SAT-325 ASSOCIATION OF CYP3A5 POLYMORPHISM WITH TACROLIMUS LEVELS AND GRAFT OUTCOMES IN INDIAN KIDNEY TRANSPLANT RECIPIENTS

Abstract

Tacrolimus which is the sheet anchor of post-transplant immunosuppression has a narrow therapeutic index. It is imperative to achieve therapeutic tacrolimus levels for optimum graft survival as sub-optimal levels can predispose to graft rejections and toxic levels pose a risk of nephrotoxicity. The inter-individual variations in the pharmacokinetics of tacrolimus can be in part attributed to polymorphism in Cytochrome P450 (CYP) enzymes. The expressor [CYP3A5*1/*1] status leads to faster metabolism of tacrolimus than that in non- expressors [CYP3A5*3/*3]. Although it is well known that these differences in genotype affect tacrolimus levels, but their effect on long term graft outcome is equivocal. It is not proven that knowing the genotype pre-transplant and adjusting the induction dose accordingly improves graft outcomes. We aim to evaluate the association of CYP3A5 genotypes on tacrolimus trough levels and graft outcomes in adult and pediatric kidney transplant recipients. In this single-center study, consecutive kidney transplant recipients, both pediatric and adults, on tacrolimus therapy for atleast 3 months were enrolled. Genotyping was done using PCR-RFLP for CYP3A5 *1/*1, [expressors] *1/*3,[intermediate expressors] *3/*3 [non -expressors] polymorphisms., and patients were divided into these 3 groups. These groups were analyzed with retrospectively available data for differences in dose-adjusted tacrolimus levels at 1,3,12 months and graft outcomes - acute biopsy-proven rejection, chronic rejection, chronic allograft dysfunction, new-onset proteinuria, eGFR at 1,3,12 months and at last followup available, and graft loss. All groups received 0.1mg/kg/day dose of tacrolimus on day 0 of transplant and then the levels were modified according to subsequent trough tacrolimus levels. Out of 142 patients, 26% were females. Median age 48yrs, 11/142 had age <18 yrs. 16% were expressors[CYP3A5 *1/*1], 40.6% were intermediate[CYP3A5*1/*3], 43.4% were non-expressors[CYP3A5*3/*3]. Dose adjusted tacrolimus trough levels were significantly higher in non-expressors at 1 month [p=0.001], 3 months [p=0.015], 12 months [p=0.018]. Acute biopsy proven rejections were more in expressors [31.4%vs 22.6% p =0.042]. Also, chronic rejections were more in expressors [21%vs 6.53% p = 0.044] Non-expressors had higher incidence of chronic allograft dysfunction [48.4% vs 25.2% p=0.0004]. After being started with 0.1mg/kg/day of tacrolimus, expressors requied more dose escalations to reach therapeutic targets - median 3[0-6] vs 0[0-3] p =0.04. Non-expressors required more dose reductions to achieve targets - median 7[4-13] vs 2.5[0-16] p=0.02. The prevalence of non-expressors [CYP3A5 *3/*3] was 43.4% in Indian transplant recipients. When started at 0.1mg/kg/day dose, expressors had higher rates of subtherapeutic levels requiring more dose-escalation, while non-expressors required dose reductions due to supratherapeutic levels. Graft rejections both acute and chronic were more common in the expressors while non-expressors were at a higher risk of chronic allograft dysfunction. Our data support the use of pretransplant CYP3A5 genotyping to facilitate the individualization of tacrolimus dosing. Genotype guided dosing from the day of transplantation can improve graft outcomes by reducing nephrotoxicity [due to high doses] and rejections [due to suboptimal doses].