The effect of variable CYP3A5 expression on cyclosporine dosing, blood pressure and long-term graft survival in renal transplant patients.

Abstract

Cyclosporine is extensively metabolized by cytochrome-P450 3A (CYP3A) enzymes in the liver and intestine including the CYP3A5 isoenzyme. CYP3A5 is also expressed in the kidney and has been implicated in blood pressure regulation. Appreciable expression of CYP3A5 occurs in carriers of the CYP3A5*1 allele, while the CYP3A5*3 allele is associated with low expression. We tested whether the presence of the CYP3A5*1 allele in renal transplant recipients and in donor kidneys influences cyclosporine dose requirements, blood pressure and long-term graft survival in renal transplant patients during chronic treatment with a cyclosporine-based immunosuppressive regimen. We studied 399 Caucasian patients from our single-center registry with stable graft function for more than 10 weeks after transplantation. The genotypes for CYP3A5*1/*3 were determined by a TaqMan PCR method. Cyclosporine dose requirements, blood pressure and graft survival were analyzed in relation to the presence or absence of the CYP3A5*1 allele in recipients and donor kidneys. The CYP3A5*1 allele was found in 15.5% of the recipients and in 11.8% of the donor kidneys. The recipient CYP3A5*1 allele had no effect on cyclosporine dose and blood concentrations at trough with and without dose-adjustment. Blood pressure, number of antihypertensive compounds used for treatment and graft survival evaluated by Kaplan-Meier curves and Cox regression analysis were also not affected by the CYP3A5*1 allele either in recipients or donor kidneys. Cyclosporine dose requirements, blood pressure and long-term renal graft survival are not influenced by the CYP3A5*1 allele in Caucasian patients.