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Acute renal failure (ARF) has traditionally been defined as the abrupt loss of kidney function that results in the retention of urea and other nitrogenous waste products and in the dysregulation of extracellular volume and electrolytes. The loss of kidney function is most easily detected by measurement of the serum creatinine which is used to estimate the glomerular filtration rate (GFR).

Three problems are associated with the use of the serum creatinine to quantitatively define ARF:

* Serum creatinine does not accurately reflect the GFR in a patient who is not in steady state. In the early stages of severe acute renal failure, the serum creatinine may be low even though the actual (not estimated) GFR is markedly reduced since there may not have been sufficient time for the creatinine to accumulate. (See "Assessment of kidney function: Serum creatinine; BUN; and GFR".)
* Creatinine is removed by dialysis. As a result, it is usually not possible to assess kidney function by measuring the serum creatinine once dialysis is initiated. One exception is when the serum creatinine continues to fall on days when hemodialysis is not performed, indicating recovery of renal function.
* Numerous epidemiologic studies and clinical trials have used different cut-off values for serum creatinine to quantitatively define ARF [1].

The lack of consensus in the quantitative definition of ARF, in particular, has hindered clinical research since it confounds comparisons between studies. Some definitions employed in clinical studies have been extremely complex with graded increments in serum creatinine for different baseline serum creatinine values [1,2]. As an example, in a classic study of the epidemiology of hospital-acquired acute renal failure, ARF was defined as a 0.5 mg/dL increase in serum creatinine if the baseline serum creatinine was ≤1.9 mg/dL, an 1.0 mg/dL increase in serum creatinine if the baseline serum creatinine was 2.0 to 4.9 mg/dL, and a 1.5 mg/dL increase in serum creatinine if the baseline serum creatinine was ≥5.0 mg/dL [2].

The Acute Dialysis Quality Initiative (ADQI) was created by a group of expert intensivists and nephrologists to develop consensus and evidence based guidelines for the treatment and prevention of acute renal failure [3]. Recognizing the need for a uniform definition for ARF, the ADQI group proposed a consensus graded definition, called the RIFLE criteria [4]. A modification of the RIFLE criteria was subsequently proposed by the Acute Kidney Injury Network, which included the ADQI group as well as representatives from other nephrology and intensive care societies [5-7].

Because of these initiatives, the term acute kidney injury (AKI) was proposed to represent the entire spectrum of acute renal failure. This topic review will address the current definitions of acute renal failure, particularly the RIFLE criteria and the AKIN modifications.

RIFLE CRITERIA — The RIFLE criteria consists of three graded levels of injury (Risk, Injury, and Failure) based upon either the magnitude of elevation in serum creatinine or urine output, and two outcome measures (Loss and End-stage renal disease). The RIFLE strata are as follows [4]:

* Risk — 1.5-fold increase in the serum creatinine or GFR decrease by 25 percent or urine output <0.5 mL/kg per hour for six hours
* Injury — Twofold increase in the serum creatinine or GFR decrease by 50 percent or urine output <0.5 mL/kg per hour for 12 hours
* Failure — Threefold increase in the serum creatinine or GFR decrease by 75 percent or urine output of <0.5 mL/kg per hour for 24 hours, or anuria for 12 hours
* Loss — Complete loss of kidney function (eg, need for renal replacement therapy) for more than four weeks
* ESRD — Complete loss of kidney function (eg, need for renal replacement therapy) for more than three months (figure 1)

The RIFLE criteria correlated with prognosis in a number of studies [8-14]. As an example, a systematic review of 13 studies demonstrated a stepwise increase in the relative risk of death in patients who met the RIFLE criteria for various stages of AKI [14]. Compared to patients who did not have AKI, patients in the RIFLE stages of "risk," "injury," and "failure" had increased relative mortality risks of 2.4 (CI 1.94-2.97), 4.15 (CI 3.14-5.48), and 6.37 (CI 5.14-7.9). Despite significant heterogeneity among studies, results from most individual reports were qualitatively similar.

Limitations — There are several important shortcomings to the RIFLE criteria:

* The "risk," "injury," and "failure" strata are defined by either changes in serum creatinine or urine output. The assignment of the corresponding changes in serum creatinine and changes in urine output to the same strata are NOT based on evidence. In the one assessment of the RIFLE classification that compared the serum creatinine and urine output criteria, the serum creatinine criteria were strong predictors of ICU mortality, whereas the urine output criteria did not independently predict mortality [12]. Thus, if the RIFLE classification is used to stratify risk, it is important that the criteria that result in the least favorable RIFLE strata be used [4].
* As mentioned above, the change in serum creatinine during acute renal failure does not directly correlate with the actual change in glomerular filtration rate, which alters the assignment of that patient to a particular RIFLE level. As an example, in a patient with an abrupt decline in renal function in the setting of severe ARF, the serum creatinine might rise from 1.0 to 1.5 mg/dL (88.4 to 133 micromol/L) on day one, 2.5 mg/dL (221 micromol/L) on day two, and 3.5 mg/dL (309 micromol/L) on day three. According to the RIFLE criteria, the patient would progress from "risk" on day one to "injury" on day two and "failure" on day three, even though the actual GFR has been <10 mL/min over the entire period. This issue is intrinsic to any assessment of acute renal failure based upon the serum creatinine level.
* It is impossible to calculate the change in serum creatinine in patients who present with ARF but without a baseline measurement of serum creatinine. The authors of the RIFLE criteria suggest back-calculating an estimated baseline serum creatinine concentration using the four-variable MDRD equation, assuming a baseline GFR of 75 mL/min per 1.73 m2 [4]. However, this approach has not been prospectively validated.

AKIN CRITERIA — Given these limitations, a modification of the RIFLE criteria has been proposed by the Acute Kidney Injury Network. The AKIN proposed both diagnostic criteria for ARF and a staging system that was based on the RIFLE criteria [5-7]. In addition, the term acute kidney injury (AKI) was proposed to represent the entire spectrum of acute renal failure.

Diagnostic criteria — The proposed diagnostic criteria for ARF are an abrupt (within 48 hours) absolute increase in the serum creatinine concentration of ≥0.3 mg/dL (26.4 micromol/L) from baseline, a percentage increase in the serum creatinine concentration of ≥50 percent, or oliguria of less than 0.5 mL/kg per hour for more than six hours (table 1).

The latter two of these criteria are identical to the RIFLE "risk" criteria. The addition of an absolute change in serum creatinine of ≥0.3 mg/dL is based on epidemiologic data that have demonstrated an 80 percent increase in mortality risk associated with changes in serum creatinine concentration of as little as 0.3 to 0.5 mg/dL [15]. Including a time constraint of 48 hours is based upon data that showed that poorer outcomes were associated with small changes in the creatinine when the rise in creatinine was observed within 24 to 48 hours [16,17].

Two additional caveats were proposed by the AKIN group:

* The diagnostic criteria should be applied only after volume status had been optimized
* Urinary tract obstruction needed to be excluded if oliguria was used as the sole diagnostic criterion.

A flaw with the last caveat is that, according to the current definition, AKI would still be used to describe the patient with acute urinary tract obstruction and an acute increase in serum creatinine. 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 [18].

Staging system — The classification or staging system for ARF is comprised of three stages of increasing severity, which correspond to risk (stage 1), injury (stage 2), and failure (stage 3) of the RIFLE criteria. Loss and ESRD are removed from the staging system and defined as outcomes.

The clinical applicability of these staging systems is uncertain. However, they will likely have some utility in standardizing the definitions for epidemiologic studies and for establishing inclusion criteria and endpoints for clinical trials.

Ultimately these definitions are likely to be replaced by more sensitive and specific biomarkers of renal injury.

CLINICAL UTILITY — The RIFLE and AKIN criteria have helped to focus attention that decrements in renal function that result in small changes in serum creatinine concentration are associated with significant clinical consequences. However, the precise clinical utility of these criteria is uncertain. There is also an inherent confusion within these criteria as to whether prerenal and obstructive etiologies of ARF are subsumed in or are external to the definition of AKI.

We believe that these criteria have greatest utility in epidemiologic studies and in defining consistent inclusion criteria and/or endpoints for clinical studies. Their utility at the bedside is less clear and it seems likely that they will eventually be replaced at least in part by sensitive and specific biomarkers of renal tubular injury. The use of such biomarkers, analogous to troponin as a marker of myocardial injury, will permit development of a new paradigm for classifying acute kidney injury that is not solely dependent upon serum creatinine or other functional markers.

We do believe that adoption of the term acute kidney injury (AKI) to replace the older terminology of acute renal failure is highly appropriate. Just as acute lung injury is used to describe acute pulmonary injury that has not progressed to overt organ failure, we believe that AKI is more representative of the full spectrum of acute kidney dysfunction.

SUMMARY

* Acute renal failure (ARF) has traditionally been defined as the abrupt loss of kidney function resulting in the retention of urea and other nitrogenous waste products and in the dysregulation of extracellular volume and electrolytes. (See 'Introduction' above.)
* Although the loss of kidney function is most easily detected by measurement of the serum creatinine, several problems are associated with the use of this measure to quantitatively define ARF, particularly the lack of consensus in the quantitative definition. (See 'Introduction' above.)
* The Acute Dialysis Quality Initiative (ADQI) has proposed a graded definition of ARF called the RIFLE criteria. The Acute Kidney Injury Network (AKIN) modified the RIFLE criteria in order to include less severe ARF, to impose a time constraint of 48 hours, and to allow for correction of volume status and obstructive causes of ARF prior to classification. (See 'Rifle criteria' above and 'AKIN criteria' above.) These criteria have their greatest utility in epidemiologic studies.
* The AKIN proposed the term acute kidney injury (AKI) to represent the entire spectrum of acute renal failure. The proposed diagnostic criteria are an abrupt (within 48 hours) absolute increase in the serum creatinine concentration of ≥0.3 mg/dL (26.4 micromol/L) from baseline, a percentage increase in the serum creatinine concentration of ≥50 percent, or oliguria of less than 0.5 mL/kg per hour for more than six hours. These criteria will likely be revised, and possibly replaced, as biomarkers of tubular injury are developed. (See 'Diagnostic criteria' above.)
* We agree that adoption of the term acute kidney injury to replace the older terminology of acute renal failure is highly appropriate. AKI better represents the full spectrum of acute kidney dysfunction. (See 'Clinical utility' above