CYP3A genotypes of donors but not those of the patients increase the risk of acute rejection in renal transplant recipients on calcineurin inhibitors: a pilot study

Abstract

Purpose: We aimed to determine whether polymorphisms in CYP3A genes may affect the risk of acute rejection episodes (ARE) in renal transplant recipients treated with calcineurin inhibitors (CNIs).

Methods: One hundred and thirty seven patients and their respective donors were screened, by RT-PCR techniques, for three polymorphisms previously related with CNI pharmacokinetics and pharmacodynamics (CYP3A4*1B, CYP3A4*22 and CYP3A5*3). Genotypes of donors and recipients were associated by logistic regression models with ARE risk and exposure to CNIs. Clinical and pharmacokinetic parameters were recorded at four time-points after transplant (1 week and 1, 5 and 12 months).

Results: Nineteen patients (13.86%) experienced ARE. Patients who received a kidney from a donor carrying the CYP3A4*1B or CYP3A5*1 variant experienced ARE more frequently than those whose donor carried wild-type genotypes [OR = 6.29 (1.62-24.39), p = 0.008 and OR = 3.42 (1.06-11.01), p = 0.039, respectively]. The combined analysis of the CYP3A4*1B/3A5*1 alleles also revealed an increased risk in patients whose donors carried both variants [OR = 6.24 (1.60-24.33), p = 0.007]. The CYP3A genotype of the recipient did not affect ARE risk, although it did determine the degree of exposure to CNI throughout the first year after transplant. Patients with one or two variant alleles displayed lower concentration-to-dose ratios (CDRs) than non-carriers, with differences increasing with time after transplant (p values = 0.039, 0.004, 6.0 e-04 and 2.7 e-07 in the four time-points).

Conclusions: Our preliminary findings suggest that the determination of the CYP3A genotype of the donor, but not that of the recipient, may be useful to predict the incidence of acute rejection in renal transplantation.

Keywords: Acute rejection; CYP3A4; CYP3A5; Renal transplant; Single nucleotide polymorphism.