Genetic Polymorphisms Affecting Tacrolimus Metabolism and the Relationship to Post-Transplant Outcomes in Kidney Transplant Recipients.

ABSTRACT

BACKGROUND: Tacrolimus is a key drug in kidney transplantation with a narrow therapeutic index. However, whether tacrolimus exposure variability affects clinical outcomes and adverse reactions remains unknown. OBJECTIVE: Our study investigated the factors that influence tacrolimus exposure in kidney transplantation recipients and the relationship between tacrolimus concentration and clinical outcomes and adverse reactions. SETTINGS AND METHODS: We examined the effect of tacrolimus concentration on clinical outcomes and adverse reactions in 201 kidney transplantation recipients, and identified clinical and pharmacogenetic factors that explain tacrolimus exposure. RESULTS: The CYP3A5 genotype was clearly associated with dose-adjusted trough blood tacrolimus concentrations (C0/D), whereas no significant difference was observed in patients with the CYP3A4*1B, CYP3A4*22, ABCB1, ABCC2, POR*28 or PXR alleles. Clinical factors such as red blood cell count, hemoglobin, and albumin were the most useful influence factors affecting tacrolimus C0/D. Besides, Wuzhi capsule increased tacrolimus C0/D in kidney transplantation recipients. Furthermore, higher tacrolimus concentrations were associated with higher diarrhea and post-transplant diabetes mellitus (PTDM) risk but not with acute rejection and chronic allograft kidney dysfunction. CONCLUSION: Clinical factors, medication, and CYP-enzyme polymorphisms accounted for tacrolimus concentration variability in kidney transplantation recipients. Furthermore, higher tacrolimus concentrations were associated with higher diarrhea and PTDM risk.