van Rijt Willem G, van Goor Harry, Ploeg Rutger J, Leuvenink Henri G D
Department of Surgery, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands; Department of Pathology and Medical Biology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands.
Transpl Int. 2014 Mar;27(3):241-8. doi: 10.1111/tri.12174. Epub 2013 Aug 22.
The protective, nonerythropoietic effects of erythropoietin (EPO) have become evident in preclinical models in renal ischaemia/reperfusion injury and kidney transplantation. However, four recently published clinical trials using high-dose EPO treatment following renal transplantation did not reveal any protective effect for short-term renal function and even reported an increased risk of thrombosis. This review focusses on the current status of protective pathways mediated by EPO, the safety concerns using high EPO dosage and discusses the discrepancies between pre-clinical and clinical studies. The protective effects are mediated by binding of EPO to a heteromeric receptor complex consisting of two β-common receptors and two EPO receptors. An important role for the activation of endothelial nitric oxide synthase is proposed. EPO-mediated cytoprotection still has enormous potential. However, only nonerythropoietic EPO derivatives may induce protection without increasing the risk of cardiovascular events. In preclinical models, nonerythropoietic EPO derivatives, such as carbamoylated EPO and ARA290, have been tested. These EPO derivatives improve renal function and do not affect erythropoiesis. Therefore, nonerythropoietic EPO derivatives may be able to render EPO-mediated cytoprotection useful and beneficial for clinical transplantation.
促红细胞生成素（EPO）的非促红细胞生成保护作用在肾缺血/再灌注损伤和肾移植的临床前模型中已变得明显。然而，最近发表的四项关于肾移植后使用高剂量EPO治疗的临床试验并未显示对短期肾功能有任何保护作用，甚至报告血栓形成风险增加。本综述聚焦于EPO介导的保护途径的现状、使用高剂量EPO的安全性问题，并讨论临床前和临床研究之间的差异。其保护作用是通过EPO与由两个β-共同受体和两个EPO受体组成的异源受体复合物结合来介导的。有人提出内皮型一氧化氮合酶的激活起重要作用。EPO介导的细胞保护作用仍有巨大潜力。然而，只有非促红细胞生成的EPO衍生物可能在不增加心血管事件风险的情况下诱导保护作用。在临床前模型中，已对非促红细胞生成的EPO衍生物，如氨甲酰化EPO和ARA290进行了测试。这些EPO衍生物可改善肾功能且不影响红细胞生成。因此，非促红细胞生成的EPO衍生物可能能够使EPO介导的细胞保护作用对临床移植有用且有益。
