The single-nucleotide polymorphism CYP3A5 rs776746 is related to a reduction in the metabolizing activity of the CYP3A5 enzyme. Persons carrying at least one copy of the wild-type allele, defined as CYP3A5 expressers, exhibit higher clearance and lower trough concentrations of tacrolimus than homozygous nonexpressers, and this difference may affect alloimmunization and allograft function.

We retrospectively studied 400 kidney transplant recipients treated with a tacrolimus-based immunosuppression regimen to detect CYP3A5 genotype, de novo formation of human leukocyte antigen (HLA) antibodies and donor-specific antibodies (DSA), and clinical outcome up to 5 years after transplant. CYP3A5 genotype was determined by pyrosequencing.

We found that 69 (17%) of the 400 patients were CYP3A5 expressers. During the first 3 years after transplant, CYP3A5 expressers tended to have lower tacrolimus trough levels than non-expressers, even though their tacrolimus dosage was as much as 80% higher. De novo anti-HLA antibodies and DSAs were found more frequently in CYP3A5 expressers than in nonexpressers (de novo anti-HLA antibodies, 24/69 [35%] vs. 83/331 [25%], p = 0.05; de novo DSAs, 13/69 [19%] vs. 33/331 [10%], p = 0.02). De novo anti-HLA antibody–free (p = 0.03) and DSA-free survival rates (p = 0.02) were significantly lower for expressers than for nonexpressers. CYP3A5 genotype had no effect on allograft failure, but CYP3A5 expressers exhibited a significantly higher frequency of antibody-mediated rejection. CYP3A5 expresser status was an independent risk factor for the development of de novo DSAs (relative risk, 2.34, p= 0.01).

Early detection of CYP3A5 expressers, enabling genotype-based dose adjustment of tacrolimus immediately after renal transplant, may be a useful strategy for reducing the risk of de novo DSA production and antibody-mediated rejection.

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