Urine neutrophil gelatinase-associated lipocalin is an early marker of acute kidney injury in critically ill children: a prospective cohort study

Abstract

Introduction: Serum creatinine is a late marker of acute kidney injury (AKI). Urine neutrophil gelatinase-associated lipocalin (uNGAL) is an early marker of AKI, where the timing of kidney injury is known. It is unknown whether uNGAL predicts AKI in the general critical care setting. We assessed the ability of uNGAL to predict AKI development and severity in critically ill children.

Methods: This was a prospective cohort study of critically ill children. Children aged between 1 month and 21 years who were mechanically ventilated and had a bladder catheter inserted were eligible. Patients with end-stage renal disease or who had just undergone kidney transplantation were excluded. Patients were enrolled within 24 to 48 hours of initiation of mechanical ventilation. Clinical data and serum creatinine were collected daily for up to 14 days from enrollment, and urine was collected once daily for up to 4 days for uNGAL measurement. AKI was graded using pRIFLE (pediatric modified Risk, Injury, Failure, Loss, End Stage Kidney Disease) criteria. Day 0 was defined as the day on which the AKI initially occurred, and pRIFLEmax was defined as the worst pRIFLE AKI grade recorded during the study period. The chi2 test was used to compare associations between categorical variables. Mann-Whitney and Kruskal-Wallis tests were used to compare continuous variables between groups. Diagnostic characteristics were evaluated by calculating sensitivity and specificity, and constructing receiver operating characteristic curves.

Results: A total of 140 patients (54% boys, mean +/- standard deviation Pediatric Risk of Mortality II score 15.0 +/- 8.0, 23% sepsis) were included. Mean and peak uNGAL concentrations increased with worsening pRIFLEmax status (P < 0.05). uNGAL concentrations rose (at least sixfold higher than in controls) in AKI, 2 days before and after a 50% or greater rise in serum creatinine, without change in control uNGAL. The parameter uNGAL was a good diagnostic marker for AKI development (area under the receiver operating characteristic curve [AUC] 0.78, 95% confidence interval [CI] 0.62 to 0.95) and persistent AKI for 48 hours or longer (AUC 0.79, 95% CI 0.61 to 0.98), but not for AKI severity, when it was recorded after a rise in serum creatinine had occurred (AUC 0.63, 95% CI 0.44 to 0.82).

Conclusion: We found uNGAL to be a useful early AKI marker that predicted development of severe AKI in a heterogeneous group of patients with unknown timing of kidney injury.

Figure 1

Description of urine collection procedures and use of urine specimens with reference to analytic time points. (a) Overall urine collection procedure. The image shows that study enrollment began shortly after initiation of ventilation and that urine was collected once per day for up to 4 days if possible. (b) Acute kidney injury (AKI) urine specimens collected before AKI development were used for assessment of urine neutrophil gelatinase-associated lipocalin (uNGAL) for early detection of AKI. (c) AKI urine specimens collected within 24 hours of AKI by pRIFLE (pediatric modified Risk, Injury, Failure, Loss, End Stage Kidney Disease) criteria were used to evaluate uNGAL as a marker of severity of renal injury. day 0, the first day the patient attained AKI; PICU, pediatric intensive care unit; pRIFLEmax, the worst pRIFLE stratum attained; SCr, serum creatinine; uNGAL, urine neutrophil gelatinase-associated lipocalin.

Figure 2

Mean and peak uNGAL concentrations. Shown are box plots of (a) mean and (b) peak urine neutrophil gelatinase-associated lipocalin (uNGAL) concentrations by pRIFLEmax strata. The mean uNGAL is the mean of uNGAL in each patient's four urine specimens, and peak uNGAL is the highest uNGAL level from each patient. AKI, acute kidney injury; pRIFLE, pediatric modified Risk, Injury, Failure, Loss, End Stage Kidney Disease; pRIFLEmax, the worst pRIFLE stratum attained; R, pRIFLEmax R AKI; I, pRIFLEmax I AKI; F, pRIFLEmax F AKI.

Figure 3

uNGAL concentrations from 3 days before to 2 days after sustaining AKI. The center lines represent the median values and the two outer lines represent the interquartile range. AKI, acute kidney injury; pRIFLE, pediatric modified Risk, Injury, Failure, Loss, End Stage Kidney Disease; uNGAL, urine neutrophil gelatinase-associated lipocalin.

Figure 4

Receiver operating characteristic curve for uNGAL. Shown are receiver operating characteristic curve for uNGAL on days -2 or -1 used to predict development of (a) acute kidney injury (AKI) within 48 hours (area under the receiver operating characteristic curve [AUC] 0.78) and (b) persistent AKI within 48 hours of first urine collection (AUC 0.80).

Figure 5

Mean and peak uNGAL concentrations according to presence or absence of sepsis. Shown are box plots of (a) peak urine neutrophil gelatinase-associated lipocalin (uNGAL) concentrations in patients with and without sepsis, by pRIFLEmax strata, and (b) mean uNGAL concentrations in patients with and without sepsis. pRIFLE, pediatric modified Risk, Injury, Failure, Loss, End Stage Kidney Disease; pRIFLEmax, the worst pRIFLE stratum attained; uNGAL, urine neutrophil gelatinase-associated lipocalin.