Vitalone M J, Ganguly B, Hsieh S, Latek R, Kulbokas E J, Townsend R, Sarwal M M
Transplant Division, California Pacific Medical Center Research Institute, California Pacific Medical Center, Sutter Health Care, San Francisco, CA; Department of Surgery, Stanford University, Palo Alto, CA.
Am J Transplant. 2014 Aug;14(8):1912-21. doi: 10.1111/ajt.12746. Epub 2014 Jun 20.
Calcineurin inhibitor (CNI) use may lead to allograft injury and compromised renal function. Gene expression profiles of 12-month kidney biopsies from a Phase 3 study of belatacept and a CNI comparator, cyclosporine (CsA), were compared with expression profiles of a set of historical, demographically matched, preimplantation control biopsies. Gene set enrichment analysis was used to test each set of differentially expressed genes (DEGs) for the enrichment of an in vitro-derived CNI toxicity (CNIT) gene set and published gene sets associated with chronic allograft injury (CAI), immune modulation and tissue remodeling. The unique set of genes differentially expressed in CNI biopsies compared with preimplantation controls was enriched for genes associated with fibrosis, early tubulointerstitial damage and in vitro CNIT. The DEGs from belatacept biopsies were not enriched for the CNIT genes but, instead, exhibited enrichment for gene sets associated with immune response and tissue remodeling. A combined analysis of DEGs across both treatment groups identified select solute transporter and cellular differentiation genes whose expression at 12 months correlated with renal function at 36 months. These results provide mechanistic insights into the reduced CAI and higher renal function observed in belatacept- versus CsA-treated patients.
使用钙调神经磷酸酶抑制剂（CNI）可能导致移植肾损伤和肾功能受损。将贝拉西普和CNI对照药物环孢素（CsA）的3期研究中12个月肾活检的基因表达谱与一组经过人口统计学匹配的历史植入前对照活检的表达谱进行了比较。基因集富集分析用于测试每组差异表达基因（DEG）是否富集体外衍生的CNI毒性（CNIT）基因集以及与慢性移植肾损伤（CAI）、免疫调节和组织重塑相关的已发表基因集。与植入前对照相比，CNI活检中差异表达的独特基因集富含与纤维化、早期肾小管间质损伤和体外CNIT相关的基因。贝拉西普活检的DEG未富集CNIT基因，而是表现出与免疫反应和组织重塑相关的基因集富集。对两个治疗组的DEG进行联合分析，确定了在12个月时表达与36个月时肾功能相关的特定溶质转运体和细胞分化基因。这些结果为贝拉西普治疗组与环孢素治疗组相比观察到的CAI减少和肾功能改善提供了机制上的见解。
