Renal Transplant Unit and Intensive Care, Necker Hospital, Paris Descartes University, 145 rue de Sèvres, Paris, France.
Pharmacol Res. 2011 Jul;64(1):25-30. doi: 10.1016/j.phrs.2011.03.013. Epub 2011 Apr 5.
Use of calcineurin inhibitors (CNIs) for immunosuppression after transplantation induces vasoconstriction of renal afferent arterioles, leading to functional changes and potentially irreversible chronic ischemic structural damage. Because CNI-induced nephrotoxicity is strongly suspected in many renal allografts and significantly contributes to interstitial fibrosis and tubular atrophy, better tests are needed to diagnose nephrotoxicity in its early stages. However, despite intensive research efforts, no reliable test is currently available that can accurately and specifically diagnose early CNI nephrotoxicity. An early diagnosis might prompt a switch to agents with a beneficial effect on renal function. This paper is a review of recent progress in toxicogenomic studies that has led to identification of epithelial-to-mesenchymal transition and endoplasmic reticulum stress as potential early markers of tubular cell response to CNI-induced injury. Detection of epithelial-to-mesenchymal transition and/or endoplasmic reticulum stress markers could help diagnose early CNI nephrotoxicity and lead to modification of the immunosuppressive regimen by replacement of CNIs with drugs that have a more acceptable toxicity profile.
使用钙调磷酸酶抑制剂（CNI）进行移植后的免疫抑制会导致肾小动脉入球小动脉收缩，从而导致功能变化和潜在的不可逆转的慢性缺血性结构损伤。由于在许多肾移植中强烈怀疑 CNI 诱导的肾毒性，并显著导致间质纤维化和肾小管萎缩，因此需要更好的测试来在早期诊断肾毒性。然而，尽管进行了密集的研究努力，但目前尚无可靠的测试方法能够准确和专门地诊断早期 CNI 肾毒性。早期诊断可能促使切换到对肾功能有有益影响的药物。本文综述了毒代动力学研究的最新进展，这些进展导致鉴定出上皮-间充质转化和内质网应激作为肾小管细胞对 CNI 诱导损伤反应的潜在早期标志物。检测上皮-间充质转化和/或内质网应激标志物可能有助于诊断早期 CNI 肾毒性，并通过用毒性谱更可接受的药物替代 CNI 来修改免疫抑制方案。
