Kidney Preservation for Transplantation

描述(由申请人提供)：肾移植是治疗终末期肾功能衰竭患者最有效和最经济的治疗方法。然而，与肾的取回、保存和移植相关的缺血再灌注损伤是影响早期移植物功能和存活率的主要免疫非依赖性因素。边缘供者的肾脏更容易受到缺血再灌注损伤的影响，往往会导致移植失败。分散因子/肝细胞生长因子是一种肾脏营养因子，具有显著的肾脏保护作用。然而，它的临床应用受到与其给药相关的后勤困难的限制。我们已经鉴定出Refanalyin，一种有机小分子分散因子/肝细胞生长因子模拟物，具有显著的细胞保护活性。在肾缺血再灌注损伤的体内模型中，瑞法林减轻了细胞死亡，改善了肾功能。在活体肾移植模型中，瑞法林治疗降低了死亡率，改善了移植物功能，并保存了移植物存活。目前的第二阶段提案探索了Refanalyin在最佳、边缘和大型动物肾移植的临床相关模型中的治疗潜力。通过减轻同种异体移植物功能障碍和预防同种异体移植失败，瑞法林可以降低受体的发病率和死亡率。通过减轻边缘肾脏的缺血再灌注损伤，Refanalyin可以挽救原本被丢弃的器官，并增加捐赠者的储备。

DESCRIPTION (provided by applicant): Renal transplantation is the most effective and cost-efficient treatment for patients in end-stage kidney failure. However ischemia-reperfusion injury, associated with the retrieval, storage and transplantation of kidneys is a major immune-independent factor adversely affecting early graft function and graft viability. Marginal donors kidneys, are even more susceptible to ischemia-reperfusion injury, and often fail transplantation. Scatter factor/hepatocyte growth factor is a renal trophic factor with significant renooprotective activity. However its clinical use is limited by the logistical difficulties associated with its administration. We have identified Refanalin, an organic small molecule scatter factor/hepatocyte growth factor mimetic, with significant cytoprotective activity. In in vivo models of renal ischemia-reperfusion injury, Refanalin attenuated cell death and improved renal function. In an in vivo model of renal transplantation, Refanalin treatment attenuated mortality, improved graft function and preserved graft viability. The present Phase II proposal explores the therapeutic potential of Refanalin in clinically relevant models of optimal, marginal and large animal renal transplantation. By attenuating allograft dysfunction and preventing allograft failure, Refanalin can reduce recipient morbidity and mortality. By attenuating ischemia-reperfusion injury in the marginal kidney, Refanalin can salvage an otherwise discarded organ, and increase the donor pool.