Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium.
Transplantation. 2011 May 27;91(10):1098-102. doi: 10.1097/TP.0b013e3182177502.
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.
实体器官移植后钙调磷酸酶抑制剂肾毒性（CNIT）的易感性可能与代谢细胞色素 P450 3A5（CYP3A5）同工酶和多药外排转运蛋白 P-糖蛋白（P-gp，ABCB1）的个体间肾表达和功能的变异性有关。
我们通过免疫组织化学比较了 32 例肾移植活检中与 CNIT 作为动脉玻璃样变的新发病灶的 CYP3A5 和 P-gp 的肾表达，与正常方案活检的对照组（n=50）和显示同种免疫损伤的方案活检进行比较（n=21）。此外，我们研究了肾表达与供体和受体单核苷酸多态性 CYP3A5 A6986G（rs776746）、ABCB1 C3435T（rs1045642）和 G2677T（rs2032582）之间的相关性。
近端肾小管刷状缘的 CYP3A5 阳性在 47%的 CNIT 和 14%的对照组活检中存在（P<0.01）。相反，在 CNIT 中，远端肾小管刷状缘 CYP3A5 的染色存在于 10%的 CNIT 和 39%的对照组活检中（P<0.01）。未检测到肾小管细胞 P-gp 表达与 CNIT 之间存在显著相关性。供体和受体中 CYP3A5 A6986G 和 ABCB1 C3435T 和 G2677T 的遗传多态性的存在不能预测这些分子的肾表达谱。
基于接受他克莫司联合吗替麦考酚酯和皮质类固醇治疗的 103 例肾移植受者的回顾性数据，我们发现 CYP3A5 而不是 P-gp 的肾表达和定位与 CNIT 的发生有关。这些蛋白的常见遗传多态性并未影响免疫组织化学测量的表达谱。
