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Association Between CYP3A5 Genetic Polymorphisms with Tacrolimus Dose Requirement and Allograft Outcomes in Iranian Kidney Transplant Recipients.

INTRODUCTION
Tacrolimus is the cornerstone of immunosuppressive therapy in organ transplantation with variable inter-individual pharmacokinetics. This study assessed the relationship between CYP3A5/3A4 polymorphisms and tacrolimus dose requirement as well as 6-month transplant outcomes in Iranian kidney transplant recipients.


METHODS
In this prospective study, 110 adult kidney transplant recipients treated with tacrolimus were genotyped for the presence of common SNPs: rs776746: A > G (CYP3A5*3). Patients who carried at least one CYP3A5*1 allele were known as CYP3A5 expressers while those who were CYP3A5*3/*3 homozygotes were classified as CYP3A5 non-expressers.


RESULTS
The daily tacrolimus dose was significantly higher and tacrolimus dose adjusted trough levels (C/D ratio) was significantly lower in CYP3A5 expressers compared with non-expressers (P < .05). Although the incidence of clinically suggested acute allograft rejection was significantly higher (OR = 0.365 [95% CI: 0.14 - 0.93]; P < .05) and median time to first acute rejection was sooner among CYP3A5 expressers compared with non-expressers (12.17 vs. 26.83 days, P < .05); however, estimated glomerular filtration rate, incidence of biopsy proven acute rejection and delayed graft function and 6-month patients' and grafts' survival did not differ between the two groups.


CONCLUSION
CYP3A5 genetic polymorphism is significantly associated with required tacrolimus dose. After achieving desired tacrolimus blood level, although some transplant outcomes such as the incidence of clinically suggested acute rejection and time to first rejection were different between CYP3A5 expressers and non-expressers, however, other clinical outcomes did not differ between groups. Therefore, it is not the time to routinely assess kidney transplant recipients for CYP3A5 genetic polymorphism before transplantation.