The single nucleotide polymorphism rs776746 in the CYP3A5 gene slows down metabolism of tacrolimus via CYP3A5 enzyme. Our previous retrospective single-center cohort study showed a trend towards low tacrolimus trough levels and an increased risk for development of de novo donor-specific anti-HLA antibodies (DSA) and antibody-mediated rejection in CYP3A5 expressers carrying at least one copy of the wild-type allele at a follow-up of 3 years. We hypothesized that detection of CYP3A5 expresser status immediately post renal transplant, allowing early genotype-based dose adjustment of tacrolimus, might prevent the occurrence of de novo DSA and ABMR and improve renal transplant outcome.

A total of 160 renal allograft recipients who underwent renal transplantation between May 2019 and 2022 were genotyped for CYP3A5 rs776746 polymorphism within the first two weeks post-transplant, and consequently genotype-based dose adjustment of tacrolimus was performed. The CYP3A5 genotype was determined by Pyrosequencing. After determination of CYP3A5 expresser status, patients were followed up for 2 years and development of calcineurin inhibitor (CNI) nephrotoxicity, rejections and de novo DSA was retrospectively analyzed.

CYP3A5 expresser status was detected in 33 (21%) patients, whereas 127 (79%) patients were non-expressers. Tacrolimus trough levels were similar in CYP3A5 expressers and non-expressers over the follow-up period of 2 years. However, we observed a trend towards slightly increased tacrolimus trough levels in CYP3A5 expressers, who as expected required tacrolimus dosages twice as high as non-expressers. Correspondingly, CYP3A5 expressers had significantly lower concentration-to-dose ratios compared to non-expressers at all indicated time points. CNI nephrotoxicity-free survival rates were comparable between CYP3A5 expressers and non-expressers (p=0.49). Rejection-free survival rates (p=0.89) and de novo anti-HLA antibody-free survival rates (p=0.57) also did not differ between the two groups. The frequency of de novo DSA (2 (6%) vs. 5 (4%), p=0.6) and de novo DSA-free survival (p=0.61) were similar in CYP3A5 expressers and non-expressers.

Early detection of CYP3A5 expresser status resulting in genotype-based adaption of tacrolimus dosage was not associated with increased incidence of CNI toxicity in CYP3A5 expressers but protected them from developement of transplant rejection and de novo DSA formation.

K.S. has no conflict of interest.