Urinary netrin-1 is an early predictive biomarker of acute kidney injury after cardiac surgery

Abstract

Background and objectives: Netrin-1, a laminin-related axon guidance molecule, is highly induced and excreted in the urine after acute kidney injury (AKI) in animals. Here, we determined the utility of urinary netrin-1 levels to predict AKI in humans undergoing cardiopulmonary bypass (CPB).

Design, setting, participants, & measurements: Serial urine samples were analyzed by enzyme-linked immunosorbent assay for netrin-1 in 26 patients who developed AKI (defined as a 50% or greater increase in serum creatinine after CPB) and 34 controls (patients who did not develop AKI after CPB).

Results: Using serum creatinine, AKI was detected on average only 48 hours after CPB. In contrast, urine netrin-1 increased at 2 hours after CPB, peaked at 6 hours (2462 +/- 370 pg/mg creatinine), and remained elevated up to 48 hours after CPB. The predictive power of netrin-1 as demonstrated by area under the receiver-operating characteristics curve for diagnosis of AKI at 2, 6, and 12 hours after CPB was 0.74, 0.86, and 0.89, respectively. The 6-hour urine netrin-1 measurement strongly correlated with duration and severity of AKI, as well as length of hospital stay (all P < 0.05). Adjusting for CPB time, the 6-hour netrin-1 remained a powerful independent predictor of AKI, with an odds ratio of 1.20 (95% confidence interval: 1.08 to 1.41; P = 0.006).

Conclusion: Our results suggest that netrin-1 is an early, predictive biomarker of AKI after CPB and may allow for the reliable early diagnosis and prognosis of AKI after CPB, before the rise in serum creatinine.

Figure 1.

Changes in serum creatinine (LS mean ± SEM) at various time points after cardiac surgery in the non-AKI and AKI groups. *P ≤ 0.0002 for differences between groups by repeated-measures ANOVA.

Figure 2.

Changes in urinary netrin-1 concentrations at various time points after CPB surgery in non-AKI and AKI patients. Error bars are LS mean ± SEM. *P ≤ 0.003 for differences between groups (non-AKI and AKI) by repeated-measures ANOVA.

Figure 3.

Changes in urinary netrin-1 concentrations at various time points after CPB surgery in non-AKI and AKI patients, stratified by pRIFLE categories. Error bars are LS mean ± SEM. *P ≤ 0.001 for differences between groups (non-AKI and each of the pRIFLE categories) by repeated-measures ANOVA.

Figure 4.

ROC curve analysis for urinary netrin-1 at 6 hours after cardiac surgery. The values 381.4, 1099.8, and 2294.1 are urinary netrin-1 concentrations (in picograms per milligrams urine creatinine) at 6 hours after CPB, which correspond to 96% sensitivity, optimal sensitivity and specificity, and 96% specificity, respectively.