Rondeau Eric, Hertig Alexandre, Rafat Cédric, Xu-Dubois Yi-chun
Urgences Néphrologiques et Transplantation rénale, et INSERM UMRS 702, Hôpital Tenon, 4 rue de la Chine, 75020 Paris.
Bull Acad Natl Med. 2009 Dec;193(9):2005-14; discussion 2014-5.
Late loss of renal grafts is primarily due to progressive sclerosis, involving both immune and non immune processes. Activation of interstitial fibroblasts responsible for graft fibrosis is known to involve proliferation and activation of resident fibroblasts, recruitment of bone marrow-derived stem cells, and epithelial-mesenchymal transition, a more recently identifled mechanism. In this latter process, tubular epithelial cells lose their epithelial phenotype, acquire mesenchymal markers and properties, and participate in the fibrotic process. Whether or not these cells move into the interstitium is controversial. By using immunohistochemistry with specific antibodies against vimentin, beta cadherin, beta catenin and other fibroblastic markers, we found that tubular epithelial cells in kidney grafts can exhibit phenotypic markers of epithelial-mesenchymal transition as early as 3 months after transplantation, before the onset of fibrosis. These changes are associated with prolonged cold ischemia and clinical or subclinical acute rejection. In addition, changes observed at 3 months seem to be predictive of both the fibrosis score at 12 months and, interestingly, the progression of fibrosis between 3 months and 12 months. Finally, renal function at 2 years was significantly poorer in patients exhibiting epithelial changes at 3 months. These results suggest that the epithelial-mesenchymal transition plays a role in the progressive fibrosis of kidney grafts, and that its early inhibition could prevent the gradual decline in renal function and late graft loss.
肾移植后期移植物丢失主要归因于进行性硬化，涉及免疫和非免疫过程。已知负责移植物纤维化的间质成纤维细胞的激活涉及驻留成纤维细胞的增殖和激活、骨髓来源干细胞的募集以及上皮-间质转化，这是一种最近才被发现的机制。在这一后期过程中，肾小管上皮细胞失去其上皮表型，获得间质标志物和特性，并参与纤维化过程。这些细胞是否迁移到间质中存在争议。通过使用针对波形蛋白、β-连环蛋白、β-钙黏蛋白和其他成纤维细胞标志物的特异性抗体进行免疫组织化学分析，我们发现肾移植中的肾小管上皮细胞早在移植后3个月，即在纤维化开始之前，就可表现出上皮-间质转化的表型标志物。这些变化与长时间冷缺血以及临床或亚临床急性排斥反应相关。此外，在3个月时观察到的变化似乎可预测12个月时的纤维化评分，有趣的是，还可预测3个月至12个月期间纤维化的进展。最后，在3个月时出现上皮变化的患者，其2年时的肾功能明显较差。这些结果表明，上皮-间质转化在肾移植的进行性纤维化中起作用，早期抑制该过程可预防肾功能的逐渐下降和后期移植物丢失。
