Plasma neutrophil gelatinase-associated lipocalin predicts acute kidney injury, morbidity and mortality after pediatric cardiac surgery: a prospective uncontrolled cohort study

Abstract

Introduction: Acute kidney injury (AKI) is a frequent complication of cardiopulmonary bypass (CPB). The lack of early biomarkers has impaired our ability to intervene in a timely manner. We previously showed in a small cohort of patients that plasma neutrophil gelatinase-associated lipocalin (NGAL), measured using a research enzyme-linked immunosorbent assay, is an early predictive biomarker of AKI after CPB. In this study we tested whether a point-of-care NGAL device can predict AKI after CPB in a larger cohort.

Method: First, in a cross-sectional pilot study including 40 plasma samples (NGAL range 60 to 730 ng/ml) and 12 calibration standards (NGAL range 0 to 1,925 ng/ml), NGAL measurements by enzyme-linked immunosorbent assay and by Triage NGAL Device (Biosite Inc., San Diego, CA, USA) were highly correlated (r = 0.94). Second, in a subsequent prospective uncontrolled cohort study, 120 children undergoing CPB were enrolled. Plasma was collected at baseline and at frequent intervals for 24 hours after CPB, and analyzed for NGAL using the Triage(R) NGAL device. The primary outcome was AKI, which was defined as a 50% or greater increase in serum creatinine.

Results: AKI developed in 45 patients (37%), but the diagnosis using serum creatinine was delayed by 2 to 3 days after CPB. In contrast, mean plasma NGAL levels increased threefold within 2 hours of CPB and remained significantly elevated for the duration of the study. By multivariate analysis, plasma NGAL at 2 hours after CPB was the most powerful independent predictor of AKI (beta = 0.004, P < 0.0001). For the 2-hour plasma NGAL measurement, the area under the curve was 0.96, sensitivity was 0.84, and specificity was 0.94 for prediction of AKI using a cut-off value of 150 ng/ml. The 2 hour postoperative plasma NGAL levels strongly correlated with change in creatinine (r = 0.46, P < 0.001), duration of AKI (r = 0.57, P < 0.001), and length of hospital stay (r = 0.44, P < 0.001). The 12-hour plasma NGAL strongly correlated with mortality (r = 0.48, P = 0.004) and all measures of morbidity mentioned above.

Conclusion: Accurate measurements of plasma NGAL are obtained using the point-of-care Triage(R) NGAL device. Plasma NGAL is an early predictive biomarker of AKI, morbidity, and mortality after pediatric CPB.

Figure 1

Correlation between Triage^® NGAL device and ELISA. Shown is the correlation between plasma NGAL measurements obtained by Triage^® NGAL device and research-based NGAL ELISA assay (Pearson r = 0.94, 95% confidence interval 0.89 to 0.96; P < 0.001). The regression line shown yielded a slope of 0.671 (95% confidence interval 0.600 to 0.741) and an intercept of 48.82 (95% confidence interval 18.66 to 78.99). ELISA, enzyme-linked immunosorbent assay; NGAL, neutrophil gelatinase-associated lipocalin.

Figure 2

Plasma NGAL measurements obtained using Triage^® NGAL device at various time points after CPB. AKI was defined as a 50% increase in serum creatinine from baseline. Values are expressed as means ± standard deviation. *P < 0.0001 comparing AKI versus no AKI groups. AKI, acute kidney injury; CPB, cardiopulmonary bypass; NGAL, neutrophil gelatinase-associated lipocalin.

Figure 3

ROC analysis of 2-hour NGAL at three cut-offs. Shown is a ROC curve analysis of the 2-hour plasma NGAL measurements with the three cut-off levels from Table 2 indicated as filled squares annotated with the corresponding NGAL concentration. The area under the curve was 0.96 (95% confidence interval 0.94 to 0.99). NGAL, neutrophil gelatinase-associated lipocalin; ROS, receiver operating characteristic.