Unique Clinical Study on DGF Using Paired Kidneys

描述：肾移植是最有效和最具成本效益的肾脏替代治疗的新兴人群，终末期肾脏疾病。虽然器官捐赠已成为国家的优先事项，但等待肾脏的患者数量与可用肾脏数量之间的差距继续成倍扩大。在欧洲联盟的许多国家，“心脏死亡后捐赠”（DCD）肾脏的利用率正在稳步增加，使供体池扩大了50%。鉴于这个国家心脏死亡的高发生率，积极追求DCD肾池可能会将等待时间缩短到几个月，如果不是几天的话。然而，延迟移植功能（DGF）的风险以及随之而来的受体发病率增加、慢性同种异体移植肾病和医疗费用增加的风险降低了DCD肾脏在这个国家的使用。制定限制恒温再灌注损伤、促进肾脏修复、减少DGF发生率和/或持续时间、改善长期预后的策略，可以极大地增强DCD肾脏的接受和招募。Angion Biomedica正在开发BB3，一种小分子肝细胞生长因子模拟物，在许多急性肾损伤模型中显示出显著的组织保护活性。重要的是，这种小分子已经在健康志愿者和肾脏损害患者中完成了临床安全性试验。目前的建议是对静脉给药BB3对有发生DGF风险的DCD供体肾脏受者的安全性和有效性进行试点评估。这项将在荷兰马斯特里赫特大学医学中心进行的试验的独特之处在于，它比较了来自同一供者的肾脏受体的药物和安慰剂结果，并直接评估了移植物的功能（肌酐清除率）。该试点研究的结果将成为开展大型多中心III期试验的基础，该试验将评估BB3在有DGF风险的DCD肾受体中的疗效和安全性。这些试验的成功完成很可能会改变美国肾脏捐赠者招募的格局。

DESCRIPTION: Renal transplantation is the most effective and cost-efficient form of renal replacement therapy for a burgeoning population that presents with end-stage renal disease. Although organ donation has become a national priority, the gap between the number of patients awaiting a kidney vs. the number of available kidneys continues to widen exponentially. In many countries within the European Union, utilization of "donation after cardiac death" (DCD) kidneys is steadily increasing, expanding the donor pool by >50%. Given the high incidence of cardiac deaths in this country, aggressive pursuit of the DCD kidney pool could potentially reduce waitlist periods to months, if not days. Risk for delayed graft function (DGF) with the attendant risks for increased recipient morbidity, chronic allograft nephropathy and increased medical costs has however tempered DCD kidney utilization in this country. Development of strategies that limit normothermic reperfusion injury, promote renal repair, reduce the incidence and/or duration of DGF and improve long-term outcome can greatly enhance acceptance and recruitment of DCD kidneys. Angion Biomedica is developing BB3, a small molecule hepatocyte growth factor mimetic that exhibits significant tissue protective activity in numerous models of acute renal injury. Importantly, this small molecule has completed clinical safety trials in both healthy volunteers and in patients with renal impairment. The present proposal is a pilot evaluation of safety and efficacy of intravenously administered BB3 in recipients of kidneys from DCD donors who are risk for developing DGF. This trial, to be conducted at Maastricht University Medical Center in the Netherlands, is unique in that it compares drug vs. placebo outcome in kidney recipients from the same donor with direct evaluation of function (creatinine clearance) in the graft. Results from this pilot study will form the basis of conducting a large multi-center Phase III trial evaluating efficacy and safety of BB3 in DCD kidney recipients at risk for DGF. Successful completion of these trials will more than likely change the kidney donor recruitment landscape here in the US. PUBLIC HEALTH RELEVANCE: The proposed study has significant clinical ramifications. A small molecule that improves post-transplantation function and outcome in higher risk donor kidneys can potentially increase the donor pool thereby reducing significantly the number of deaths in patients awaiting kidney transplant.