Impact of CYP3A5 gene polymorphism on tacrolimus pharmacokinetics in kidney transplant patients: evidence in Kazakh population

With the improvement of donor selection, surgical technique and rational immunosuppressive treatment rates of short-term graft survival great increased. 1 –year graft survival from deceased donor is 95% whereas from living related donor is 98%. In Kazakhstan 1-year graft survival from living related donor is 91%. Despite these high indicators of 1-year graft survival, 5-year graft survival rates remain to be low. For example, in USA 5-year graft survival from decease donor is up to 80%, whereas from living donor is form 82 to 90 %, respectively. Thus, despite the improvement of short-term graft survival rates, long-term graft survival rates remain to be low. 

Recently there are many transplant centers where genetic factors and their influence of kidney graft function are investigated. In this way investigation of CYP3A5 genetic polymorphism, as a regulatory factor of tacrolimus pharmacokinetics is being more relevant. The aim of this work is to investigate the influence of CYP 3A5 genetic polymorphism of tacrolimus pharmacokinetics.

We conducted a clinical trial, where we include 80 kidney recipients. Of them, 47 were male and 33 female patients. Mean age of patients was 43±4.1 years. All patients had been taking tacrolimus 0.1 mg/kg initially. Dose adjustment was by 1.0 mg a day up to target concentration (10-12 ng/ml). All patients were studied for CYP3A5 genetic polymorphism.     

According to the results in our study 61.25% (n=49) of patients were homozygotes, CYP3A5*3*3 carriers (non-expressers) and 38.75% (n=31) were heterozygotes, CYP3A5*1*3 carriers (with one expressor allele).  Patients were arranged by sex/type of polymorphism by Fisher’s test. There were no significant differences in sex/CYP3A5 genetic polymorphism in patients. Patients were divided into 2 groups: homozygotes and heterozygotes.Тасrolimus concentration was measured on 2, 5th , 7th , 10th  and 14th  days after surgery and at discharge. There were significant differences in concentrations on 2nd, 5th, 7th and 10th days in both groups (p = 0.02, 0.01, 0.12 and 0.016, respectively). There were no significant statistical differences in tacrolimus concentration on 14 day after the surgery and at discharge (p = 0.085 and 0.171, respectively). In both groups tacrolimus almost reached target level at the end of 2nd week, but in heterozygotes increase was more gradual and predictable rather than in homozygotes. There were no substantial differences in graft function. Creatinine level normalized gradually in both groups and there were not significant differences in both groups at discharge

It is obvious from received results, that genetic polymorphism of CYP3A5 influences tacrolimus blood concentrations, that appears to be key factor in immunosuppression. Even in rational choice of dose of immunosuppressive agent, genetic factor must be considered as well. In order to improve long-term graft survival rates it is important to maintain therapeutic concentration of tacrolimus in blood. In this way in might important to determine the CYP3A5 genetic polymorphism preoperatively, as one of approved genetic determinants of graft survival. It is also important for the correct selection of initial dose.