Derivation and Validation of Urinary TIMP-1 for Prediction of Acute Kidney Injury and Mortality in Critically Ill Children

Abstract Background : Acute kidney injury (AKI) is associated with high morbidity and mortality. Multiple urinary biomarkers have been identified to associate with the prediction of AKI and outcomes. However, the accuracy of these urinary biomarkers for AKI and associated outcomes has not been clearly defined, especially in heterogeneous populations. The aims of the study were to compare the ability of 10 existing or potential urinary biomarkers for prediction of AKI and pediatric intensive care unit (PICU) mortality, and identify and validate the best biomarker of urinary tissue inhibitor of metalloproteinases-1 (uTIMP-1) for early prediction in heterogeneous critically ill children. Methods: A derivation-validation approach with separate critically ill cohorts was designed. We first conducted a prospective cohort study to determine the ability of 10 candidate urinary biomarkers serially measured in 123 children during the first 7 days of PICU stay and identify the best biomarker for predicting AKI and PICU mortality (derivation study). The best biomarker of uTIMP-1 from derivation was validated in a separate cohort of 357 critically ill children (validation study). AKI diagnosis was based on KDIGO classification with serum creatinine and urine output. Results: In the derivation cohort, 17 of 123 (13.8%) children developed AKI stage 3 or died during PICU stay, and both the initial and peak uTIMP-1 displayed the highest AUC of 0.87 (0.79-0.94) and 0.90 (0.84-0.96), respectively, for predicting AKI stage 3 or death. In the validation cohort, 47 of 357 (13.2%) developed AKI during the first week after admission, and 38 (10.6%) died during PICU stay. The initial uTIMP-1 level was validated to be independently associated with AKI (AOR=1.88, P=0.001), severe AKI (AOR=2.35, P<0.001), AKI stage 3 (AOR=2.87, P<0.001) and PICU mortality (AOR=1.92, P=0.019) after adjustment for potential confounders. The predictive values of uTIMP-1 for AKI, severe AKI, AKI stage 3 and PICU mortality were 0.82 (0.75-0.88), 0.84 (95%CI 0.77-0.91), 0.87 (0.81-0.94) and 0.83 (0.76-0.89), respectively. Conclusions : Urinary TIMP-1 level has been identified and validated to be independently associated with AKI and PICU mortality in independent prospective cohorts, and may be an early potential indicator of AKI and PICU mortality in critically ill children.