Department of Pediatric Nephrology and Solid Organ Transplantation, UZ Leuven, University Hospitals Leuven, Leuven, Belgium.
Laboratory of Pediatric Nephrology, Department of Growth and Regeneration, University of Leuven, Leuven, Belgium.
Nephrol Dial Transplant. 2023 Feb 28;38(3):599-609. doi: 10.1093/ndt/gfac237.
Common genetic variants of the enzymes and efflux pump involved in tacrolimus disposition have been associated with calcineurin inhibitor nephrotoxicity, but their importance is unclear because of the multifactorial background of renal fibrosis. This study explores the pro-fibrotic response of tacrolimus exposure in relation to the differential capacity for tacrolimus metabolism in proximal tubule cells (PTCs) with a variable (pharmaco)genetic background.
PTCs were obtained from protocol allograft biopsies with different combinations of CYP3A5 and ABCB1 variants and were incubated with tacrolimus within the concentration range found in vivo. Gene and protein expression, CYP3A5 and P-glycoprotein function, and tacrolimus metabolites were measured in PTC. Connective tissue growth factor (CTGF) expression was assessed in protocol biopsies of kidney allograft recipients.
PTCs produce CTGF in response to escalating tacrolimus exposure, which is approximately 2-fold higher in cells with the CYP3A5*1 and ABCB1 TT combination in vitro. Increasing tacrolimus exposure results in relative higher generation of the main tacrolimus metabolite {13-O-desmethyl tacrolimus [M1]} in cells with this same genetic background. Protocol biopsies show a larger increase in in vivo CTGF tissue expression over time in TT vs. CC/CT but was not affected by the CYP3A5 genotype.
Tacrolimus exposure induces a pro-fibrotic response in a PTC model in function of the donor pharmacogenetic background associated with tacrolimus metabolism. This finding provides a mechanistic insight into the nephrotoxicity associated with tacrolimus treatment and offers opportunities for a tailored immunosuppressive treatment.
参与他克莫司处置的酶和外排泵的常见遗传变异与钙调磷酸酶抑制剂肾毒性有关，但由于肾纤维化的多因素背景，其重要性尚不清楚。本研究探讨了具有不同（药物）遗传背景的近端肾小管细胞（PTC）中他克莫司代谢能力差异与他克莫司暴露的促纤维化反应之间的关系。
从具有不同 CYP3A5 和 ABCB1 变异组合的协议同种异体移植活检中获得 PTC，并在体内发现的浓度范围内用他克莫司孵育。在 PTC 中测量基因和蛋白质表达、CYP3A5 和 P-糖蛋白功能以及他克莫司代谢物。评估肾移植受者协议活检中结缔组织生长因子（CTGF）的表达。
PTC 会产生 CTGF 以响应逐渐增加的他克莫司暴露，在体外，CYP3A5*1 和 ABCB1 TT 组合的细胞中约高 2 倍。增加他克莫司暴露会导致具有相同遗传背景的细胞中主要他克莫司代谢物{13-O-去甲基他克莫司[M1]}的相对生成增加。协议活检显示，与 CC/CT 相比，TT 中体内 CTGF 组织表达随时间的增加幅度更大，但不受 CYP3A5 基因型的影响。
他克莫司暴露以与他克莫司代谢相关的供体药物遗传学背景为功能，在 PTC 模型中诱导促纤维化反应。这一发现为与他克莫司治疗相关的肾毒性提供了机制上的见解，并为量身定制的免疫抑制治疗提供了机会。
