This is the first multicenter study to comprehensively compare the diagnostic and predictive abilities of urinary biomarkers. Our goals were to evaluate their ability to: 1) distinguish iAKI from pAKI, stable CKD, and normal kidney function; and 2) facilitate a prospective risk assessment regarding a requirement for dialysis or the death of the patient during subsequent hospitalization.
Every patient who entered the ED and was subsequently hospitalized for >24 h was included in the study. Although the exclusion of patients hospitalized for <24 h may have introduced some bias in favor of sicker patients compared with the inclusion of all comers, derivation of the test characteristics of biomarkers compared with standard clinical information necessitated a reasonable period in which to accumulate follow-up data.
Our study was limited by the absence of a diagnostic gold standard of iAKI. We addressed this limitation by establishing a standardized adjudication procedure to define iAKI, which was based on sCr dynamics, the etiology of AKI, and the response to therapy considering kidney physiology in addition to AKI pathogenesis (16
). Using this strict approach, we could analyze three fourths of the cohort without ambiguity, but because we could not assign a definitive diagnosis to approximately one fourth, we performed adjudication-independent secondary analyses across the entire cohort and found these approaches to be complementary: the utility to diagnose iAKI in a strictly defined cohort paralleled the biomarkers' ability to predict the intensity and duration of AKI in all comers. For instance, uNGAL performed significantly better than the other biomarkers in diagnosing iAKI, and consistently uNGAL displayed a closer association with severity and duration of AKI compared with the other biomarkers. Importantly, uNGAL was progressively more effective in predicting increasing RIFLE classes, a finding consistent with previous studies (26
It is noteworthy that both the presenting sCr level and its change from baseline highly discriminated iAKI patients from other diagnostic groups. This may in part be related to the fact that sCr level was a major determinant of the diagnostic adjudication procedure itself and that most patients had already achieved their peak RIFLE severity class at presentation to the ED. This also implies that urinary biomarkers will be most useful when sCr dynamics are unknown or when the sCr level is in the middle of its range.
Our study confirmed the known association of the type of AKI with the clinical outcome. Although <4% of patients with normal kidney function, stable CKD, or pAKI experienced the composite outcome of in-hospital mortality or the requirement to initiate in-hospital hemodialysis, 33.5% of the patients with iAKI experienced this outcome. Several smaller studies linked high urinary biomarker levels with these unfavorable clinical events (16
), and here we confirmed this association. However, our large sample size enabled us to characterize the contribution of each bio-marker; uNGAL and uKIM-1 were the most accurate predictors of subsequent clinical events, and each markedly improved risk assessment when combined with the conventional sCr-assisted prediction models, as determined by IDI and NRI. In contrast, the combination of uNGAL and uKIM-1 did not further improve risk classification, nor were we able to find evidence of the superiority of 1 of the 2 markers in head-to-head comparisons.
Besides the issues discussed above, there are additional limitations to this study. Even with the biomarker-aided improvement in risk stratification, we cannot assess its potential implications for clinical management without a prospective randomized trial. Also, most of the biomarkers were assayed using single clinical assays, except for uNGAL, where we were able to determine the molecular identity of the AKI-specific NGAL monomer using immunoblots and correlating these findings with an established clinical platform. However, we were unable to achieve a comparable molecular assessment of the other biomarkers. For each biomarker, the diagnostic and prognostic utility may be different when other clinical platforms are used.