Background: Tacrolimus is a major immunosuppressant, which has a narrow therapeutic range and wide interindividual variation. The effects of genetic polymorphisms of cytochrome P450 3A (CYP3A) 5 and Adenosine triphosphate-binding cassette subfamily B member 1 (ABCB1) genes on the achievement of target tacrolimus trough levels and clinical outcomes in renal transplants were evaluated.
Methods: A total of 62 patients participated in this prospective study. After an initial fixed oral dose (0.08 mg/kg two times per day), tacrolimus doses were adjusted to a target range based on daily measurement of blood trough concentration. Every patient underwent 10-day scheduled biopsy. Both the patients and investigators were blinded for the genetic polymorphisms.
Results: Those subjects expressing CYP3A5 (n=29) evidenced significantly lower tacrolimus trough levels between days 1 and 5 after transplantation, when compared with nonexpressers (n=33). Significantly higher overall incidences of early T-cell-mediated rejection (TCR) of at least Banff grade 1 in severity (P=0.017), including clinical rejection within 10 days and subclinical rejection in biopsies at postoperative day 10 were detected in CYP3A5 expressers. The severity of TCR according to Banff '07 classification was associated with CYP3A5 genotypes (P=0.012). Moreover, multivariate analysis identified CYP3A5 expression as an independent risk factor for TCR (odds ratio: 2.79; P=0.043). Significantly lower estimated glomerular filtration rates until 1 month and numerically lower estimated glomerular filtration rates by 12 months were noted in the CYP3A5 expressers. The genetic polymorphisms of the ABCB1 genes exerted no significant effects.
Conclusion: We confirmed the significant effects of CYP3A5 polymorphism on the achievement of target tacrolimus trough levels and the development of acute rejection in early period after transplantation and consequent renal allograft function.