The Cytochrome P450 3A5 Non-Expressor Kidney Allograft as a Risk Factor for Calcineurin Inhibitor Nephrotoxicity

Abstract

Background: Tacrolimus is mainly metabolized by cytochrome P450 3A5 (CYP3A5), which is expressed in the liver. However, CYP3A5 is also expressed in the kidney tissue and may contribute to local tacrolimus clearance in the kidney allograft. We aimed to evaluate the association between the allograft CYP3A5 genotype and transplant outcomes. Methods: We conducted a retrospective cohort study at the King Chulalongkorn Memorial Hospital, Thailand, comparing 2 groups of donor and recipient CYP3A5 genotypes, the expressor (*1/*1 and *1/*3) and the non-expressor (*3/*3). The primary outcomes were allograft complications including calcineurin inhibitor (CNI) nephrotoxicity and acute rejection episode. Results: Of the 50 enrolled patients, 21 donors were expressors and 29 donors were the non-expressors. Tacrolimus trough concentrations were similar between the 2 genotypes. The incidence of CNI nephrotoxicity was higher in recipients with non-expressor donor genotype compared with the expressor donor genotype (72.4 vs. 33.3%, p = 0.006). CNI nephrotoxicity incidence was not different when recipient’s genotypes were compared. Multivariate analysis from Cox-regression showed a hazard ratio of 3.18 (p = 0.026) for CNI nephrotoxicity in the non-expressor compared with the expressor donor. The recipient CYP3A5 genotypes did not significantly contribute to CNI nephrotoxicity. Kaplan-Meier analysis demonstrated the lowest CNI nephrotoxicity-free survival in recipients with the expressor genotype who received allograft from the non-expressor donors (p = 0.005). Conclusion: In conclusion, our results suggest that donor CYP3A5 non-expressor genotype (*3/*3) is a risk for CNI nephrotoxicity.

Tacrolimus dose, blood concentrations and acute nephrotoxicity, but not CYP3A5/ABCB1 genetics, are associated with allograft tacrolimus concentrations in renal transplant recipients

“…Interindividual variability in their activities may cause variability in C Graft even when C 0Blood is controlled by TDM, potentially altering the risk of acute nephrotoxicity and the rate of development of chronic nephrotoxicity. Currently, the association between CNI nephrotoxicity and donor CYP3A5 expressor status is contradictory 21–24 . Donor ABCB1 SNPs previously linked with low P‐gp expression/activity are associated with increased risk of allograft damage, 22 CNI nephrotoxicity 25,26 and allograft loss 27 .…”

Tacrolimus: 20 years of use in adult kidney transplantation. What we should know about its nephrotoxicity

“…Therefore, the non‐expressor recipient may have a higher risk of CNI nephrotoxicity, while the expressor recipient may be prone to acute rejection . The expressor recipient with non‐expressor allograft has the highest risk of CNI nephrotoxicity . However, the CYP3A4*22 allele is an intronic variant associated with reduced CYP3A4 mRNA levels and CYP3A4 activity in the human liver and was estimated to be responsible for 7% of the variability in mRNA expression .…”

Tacrolimus induces a pro-fibrotic response in donor-derived human proximal tubule cells dependent on common variants of theCYP3A5andABCB1genes

“…[ 29 ] did demonstrate a correlation between interstitial CTGF expression and IFTA, but 5 years after kidney transplantation in contrast to the 24 months in our study. Interestingly, a larger retrospective study in 50 patients suggested an increased risk (hazard ratio, 3.18; P = .026) for developing CNIT in *1 expressors in whose who received a *3/*3 kidney allograft [ 15 ]. Alternatively, the effect of the CYP3A5 PTC genotype may be of lesser importance in the in vivo situation, in which the potential effects of higher metabolite generation is attenuated by a continuous process of removal via the urine vs. the enclosed in vitro situation, where metabolites remain in situ and the effect of the pump is less important.…”

“…The vast majority of tacrolimus metabolism occurs in the gut and liver, and the genotype of these organs plays an important role in individual tacrolimus disposition. The specific genotype of the kidney for CYP3A5 and ABCB1, however, has also been associated with a differential potential for developing CNIT [11][12][13][14][15].…”