AJNT

Arab Journal of Nephrology and Transplantation. 2013 Sep;6(3):145-52

Review

The Definitions and Staging Systems of Acute Kidney Injury and Their Limitations
in Practice
Norbert Lameire*
Former Chief of the Renal Division, University Hospital, Belgium

Abstract
Introduction: It is now evident that even minimal
reductions in glomerular filtration rate (GFR) are
associated with a dramatic increase in mortality. The
term acute kidney injury (AKI) describes an acute fall of
estimated GFR (eGFR) and allows patient stratification
based on AKI severity.
Review: The Risk, Injury, Failure, Loss and End-stage
kidney disease (RIFLE) system defines AKI by a
change in serum creatinine (SCr) level or eGFR from a
baseline value, and urine output per kilogram of body
weight over a specified time period. The Acute Kidney
Injury Network (AKIN) definition was based on the
RIFLE system but added an absolute change in SCr of
0.3 mg/dL, omitted eGFR criteria and included a time
constraint of 48 hours. The AKIN system also omitted
the stages Loss and End-stage and allocated patients
who needed acute dialysis to stage-3. The most recent
Kidney Disease Improving Global Outcomes (KDIGO)
guidelines retained the AKIN staging criteria but allowed
a time frame of seven days for a 50% increase in SCr.
The KDIGO criteria do not rely on changes in GFR for
staging except in children under the age of 18 years. AKI
misclassification may result from the lack of a uniform
approach to estimate baseline SCr and the changes in
SCr concentrations resulting from acute severe illness
and altered fluid balance. In addition, exact data on
urine output are not always available resulting in
underutilization of the urine output criteria.

Keywords: Acute Kidney Injury; AKIN; KDIGO;

RIFLE

The authors declared no conflict of interest

Introduction
Before 2004, the generic term acute renal failure (ARF)
was used for an abrupt and sustained decrease in
glomerular filtration rate (GFR) resulting in retention of
nitrogenous (urea and creatinine) and non-nitrogenous
waste products. Depending on the severity and duration of
the renal dysfunction, their accumulation is accompanied
by metabolic disturbances, such as metabolic acidosis
and hyperkalemia, changes in body fluid balance, and by
effects on many other organ systems [1].
The lack of a precise biochemical definition of ARF
resulted in at least 35 definitions in the medical literature
[2], which gave rise to a wide variation in reported
incidence and clinical significance of ARF, impeded a
meaningful comparison of studies that assess preventive
and therapeutic strategies and made generalization of
data generated from single center studies difficult and,
finally, prevented patient stratification based on acute
kidney injury (AKI) severity.

Conclusion: The existing definitions of AKI rely on

imperfect markers of renal function rather than direct
measures of kidney damage, but remain an important
diagnostic and prognostic tool.

Furthermore, the conventional term ARF was often

used in reference to the subset of critically ill patients,
often admitted to the ICU, with a need for acute dialysis
support. Because of accumulating evidence in the years
2004 - 2006, that even minimal increases in serum
creatinine (SCr) are associated with a dramatic impact
on the risk for mortality [3-6], the Acute Kidney Injury
Network (AKIN) proposed to replace the term ARF by
that of AKI [7].

* Corresponding author; University Hospital; 185, De Pintelaan; 9000

Gent, Belgium; E. mail: norbert.lameire@ugent.be

AKI is thus not limited to ARF and is independent of the

presence of underlying histopathological alterations or of
the pattern of functional recovery. It is a broad clinical
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Norbert Lameire

syndrome, at present defined by an acute fall of GFR as

reflected by an acute rise of serum creatinine (SCr) and/
or decline in urine output over a given time interval.

(AKIN) working group modified some of the RIFLE

criteria.

A traditional classification of AKI is based on various

etiologies including pre-renal AKI, acute post-renal
obstructive nephropathy and intrinsic acute kidney
diseases, i.e. acute tubular necrosis (ATN), acute
interstitial nephritis (AIN), and acute glomerular and
renal vasculitis diseases. Of these, only intrinsic renal
AKI represents true kidney disease while pre-renal
and most cases of post-renal AKI are the consequence
of extra-renal diseases, leading to the decreased GFR.
If these pre- and/or post-renal conditions persist, they
will eventually evolve to renal cellular damage and to
intrinsic renal disease. Because the manifestations and
clinical consequences of AKI can be quite similar (even
indistinguishable) regardless of whether the etiology is
predominantly within the kidney or predominantly from
outside stresses on the kidney, the syndrome of AKI
encompasses both direct injury to the kidney as well as
acute impairment of function.

AKIN

Definition and staging of acute kidney injury

(AKI)
RIFLE
A broad consensus of experts assembled in The Acute
Dialysis Quality Initiative (ADQI) group developed the
Risk, Injury, Failure, Loss and End-stage kidney disease
(RIFLE) system for diagnosis and classification of a broad
range of acute impairments of kidney function [8]. In
RIFLE, renal dysfunction is assessed by two parameters:
a change in SCr level or estimated glomerular filtration
rate (eGFR) from a baseline value, and urine output per
kilogram of body weight over a specified time period.
AKI stage is determined on the basis of the parameter
that places the patient in the worst disease category.
Not unexpectedly, many studies in populations [9],
hospitalized patients [6] as well as in critically ill patients
[4, 10-12], from around the world have shown that AKI
defined by RIFLE is associated with decreased survival
and that increasing RIFLE stage leads to increased risk of
death, a longer ICU and hospital stay, and a more limited
renal recovery.
There are some inherent limitations of the RIFLE
definition and classification, which are reflected in some
variation in how the criteria are interpreted and used in
the literature, like including use/non-use of urine output
criteria, use of change in estimated GFR rather than
change in SCr, and choice of a baseline SCr [13]. Given
these limitations, the Acute Kidney Injury Network
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146

Although the diagnostic criteria for AKI and the staging

system were based on the RIFLE criteria [7], a number of
important modifications were added. First, the addition
of an absolute change in serum creatinine of 0.3 mg/
dL (26.4 mol/L) is based on epidemiologic data
demonstrating an 80 percent increase in mortality risk
associated with these small changes [3, 5]. Second, the
eGFR criteria and the stages Loss and End-stage
were omitted. Third, the inclusion of a time constraint
of 48 hours is based upon data that showed that poorer
outcomes were associated when the rise in creatinine
was observed within 24 to 48 hours [5, 14]. It should be
remembered that the AKIN diagnostic criteria include
both an absolute and a percentage change in SCr, to
accommodate variations related to age, gender, and
body mass index and to reduce the need for a baseline
creatinine; on the other hand, they do require at least two
creatinine values within 48 hours.
Fourth, AKI patients who need acute dialysis were
automatically allocated to stage-3, regardless of the
severity of their AKI.
Two additional caveats were proposed: the first is that the
diagnostic criteria should be applied only after volume
status had been optimized, and the second is that urinary
tract obstruction needed to be excluded if oliguria was
used as the sole diagnostic criterion.
At first sight, it is not clear whether the AKIN
modifications to RIFLE have substantively changed the
classification of patients with AKI or improved its ability
to predict hospital mortality [15]. However, although
the modifications may appear small, Joannidis et al [16]
calculated that they translate into potentially important
changes in the diagnosis and classification of AKI. In the
multicenter simplified acute Physiology score (SAPs)
3 data base, and using both SCr levels and 24 h urine
output data, in critically ill patients, AKI was classified
using the AKIN and RIFLE criteria [16]. According to the
calculations of Bagshaw, the same results were translated
into an absolute 7% difference in AKI diagnosis between
AKIN and RIFLE criteria. In total, 10.5% classified as
having AKI by RIFLE criteria were missed by AKIN
criteria; by contrast, RIFLE criteria missed only 3.5%
classified as having AKI by AKIN criteria [17].

Acute Kidney Injury

Kidney Diseases: Improving Global

Outcomes (KDIGO) Guidelines [18]
Rationale for KDIGO AKI guidelines
In view of the universal importance of AKI, the absence of
evidence-based clinical practice guidelines on this topic,
and in accordance with its mission, Kidney Diseases Improving Global Outcomes (KDIGO), realized that
there is room for improving international cooperation in
the development, dissemination, and implementation of
clinical practice guidelines, also in the field of AKI. In
addition, because two similar definitions based on SCr
and urine output (RIFLE and AKIN) were proposed
and validated, the KDIGO working group members
concluded that there was a need for a single definition of
AKI for practice, research, and public health. In addition,
KDIGO felt that addressing the unique circumstances and
needs of developing countries, especially in the detection
of AKI in its early and potentially reversible stages to
prevent its progression to end stage renal failure, is of
paramount importance.
Brief discussion of the KDIGO guidelines
The KDIGO clinical practice guidelines included a
revised definition of AKI while retaining the AKIN
staging criteria (Table-1). In the KDIGO definition, the
time frame for an absolute increase in SCr of 0.3 mg/
dL (26.4 mol/L) is retained from the AKIN definition
(48 hours) while the time frame for a 50 percent increase
in SCr is the seven days, as originally suggested by the
RIFLE criteria. The KDIGO criteria only utilize changes
in SCr and urine output, and not changes in GFR for
staging, with the exception of children under the age of
18 years, for whom an acute decrease in estimated GFR
to < 35 ml/min per 1.73m is included in the criteria for
stage-3 AKI [19]. As with the RIFLE and AKIN staging
systems, patients should be classified according to
criteria that result in the highest (i.e., most severe) stage
of injury.
KDIGO made one additional change in the criteria for
the sake of clarity and simplicity. For patients reaching
Stage-3 by SCr >4.0 mg/dl (353.6 mol/L), rather than
require an acute increase of 0.5 mg/dl (44.2 mol/L)
over an unspecified time period, KDIGO instead requires
that the patient first achieves the creatinine-based change
specified in the definition, either 0.3 mg/dl (26.4 mol/L)
within a 48-hour time window or an increase of 1.5 times
baseline. This change brings the definition and staging
criteria to greater parity and simplifies the criteria. For
example, if a patient shows an increase of SCr 0.3 mg/
dl (26.4 mol/L) within 48 hours and the absolute SCr
increases to a level 4.0 mg/dl (354 mol/L), this patient

should be classified a stage-3. It goes without saying that

a patient developing acute on chronic kidney injury will
more rapidly arrive in AKI stage-3 than a patient with
AKI starting with normal kidney function.
Additional remarks on the KDIGO definitions
In applying the definitions and staging of AKI some
important additional remarks should be made. Firstly,
the purpose of setting a timeframe for diagnosis of AKI
is to clarify the meaning of the word acute. A disease
process that results in a change in SCr over many weeks
is not AKI (though it may still be an important clinical
entity). AKI is defined in terms of a process that results in
a 50% increase in SCr within 1 week or a 0.3 mg/dl (26.5
mol/l) increase within 48 hours. Importantly, there is
no stipulation as to when the 1-week or 48-hour time
periods can occur; it does not need to be the first week or
first 48 hours of a hospital or ICU stay. Neither does the
time window refer to duration of the inciting event. For
example, a patient may have a 2-week course of sepsis
but only develop AKI in the second week. Importantly,
the 1-week or 48-hour timeframe is for diagnosis of
AKI, not staging. Secondly, the AKIN recommendation
that the criteria should be used following adequate fluid
resuscitation, when applicable, has disappeared from the
KDIGO definition.

Problems related to the different definition

and classifications systems
The baseline serum creatinine
Although all these consensus criteria (RIFLE, AKIN, and
KDIGO) have helped standardize the approach to the
diagnosis and staging of AKI, there still remain specificity
limitations. One of the most discussed limitations is the
importance of determining the baseline kidney function
in patients admitted in AKI and in whom this baseline is
not known. The lack of a uniform approach to estimate
this baseline has recently been shown to compound
the risk for AKI misclassification, hindering effective
comparisons of this disease between settings [20-22].
Several strategies for estimating the basal SCr have been
proposed [22-25], ranging from the use of an estimation
of SCr by backward calculation from a presumed
standard GFR of 75 mL/min/1.73 m, use of the SCr
value at admission, or the peak SCr in the AKI episode
under consideration. Whereas RIFLE and KDIGO
suggest the use of back calculation, AKIN recommends
to use the evolution of SCr relative to the first observed
value in that episode, while the European Renal Best
Practice position statement and others [26] recommend
the admission SCr [27].
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Norbert Lameire

Table 1: Summary of the classification of AKI according to KDIGO [18]

Stage

Serum creatinine

Urine output

1.5-1.9 times baseline OR

0.3 mg/dl (26.5 mol/l) increase

<0.5 ml/kg/h for 6-12 hours

2.0-2.9 times baseline

<0.5 ml/kg/h for 12 hours

3.0 times baseline OR

Increase in serum creatinine to 4.0 mg/dl (353.6 mol/l) OR
Initiation of renal replacement therapy OR
In patients <18 years, decrease in eGFR to <35 ml/min per 1.73 m2

<0.3 ml/kg/h for 24 hours OR

Anuria for 12 hours

However, Siew et al [22] reported that the use of the

admission SCr value as a baseline resulted in nearly
50% reduction in the detection of AKI compared with
that using a known baseline SCr. The MDRD-estimated
baseline SCr had a significantly higher sensitivity for
detecting AKI than the 2 other methods. Although
the use of SCr levels at admission resulted in the least
amount of misclassification, this parameter also had the
lowest sensitivity (38.9%) for diagnosis of AKI. When
admission SCr levels were used, nearly half of the
true AKI cases were missed: 25.5% of the cohort had
AKI when true baseline SCr levels were used, versus
13.7% with use of admission SCr levels. This decrease
is perhaps best explained by the missed diagnosis of
community-acquired AKI that improves or stabilizes
during hospitalization [28]. Zavada et al [25] found that
use of an MDRD-estimated baseline creatinine could
result in either overestimation or underestimation of
some mild (Risk) AKI cases but is unlikely to misclassify
patients in Injury and Failure. Thus, it is important to
consider the goal of AKI classification when selecting a
baseline. For clinical purposes, it may be important not
to miss any case of potential AKI. Therefore, using the
MDRD equation to estimate a baseline kidney function,
at least provisionally, makes sense. The same may hold
true for epidemiologic studies where some degree of
overestimation or underestimation may average out and
not affect overall rates. On the contrary, for research
studies where precise case adjudication is critical,
estimated creatinine should be used with caution, if at
all, especially for defining mild (stage-1) AKI [28].
In a large hospitalized population with AKI the baseline
kidney function was estimated by calculating the eGFR
using a baseline SCr, which was derived from the nadir (or
lowest) value recorded in the first 3 days of hospitalization
[29]. Different thresholds of nadir-to-peak SCr were
found to be independently associated with increased inArab Journal of Nephrology and Transplantation

148

hospital mortality according to baseline eGFR strata. A

nadir-to-peak SCr minimum threshold of 0.2, 0.3, and
0.5 mg/dl was required to be independently associated
with increased in-hospital mortality among patients with
baseline eGFR 60 ml/min/1.73 m, 30 to 59 ml/min/1.73
m, and <30 ml/min/1.73 m, respectively. There was
a significant interaction between the nadir-to-peak SCr
and baseline eGFR for in-hospital mortality (P < 0.001).
Using these thresholds, survivors of AKI episodes also
had an increased hospital length of stay and were more
likely to be discharged to a facility rather than home.
Limitations of the SCr
A first caveat illustrating the limitations of plasma
creatinine concentrations for the diagnosis of AKI in
the setting of critical illness comes from the recent data
published by Pickering et al [30]. To examine the effect of
acute severe illness on SCr concentrations, they applied
a 2compartment, variable volume model of creatinine
kinetics to serial creatinine measurements and fluid
balance in 49 patients admitted to hospital after cardiac
arrest. They found that in the majority of patients (n =
39), SCr concentrations decreased during the first 24 h
after admission (median decrease of 32%). According to
their kinetic model, hemodilution (see below) only partly
accounted for this decrease, suggesting an acute reduction
in the creatinine generation rate. Application of the kinetic
model to patients who had unchanged creatinine levels
24 h after hospital admission (n = 6) suggested that their
GFRs had declined to ~50% of baseline. The presence of
clinically significant AKI in these patients was confirmed
by increased levels of AKI biomarkers and increased
mortality. The researchers conclude that diagnosis of AKI
after cardiac arrest might be missed or delayed if changes
in SCr concentrations are solely relied on as a marker of
injury. As further illustrated in an accompanying editorial
[31] such reductions in creatinine generation rate could
have a major impact on the timing of AKI diagnosis and

Acute Kidney Injury

the assessment of its severity, in particular in critically ill,

septic patients. The study by Pickering et al [30] suggests
that a reduction in GFR can occur in critically ill patients
with unchanged creatinine levels. Importantly, the
magnitude of the decrease in creatinine generation rate
might correlate with illness severity [32]; thus in sicker
patients, increases in creatinine concentration could be
smaller and occur more slowly than in less-sick patients
with the same AKI severity.
Adding further to the uncertainty is the identification
of changes in the patients fluid balance as additional
confounder impacting the SCr. Liu et al [33] examined
the occurrence of AKI in critically ill patients with the
acute respiratory distress syndrome randomized to a fluid
conservative versus fluid liberal management strategy in
the ARDS Network Fluid and Catheter Treatment study.
After adjusting SCr measurements for fluid balance,
notable increases in the incidence of stage-1 AKI were
noted in each study arm [(conservative, 57 vs. 51% )
(liberal 66 vs. 58%)]. No impact of the different fluid
management strategies on the incidence of AKI in AKI
stages 2 or 3 was noted. Comparable mortality rates
between those patients in whom the AKI diagnosis was
masked versus those with known AKI before fluid
correction were also observed (31 vs. 38%). These
findings suggest that in addition to being an important
prognostic factor [34, 35], variations in fluid balance
can cause the diagnosis of AKI to be missed or delayed
in high-risk patients when using SCr-based definitions
alone. As further iterations of these definitions are
refined, these limitations continue to underscore the need
to effectively segregate evolving aspects of injury from
changes in function.
Estimation of the basal SCr
A standard definition for baseline SCr does not exist,
leading to heterogeneity across research studies [36]
and the potential for misinterpreting the true nature of
perturbed kidney function in hospitalised patients [21].
The baseline SCr value has been estimated in various
ways, such as the level on hospital admission [16, 37],
the minimum SCr level (nadir value) during the hospital
stay [37, 38], the value back-estimated from the MDRD
equation [6, 15] or the lowest value among these. The
choice of estimation technique used to obtain the baseline
SCr value has an effect on the prevalence of AKI, the
severity (or stage) of disease, and on the mortality risk
associated with various stages of AKI [36, 39].
The accuracy of commonly used methods for estimating
baseline SCr was compared with that of a reference
standard adjudicated by a panel of board-certified
nephrologists in 379 patients with AKI or CKD admitted
to a tertiary referral center [22]. It was found that

agreement between estimating methods and the reference

standard was highest when using SCr values measured
7365 days before admission, suggesting that the mean
outpatient SCr measured within a year of hospitalisation
most closely approximates nephrologist-adjudicated
basal SCr values. A follow-up study confirmed that the
use of these averaged outpatient SCr values also yields a
reliable value among high-risk patients, already suffering
from pre-existing CKD [40].

The urine output

RIFLE, AKIN and KDIGO use the same urine output
criteria to define AKI and to determine its severity. Since
exact data on urine output are not always available, only
a minority of retrospective studies have included urinary
output criteria. Theoretically, measuring the urine output
per hour in 6 or 12 h intervals as proposed by RIFLE,
AKIN and KDIGO requires continuous monitoring of the
diuresis which is practically limited to critically ill patients
admitted in an Intensive Care Unit (ICU). However, the
finding of acute oliguria, even crudely measured in a
24 hour urine collection can be an important and early
diagnostic tool of kidney dysfunction. Since many cases
of AKI occur in patients hospitalized in clinical wards it
could be recommended to instruct the patients to collect
the urine over 8 hours intervals in parallel with the
normal nursing shifts. When defined in these 6-8 hour
blocks, urinary output is independently associated with
mortality, morbidity, and renal outcomes [41, 42].
The importance of the urine volume output as parameter of
the AKI definition particularly in critically ill ICU patients
is illustrated by the study of Wlodzimirow and colleagues
[43], who prospectively studied the Risk Injury Failure
Loss End-stage renal disease (RIFLE) classification
with SCr and urine output (UO) (RIFLESCr+UO) and
without UO criteria (RIFLESCr) for AKI in 260 critically
ill patients. RIFLESCr significantly underestimated the
presence of AKI on admission and during the first week
in the ICU and significantly delayed AKI diagnosis.
In addition, using a large cohort of unselected critically
ill patients, another recent study [44] investigated
the empirical relationships among SCr, urine output,
observation period, in-hospital mortality, and renal
replacement therapy (RRT). To visualize the dependence
of adjusted mortality and RRT rate on SCr, the urine
output, and the observation period, contour plots were
generated that provide physicians with more complete
pictures of AKI with respect to in-hospital mortality risk
and anticipated need for RRT. In general, the severity of
AKI was high when (1) absolute SCr increase was high
regardless of observation period, (2) percentage SCr
increase was high and the observation period was long,
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Norbert Lameire

and (3) oliguria was sustained for a long period of time.

Similar contour patterns emerged for both in-hospital
mortality and RRT rates. Also this study illustrates the
importance of considering the duration of oliguria as one
of the parameters determining the outcome of critically
ill patients with AKI.
Validation of the KDIGO definition proposals
Not many studies have validated the definitions and
classification proposed by the KDIGO guidelines; some
critical remarks on the KDIGO proposal have been
formulated by other guideline making bodies such as
the ad-hoc working group of the European Renal Best
Practice working party [27], the Canadian Society of
Nephrology [45], the KDOQI US Commentary [46]
and the reader is referred to this literature. Most of the
concerns on the definitions of AKI as formulated by
KDIGO are focusing on the clinical application in the
individual patient of small increases in absolute SCr
values, the added value of considering urine output, the
determination of the baseline SCr, and the suggestion
of stage-based diagnostic and therapeutic interventions.
A recent study [26] proposed a novel approach to
classification and staging of AKI using absolute rather
than relative increases in SCr. Compared with the current
KDIGO consensus AKI staging, Delta-Creatinine staging
was found to be relatively simple and of better utility for
large-scale epidemiologic studies.
In this proposal, using delta-SCr allows for use of an index
SCr derived from samples mostly obtained on admission
of the patient rather than referring to pre hospitalization
baseline values, which are indeed not always readily
available. Of course, making a classification simpler not
necessarily means that it is more exact. As explained
above the use of an admission SCr is less sensitive for
diagnosing AKI and the admission index SCr is even more
susceptible to the same potential confounding influences
such as fluid overload and eventually decreased creatinine
production.
To the best of our knowledge there is only one study
where the 3 classical definitions and classifications for
AKI (RIFLE, AKIN, KDIGO) have been compared
with a more traditional worsening renal function (WRF)
definition, as used in the particular case of acute cardiorenal syndrome [47]. The comparison revealed that
there was a stepwise increase in primary outcome with
increasing stages of AKI severity using RIFLE, KDIGO,
or AKIN (p < 0.001). In direct comparison, there were
only small differences in predictive abilities between
RIFLE and KDIGO and WRF concerning clinical
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150

outcomes at 30 days (AUC 0.76 and 0.74 vs. 0.72) as

well as for KDIGO and WRF at 1 year (AUC 0.67 vs.
0.65).

Conclusion
The existing criteria proposed by RIFLE, AKIN, and
their adaptation by KDIGO are certainly useful and have
already been widely validated. As pointed out in this
paper, existing definitions of AKI are far from perfect
in that they rely on imperfect markers of renal function
rather than direct measures of kidney damage. However,
there is hope that in the future these considerations may be
made obsolete [28]. Novel biomarkers probably assessing
directly kidney injury are under intense investigation
[48]. However, kidney function will still remain a valid
and important parameter and it is likely that the next
generation of AKI criteria, besides functional parameters
will also include one or multiple injury biomarkers [49].

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