What Is Acute Kidney Injury (AKI)?

Acute kidney injury (AKI) is a subset of acute kidney diseases and disorders (AKD), that encompasses all acute renal conditions and is contrasted by chronic kidney disease (CKD).1

According to the International Society of Nephrology, approximately 1.7 million deaths per year worldwide can be attributed to AKI. In addition to long lengths of hospital stays (LOS), severe AKI sequelae can range from life-long dialysis to kidney transplantation.1

A sudden decrease in renal function, indicated by renal failure and/or a decline in glomerular filtration rate (GFR), is considered an AKI. 

The diagnostic criteria and severity classifications for AKI use serum creatinine (SCr) and urine output (UO) as surrogate parameters (Figure 1).2 However, in a study by Chertow et al., modest changes in SCr were significantly correlated with mortality, LOS, and hospital costs. This correlation remained even after adjustment for a variety of factors such as age, gender, admission by the International Classification of Diseases (ICD), modification diagnosis, severity of illness (diagnosis-related group weight), and CKD status. An increase in SCr greater than 0.5 mg/dL was associated with a 6.5-fold (95% CI [5.0, 8.5]) increase in the odds of death (Figure 2), a 3.5-day increase in LOS, and nearly$7500 excess in hospital costs (Figure 3).3

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Risk, Injury, Failure, Loss, and End-Stage Renal Disease (RIFLE)

In 2002, the Acute Dialysis Quality Initiative (ADQI) proposed the Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease (RIFLE) classification for AKI. This classification would allow for both the detection of patients with slightly affected renal function (high sensitivity but low specificity) and of those with severe kidney function deterioration (high specificity with diminishing sensitivity).4

RIFLE was the first AKI risk stratification system. Risk, Injury, and Failure severity classes were defined according to the degree of SCr increase or UO decrease, whichever is greater. Loss and end-stage renal disease (ESRD) were outcome classes determined by the duration of kidney function loss.4

RIFLE allows the stratification of AKI prognosis with each successive category reflecting a progressively higher patient mortality. A nearly linear increase in hospital mortality was found in a retrospective, single-center study by Uchino et al. evidencing correlation with the RIFLE classes (normal, 4.4%; Risk, 15.1%; Injury, 29.2%; and Failure, 41.1%), with patients at risk having upwards of three times the mortality rate of patients without AKI. The odds ratio of hospital mortality was 2.5 for Risk class, 5.4 for Injury class, and 10.1 for Failure class.6

RIFLE has proven itself an important tool in predicting patient outcomes, but it is not without limitations:

• It is unable to detect kidney failure before it is already underway. A baseline level of SCr is necessary to define and classify AKI, but a baseline level is frequently not known.
  

• Using SCr as a surrogate for renal function has several limitations:5
  

• There are a number of variables influencing creatinine levels (age, gender, diet, race, and muscle mass) thus SCr is not entirely determined by changes in renal clearance.
  

• In addition to filtration, tubular secretion accounts for 10-40% of creatinine elimination, leading to an overestimation of renal function in AKI patients if only assessing GFR.
  

• SCr will increase when there is reduced tubular secretion of creatinine, unrelated to changes in renal function. This reduction can be caused by commonly used drugs such as trimethoprim and cimetidine.
  

• The kidney is remarkably resilient, and as such, renal function and SCr can remain unchanged even in the presence of renal lesions.
  

• Stratifications by SCr and UO are not synonymous, and they are not equivalent in defining the severity of illness. Within the same class, patients stratified according to SCr are more severely ill than those stratified according to UO (in-hospital Failure class based on GFR of 27.9% vs UO of 21.9%, p = 0.020).7 
  

• UO inclusion is critical for the incidence and grading of AKI, however the predictive ability of UO for AKI is hindered by interfering variables:
  

• The use of diuretics can significantly limit the sensitivity and specificity of UO.
  

• The UO can only be accurately determined in patients with a bladder catheter, and it requires measurements over a period of 6 hours and 12 hours since admission.  
  

• The RIFLE classification does not take into account the etiology of AKI and the need for renal replacement therapy (RRT) and dialysis.
  

• The RIFLE classification does not provide any information regarding the origin of renal lesions, since its indicators of UO and SCr are not subtle enough to detect them. Recently identified biomarkers such as interleukin-18 (IL-18), kidney injury molecule-1 (KIM-1), and neutrophil gelatinase-associated lipocalin (NGAL) would provide more information. These new biomarkers not only have good sensitivity and specificity in the diagnosis of AKI, as well as a good correlation with mortality and the need for RRT, but they also display changes one to three days before an increase in SCr can be observed.
  

• The data collected since RIFLE’s introduction have revealed that changes in SCr smaller than those defined in RIFLE are likely still associated with adverse outcomes yet left undetected, due to lack of testing sensitivity. 

Acute Kidney Injury Network (AKIN)

The Acute Kidney Injury Network (AKIN) classification, a modification of RIFLE, was released in 2007 in order to improve the sensitivity and specificity of AKI diagnosis. The following modifications to RIFLE were made:8

• The inclusion of an increase in SCr of at least 0.3 mg/dL, even if this does not reach the 50% threshold, widening the Risk category of RIFLE.9
  

• The baseline SCr is no longer considered, only that two SCr measurements are required, within 48 hours, displaying the aforementioned increase.
  

• The categorization of RRT patients as Failure independently of what their SCr or UO was at hospital admission.9

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The following illustration shows the differences between the original RIFLE and the AKIN modifications.

Thus, the main changes introduced between the two classifications are:5

• The diagnosis of AKI only occurs after reaching an adequate degree of hydration in the patient, ruling out the possibility of urinary obstruction as an etiology. 
  

• AKIN takes into account two staging criteria – absolute and relative increases in SCr – while RIFLE focuses solely on a relative change from a baseline level, eliminating issues with GFR determination which requires absolute SCr levels. 
  

• The diagnostic criteria of AKIN requires at least 2 measurements of SCr within the same 48-hour period, providing a firm framework for the rate of progression in acute renal failure.
  

• The two outcome classes (loss of kidney function and ESRD) from RIFLE were removed from the AKIN classification.
  

The AKIN classification could theoretically have better sensitivity and specificity than the RIFLE criteria. However, when comparing the two classifications, although the RIFLE classification did not show a better prognostic acuity in terms of in-hospital mortality, it did enable the identification of a greater number of patients with AKI.5

Bagshaw et al. conducted a retrospective, multi-center analysis comparing the RIFLE and AKIN schemes according to AKI incidence, mortality, area under the receiver operating characteristics (AuROC) curve. AKIN’s modifications to the RIFLE criteria increased the sensitivity of the RIFLE Risk class but had no significant impact on incidence or mortality.

In addition to the limitation presented above, there are other drawbacks in the AKIN classification:5

• The 48-hour window for SCr measurement may not provide enough time for the more slowly progressive etiologies to manifest.
  

• The optimal state of hydration is not a strictly defined state, leading to potential ambiguity.
  

• Stage 3 includes patients subjected to RRT regardless of the therapy’s indication.
  

Kidney Disease Improving Global Outcomes (KDIGO)

Kidney Disease Improving Global Outcomes (KDIGO) is the product of the lessons learned from the limitations of the RIFLE and AKIN classifications. This novel classification introduces changes, especially with regard to time, that attempt to standardize the definition of AKI allowing coherence in peer-reviewed research.10

KDIGO introduced two major modifications of the former classifications:

• Diagnostic criteria for AKI include a SCr increase of at least 50% over 7 days as opposed to 48 hours as outlined in AKIN. Alternatively, an absolute increase of 0.3 mg/dL over the course of 48 hours is consistent between KDIGO and AKIN.
  

• Pediatric patients under 18 years of age with a GFR below 35 mL/min or with a SCr of at least 4.0 mg/dL became a part of KDIGO stage 3 AKI.

RIFLE vs AKIN vs KDIGO

When comparing the three classifications, one may ask which should be used when stratifying patients? In a prospective cohort study by Levi et al., the researchers investigated whether RIFLE, AKIN and KDIGO classifications were adequate in predicting mortality in critically ill patients.12

APACHE II score (Acute Physiology And Chronic Health Evaluation II).

The study found no significant differences among the three classifications regarding their predictive power in mortality (AuROC, RIFLE = 0.735, AKIN = 0.74, KDIGO = 0.733, p<0.001 for all 3 criteria):12