Association between nitric oxide synthase 3 genetic variant and acute kidney injury following pediatric cardiac surgery

Abstract

Background: Acute kidney injury (AKI) complicates 30% to 50% of cardiac surgeries in pediatric patients. Genetic variants that affect renal blood flow and inflammation have been associated with AKI after cardiac surgery in diverse populations of adults but have not been studied in children. The objective of this study is to test the hypothesis that common candidate genetic variants are associated with AKI following pediatric cardiac surgery.

Methods: This is a retrospective cohort study at a single tertiary referral children's hospital of 2,062 individual patients undergoing surgery for congenital heart disease from September 2007 to July 2020. Pre-specified variants in candidate genes (AGTR1, APOE, IL6, NOS3, and TNF) were chosen. AKI was defined using Kidney Disease: Improving Global Outcomes serum creatinine criteria in the first week following surgery. Outcomes were analyzed by univariate and multivariable analysis of demographic, clinical, and genetic factors.

Results: The study population had median age of 6 (interquartile range [IQR], 1-53) months, 759 (37%) of whom met criteria for postoperative AKI. In unadjusted analyses of each genetic variant, only NOS3 (rs2070744) was associated with lower risk for AKI (OR 0.75, 95% CI 0.62-0.9, P = .002). In logistic regression analyses adjusting for body surface area, previously identified genetic syndrome, Society of Thoracic Surgeons-European Association for Cardio-Thoracic Surgery (STAT) score, cardiopulmonary bypass time, and nephrotoxic medication exposure, the NOS3 variant remained protective against AKI (OR 0.7, 95% CI 0.58-0.85, P<.001).

Conclusions: A common variant in NOS3 is associated with decreased incidence of AKI in children undergoing cardiac surgery. Further analysis of the genetic contributions to postoperative AKI may help identify individual risk in the pediatric population.

Figure 1

Multivariable Analysis for AKI as Dichotomous Predictor. Odds ratios (ORs) and 95% CIs for each of the clinical variables in the dichotomous multivariable logistic regression analysis for association with acute kidney injury. Odds ratios are for the following: Body surface area (BSA), identified preexisting genetic syndrome including (DiGeorge, Down, Noonan, Turner, Holt-Oram, Williams, CHARGE, VACTERL syndrome, or other identified genetic abnormality), Society of Thoracic Surgeons-European Association for Cardio-Thoracic Surgery (STAT) score, Cardiopulmonary bypass (CPB) time (per 10 minutes), Nephrotoxin Risk score which was equal to total number of unique exposures to high and moderate risk nephrotoxic medications, and presence of NOS3 rs2070744 allele variant. Point estimates and 95% CIs are shown to the left of each plot.