Association of CYP3A5, ABCB1, and CYP2C8 Polymorphisms with Renal Function in Kidney Transplant Recipients Receiving Tacrolimus.

Abstract

Background/objectives: Tacrolimus (TAC, FK-506) is a calcineurin inhibitor commonly used to prevent organ rejection in transplant patients. It has a narrow therapeutic index and nephrotoxic effects, characterized by interindividual dose variability. TAC is metabolized by the CYP450 (CYP3A5, CYP3A4) enzyme system and transported by P-glycoprotein (ABCB1). Additionally, the CYP2C8 enzyme has been suggested to play a protective role against both graft rejection and drug-induced toxicity. Genetic polymorphisms in these pathways may influence the risk of tacrolimus-related nephrotoxicity. This retrospective cohort study was conducted to evaluate the association between CYP3A5, ABCB1, and CYP2C8 gene polymorphisms and renal function in kidney transplant recipients METHODS: This study investigated the impact of CYP3A5, ABCB1 and CYP2C8 polymorphisms on blood TAC level and kidney function in renal transplant patients. Genotyping was conducted to determine allele frequencies for CYP3A5 (6986A>G), ABCB1 (13435C>T), and CYP2C8 (A1196G) polymorphisms. Renal function was assessed by measuring serum creatinine, estimated glomerular filtration rate (eGFR), and protein/creatinine ratios at 3, 6, and 12 months post-transplantation.

Result: At 12 months post-transplant, the median serum creatinine level was significantly higher in patients with CYP2C8 (*1/*3 and *3/*3) genotypes compared to those with the CYP2C8*1/*1 genotype (p = 0.021). Additionally, the increase in creatinine from the 3rd to the 12th month was significantly greater in the CYP2C8 (*1/*3 and *3/*3) group (p = 0.036). No significant differences were observed in TAC dosage, blood concentration, or renal function between ABCB1 genotype groups. Although daily TAC doses differed significantly between CYP3A5 genotypes, renal function did not significantly vary.

Conclusion: In light of these data, CYP2C8 gene polymorphism has been associated with an increase in serum creatinine, one of the key markers of renal function. ABCB1 gene polymorphism showed no association while CYP3A5 gene polymorphism influenced TAC dose; however, further studies with larger cohorts are required to clarify these associations.