CYP3A5*1/*3 Genetic Polymorphism Is Associated with Post Cardiac Transplant Renal Dysfunction in Patients Treated with Calcineurin Inhibitors

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Introduction: Post transplant renal dysfunction is a largely irreversible process that is associated with increased mortality. Renal expression of the cytochrome P450 3A5 (CYP3A5) isoenzyme and of the ATP-binding cassette (ABC) efflux transporter p-glycoprotein are inversely associated with calcineurin-induced nephrotoxicity. Hypothesis: Genetic variants of genes encoding this isoenzyme (CYP3A5) and this transporter (ABCB1) are associated with post heart transplant renal function. Methods: Retrospective cohort study of heart transplant recipients from two institutions who were discharged alive after transplant and who received calcineurin inhibitors during follow-up. The primary endpoint of the study was to evaluate the impact of these genetic variants on changes in estimated glomerular filtration rate (eGFR) calculated by the modification of diet in renal disease (MDRD) simplified formula using a general linear mixed model. Data on renal function were collected at hospital discharge following the heart transplant and then at 3, 6, 12, 18, 24 months, and then every year for up to nine years. The secondary endpoint was the concentration/dose/kg ratio of cyclosporine and tacrolimus during follow-up. Genotyping for ABCB1 G2677T/A and C3435T CYP3A5*1/*3 was performed by previously published polymerase chain reaction methods. Results A total of 160 patients were included. Patients were mainly males (79.4%) and had a median age of 53.2 years. There was no significant difference in pretransplant eGFR between genotypes. Mean follow-up was 4.2 years. After adjusting for independent predictors of eGFR during follow-up, CYP3A5*1/*3 was significantly associated with eGFR following transplant (p=0,0002). More specifically, non expressors of CYP3A5 (CYP3A5*3/*3 carriers) had a lower eGFR during follow-up compared to CYP3A5*1 carriers. Moreover, CYP3A5*3/*3 carriers had lower dosage requirement for tacrolimus, as illustrated by a higher concentration/dose ratio of tacrolimus (p=0.004). Conclusions: The CYP3A5*1/*3 genetic polymorphism is a promising genetic marker to identify heart transplant recipients most likely to develop renal dysfunction during treatment with calcineurin inhibitors, in addition to guide tacrolimus dosing.