J Am Soc Nephrol 14: 21782187, 2003
Acute Renal Failure Definitions and Classification:
Time for Change?
RAVINDRA L. MEHTA* and GLENN M. CHERTOW
Divisions of Nephrology, Departments of Medicine, *University of California San Diego and University of
California San Francisco, for the PICARD Study Group.
Epidemiology of Acute Renal Failure
The development of acute renal failure (ARF) in the hospital
setting continues to be associated with poor outcomes (17).
Over the last three decades, several experimental models have
identified pathophysiologic mechanisms associated with ARF
and have enhanced our understanding of the disease (8 10). It
is evident that ARF can result from alterations in renal perfu-
sion, changes in glomerular filtration, and tubular dysfunction,
and that correction of these factors can ameliorate the effects of
ARF (11,12). On the basis of the identification of the under-
lying mechanisms, several new potential interventions have
been developed that have been shown to alter the course of
incipient and established ARF in experimental models (1315).
Application of these findings has resulted in improvements in
the prevention of ARF due to radiocontrast agents, aminogly-
coside antibiotics, and rhabdomyolysis (16,17). Several other
agents are now in advanced stages of development or initial
phases of clinical trials (18,19). In concert, advances in dialysis
have occurred with the availability of continuous renal replace-
ment therapies in addition to intermittent hemodialysis and
acute peritoneal dialysis (20 22).
It is well recognized that uncomplicated ARF can usually be
managed outside the intensive care unit (ICU) setting and
carries a good prognosis, with mortality rates less than 5% to
10% (23,24). In contrast, ARF complicating nonrenal organ
system failure in the ICU setting is associated with mortality
rates of 50% to 70%, which has not changed for several
decades (6,2530). These figures are in sharp contrast to the
experience with acute myocardial infarction (AMI), where
in-hospital mortality rates have declined from the range of 50%
to approximately 6% over the past 25 to 30 yr. Much of the
credit for improved AMI outcomes has been attributed to the
use of coronary care units, cardiac catheterization, aspirin,
-adrenergic antagonists, thrombolytic therapy, and, more re-
cently, specialized percutaneous coronary interventions and
glycoprotein IIbIIIa inhibitors (3134). In spite of improved
dialytic technology, including the development and refinement
Correspondence to Dr. Ravindra L. Mehta, UCSD Medical Center, 200 W.
Arbor Drive 8342, San Diego, CA 92103. Phone: 619-543-7310; Fax: 619-
543-7420; E-mail: rmehta@ucsd.edu
1046-6673/1408-2178
Journal of the American Society of Nephrology
Copyright 2003 by the American Society of Nephrology
DOI: 10.1097/01.ASN.0000079042.13465.1A
of continuous renal replacement therapies for the most criti-
cally ill patients, we have seen no material change in the high
mortality rates associated with ARF. Indeed, we have not
demonstrated any pharmacologic or other intervention effec-
tive in the early management of ARF. Interventions that have
been deemed ineffective (or potentially harmful) include the
following: loop and osmotic diuretic agents (35,36), renal
dose dopamine (37,38), atrial natriuretic peptide (39,40), in-
sulin-like growth factor-1 (41), and endothelin receptor antag-
onists (42).
Although ARF may develop in 5% or more of hospitalized
patients, the heterogeneity of ARF and associated comorbidity
make its study more difficult than AMI and other, more dis-
crete conditions. Among the impediments to progress in ARF
research is the lack of a uniform definition of ARF that might
be used to compare and contrast observational studies, and to
allow for rational design of clinical trials.
Relatively few studies have examined the incidence of hos-
pital-acquired ARF. The oft-cited study by Hou et al. (23)
reported an ARF incidence estimate of 4.9%. Shusterman et al.
(24) conducted a similar study identifying ARF in 1.9% of
hospitalized patients. A follow-up study recently published by
Hou and colleagues (43) showed an increase in incidence (7%),
but a similar spectrum of risk factors.
ARF in the ICU setting has also been characterized in the
last two decades. Liano et al. (6) found ICU patients with ARF
to have associated organ failure, sepsis, and other complica-
tions. It is well recognized that the development of ARF is
associated with an increase in mortality (22,25,26,44,45). It is
also known that patients with ARF as part of multiorgan failure
have the highest mortality rates. In several studies, sepsis-
related ARF had a significantly worse prognosis than ARF in
the absence of sepsis (46,47). It is also recognized that un-
treated ARF may contribute to a higher incidence of new-onset
sepsis (48).
Definition of ARF
The spectrum of definitions in published studies of ARF is
striking, ranging from severe (e.g., ARF requiring dialysis) to
relatively modest observable increases in serum creatinine
concentration (e.g., increase in serum creatinine of 0.3 to 0.5
mg/dl above baseline). Solomon et al. (36) used the definition
of an increase in serum creatinine of 0.5 mg/dl within 48 h of
radiocontrast exposure in a widely cited study that showed a
borderline significant difference in ARF among individuals
J Am Soc Nephrol 14: 21782187, 2003
given saline infusion versus furosemide or mannitol before
radiocontrast exposure. However, neither the Solomon et al.
study nor others that use this ARF definition (including the
Tepel et al. (49) and Kay et al. (50) publications on N-acetyl
cysteine) have shown an association between a transient
change in serum creatinine and morbidity, or the likelihood of
long-term recovery of renal function. Many other definitions of
ARF have been applied; some are outlined in Table 1. The
most liberal of definitions have been used in intervention
studies aimed at ARF prevention, usually in the context of
radiocontrast exposure, one of the few instances in which ARF
can be anticipated.
Several of the definitions are extremely complex (see Liano
et al. (6) and others) and could allow excessive subjectivity in
ARF determination. These would likely be impractical for
prospective, multicenter investigations. Moreover, none of the
definitions used to date take into account the modifying effects
of age, gender, and race on creatinine generation (and thereby
serum creatinine concentration in ARF). It is noteworthy that
creatinine generation is typically higher among individuals
who are younger, male, and African American (51). Therefore,
at the same decrement in GFR, persons with different demo-
graphic characteristics may be more likely to qualify with
ARF diagnoses, particularly those definitions that require a
minimum peak creatinine (e.g., 50% increase, to at least 2.0
mg/dl). By use of this definition, we found a twofold increase
in the incidence of amphotericin Bassociated ARF among
men (52). Whether male gender is a true risk for ARF or
simply a risk for being diagnosed with ARF is unclear. Re-
gardless, the association of ARF with male gender highlights
one of the limitations of the use of a definition of ARF that is
creatinine based and not age, gender, and race adjusted.
Changes in serum creatinine are not specific and do not
discriminate the nature and type of renal insult (e.g., ischemic,
nephrotoxic) or the site and extent of glomerular or tubular
injury, and levels are relatively insensitive to small changes in
GFR (53). Moreover, changes in serum creatinine may lag
behind changes (decline or recovery) in GFR by several days.
Finally, because serum creatinine is influenced by one of the
potential interventions for ARF (e.g., creatinine is removed by
dialysis), its specificity for renal recovery is even more
problematic.
Empiric Evidence of the Focus on Creatinine and
Urine Output
We recently completed an analysis focusing on correlates of
timing of nephrology consultation for ARF in the ICU (54). To
avoid the complexities of comparing individuals whose ARF
developed during a complicated ICU stay, we restricted our
analysis to those patients with evidence of ARF at ICU admis-
sion and excluded individuals designated as do not resusci-
tate. We considered a wide array of demographic, clinical,
laboratory, and physiologic variables (including pulmonary
artery catheter data in some patients). The serum creatinine
concentration and urine output (either as a continuous variable
or the dichotomous oliguria) (400 ml/d) were associated instance, the transition from sepsis to severe sepsis requires the
with the timing of consultation. There was no relation between
ARF Definitions 2179
the timing of consultation and hospital service, medical history,
physiologic parameters, other laboratory studies, or the pres-
ence or absence of organ system failure, despite the fact that
many of these factors have been shown to predict mortality in
ARF in other studies. In other words, empiric evidence dem-
onstrates that the definitions used in published reports are
operative in practice, with little attention to risk profiles or
associated nonrenal organ system failure.
Analogous Definitions in Other Conditions
Conceptual Framework for Disease Definitions. Dis-
ease definitions may be used to ascertain the presence of a
disease in an individual or a population, guide the nature and
timing of diagnostic and therapeutic interventions, and, in
individual patients, help determine prognosis. The presence of
any disease is inferred from a combination of clinical symp-
toms and signs, and alterations in biologic markers that can be
reproducibly measured. Measures defining a disease should be
responsive to change, track the natural history of the disease,
and provide an assessment of the severity of injury. Conse-
quences of the untreated disease and its response to specific
interventions are additional criteria that might be considered
when evaluating the choice of variables to define and classify
a disease. Most disease definitions rely on the presence of
specific markers that are measurably altered in response to an
injury, and the sensitivity and specificity of any definition
depends on the criteria used. These response variables may
appear at varying time points in the disease and help define the
course of the disease. Ideally, the magnitude and pattern of
change of the response variable correlate with disease
outcomes.
For instance, AMI can be diagnosed with the combination of
chest pain and elevated cardiac troponins or creatine phos-
phokinase. Gradations in the severity of signs (including elec-
trocardiography) and symptoms and the levels of troponin and
creatine phosphokinase profile allow further classification of
the disease spectrum (e.g., angina, unstable angina, demand
ischemia, silent ischemia, myocardial infarction). A key fea-
ture for AMI is that the clinical presentation is directly related
to an underlying event (i.e., coronary thrombosis). Moreover,
the markers are sensitive, specific, and correlate with the
severity of injury, even in the absence of typical clinical
features.
In contrast, sepsis is heterogeneous in its presentation and
affects multiple organs, so no single marker can be used to
define the presence or absence of disease. Recognizing this
limitation, a functional definition for sepsis has been based on
events in the natural history of the sepsis syndrome: systemic
inflammatory response syndrome, sepsis, severe sepsis, and
septic shock (55).
In the absence of specific markers, effective definitions for
a disease rely on multiple parameters, some of which represent
the specific response to the disease, whereas others reflect
nonspecific consequences of the disease. Disease severity is
graded on the basis of the presence of specific parameters. For
presence of sepsis-related organ dysfunction. These graded
2180 Journal of the American Society of Nephrology J Am Soc Nephrol 14: 21782187, 2003

Table 1. Alternative ARF definitions from several published studies

Author Definition

Solomon et al. (36), Tepel et al. (49), 0.5 mg/dl increase in (SCra) within 48 h
Schwab et al. (81), Weisberg et al.
(82), Stevens et al. (83), and others

Hou et al. (23) 0.5 mg/dl increase in SCr if baseline SCr 1.9 mg/dl, or 1.0 mg/dl
increase in SCr if baseline SCr 2.0 to 4.9 mg/dl, or 1.5 mg/dl increase in
SCr if baseline SCr 5.0 mg/dl
Shusterman et al. (24) 0.9 mg/dl increase in SCr if baseline SCr 2.0 mg/dl, or 1.5 mg/dl
increase in SCr if baseline SCr 2.0 mg/dl, and remained elevated for at
least one additional consecutive determination

Liano and Pascual (84) Sudden rise of 2 mg/dl in subjects with prior normal renal function,
or sudden increase in SCr of 50% with mild to moderate basal
chronic renal failure with SCr 3.0 mg/dl, or elevation of SCr at
admission with normal or increased renal size (except with myeloma or
hydronephrosis with cortical atrophy)

Bates et al. (52) 50% increase in SCr to at least SCr of 2.0 mg/dl (ARF)
100% increase in SCr to at least SCr of 3.0 mg/dl (severe ARF)

Levy et al. (48) 25% increase in SCr to at least SCr of 2.0 mg/dl within two days

Behrend and Miller (1) 0.9 mg/dl increase in SCr if baseline SCr 2.0 mg/dl to at least 2.0 mg/dl,
or 1.5 mg/dl increase in SCr if baseline SCr 2.0 mg/dl (baseline defined
as lower of most recent SCr in past 3 mo or lowest value during
hospitalization)

Obialo et al. (51) 0.5 mg/dl increase in SCr to at least 2.0 mg/dl, or admission SCr 2.0
mg/dl with no history of renal disease

Kurnik et al. (85) 0.5 mg/dl increase in SCr or 25% increase from baseline within 48 h
Wang et al. (42)

Hirschberg et al. (41) SCr 3.0 mg/dl with baseline SCr 1.8 mg/dl, or acute decrease in
creatinine clearance to 25 mL/min after surgery, trauma, hypotension, or
sepsis

Allgren et al. (39) 1.0 mg/dl increase in SCr over 2 days

Parfrey et al. (86) 50% increase in SCr to at least 1.4 mg/dl

Cochran et al. (87) 0.3 mg/dl and 20% increase in SCr

Eisenberg et al. (88) 1.0 mg/dl increase in SCr, or 20 mg/dl or 50% increase in BUN

Lautin et al. (89) 6 graded criteria

0.3 mg/dl and 20% increase in SCr on day 1, 2, or 3, and day 5, 6, or
7, or 0.3 mg/dl increase in SCr on day 1, 2, or 3, or 0.3 mg/dl and
20% increase in SCr on day 1 or 2, or 2.0 mg/dl increase in SCr on
day 1 or 2, or 1.0 mg/dl increase in SCr on day 1, or 20 mg/dl or
50% increase in BUN on day 1

Fiaccadori et al. (90) 50% increase in SCr in absence of volume responsive prerenal status,
or 1 mg/dl increase in SCr with known renal insufficiency

Taylor et al. (91) 0.3 mg/dl increase in SCr

a
ARF, acute renal failure; SCr, serum creatinine.
J Am Soc Nephrol 14: 21782187, 2003
definitions are more readily applied to classify populations,
although they have also been used to guide interventions in
individual patients and research subjects (56,57).
The multidimensional definition and classification construct
has been applied to several diseases where a single specific
diagnostic criterion is not available or is otherwise unsuitable.
For example, the Ranson criteria enable early classification of
severe acute pancreatitis (58). These criteria rely on the pres-
ence of three or more of the 11 criteria evident within 48 h of
admission. Criteria include age and a series of laboratory
parameters that reflect consequences of disordered pancreatic
function (i.e., hyperglycemia in absence of diabetes, hypocal-
cemia, azotemia, anemia, hypoalbuminemia, leukocytosis, el-
evations of the hepatic enzymes lactate dehydrogenase and
aspartate aminotransferase) and physiologic variables (i.e.,
metabolic acidosis, hypoxia) to grade the response. Interest-
ingly, serum amylase and lipase, enzymes directly related to
pancreatic injury (and analogous to creatinine in ARF), are not
included in the scoring system. The number of positive criteria
are associated with mortality ranging from 5% for zero to
two criteria to 100% for seven to eight criteria (58). Similarly,
the Child-Pugh classification is a means of assessing the se-
verity of hepatic cirrhosis (59). It assigns scores for each of
three laboratory parameters (bilirubin, albumin, and prothrom-
bin time) and two clinical criteria representing the conse-
quences of liver failure (encephalopathy and ascites). The
individual scores are summed and then grouped as 7 (A), 7
to 9 (B), and 9 (C). A Child-Pugh C classification forecasts the lack of demonstrable benefit. It is also recognized that
survival of less than 12 mo. Cancer staging similarly uses the
tumor node metastasis grading system to classify malignant
disease. Common to all of these classification systems is the
lack of any single criterion to diagnose the disease and reliance
on the consequences of the disease and on other factors influ-
encing the course of the disease for classification. We propose
that ARF be viewed in a similar manner; in terms of complex-
ity of diagnosis and subsequent organ effects, ARF has more in
common with sepsis or pancreatitis than with AMI.
What Are Desired Characteristics of Disease-Defining
Variables in ARF? For any condition, the clinician needs to
know whether the disease is present, and where and when the
patient falls in the natural history of the disease. The former
facilitates recognition, whereas the latter could identify time
points for intervention. Thus, disease-defining variables should
allow recognition of the disease and provide a mechanism to
determine the time course of the disease. Renal functional
alterations encompass many dimensions (e.g., vascular, endo-
thelial, tubular, glomerular), and markers specific for the site
and pattern of injury are lacking. Several new techniques are
emerging to study ARF and are poised to be adapted for human
studies (60). Recently, Ichimura et al. (61) and Han et al. (62)
demonstrated that KIM-1 may be an early marker for renal
injury specific for the renal tubule. Star et al. (63) and Mura-
matsu et al. (64) have described new markers for kidney
disease, including a new cysteine-rich protein (CYP 61) that is
found in urine after ischemia-reperfusion injury. Other studies
have utilized a spectrum of markers for renal injury but none
have been tested in a large number of patients (65). Recent
ARF Definitions 2181
advances in proteomics will likely provide new targets for
assessment (66).
Several methods exist for estimating changes in GFR (Table
2); however, each technique has limitations. Urinary markers
may be the most practical, and techniques for rapid assessment
of changes in GFR and these markers are being validated
(60,67). Cystatin C appears to be a promising marker for
changes in GFR but requires validation in the ICU and other
settings (68). Magnetic resonance imaging methods that use
newer contrast agents are being tested in experimental models
of ARF and could provide information on intrarenal hemody-
namics (69), the level and extent of proximal tubule dysfunc-
tion (70), and the presence of renal inflammation (71). It is
evident that knowledge of the site and extent of injury would
permit a precise determination of the underlying severity of
renal dysfunction, could facilitate clinicopathologic correla-
tions, and could help guide specific therapeutic interventions.
Applying Lessons from Other Diseases to ARF
Why Change? It is evident that current definitions of ARF
that rely on serum creatinine and urine output do not ade-
quately characterize the spectrum of ARF observed in clinical
practice. Additionally, in their current form, they do not sup-
port the clinical need to inform decisions for therapeutic inter-
ventions. Indeed, variation in the timing of drug delivery
relative to renal injury has contributed to heterogeneity in
intervention studies in ARF and may be partly responsible for
processes of care (including the timing of initiation of dialysis,
provision of nutrition, and the use of diuretics) likely influence
the course of, and outcomes from, ARF. Simply put, better
diagnostic and classification tools are required to allow for
advances in ARF research and clinical practice.
What Is Required? We must focus on two separate but
related issues. First, we need to expand the repertoire of sen-
sitive and specific markers to quantify the site and severity of
renal injury and to track functional change over time. Second,
we need to more clearly define the course of ARF in a variety
of settings and identify factors that condition the renal response
to injury and influence outcomes from ARF. Gaining this
knowledge will increase diagnostic specificity and allow for
more appropriate evaluation of interventions. For instance, the
Table 2. Comparison of methods for determination of GFR
Testing Clinical
Clearance Method Accuracy
Complexity Utility
Classic inulin clearance
Radioisotope clearance 1/2
Radioisotope plasma
disappearance
Creatinine clearance
Nomogram creatinine 1/2 1/2
clearance
Serum creatinine
2182 Journal of the American Society of Nephrology J Am Soc Nephrol 14: 21782187, 2003

dose of radiocontrast agent and underlying renal function de-
termine the trajectory of creatinine elevation and incidence of
radiocontrast-associated nephropathy (72). In most circum-
stances, elevations in serum creatinine are seen within 48 h
after radiocontrast exposure, so that the efficacy of a preven-
tive therapy or early therapeutic intervention can be assessed
perievent (50). In contrast, when the nature and timing of insult
are less well characterized (e.g., episodes of hypotension in a
postoperative patient with sepsis), trends in serum creatinine
and urine output are less predictable (7375). Comparison of
the actual pattern of illness with the predicted response could
help to guide the timing of specific interventions, and ulti-
mately compare two or more interventions in clinical trials.
How Can We Do It? Given the heterogeneity of ARF and
the absence of specific markers for renal injury, an effective
diagnostic and classification scheme should consider parame-
ters other than the renal response to injury. Nonrenal organ
system dysfunction also affects the ARF episode. For instance,
serum creatinine levels may underestimate the severity of renal
dysfunction in hepatic failure with elevated bilirubin levels
(53) and the requirement for mechanical ventilation may fur-
ther reduce GFR (76). In other diseases, susceptibility and
response factors have been incorporated in the definition and
classification of disease (see above, and the recent Predisposi-
tion, Infection, Response, Organ Failure [PIRO] classification
for sepsis (77)).
Defining ARF: Multidimensional Criteria
To optimize the approach to ARF, we should gain insight
into several domains: factors that predispose to injury, the
nature and timing of the inciting event, the response of the
kidney to the insult, and the later consequences of the ARF
episode. We propose that a new definition for ARF should
incorporate elements from each of these domains. This ap-
proach would lead to a more robust definition for the ARF
syndrome and would facilitate the assessment of future inter-
ventions in this field. Table 3 describes a proposed definition
for ARF that incorporates variables from each of the four
domains noted above. Each domain is graded. An increasing
grade reflects an increased risk of adverse outcomes.
We propose a framework for staging ARF that is based on
the criteria within each domain. We based susceptibility
grade roughly on the risk of ARF derived from epidemiologic
studies. We grade the nature and timing of the insult on the
basis of knowledge of the specific insult and the time interval
from the insult to the point of evaluation. We grade the re-
sponse variables after the RIFLE (Risk, Injury, Function, Loss,
End Stage) criteria suggested by the Acute Dialysis Quality

Table 3. Proposed classification of acute renal dysfunction

Stage
Domain (44, 54, 92)
1 2 3 4

Susceptibility None Known pre-existing Pre-existing chronic Pre-existing kidney disease

Baseline GFR kidney disease kidney disease (CKD stage 2 or 3 or
90 ml/min/ (CKD stage 2)a (CKD stages 3 above) GFR 89 ml/
1.73 m2 baseline GFR 60 and above); min/1.73 m2 presence
to 89 mL/min/ baseline GFR of one risk factorb
1.73 m2 60 mL/min/
1.73 m2
Insult
nature Known Known Unknown Unknown
timing Within 24 h 24 to 48 h 48 h Unknown
Responsec
biomarker creatinine/ Increase 0.5 to 1 Increase 1 to 2 mg, Increase 2.0 mg/ Increase 3.0 mg/dl, GFR
GFR mg, GFR GFR decrease by dl, GFR decrease 10 ml/min/1.73 m2
decrease 25 to 50 to 74% 75%
49%
physiologic urine UO 0.5 ml/kg/ UO 0.5 mL/kg/h UO 0.3 ml/kg/h for Anuria
output h for 3 h for 12 to 23 h 24 h or anuria
for 12 h
End-organ consequences
Nonrenal organs None Single organ Two organs 2 organs
failingd
a
K/DOQI Clinical Practice Guidelines for Chronic Kidney Disease (CKD) (93).
b
Risk factors include diabetes mellitus with microalbuminuria, dehydration, multiple myeloma, congestive heart failure, and
decompensated cirrhosis.
c
Based on consensus RIFLE criteria proposed by ADQI (78).
d
Respiratory, CV, neurological, hematological, liver, based on organ system failure criteria (44).
J Am Soc Nephrol 14: 21782187, 2003
Initiative (ADQI) consensus conference (78). We define non-
renal organ dysfunction by using standardized organ failure
scores (44). Gradations in the susceptibility and insult vention (79). This approach is similar in concept to sepsis
domains reflect increasing levels of risk for an adverse out-
come, whereas those in the response and end-organ do- defined for targeted therapeutic intervention. The multicenter
mains reflect an increasing severity of illness. We anticipate
that at each point of assessment, individual patients would be
graded within each domain. On the basis of the overall status
in the four domains, patients would be categorized into the
stage of ARF and would move through various stages during
the course of the disease (Table 3).
Past and Present Constructs in ARF
Myers et al. (75) demonstrated three distinct patterns of
ARF after surgery. On the basis of these observations, it is
widely taught that clinical ARF has three phases: initiation,
maintenance, and recovery. The duration of each phase varies
on the basis of the presence of pre-existing kidney disease and
the nature and type of insult. Sutton et al. (12) and Molitoris
(79) have recently proposed a mechanistic classification for
ischemic ARF that delineates four distinct phases for this
disease: initiation, extension, maintenance, and recovery (Fig-
ure 1). Variability in response has also been established in
experimental ARF wherein the response can be graded on the
basis of preconditioning for the model, and this variability is
being explored as a therapeutic strategy (e.g., ischemic precon-
ditioning may reduce the response to subsequent insults) (80).
Multifactorial insults accelerate the decline in renal function in
ARF. For any given patient, the pattern of ARF will depend on
his or her susceptibility to injury and the nature (type, site) and
severity (single or multiple, duration) of injury. The renal
response is likely to be dependent on these two factors and may
in turn determine nonrenal organ dysfunction. If the course is
prolonged, nonrenal organ dysfunction will further affect the
renal response.
By characterizing individuals on the basis of four domains,
Figure 1. Phases of ischemic acute renal failure (ARF). Therapies
aimed at (A) preventing, (B) limiting the extension phase, and (C)
treating established ARF. Reprinted from reference 79, with
permission.
ARF Definitions 2183
it may be possible to more accurately define the time course of
disease and consequently detect distinct time points for inter-
syndrome, where distinct windows of opportunity have been
trial of recombinant activated protein C required the drug to be
initiated within 24 h of the first sepsis-induced organ system
failure (57). If the nature and timing of the insult in ARF were
clearly defined, one could select a specific therapeutic agent
directed to ameliorate the injury and deliver the agent within a
known therapeutic window. If the renal response can be char-
acterized, supportive therapy can be instituted, and depending
on the presence or absence of the underlying nonrenal organ
dysfunction, specific interventions, such as dialysis support,
could be optimized.
How Could the Clinician Use These Definitions?
The proposed definitions could be used to establish the pres-
ence of disease by using the response variable graded for the
susceptibility for ARF and knowledge of the insult. An increase in
serum creatinine of 0.7 mg/dl with a susceptibility grade of 4 and
an insult grade of 3 is more likely to represent significant injury
(and to be accompanied by more dire consequences) than if the
susceptibility and insult grades were 1 and 1, respectively. With
an end-organ grade of 3, a similar increase in serum creatinine
might require dialytic intervention.
A comparison of patients actual versus predicted course
could be useful in refining diagnostic and classification crite-
riaand ultimately in efforts aimed at quality assurance and
improvement. The multidimensional approach can be illus-
trated with hypothetical cases. A patient with diabetes mellitus,
baseline creatinine 1.2 mg/dl, and no proteinuria (susceptibility
grade 2) seen 36 h after a contrast load (insult grade 2) with a
urine output of 2 L/d and a follow-up serum creatinine of 2.5
mg/dl (response grade 2) with no nonrenal end-organ damage
(end-organ grade 1) would be classified S2-I2-R2-E1. A
revaluation 48 h later shows a change in serum creatinine to 3.5
mg/dl and a decrease in urine output to 400 ml/d without
evidence of end-organ dysfunction (now stage S2-N2-R3-E1).
On the basis of these two time points, it is evident that this
hypothetical patient has experienced a continued decline in
renal function, representing either an extension phase from the
original injury or ongoing injury. Because the expected trajec-
tory for change in renal function based on the timing of the
contrast load would have been a return to baseline creatinine
within roughly 96 h, the deviation from the predicted response
would suggest an extension of the initial injury (Figure 1). A
targeted therapeutic intervention with a molecule that could
ameliorate injury or promote repair could then be timed for this
phase.
In a second example, a postcardiac surgery patient who
required emergency coronary artery bypass grafting and aortic
valve replacement is evaluated 5 d after surgery. The patient is
80 yr old with a baseline creatinine of 2.0 mg/dl and a history
of hypertension. Postoperatively, his serum creatinine in-
creased slowly from 1.8 to 3.5 mg/dl with adequate urine
output (900 ml/d) on an intravenous bumetanide drip. There
2184 Journal of the American Society of Nephrology
was no decline in blood pressure during surgery or postoper-
atively, and he has not received any nephrotoxic agents. There
was no evidence for infection or sepsis. At evaluation on
postoperative day 5, he is mechanically ventilated with satis-
factory oxygenation on supplemental oxygen and requires two
vasopressors to maintain a mean arterial blood pressure of 60
mmHg. His total bilirubin is 7 mg/dl and serum albumin 2.8
g/dl. On the basis of records of daily fluid balance, he is
estimated to have 6 L of extracellular volume excess. Accord-
ing to current nomenclature and diagnostic methods, he would
be considered to be nonoliguric, acute on chronic renal failure.
Many internal medicine and critical care physicians (and neph-
rologists) would not intervene with dialysis or hemodiafiltra-
tion in this case because the patient is still making urine and
has no life-threatening biochemical abnormalities. By use of
the proposed classification scheme, this patient would be S3-
I4-R3-E3. Given the presence of end-organ damage and ongo-
ing reduction in renal function, a case could be made to
institute dialytic support, although currently there is no evi-
dence base on which to make this recommendation. Certainly,
providing detailed data on outcomes associated with S3-I4-
R3-E3 patients (not unusual in clinical practice) would be more
valuable to decision making than data on all patients classified
as nonoliguric, acute on chronic renal failure.
Providing a Framework for Experimental and
Clinical Research
Although a more detailed diagnostic and classification sys-
tem would be valuable to clinicians, it could also be used to
rationalize certain aspects of research. For example, in a trial
comparing dialysis modality or intensity, one could specify
that dialysis should begin for S2-I3 subjects with R3 re- rates in the single digits.
gardless of E, or R2 with E stage of 2 or greater. A more
comprehensive and flexible classification scheme could ac-
commodate new and improving markers derived from genomic
and proteomics investigations. For instance, if susceptibility
genes were discovered that predict the renal response, these
could be included as new criteria in the susceptibility domain.
Similarly, new injury markers could be included in the insult
domain and provide more specific information on the nature
and severity of disease. Other markers of renal function (e.g.,
cystatin C) or of organ dysfunction (e.g., cytokines) could be
included to enhance other domains.
Advantages and Limitations
The proposed definitions are based on concepts tested in
other settings such as acute pancreatitis, liver disease, and
sepsis. The suggested criteria are universally applicable and
easy to obtain. The schema could be applied to describe a
population or for individual bedside decision making. The
schema proposed could also facilitate and accommodate future
discoveries. However, there are several limitations to (and
concerns with) our proposal. First, we believe that the four
domains described are important, but the performance and
relative contribution of each domain to the definition and
classification scheme has not been tested. We do not know
whether these domains are the correct ones or whether there are
J Am Soc Nephrol 14: 21782187, 2003
others that need to be identified. We do not have sensitive
markers for defining the consequences of renal dysfunction.
We need to define the nature and severity of underlying disease
with the markers at hand. We need proof that the cutpoints
established for response variables are related to outcomes and
are appropriate ones. We must explore the interactions of the
variables to determine whether additional conditional defini-
tions would be preferred. It is evident that future studies need
to evaluate the utility of the proposed definition in several
settings. However, we propose a new diagnostic and classifi-
cation scheme to help rationalize bedside management and
intellectual inquiry into this condition.
Summary
ARF continues to be a vexing problem occupying a signif-
icant amount of time for clinicians and offering numerous
challenges to investigators. Despite the recognition that ARF
contributes to adverse outcomes in the critically ill, little
progress has been made in managing this condition. One of the
key impediments to progress is the lack of a uniform definition
for this disease. Current definitions that rely on changes in
serum creatinine and urine output are neither sensitive nor
specific. We propose a new classification for ARF that incor-
porates information from other domains in an effort to enhance
descriptive data and, we hope, improve decision making. Fu-
ture studies will need to validate the multidimensional diag-
nosis of ARF construct and to improve the content and pre-
cision of components within each domain. What we present
here (or a variation thereof) is not definitive, just a necessary
first step. On the frontier, we see much more precision in ARF
definitions, effective interventions, and, ultimately, mortality
Acknowledgments
This study was supported by a grant from the Agency for Health
Care Policy Research (ROI HS06466) and by NIH NIDDK R01
DK53412-02. The Project to Improve Care in Acute Renal Disease
(PICARD) study group includes the University of California San
Diego, University of California San Francisco, Cleveland Clinic
Foundation, Vanderbilt University, and Maine Medical Center.
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