FOCUS ON AKI IN CRITICAL CARE

Classification and staging of acute kidney

injury: beyond the RIFLE and AKIN criteria
Zaccaria Ricci, Dinna N. Cruz and Claudio Ronco
Abstract | Acute kidney injury (AKI) is often overlooked in hospitalized patients, despite the fact that even
mild forms are strongly associated with poor clinical outcomes such as increased mortality, morbidity,
cardiovascular failure and infections. Research endorsed by the Acute Dialysis Quality Initiative led to the
publication of a consensus definition for AKI—the RIFLE criteria (Risk, Injury, Failure, Loss of function, and
End-stage renal disease)—which was designed to standardize and classify renal dysfunction. These criteria,
along with revised versions developed by the AKI Network (AKIN), can detect AKI with high sensitivity and
high specificity and describe different severity levels that aim to predict the prognosis of affected patients.
The RIFLE and AKIN criteria are easy to use in a variety of clinical and research settings, but have several
limitations: both utilize an increase in serum creatinine level from a hypothetical baseline value and a
decrease in urine output, but these surrogate markers of renal impairment manifest relatively late after injury
has occurred and do not consider the nature or site of the kidney injury. New biomarkers for AKI have shown
promise for early diagnosis and prediction of the prognosis of AKI. As more data become available, they could,
in the future, be incorporated into improved definitions or criteria for AKI.
Ricci, Z. et al. Nat. Rev. Nephrol. 7, 201–208 (2011); published online 1 March 2011; doi:10.1038/nrneph.2011.14

Introduction
The term ‘acute kidney injury’ (AKI) is currently recog­
nized as the preferred nomenclature for the complex
clinical syndrome formerly known as acute renal failure
(ARF). This transition in terminology also serves to
emphasize that the spectrum of disease is much broader
than the subset of patients who experience renal failure
requiring dialysis treatment. AKI occurs in a variety of
settings, and has clinical manifestations ranging from a
minimal elevation in serum creatinine levels to anuric
renal failure.1 In fact, AKI exists along a continuum of
disease: the acute decline in kidney function is often sec­
ondary to an injury that causes functional or structural
changes in the kidneys. As the severity of the under­
lying renal injury increases, the risk of an unfavorable
outcome rises.
However, AKI is often overlooked, especially its milder
forms, even though all AKI severities can be associated
with adverse outcomes. For example, in 2010 investiga­
tors reported that transient azotemia (defined as a rapid
recovery from AKI, within 72 h of its onset)2 was not a
benign condition. Transient azotemia represents about
one-third of all cases of AKI in hospitalized patients, and
is independently correlated with a significantly increased
risk of death (P <0.0001).2 An epidemiological study pub­
lished in 2004 demonstrated a wide variation in etiologies
and risk factors for AKI and confirmed that this disease
is associated with increased mortality (particularly when
dialysis is required).3
Competing interests
The authors declare no competing interests.
Responses to a survey conducted in 2004 during an
international meeting on Critical Care Nephrology
revealed that clinicians tended to modify the AKI defi­
nition according to the practices at their institution; more
than 200 different definitions of AKI were provided.4 A
consensus definition was needed to bring order to the
literature on AKI. The success of this initiative can be
gauged by the fact that in a similar survey conducted
during an international meeting on Critical Care
Nephrology in 2007, the number of individualized AKI
definitions had dropped to <20 and the vast majority of
respondents were using the new consensus definition
of AKI to stratify the severity of renal dysfunction.5 In this
Review, we briefly present the history, development and
clinical validation of the consensus definitions of AKI, Department of Pediatric
which have been one of the most important develop­ Cardiac Surgery,
ments in the management of this disorder. We also Bambino Gesù
Children’s Hospital,
describe possible modifications to these criteria based Piazza S. Onofrio 4,
on new biomarkers and alternative measures of renal 00165 Rome, Italy
(Z. Ricci). International
impairment, and consider their future role in studies Renal Research
of AKI. Institute Vicenza, Viale
Rodolfi 37, 36100
Vicenza, Italy
The RIFLE criteria (D. N. Cruz).
A consensus definition of AKI was published by the Department of
Nephrology, Dialysis
Acute Dialysis Quality Initiative (ADQI) in 2004.6 This and Transplantation, St
consensus definition is termed the RIFLE criteria, and Bortolo Hospital, Viale
uses the following categories: ‘at Risk’ is the least severe Rodolfi 37, 36100
Vicenza, Italy
category of AKI, followed by ‘Injury’, ‘Failure’, ‘Loss’ and (C. Ronco).
‘End-stage renal disease’. This definition was intended
Correspondence to:
to establish the presence or absence of clinical AKI in a Z. Ricci
given patient or situation, and to describe the severity z.ricci@libero.it

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© 2011 Macmillan Publishers Limited. All rights reserved
REVIEWS
Key points
■■ A widely accepted definition of and classification criteria for acute kidney
injury (AKI) is one of the most important acquisitions for research into AKI
epidemiology, prevention and management
■■ A consensus definition of AKI should be simple to apply in clinical and research
settings, highly sensitive and specific, represent the spectrum of disease
severity, and correlate well with outcome
■■ The RIFLE and AKIN criteria enable the reliable clinical diagnosis of AKI and
indicate a direct relationship between the severity of AKI and patients outcome
■■ The RIFLE and AKIN criteria have limitations, and further refinements that can
provide a definitive classification are anticipated in the near future
■■ Tests for neutrophil gelatinase-associated lipocalin and cystatin C are widely
available; these biomarkers exhibit optimal qualities to predict the occurrence
and prognosis of AKI
Table 1 | Classification and staging systems for AKI
System Serum creatinine criteria Urine output criteria
RIFLE class
Risk Serum creatinine increase to 1.5-fold OR GFR <0.5 ml/kg/h for 6 h
decrease >25% from baseline
Injury Serum creatinine increase to 2.0-fold OR GFR <0.5 ml/kg/h for 12 h
decrease >50% from baseline
Failure Serum creatinine increase to 3.0-fold OR GFR Anuria for 12 h
decrease >75% from baseline OR serum creatinine
≥354 μmol/l (≥4 mg/dl) with an acute increase of at
least 44 μmol/l (0.5 mg/dl)
AKIN Stage
1 Serum creatinine increase ≥26.5 μmol/l (≥0.3 mg/dl) <0.5 ml/kg/h for 6 h
OR increase to 1.5–2.0-fold from baseline
2 Serum creatinine increase >2.0–3.0-fold from <0.5 ml/kg/h for 12 h
baseline
3 Serum creatinine increase >3.0-fold from baseline <0.3 ml/kg/h for 24 h
OR serum creatinine ≥354 μmol/l (≥4.0 mg/dl) with OR anuria for 12 h OR
an acute increase of at least 44 μmol/l (0.5 mg/dl) need for RRT
OR need for RRT
Small but important differences are observed between the two systems. A time constraint of 48 h for
diagnosis (using either serum creatinine levels or urine output) is required in AKIN criteria. GFR decreases
are used for diagnosis only in RIFLE criteria. In both systems, only one criterion (creatinine or urine output)
has to be met to qualify for a given class or stage of AKI. Classes L and E of the RIFLE criteria are not
reported. Owing to the wide variation in indications for and timing of initiation of RRT, individuals who
receive RRT are considered to have AKIN Stage 3 AKI irrespective of their serum creatinine level and urine
output.6,15 Abbreviations: AKI, acute kidney injury; AKIN, AKI Network; GFR, glomerular filtration rate; RIFLE,
Risk, Injury Failure, Loss, End-stage renal disease; RRT, renal replacement therapy.
of this syndrome (Table 1).6 It did not aim to predict
mortality or adverse outcomes, nor to trigger standard­
ized therapeutic interventions. However, the assumption
that more-severe disease should result in worse outcomes
seems logical, and consequently renal dys­function is
assessed by two parameters: a change in blood creati­
nine level or glomerular filtration rate (GFR) from a
baseline value, and urine output per kilogram of body
weight over a specified time period (Table 1). AKI stage
is determined on the basis of the parameter that places
the patient in the worst disease category. Risk is the least
severe category of AKI, followed by Injury, and Failure
is the most severe AKI category.
In 2008, our research group published a systematic
review of 24 studies that described the epidemiology of
AKI by means of the RIFLE criteria, and attempted to
associate the severity of AKI with clinical outcome.7 The
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© 2011 Macmillan Publishers Limited. All rights reserved
majority of the studies looked at hospitalized patients
in general or in intensive care unit (ICU) settings. In
one study, investigators analyzed all hospital admissions
over a 3‑year period, while another made a population-
based estimate of AKI incidence in Scotland. All but
two studies were retrospective in design and used only
changes in serum creatinine levels and/or GFR for AKI
staging. The creatinine level and urine output criteria
were only used together in 12% of the pooled popula­
tion. The analysis showed that a stepwise increase in the
relative risk of death occurred with each successive AKI
category (at Risk, 2.40; Injury 4.15; Failure 6.37 versus
non-AKI patients). This biological gradient was gen­
erally present regardless of the population of patients
studied, with the possible exception of patients who were
on dialy­sis as a result of AKI. Overall, epidemiological
studies demon­strate that the worse the RIFLE class, the
higher the mortal­ity, the longer the ICU and hospital stay
and the more limited the renal recovery.
The RIFLE criteria are also currently being used in
trials of therapies for AKI8 and in studies on AKI physio­
pathology,9 where a uniform and standardized defini­
tion of the disease is mandatory. The RIFLE criteria
have also been modified for use in the pediatric setting.10
However, after more than 6 years of clinical utilization,
several limitations of the RIFLE criteria have emerged.11
First, any clinical sign of AKI appear only after a notable
decline in GFR, whereas novel biomarkers could be used
to make the diagnosis at an earlier stage (for example,
at the time of tubular damage, before any change in
GFR has occurred). Conversely, these biomarkers could
signal damage at the molecular and cellular level that
does not necessarily translate into a subsequent, clini­
cally relevant reduction in GFR. Second, the use of 6 h
and 12 h urine output measurements is unsuitable for
retrospective studies, since such data are not collected as
part of routine clinical practice. Not only is urine output
affected by diuretic use, but this parameter can only be
accurately assessed in patients with a urinary catheter. A
third limitation of the RIFLE criteria is that the serum
creatinine and GFR measurements are based on changes
from a baseline value, which are not always available. In
the absence of suitable baseline data, the ADQI recom­
mends an estimation of serum creatinine levels based on
back-calculation from the Modification of Diet in Renal
Disease (MDRD) formula assuming a ‘normal’ GFR of
approximately 75–100 ml/min/1.73 m2.6 Although this
method provides a very convenient and useful estimate
of the baseline serum creatinine level, its accuracy has
been called into question.12 Fourth, investigators might
be tempted to use the change in estimated GFR rather
than changes in measured GFR to assess the severity of
AKI—an approach that should be considered inherently
incorrect, since the MDRD equation (as with all GFR or
creatinine clearance equations) is valid only in steady-
state conditions, and is certainly invalid in situations
where renal function is rapidly changing, as is the case
in AKI.11 Fifth, a study published in 2004 demonstrated
that even small increases in serum creatinine levels, such
as an absolute increase of 26.5 μmol/l (0.3 mg/dl)—below

those specified for the RIFLE class ‘at Risk’—are associ­
ated with poor outcomes.13 Finally, the RIFLE criteria do
not consider the nature or site of the precipitating injury,
although the same could be said of consensus definitions
used for other diseases.14
AKIN criteria
In 2007, a modified version of the RIFLE criteria was
published by the AKI Network (AKIN)—known as the
AKIN criteria (Table 1).15 A number of national and
international societies in the fields of nephrology
and critical care endorsed this initiative. 6 One of the
tasks of the AKIN was further refinement of the defini­
tion of AKI: the categories of Risk, Injury, and Failure
were replaced with Stages 1, 2 and 3, respectively, and
the outcome categories Loss and ESRD were eliminated.
An absolute increase in serum creatinine levels of at least
26.5 μmol/l (0.3 mg/dl) has been added to the minimum
requirements for Stage 1. Patients starting renal replace­
ment therapy (RRT) are automatically classified as having
Stage 3 AKI, regardless of their serum creatinine levels
and urine output.
The AKIN criteria have partially addressed some of the
limitations of the RIFLE criteria. However, some small
details might have been overlooked. Although the AKIN
criteria still do not define the nature of the renal injury,
some attempt has been made to exclude easily reversible
causes of azotemia (such as volume depletion or urinary
obstruction) from being classified as AKI.15 Thus, the
AKIN criteria state that “diagnosis based on the urine
criterion alone will require exclusion of urinary tract
obstructions that reduce urine output or of other easily
reversible causes of decreased urine output” and that
application of the diagnostic criteria “should be used
in the context of the clinical presentation and following
adequate resuscitation when applicable”.15 This approach
attempts to address the inability of the RIFLE criteria to
exclude prerenal azotemia. However, since the presence
of these factors is virtually impossible to either verify or
exclude in retrospective studies, transient azotemia must
indeed be acknowledged as a form of AKI that, even if
mild, can lead to adverse outcomes.2 Consequently, the
negative prognostic value of small changes in serum
creatinine levels has been recognized. Another crucial
difference between the RIFLE and AKIN criteria is the
48 h time-frame within which the diagnosis of AKI
must be made to fulfill the AKIN criteria (Table 1). For
patients whose serum creatinine levels are not measured
at least every other day, which includes many patients
in general hospital wards, a diagnosis within this time-
frame would be difficult to achieve. The GFR criteria
have been eliminated, which helps to discourage the
incorrect use of changes in estimated GFR for AKI diag­
nosis, as described above. Finally, because of the lack of
universal guidelines for RRT initiation, this decision is
highly subjective: therefore, using RRT initiation as a
criterion for AKI staging could result in an unforeseen
confounding effect.
Generally speaking, studies that have used the AKIN
criteria rather than the RIFLE criteria did not seem to
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FOCUS ON AKI IN CRITICAL CARE
show any improvement in the sensitivity, robustness
and predictive ability of the definition and classifica­
tion of AKI.11,16 A secondary analysis of the Simplified
Acute Physiology Score (SAPS) 3 database, published
in 2009, evaluated and compared the performance of
the RIFLE and AKIN criteria. 17 The SAPS 3 database
recorded serum creatinine levels and urine output for
16,784 critically ill patients during the first 48 h after
ICU admission. In total, 1,504 patients (10.5%) were
classified as having AKI by the RIFLE criteria but not
by the AKIN criteria. The majority of these indivi­
duals were classified as ‘at Risk’ by the RIFLE crite­
ria, and none showed a rise in serum creatinine level
≥26.5 μmol/l (0.3 mg/dl) within 48 h of ICU admis­
sion. By contrast, 504 patients (3.5%) were classified as
having AKI by the AKIN criteria but not by the RIFLE
criteria. Over 90% of these patients were considered to
have Stage 1 AKI: of these, 54.5% had a serum creati­
nine level <70.7 μmol/l (0.8 mg/dl) at ICU admission
and the remainder showed a rise in serum creatinine
levels of ≥26.5 μmol/l (0.3 mg/dl) within 48 h of ICU
admission. Several conclusions can be drawn from
these results, as highlighted by Bagshaw in an edito­
rial:18 the diagnosis of any AKI stage correlates with
clinical outcome; the RIFLE criteria seem to be more
sensitive for diagnosing AKI and to have greater preci­
sion for predicting mortality than the AKIN criteria; at
best, these data confirm that neither classification offers
clear advantages over the other; and both systems still
have imperfections and limitations. For example, both
criteria diagnose AKI using surrogate markers of renal
impairment that manifest at a relatively late stage after
injury has occurred, both rely on knowing the patient’s
baseline serum creatinine levels, and both provide equal
weighting to urine output and serum creatinine level for
classifying the severity of AKI.
The issue of baseline renal function
The conceptual model of AKI is one of a rapid decline in
renal function from baseline levels. Aside from requir­
ing a time-frame within which this decline occurs (for
example, 48 h or 1 week), this model assumes that the
patient’s baseline serum creatinine level (which is reflec­
tive of the patient’s premorbid kidney function) is known.
Furthermore, the baseline serum creatinine level is
required to ascertain the extent of recovery of renal func­
tion after the AKI event, which is a clinically important
end point. Unfortunately, the baseline serum creatinine
level might not be known in many patients, depending
on the population being studied. The baseline serum
creatinine value has been estimated in various ways, such
as the serum creatinine level on hospital admission,17,19
the minimum serum creatinine level during the hospital
stay,19,20 the serum creatinine value back-estimated from
the MDRD equation,21,22 or the lowest value among these.
The choice of estimation technique used to obtain the
baseline serum creatinine value has a marked effect on
the prevalence of AKI, the severity (or stage) of disease,
and on the mortality risk associated with various stages
of AKI.11,12
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Table 2 | Surrogate measures for baseline serum creatinine used to establish AKI diagnosis and severity 24
Surrogate measures for AKI diagnosis (%)
baseline serum creatinine
Frequency* Sensitivity
level
MDRD back-estimation 38.3 84.2
Nadir level in hospital 35.9 81.7
Level at hospital admission 13.7 38.9
*For comparison purposes, the frequency of AKI in patients for whom baseline serum creatinine levels were available was 25.5%. 24 Values <0.1 were imputed
at 0.05 to compose this table.24 Abbreviations: AKI, acute kidney injury; AKIN, AKI Network; MDRD; Modification of Diet in Renal Disease.
The serum creatinine level at hospital admission could
have been modified by the acute illness that prompted
hospitalization and is unlikely to be representative of
the true baseline state. The lowest serum creatinine level
measured during the hospital stay also has a number of
disadvantages. First, this measurement is, by definition, a
retrospective baseline (the patient’s hospitalization must
have ended to identify the nadir value and, therefore, this
measurement cannot be used in daily clinical practice).
Second, the nadir serum creatinine value is likely to be
lower than the true baseline level, thereby over­estimating
the incidence of AKI. When no information on pre­
morbid renal function is available, for adults, the Acute
Dialysis Quality Initiative (ADQI) has recommended
back-estimation of the baseline serum creatinine value
using the MDRD formula, assuming an estimated GFR of
75 ml/min/1.73 m2.6 Although convenient, the validity
of this approximation, as well as that of other surrogate
measures of baseline renal function, has been the subject
of studies published since 2009.23–25 A study addressing
the issue of baseline serum creatinine levels in pediatric
patients with AKI has also been published.26
In a study published in 2010, involving 4,863 hospital­
ized patients, investigators evaluated the performance of
these three potential surrogates for baseline serum creati­
nine level (the serum creatinine value back-estimated
from the MDRD equation [as per ADQI recommenda­
tions], the serum creatinine level on hospital admission,
and the nadir inpatient serum creatinine level).24 The
authors concluded that all three surrogates resulted in
bidirectional misclassification of AKI. Although the
use of serum creatinine levels at admission resulted in
the least amount of misclassification in this study, this
parameter also had the lowest sensitivity (38.9%) for
diagnosis of AKI (Table 2). When admission serum
creatinine levels were used, nearly half of the ‘true’ AKI
cases were missed: 25.5% of the cohort had AKI when
true baseline serum creatinine levels were used, versus
13.7% with use of admission serum creatinine levels.
The missed cases included community-acquired AKI,
which might improve or stabilize during hospitaliza­
tion. Increased mortality rates were associated with
each AKIN stage when admission serum creatinine
levels were used, but this finding reflects the bias inher­
ent in this method. Only AKI that continues to worsen
during hospitalization can be detected by this method,
and such a condition is associated with higher mortality
than transient AKI. In the same study, use of the MDRD
equation to back-estimate the baseline serum creatinine
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Misclassification of AKI severity by AKIN Stage (%)
Specificity Any AKIN stage AKIN Stage 1 and 2 only
77.4 29.5 11.6
79.8 24.0 5.2
94.9 18.0 4.9
value overestimated the incidence of AKI at 38.3%; the
sensitivity of this approach was 84.2% and its specificity
was 77.4% (Table 2).
A post hoc analysis of data from the Beginning and
Ending Supportive Therapy for the Kidney (BEST) study
also compared observed baseline serum creatinine levels
with MDRD back-estimated values for determination of
RIFLE class.23 Use of the MDRD back-estimated values
resulted in a false-positive rate of 18.8% and a false-
­negative rate of 7.3% for detecting AKI. Misclassification
rates were lower when patients with chronic kidney
disease (CKD) were excluded. The authors concluded
that the MDRD back-estimated serum creatinine value
performed reasonably well for the determination of the
RIFLE categories when premorbid renal function was
near-normal, but cautioned against the use of MDRD
back-estimated serum creatinine values in patients with
suspected CKD. This warning is clearly logical, since the
MDRD estimation method assumes that the patient has
near-normal premorbid renal function, an assumption
that is obviously invalid in individuals with suspected
CKD—for example, patients with proteinuria on routine
admission urinalysis, or patients with multiple risk
factors for CKD.
In a study published in 2010, the researchers compared
the bias and accuracy of three methods that estimate
baseline serum creatinine values and the incidence of AKI
in the ICU setting using the RIFLE criteria:25 the MDRD
back-estimated serum creatinine value, serum creatinine
values back-estimated by a newly developed equation, and
a sex-specific, fixed baseline serum creatinine value of
70 μmol/l (0.8 mg/dl) for women and 88 μmol/l (1 mg/dl)
for men. Neither of the alternative methods offered a
consistent improvement in the accuracy of AKI diagnosis
compared with MDRD-based estimates. Moreover, use
of the MDRD equation to back-estimate baseline serum
creatinine values overestimated or underestimated cases
of ‘Risk’, but rarely misclassified patients in ‘Injury’ and
‘Failure’ categories. The same trend was seen in the study
of Siew et al. (Table 2).24
Back-estimation of baseline serum creatinine values
is thought to be more reliable in pediatric populations
than in adults, owing to the reduced prevalence of CKD
among children.26 Zappitelli and colleagues26 compared
the performance of true baseline serum creatinine levels
with that of five methods for estimating baseline serum
creatinine values in critically ill and non-critically-ill
pediatric populations: serum creatinine levels at ICU
admission (although none of the non-critically-ill

patients had serum creatinine levels measured at admis­
sion); serum creatinine values back-calculated from
the Schwartz formula27 assuming an estimated creati­
nine clearance of either 100 ml/min/1.73 m2 or 120 ml/
min/1.73 m2; and use of either the upper limit or lower
limit of normal serum creatinine levels adjusted for
age and sex. Different methods of estimating baseline
serum creatinine values led to marked differences in
the calculated incidence of AKI in the pediatric ICU,
from 12% using the admission serum creatinine value
to 87.8% using the lower limit of normal serum creati­
nine level adjusted for age and sex. A similar trend was
seen in the non-critically-ill group. When the research­
ers compared the performance of estimated creatinine
values back-calculated using a creatinine clearance rate
of 120 ml/min/1.73 m2 with the performance of using the
lower limit of normal serum creatinine level adjusted for
age and sex, the median absolute percentage error was
smallest using the adjusted lower limit of normal serum
creatinine level estimation method, but the 5–95th per­
centile range of this error was substantially narrower
when estimated creatinine values were back-calculated
using a creatinine clearance rate of 120 ml/min/1.73 m2.
The authors of the study proposed that the latter method
should be used to estimate baseline serum creatinine
levels when the true value is unknown.
Clearly, some degree of misclassification of AKI occurs
when using any method of estimating the baseline
serum creatinine value in both adults and children, an
observation that highlights the need for investigators to
make every effort to find and use a true baseline serum
creatinine level before resorting to the use of estimated
values.11,12 A baseline serum creatinine level that is appro­
priate for use in diagnosis of AKI should be representa­
tive of the patient’s normal renal function, such as an
outpatient serum creatinine level measured within the
previous year (preferably within the past 3 months).28
When an outpatient serum creatinine level is simply
not available, the serum creatinine measurement taken
at either hospital or ICU admission seems to result in less
misclassification of AKI cases than does back-­estimation
using the MDRD equation. However, use of admission
serum creatinine levels is specific but insensitive, and
is likely to underestimate the incidence of AKI. 24,26
Furthermore, this approach can only detect hospital-
acquired AKI. Nevertheless, as remarked by the Program
to Improve Care in Acute Renal Disease (PICARD) study
investigators,29 serum creatinine levels throughout ICU
admission might be affected by hemodilution, which fre­
quently occurs in critically ill patients. This factor could
lead to underestimation of the severity of AKI in these
patients; if this factor is not taken into account, hemo­
dilution could mask the increase in serum creatinine
levels associated with AKI. In the PICARD study, this
effect was revealed by daily evaluations and adjustments
of serum creatinine levels according to the patient’s fluid
balance. Use of nonadjusted serum creatinine levels
would have led to a median underestimation of the true
serum levels of 2.1% on day 1, with a progressive increase
to a median of 14.3% on day 6.29
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FOCUS ON AKI IN CRITICAL CARE
The issue of how to approach the lack of a true
baseline serum creatinine level in a patient with
community-­acquired AKI also remains unresolved. For
example, if a patient presents to the emergency room
with an elevated serum creatinine level, the absence of a
known baseline serum creatinine level means that only
a retro­spective diagnosis of community-acquired AKI
is possible, inferred from the downward trajectory of
serum creatinine levels during the patient’s hospitaliza­
tion. The studies discussed above have pointed out the
drawbacks associated with using back-estimated serum
creatinine values (using either the MDRD or Schwartz
equations); however, none has been able to suggest a
suitable alternative. As expected, the estimated values
seem to result in more bias in a CKD population (com­
pared with a non-CKD population). Moving forward
from this finding, a potential solution to the dilemma
would be to use a different method of estimating the
baseline serum creatinine value (for example, back-
estimation using a GFR of 60 ml/min/1.73 m2 or 45 ml/
min/1.73 m 2) in patients with community-acquired
AKI who have multiple risk factors for CKD but lack
a measurement of their premorbid serum creatinine
level. Such an approach would need to be tested in
rigorous study.
The issue of urine output criteria
Urine output is one of the most commonly used AKI
markers: it can be measured in real time at the hospi­
tal bedside, it is easy and inexpensive to determine and
urine flow variations generally trigger first attempts of
therapy. However, urine output is affected by the patient’s
blood volume status and by diuretic use. Furthermore,
6 h and 12 h urine output can only be accurately assessed
in patients with a urinary catheter. The AKIN and RIFLE
criteria both use urine output to define the severity of
AKI, but the accuracy of this parameter has been less
studied than have changes in serum creatinine levels,
since exact data on urine output are not always avail­
able in retrospective studies.8 In the aforementioned
systematic review,7 the relative risk of death in studies
that used both changes in serum creatinine level and
urine output criteria to assess the severity of AKI was
lower than in studies that used the creatinine criteria
only. A possible explanation for this finding is that the
urine output criteria overestimate the severity of AKI;
thus, a sudden decrease in urine output (which would
eventually be corrected by fluid infusion or diuretic
administration) might not correspond to an actual
increase in serum creati­nine levels but would still be
ranked as a high-severity AKI class. Finally, urine output
is probably reduced early in the pathogenesis of prerenal
azotemia but late in the course of established AKI and,
consequently, the therapy prescribed might correspond
to markedly different clinical situations even if such
patients exhibit similar AKI stages.
Consensus definitions using novel biomarkers
In view of the limitations of using either urine output or
changes in serum creatinine levels to assess the severity
REVIEWS
Table 3 | Relationship between biomarkers and RIFLE class or AKIN stage in adults
Study Biomarker
Siew et al. (2009) 32
Urine NGAL*
Cruz et al. (2010)31 Plasma NGAL||
Haase-Fielitz et al. Plasma NGAL (ng/ml)¶
(2009)40
Herget-Rosenthal Serum cystatin C (%
et al. (2004)35 increase from baseline)#
*At enrollment. ‡Values presented as median (interquartile range). §Values for pooled group of Stage 2 and Stage 3 patients. ||Peak levels during the first 4 days
in the ICU. ¶Measured 6 h after the start of cardiopulmonary bypass. #Levels at enrollment were used to define AKI. Abbreviations: AKI, acute kidney injury; AKIN,
AKI Network; ICU, intensive care unit; NGAL, neutrophil gelatinase-associated lipocalin; RIFLE, Risk, Injury, Failure, Loss, End-stage renal disease.
of AKI discussed above, various research groups have
proposed that novel AKI biomarkers could be used to
define and stage AKI in conjunction with the RIFLE and
AKIN criteria. The Neutrophil Gelatinase-Associated
Lipocalin (NGAL) Investigator Group has published the
results of a meta-analysis of data from 19 studies con­
ducted in eight countries, involving 2,538 patients, of
whom 487 (19.2%) developed AKI.30 The group reported
that NGAL levels in plasma, serum or urine seem to be
of diagnostic and prognostic value for AKI, RRT and
mortal­ity, especially in patients who have undergone
cardiac surgery, and in children. NGAL allows AKI diag­
nosis a few hours after the onset of kidney damage with
elevated specificity and sensitivity. At present, limited
data are available describing the associations between
levels of this biomarker and either RIFLE class or AKIN
stage, but a few studies have demonstrated a correla­
tion between the severity of AKI and levels of NGAL
in blood and urine. In an adult ICU population, peak
plasma levels of NGAL were increased among patients
with high RIFLE class AKI (Table 3), and a significant
correlation existed between the two (r = 0.55, P <0.001).31
The same relationship was seen when looking at either
peak or median plasma NGAL levels over the first 4 days
spent in the ICU, or NGAL level during the first ICU day.
Similarly, urine NGAL values were higher in the group
of adult patients with AKIN stages 2 and 3 than in those
with AKIN Stage 1 in the ICU (Table 3).32
Similarly, urinary levels of both NGAL and inter­
leukin (IL)‑18 have been studied in critically ill pediatric
patients requiring mechanical ventilation (Table 4). 33,34
A strong association exists between worse AKI as
assessed by the pediatric RIFLE class, and increasing
mean and peak levels of NGAL in urine.33 Peak urine
IL‑18 concentra­t ions also demonstrated a stepwise
increase with worsening AKI class as assessed by the
pediatric RIFLE criteria.34 Finally, in a small study of 85
pediatric patients in the ICU, researchers tried to define
the severity of AKI according to the percentage change
206  |  APRIL 2011  |  VOLUME 7  www.nature.com/nrneph
© 2011 Macmillan Publishers Limited. All rights reserved
Setting AKI criteria AKI severity by level of biomarkers
ICU AKIN Non-AKI: 48.1 (12.7–179.3) ng/ml‡
Stage 1: 158 (27–430) ng/ml‡
Stage 2: 390 (39–4,317) ng/ml‡§
Stage 3: 390 (39–4,317) ng/ml‡§
ICU RIFLE Non-AKI: 102.4 (67.4–147.5) ng/ml‡
Risk: 171.4 (101.9–281.7) ng/ml‡
Injury 2: 214.9 (137.5–419.5) ng/ml‡
Failure: 620.3 (406.4–1,300.0) ng/ml‡
Undergoing RIFLE and AKIN Non-AKI: ≤150 ng/ml
cardiac surgery Risk or Stage 1: >150 ng/ml
Injury or Stage 2: >150 ng/ml
Failure or Stage 3: >240 ng/ml
ICU and high risk RIFLE Non-AKI: 48.1 <50% increase
of AKI Risk: ≥50% increase
Injury: ≥100% increase
Failure: ≥200% increase
in serum cystatin C level from a baseline value, using
cut-offs analogous to those for serum creatinine in the
RIFLE criteria.35
Overall, these studies suggest that new biomarkers
could be potentially useful in determining a patient’s
RIFLE or AKIN class. If confirmed by future studies, the
incorporation of new biomarkers into current consensus
AKI definitions could represent an important and very
useful improvement.11 These results are encouraging, but
are far from definitive. Important challenges remain in
creating a novel biomarker-based definition of AKI for
clinical use. For example, all biomarker studies have used
serum creatinine levels, with or without urine output, as
the reference standard to which the new biomarker is
compared. Experts have, however, lamented the inad­
equacies of both serum creatinine changes and urine
output as biomarkers of renal impairment. If we ‘validate’
new tests against flawed reference standards, then this
methodology should be considered in the interpretation
of results. Less than ideal specificities or positive predic­
tive values could potentially reflect not the inadequacy of
the new biomarker to detect renal tubular injury or stress,
but rather the limitation of the serum-creatinine-based
reference standard.
Many studies of new biomarkers have also exam­
ined their capability to predict ‘hard’ outcomes, such
as the need for RRT or death.30 In the absence of broad
consensus with regard to the time of initiation of
RRT, however, this ‘hard’ end point is subjective, and
one that is strongly influenced not only by physician
practice, but also by serum creatinine levels and urine
output. Renal biopsies would enable histopathologic
confirma­tion of tubular damage but are clearly imprac­
tical for large studies. Important steps forward for AKI
biomarker research would include the identifica­t ion
of a better gold standard than either serum creati­
nine level or urine output, as well as evidence that a
biomarker-­directed therapeutic approach can improve
clinical outcomes.

It is important to remember that a fundamental
requirement for a good consensus definition is that
it is easy to apply in a variety of clinical and research
settings.11 However, the novel biomarkers described
above are not readily available in many countries, and
are likely to remain economically impractical for wide
use in many developing countries in the foreseeable
future. If one of the objectives of having a consensus
definition is to have the medical community speaking
the same language, these restrictions must be taken into
considera­tion. If the epidemiology of AKI in a devel­
oped country is described using a biomarker-based
definition, it will be poorly comparable to an epi­
demiological study that used serum-creatinine-based
definitions. Although researchers in AKI are all famil­
iar with the limitations of serum creatinine levels as a
measure of renal impairment, they should be equally
familiar with its merits—it is universally available and
inexpensive to measure. A prudent approach, at least
in the immediate future, would be to integrate novel
bio­markers into the existing RIFLE and AKIN criteria,
with the objective of enhancing and improving current
serum-creatinine-based consensus definitions for
AKI. These biomarkers would only be able to replace
the currently used consensus definitions after defini­
tive evidence is obtained of their cost-effectiveness. A
potentially appropriate use for the novel bio­markers
described above would be as enrollment criteria for
clinical trials to evaluate the efficacy of therapies
for patients with early stages of AKI, or as a clinical
end point in studies describing the amount of tubular
damage irrespective of renal function.
Conclusions
Both the RIFLE and AKIN criteria for classifying AKI
have advantages and disadvantages, as discussed above.
In 2009, another creatinine-based definition of AKI was
proposed on the rationale that the amount of time needed
to reach a relative change in creatinine (for example, a
50% increase or a 100% increase) might be more vari­
able than the amount of time needed to reach specific
absolute changes in creatinine level.36 Consequently,
the authors of this study proposed an alternative three-
stage AKI classification that considered absolute changes
in serum creatinine level over a 24–48 h time period in
each stage. In clinical practice, however, the presence of
AKI in the majority of patients would be detected simi­
larly by each classification and only small differences
might be evident in the actual sensitivity or specificity
of the AKI severity staging criteria. A logical next step
would be to reconcile the existing serum-creatinine-
based definitions for AKI, a current work-in-progress
by the Kidney Disease Improving Global Outcomes
(KDIGO) Workgroup.
No single definition for or classification of a complex
disease, such as AKI, will be perfect. The essential com­
ponents of a workable consensus definition are that,
firstly, it should clearly establish the presence or absence
of the disease; secondly, it must give an idea of the sever­
ity of the disease; thirdly, it should correlate disease
NATURE REVIEWS | NEPHROLOGY VOLUME 7  |  APRIL 2011  |  207
© 2011 Macmillan Publishers Limited. All rights reserved
FOCUS ON AKI IN CRITICAL CARE
Table 4 | Relationship between biomarkers and RIFLE class in children in the ICU
Study Biomarker AKI severity by level of biomarker
Zappitelli et al. (2007)33 Urine NGAL* Non-AKI:‡ 24.6 ± 45.5 ng/ml
Risk:‡ 34.5 ± 47.4 ng/ml
Injury:‡ 82.9 ± 122.9 ng/ml
Failure:‡ 103.2 ± 107.3 ng/ml
Washburn et al. (2008)34 Urine IL‑18* Non-AKI:‡ 102.8 ± 175.1 pg/ml
Risk:‡ 128.9 ± 259.7 pg/ml
Injury:‡ 179.9 ± 224.2 pg/ml
Failure:‡ 366.1 ± 631.0 pg/ml
*Peak levels in the first 4 ICU days. ‡All values are presented as mean ± standard deviation. Abbreviations:
AKI, acute kidney injury; ICU, intensive care unit; IL, interleukin; NGAL, neutrophil gelatinase-associated
lipocalin; RIFLE, Risk, Injury, Failure, Loss, End-stage renal disease.
severity with outcome, and finally, and most importantly,
it should be easy to understand and apply in a variety of
clinical and research settings. The use of the consensus
definitions of AKI (RIFLE and AKIN) in the contempo­
rary literature has increased substantially, and a direct
relationship has been clearly demonstrated between the
severity of AKI by such classification and the patient’s
outcome—two very important and positive steps. Some
variation remains in how the criteria are interpreted and
used in the literature, including the inclusion or exclusion
of urine output criteria, the use of changes in estimated
GFR rather than changes in serum creatinine level, and
the choice of parameter used to determine the baseline
serum creatinine level.
Future studies evaluating the performance of new AKI
criteria must be prospective to increase the usefulness
and improve the quality of data collection. Furthermore,
some research might test the effect of using possible
new classifications on the time of initiation or choice of
therapeutic interventions, to guide clinicians towards
the best possible standard of AKI care: such prospec­
tive studies should tailor therapeutic and/or preven­
tive strategies to each AKI severity stage and finally
improve AKI outcomes. Few studies have attempted to
use AKI staging criteria for these purposes, so far, and
the most intriguing expectations are currently posed
in the identifica­tion, by AKI staging, of the ideal timing
of RRT.37–39 As new data emerge, the integration of novel
biomarkers into the consensus definition might offer a
welcome refinement.
Review criteria
The authors attempted to identify all relevant studies
published in the English language. The MEDLINE,
EMBASE and Cochrane electronic databases were
searched for articles published between January 2002
and August 2010 using the terms “acute kidney injury
AND classification”, “RIFLE AND classification” and
“AKIN AND classification”. In addition, a manual search
of relevant review articles and correlated original papers
was performed in order to identify studies that might have
been missed by database screening. Studies published
in abstract form only and articles not yet accepted for
publication were excluded.
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Author contributions
Z. Ricci and D. N. Cruz researched data for the article
and wrote the manuscript. C. Ronco reviewed and
edited the manuscript before submission, and all
authors contributed to discussions of the content.