Worsening of Kidney Transplant Function During 2-Year Follow-up Is Associated With the Genetic Variants of CYP3A4, MDR1, and UGT1A9

Abstract

Background: Calcineurin inhibitors (CNIs), tacrolimus and cyclosporine, undergo pharmacokinetic processes. Enzymes and transport proteins found in various organs are involved. It is possible that genetic polymorphisms of these proteins influence CNIs pharmacokinetics and the generation of CNIs metabolites. CNIs may be nephrotoxic, and it is thought that some CNIs' metabolites may have a similar effect. The study was aimed at the assessment of the relationship between selected gene polymorphisms for enzymes and transport proteins and change of estimated glomerular filtration rate (eGFR) during a 2-year follow-up in kidney transplant (KTX) patients.

Methods: The study involved 366 patients after KTX (160 women; 43.7%) receiving tacrolimus (62.57%) and cyclosporine (37.43%). The mean age was 50.1 years, and the median time after KTX was 60.5 months. The study protocol conformed with the Declaration of Helsinki. The percent of difference between eGFR at baseline and at 24 months (ΔeGFR) was calculated. We evaluated selected genetic polymorphisms of CYP3A4, CYP3A5, MDR1, UGT1A9, UGT2B7, UGT1A8, and MRP2.

Results: In the tacrolimus group, there were no significant differences of ΔeGFR between groups distinguished based on analyzed genotypes. In the cyclosporine group, differences were found for CYP3A4^∗22 C/C -12.3 (-26.8 to -1.8) versus C/T 13.2 (12.4 to 13.9), P = .034; MDR1 3435C>T C/T -18.2 (-31.5 to -5.7) versus C/C -1.8 (-17.1 to 6.9) vs T/T -8.1 (-18.4 to 12.4), P = .031; and UGT1A9 2152C>T C/C -9.0 (-25.5 to 2.8) versus C/T -26.8 (-31.9 to -24.1), P = .017.

Conclusion: The study results suggest that in KTX metabolic transformations and transport, especially of cyclosporine, dependence on the genetic variability of CYP3A4, UGT1A9, and MDR1 may contribute to kidney damage.