed graft function following
renal transplant81
Summary of data on the four most frequently investigated biomarkers of AKI. The table, which is not exhaustive, notes the biologic function of the
biomarkers as well as the variety of clinical settings (AKI and CKD) in which the biomarkers have been investigated. ATN 5 acute tubular necrosis;
KIM-1 5 kidney injury molecule-1; NGAL 5 neutrophil gelatinase-associated lipocalin. See Table 1 and 2 legends for expansion of other abbreviations.

AKI/RRT events. Additionally, there is an inherent that designated subjects as NGAL(1) or NGAL(2)
bias in this table because negative studies often go and creatinine(1) or creatinine(2) (AKI was defined
unpublished. Finally, Table 5 makes no attempt to as RIFLE “risk”), individuals who were NGAL(1)
quantify the results of these investigations. but creatinine(2) needed more RRT (OR, 16.4;
It is our opinion that no single biomarker will be 95% CI, 3.6-76.9; P , .001) compared with those
able to predict early AKI (prior to changes in serum who were NGAL(2) and creatinine(2).98 There was
creatinine) as well as AKI severity and duration in all a stepwise increase in ICU stay, hospital stay, and
clinical settings. The pathophysiology of ischemia- mortality across the four study groups:
reperfusion-AKI is different from that of sepsis-AKI,
which is different from radiocontrast nephropathy. NGAL(2)creat (2) , NGAL(1)creat(2) , NGAL
As such, each of these clinical entities may be best (2)creat (1) , NGAL(1)creat(1)
detected by a different set of biomarkers at different
clinical time points. This ability to detect adverse patient outcomes in
Increasingly, biomarkers are being investigated for the absence of significant changes in creatinine is a
their ability to complement, rather than replace, cre- paradigm shift for physicians and will certainly need
atinine. In a pooled prospective study (n 5 2,322) to be validated in follow-up studies.

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© 2012 American College of Chest Physicians
 There is growing evidence to support the role of ated with increased mortality and can also lead to the
biomarkers at the time of AKI, with two separate transient or permanent need for RRT. Even when not
publications showing that urine NGAL at the time of requiring RRT, patients can develop post-AKI CKD,
clinical creatinine increase (AKIN stage 1 or RIFLE which carries an increased risk of ESRD and death.
“risk”) can predict the severity of AKI (who will pro- This complex interplay of AKI and CKD will con-
gress to AKIN stage 2 or 3 or RIFLE “injury” or tinue to be defined as nephrologists and intensivists
“failure”).72,80 If validated, routine measurement of further explore novel methods to assess renal function
NGAL in those with newly diagnosed AKI may iden- in the ICU.
tify those at highest risk of the most adverse patient
outcomes and those who would be ideal participants
Acknowledgments
in future interventional trials.
Novel biomarkers are inching closer toward clin- Financial/nonfinancial disclosures: The author has reported to
CHEST the following conflicts of interest: Dr Koyner has received
ical relevance, but there is still much we do not know money from Abbott Laboratories for patient enrollment for
about their usefulness. Several investigations have research conducted investigating urine NGAL as a biomarker of
recently shown that the ability of a biomarker to acute kidney injury following adult cardiac surgery.
Role of sponsors: The sponsor had no role in the design of the
detect AKI may be impacted by underlying CKD.73,74,85 study, the collection and analysis of the data, or in the preparation
Additionally, the impact of medications (diuretics, pres- of the manuscript.
sors, angiotensin-converting enzyme inhibitors) and Other contributions: The author expresses gratitude to Jason
Poston, MD, University of Chicago, for his invaluable assistance
clinical care on biomarker values is unknown. Until in preparing this manuscript.
these issues are clarified and biomarkers are uniformly
validated, we will remain reliant on our current “bronze
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 Assessment and Diagnosis of Renal Dysfunction in the ICU
Jay L. Koyner
Chest 2012;141; 1584-1594
DOI 10.1378/chest.11-1513
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