Anticalcineurins long-term use is associated with interstitial fibrosis, partly responsible for chronic graft dysfunction in kidney transplantation. Studies in patients treated with cyclosporine show that fibrosis is preceded by a process of epithelial-to-mesenchymal transition (EMT) whose extent is predictive of the level of renal function in the medium term. The involvement of Tacrolimus in induction of EMT has not yet been evaluated.
Patients and methods
We retrospectively studied 140 renal transplant patients treated with Tacrolimus and analyzed two EMT markers (de novo expression of vimentin and translocation of Β-catenin by tubular cells) in protocol biopsies performed 3 months after transplantation. To determine influence of Tacrolimus metabolism on EMT process, the Single Nucleotide Polymorphism (SNP) of CYP3A5 and ABCB1 genes, coding for proteins involved in the transport and metabolism of Tacrolimus, were determined in donors and recipients. The minimum follow-up of patients was 2 years.
This study confirms that recipients carrying at least one CYP3A5 * 1 functional allele require higher doses of Tacrolimus (1.13 ± 0.03 mg/kg/day vs. 0.78 ± 0.03, p <0.001 at 3 months) and have lower blood concentrations (7.1 ± 1.9 vs 9.22 ± 2.7, p <0.001 at 3 months), regardless the time of transplantation. However, we havent found a link between exposure to Tacrolimus and intensity of EMT markers. Contrary to what is reported with cyclosporine, we did not reveal any correlation between EMT score and graft function. In contrast, the presence of the CYP3A5 * 1 in the donor is associated with a lower score TEM (0.18 ± 0.3 vs 0.42 ± 0.49, p <0.01). Finally, the 3435T mutation affecting donor ABCB1 significantly influences interstitial fibrosis score ci (0.54 ± 0.56 vs 0.91 ± 0.65, p <0.01), arteriolar hyalinosis (0.44 ± 0, 66 vs 0.83 ± 0.95, p <0.01) and EMT (1.27 ± 0.74 vs 1.7 ± 0.73, p <0.01).
These data suggest that Tacrolimus nephrotoxicity may depend in part on the metabolism of this molecule in the transplanted kidney, and would be associated with CYP3A5 and ABCB1 polymorphisms in donors genome.
To cite this abstract in AMA style:Bloch J, Glowacki F, Cauffiez C, Buob D, Noel C, Hauwaert CVanDer, Hazzan M. Epithelial-to-Mesenchymal Transition and Tacrolimus Toxicity in Renal Transplant Recipient [abstract]. Am J Transplant. 2013; 13 (suppl 5). https://atcmeetingabstracts.com/abstract/epithelial-to-mesenchymal-transition-and-tacrolimus-toxicity-in-renal-transplant-recipient/. Accessed May 9, 2021.
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