in abnormalities in the central nervous, immune, and coagulation systems. Many patients Figure 1 | The RIFLE criteria for AKI. ARF, acute renal failure; GFR, glomerular filtration rate; Screat, serum creatinine concentration; UO, urine output. Reprinted from Bellomo R, Ronco C, Kellum JA, et al. Acute renal failure—definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care 2004; 8: R204-212 with permission from Bellomo R et al.;22 accessed http://ccforum.com/ content/8/4/R204 14 Kidney International Supplements (2012) 2, 13–18 chapter 1.1 with AKI already have multisystem organ failure. What is the incremental influence of AKI on remote organ function and how does it affect outcome? A recent study by Levy et al. examined outcomes for over 1000 patients enrolled in the control arms of two large sepsis trials.24 Early improvement (within 24 hours) in cardiovascular (P ¼ 0.0010), renal (Po0.0001), or respiratory (P ¼ 0.0469) function was significantly related to survival. This study suggests that outcomes for patients with severe sepsis in the ICU are closely related to early resolution of AKI. While rapid resolution of AKI may simply be a marker of a good prognosis, it may also indicate a window of therapeutic opportunity to improve outcome in such patients. Validation studies using RIFLE As of early 2010, over half a million patients have been studied to evaluate the RIFLE criteria as a means of classifying patients with AKI.25–28 Large series from the USA,28 Europe,29,30 and Australia,25 each including several thousand patients, have provided a consistent picture. AKI defined by RIFLE is associated with significantly decreased survival and furthermore, increasing severity of AKI defined by RIFLE stage leads to increased risk of death. An early study from Uchino et al. focused on the predictive ability of the RIFLE classification in a cohort of 20 126 patients admitted to a teaching hospital for 424 hours over a 3-year period.5 The authors used an electronic laboratory database to classify patients into RIFLE-R, I, and F and followed them to hospital discharge or death. Nearly 10% of patients achieved a maximum RIFLE-R, 5% I, and 3.5% F. There was a nearly linear increase in hospital mortality with increasing RIFLE class, with patients at R having more than three times the mortality rate of patients without AKI. Patients with I had close to twice the mortality of R and patients with F had 10 times the mortality rate of hospitalized patients without AKI. The investigators performed multivariate logistic regression analysis to test whether RIFLE classification was an independent predictor of hospital mortality. They found that class R carried an odds ratio of hospital mortality of 2.5, I of 5.4, and F of 10.1. Ali et al. studied the incidence of AKI in Northern Scotland, a geographical population base of 523 390. The incidence of AKI was 2147 per million population.31 Sepsis was a precipitating factor in 47% of patients. RIFLE classification was useful for predicting recovery of renal function (Po0.001), requirement for RRT (Po0.001), length of hospital stay for survivors (Po0.001), and in-hospital mortality (P ¼ 0.035). Although no longer statistically significant, subjects with AKI had a high mortality at 3 and 6 months as well. More recently, the Acute Kidney Injury Network (AKIN), an international network of AKI researchers, organized a summit of nephrology and critical care societies from around the world. The group endorsed the RIFLE criteria with a small modification to include small changes in SCr (X0.3 mg/dl or X26.5 mmol/l) when they occur within a 48-hour period.23 Two recent studies examining large databases in the USA28 and Europe29 validated these modified criteria. Thakar et al. found that increased severity of AKI was associated with an increased risk of death independent of comorbidity.28 Patients with Stage 1 (X0.3 mg/dl or X26.5 mmol/l) increase in SCr but less than a two-fold increase had an odds ratio of 2.2; with Stage 2 (corresponding to RIFLE-I), there was an odds ratio of 6.1; and in Stage 3 (RIFLE-F), an odds ratio of 8.6 for hospital mortality was calculated. An additional modification to the RIFLE criteria has been proposed for pediatric patients in order to better classify small children with acute-on-chronic disease.32 Limitations to current definitions for AKI Unfortunately, the existing criteria—while extremely useful and widely validated—are still limited. First, despite efforts to standardize the definition and classification of AKI, there is still inconsistency in application.26,27 A minority of studies have included urinary output criteria despite its apparent ability to identify additional cases6,29 and many studies have excluded patients whose initial SCr is already elevated. Preliminary data from a 20 000-patient database from the University of Pittsburgh suggests that roughly a third of AKI cases are community-acquired33 and many cases may be missed by limiting analysis to documented increases in SCr. Indeed, the majority of cases of AKI in the developing world are likely to be community-acquired. Thus, few studies can provide accurate incidence data. An additional problem relates to the limitations of SCr and urine output for detecting AKI. In the future, biomarkers of renal