Improved performance of urinary biomarkers of acute kidney injury in the critically ill by stratification for injury duration and baseline renal function

Abstract

To better understand the diagnostic and predictive performance of urinary biomarkers of kidney injury, we evaluated γ-glutamyltranspeptidase (GGT), alkaline phosphatase (AP), neutrophil-gelatinase-associated lipocalin (NGAL), cystatin C (CysC), kidney injury molecule-1 (KIM-1), and interleukin-18 (IL-18) in a prospective observational study of 529 patients in 2 general intensive care units (ICUs). Comparisons were made using the area under the receiver operator characteristic curve (AUC) for diagnosis or prediction of acute kidney injury (AKI), dialysis, or death, and reassessed after patient stratification by baseline renal function (estimated glomerular filtration rate, eGFR) and time after renal insult. On ICU entry, no biomarker had an AUC above 0.7 in the diagnosis or prediction of AKI. Several biomarkers (NGAL, CysC, and IL-18) predicted dialysis (AUC over 0.7), and all except KIM-1 predicted death at 7 days (AUC between 0.61 and 0.69). Performance was improved by stratification for eGFR or time or both. With eGFR <60 ml/min, CysC and KIM-1 had AUCs of 0.69 and 0.73, respectively, within 6 h of injury, and between 12 and 36 h, CysC (0.88), NGAL (0.85), and IL-18 (0.94) had utility. With eGFR >60 ml/min, GGT (0.73), CysC (0.68), and NGAL (0.68) had the highest AUCs within 6 h of injury, and between 6 and 12 h, all AUCs except AP were between 0.68 and 0.78. Beyond 12 h, NGAL (0.71) and KIM-1 (0.66) performed best. Thus, the duration of injury and baseline renal function should be considered in evaluating biomarker performance to diagnose AKI.

Figure 1. Scatter plot of all six urinary biomarkers according to the AKI status of the patient

(a) On entry to the ICU (AKI on entry) and (b) for those not AKI on entry, according to RIFLE24. It must be noted that for IL-18/uCr, the median line for the ‘no AKI’ group lies within the subthreshold values. AKI, acute kidney injury; AP, alkaline phosphatase; CysC, cystatin C; GGT, γ-glutamyltranspeptidase; ICU, intensive care unit; IL-18, interleukin-18; KIM-1, kidney injury molecule-1; NGAL, neutrophil-gelatinase-associated lipocalin; uCr, urinary creatinine.

Figure 2. Time course of each urinary biomarker from putative insult

(a) GGT, γ-glutamyltranspeptidase, (b) AP, alkaline phosphatase, (c) CysC, cystatin C, (d) NGAL, neutrophil-gelatinase-associated lipocalin, (e) IL-18, interleukin-18, and (f) KIM-1, kidney injury molecule-1. All patients are included. AKI is AKI on entry or AKIN48 (AKI at any time within 48 h of entry to the ICU). Values shown are mean±s.e.m. There are approximately 50 measures at each time point for the AKI group. AKI, acute kidney injury; ICU, intensive care unit.

Figure 3. Schematic interpretation of biomarker diagnostic performance, stratified for both time after renal insult and for baseline (pre-entry) renal function

Contour plots of the AUCs for each urinary biomarker indexed to urinary creatinine for diagnosis of AKI (AKIN) on entry to the ICU, illustrating that the diagnostic performance of a biomarker depends on both the individual’s normal renal status (eGFR) and the time of the measurement from insult. An AUC of 0.5 indicates no diagnostic capability. An AUC above 0.5 (red end of the color spectrum) indicates that high biomarker concentrations are diagnostic, and an AUC below 0.5 (blue end) illustrates that low biomarker concentrations are diagnostic. Contour lines are at AUC 0.05 intervals. Plots are based on the AUCs in Appendix Table 1. It must be noted that the contour lines are evenly spaced, interpolated lines between 16 points in each. These should not be interpreted as linear scales. AKI, acute kidney injury; AP, alkaline phosphatase; AUC, area under the receiver operator characteristic curve; CysC, cystatin C; eGFR, estimated glomerular filtration rate; GGT, γ-glutamyltranspeptidase; ICU, intensive care unit; IL-18, interleukin-18; KIM-1, kidney injury molecule-1; NGAL, neutrophil-gelatinase-associated lipocalin.