The Association of Early Graft Dysfunction and CYP3A5 Genotype With Tacrolimus Exposure in Adult Kidney Transplant Recipients

INTRODUCTION: The incidence of early graft dysfunction following kidney transplantation is rising due to the expanded use of marginal organs. Prior studies have suggested that acute kidney dysfunction causes renohepatic crosstalk and tacrolimus metabolism may be decreased. It is also well known that tacrolimus metabolism and dosing requirements differ significantly based on a recipient's CYP3A5 genotype. The objective of this study was to investigate the interplay between early graft function and pharmacogenetics on tacrolimus dose requirements in adult kidney transplant recipients. METHODS: This was a single-center, retrospective cohort study of adult kidney transplant recipients who received immediate-release tacrolimus and had CYP3A5 genotypes available. Immediate graft function (IGF) was defined as serum creatinine decrease of ≥ 10% from baseline and urine output ≥ 0.5 mL/kg/h on post-operative day (POD) 1. Tacrolimus dose-normalized trough concentration (C/D) on POD 2 was compared between patients with IGF and non-IGF using Mann-Whitney U test. Patients were then grouped by both IGF and CYP3A5 genotype, and the differences in C/D considering these factors were analyzed by Mann Whitney U test and a multivariable linear regression analysis. RESULTS: A total of 242 patients were included, 185 with IGF and 57 with non-IGF. The median [IQR: interquartile range] of tacrolimus C/D was higher in non-IGF than IGF (200.0 [129.7-327.1] vs. 134.0 [95.0-197.4] [ng/ml]/[mg/kg/day], p < 0.001). Among CYP3A5 nonexpressers, the median [IQR] of tacrolimus C/D was 73% higher in non-IGF than IGF (263.3 [177.5-390.1] vs. 151.8 [105.1-214.1] [ng/ml]/[mg/kg/day], p < 0.001), and 16% higher in CYP3A5 expressers with non-IGF versus IGF (116.2 [102.3-199.5] vs. 101.1 [72.5-131.0] [ng/ml]/[mg/kg/day], p = 0.01). In the multivariable linear regression model, the effects of IGF and CYP3A5 expression on tacrolimus C/D remained significant. CONCLUSION: Patients with early graft dysfunction who were CYP3A5 nonexpressers had the highest tacrolimus exposure. Initial tacrolimus dose reductions may be considered in kidney transplant recipients who are at risk for non-IGF, especially in CYP3A5 nonexpressers.