Expression of CYP3A5 and P-glycoprotein in Renal Allografts With Histological Signs of Calcineurin Inhibitor Nephrotoxicity

Abstract

Susceptibility to calcineurin inhibitor nephrotoxicity (CNIT) after solid organ transplantation could be related to an interindividual variability in renal expression and function of the metabolizing cytochrome P450 3A5 (CYP3A5) isoenzyme and of the multidrug efflux transporter P-glycoprotein (P-gp, ABCB1). We compared renal expression of CYP3A5 and P-gp, measured by immunohistochemistry, in 32 renal allograft biopsies with de novo arteriolar hyalinosis as a sign of CNIT with a control group, consisting of normal protocol allograft biopsies (n=50) and protocol biopsies demonstrating alloimmune injury (n=21). In addition, we studied the association between renal expression and donor and recipient single-nucleotide polymorphisms CYP3A5 A6986G (rs776746), ABCB1 C3435T (rs1045642), and G2677T (rs2032582). CYP3A5 positivity at the brushborder of the proximal tubules was present in 47% of CNIT and 14% of control biopsies (P<0.01). In contrast, brushborder staining for CYP3A5 in distal tubules was present in 10% of CNIT and 39% of control biopsies (P<0.01). No significant association between tubular cell P-gp expression and CNIT was detected. The presence of genetic polymorphisms CYP3A5 A6986G and ABCB1 C3435T and G2677T in donors and recipients was not predictive of the renal expression profile of these molecules. Based on retrospectively collected data of 103 renal transplant recipients receiving tacrolimus in combination with mycophenolate mofetil and corticosteroids, we found that renal expression and localization of CYP3A5 but not P-gp is associated with the occurrence of CNIT. Common genetic polymorphisms in these proteins did not influence their expression profile as measured by immunohistochemistry.