Assessment of Donor Quality for Improving Kidney Transplant Outcomes

对于大多数终末期肾病(ESRD)患者来说，成功的肾移植(KT)提供了更长的时间 生存和比透析更好的生活质量。不幸的是，器官接受度之间的一致平衡 在缺乏评估捐助者的准确工具的情况下，很难实现采购后的报废率 肾脏质量与预后。具体地说，正如最近报道的那样，已去世的供者(DD)肾脏被取出用于 移植越来越多地被丢弃，而丢弃肾脏的最常见原因是 组织学活检结果。最近的两项研究表明，采购活检的组织学评估是 不能预测移植后的结果，并可能导致劝阻使用否则会 适合移植。这些发现表明，在权衡是否要 移植了一个DD肾。在移植时评估器官质量，作为移植性能的预测指标， 是影响器官接受度和移植后个体化的关键临床挑战 管理层。尽管如此，临床评分和KT时基于组织病理学的评估已被发现 KT术后预后预测不佳。目前，还没有专门与器官生物学相关的标记。 这可能会被包括在捐赠者的风险评分中。唯一匹配的供受者队列，包括298名DD初级患者 肾移植受者获得4.1±0.8年的随访期，移植肾在植入前、再灌注后和再灌注后取材。 KT和相关的表型数据可用于拟议的研究。此外，匹配的捐赠者/接受者 来自3个不同机构的250名DD初级KT获奖者的队列可用(方法包括培训， 验证和复制集)。因此，我们假设增加对生物特异的筛查 评估DD器官质量和功能的分子生物标志物对肾移植的预测更准确 结果比仅仅基于临床和组织病理学的评估要好。具体目标(SA)包括： SA1：开发一个综合评分模型来评估肾移植时的器官质量并预测 短期结果； SA2：开发预测长期肾移植结果的综合评分模型；以及 SA3：验证预测短期和长期结果的生物标志物，并得出综合评分 系统为临床应用提供了一个护理点测试平台。 目前的方法将评估在目前的基础上增加分子标记的临床适用性和益处。 可用于预测移植结果的评分系统：(1)准确评估供体器官质量 使用系统生物学方法，(2)使用多中心发现和验证生物标记物/分数 已有结果和信使核糖核酸谱的前瞻性评估患者的回顾队列， 以及(3)使用临床可用的反应独立复制生物标记物/分数。这项研究将产生 器官质量评估的标志物和评分系统，可以在一项大型研究中进行前瞻性测试。

For most end-stage renal disease (ESRD) patients, successful kidney transplantation (KT) provides longer survival and better quality of life than dialysis. Unfortunately, a consistent balance between organ acceptance and discard rates after procurement has been difficult to achieve given a lack of precise tools to assess donor kidney quality and prognosis. Specifically, as recently reported, deceased donor (DD) kidneys retrieved for transplantation are increasingly being discarded, and the most common reason given for discarding kidneys is histological biopsy results. Two recent studies suggest that histological evaluation of procurement biopsies are not predictive of post-transplant outcomes and may lead to dissuade the use of kidneys that are otherwise suitable for transplant. These findings indicate that additional methods are needed when weighing whether to transplant a DD kidney. Evaluation of organ quality at transplantation time, as a predictor of graft performance, is a critical clinical challenge impacting acceptance of an organ, as well as individualization of post-transplant management. Still, clinical scores and histopathology-based assessments at time of KT have been found to be poor predictors of post-KT outcomes. Currently, there are no markers that specifically relate to organ biology that could be included in a donor risk score. A unique matched donor/recipient cohort including 298 DD primary kidney recipients with 4.1 ± 0.8 years of follow-up, graft biopsies at pre-implantation, post-reperfusion and post- KT and associated phenotypic data is available for the proposed studies. Also, a matched donor/recipient cohort of 250 DD primary KT recipients from 3 different institutions is available (approach including training, validation, and replication sets). Hereby, we hypothesize that the addition of biologically-specific screening for molecular biomarkers to evaluate DD organ quality and function is more accurate in predicting kidney graft outcomes than clinical and histopathological-based assessments alone. The specific aims (SA) include: SA1: Develop a composite score model to evaluate organ quality at kidney transplantation time and predict short-term outcomes; SA2: Develop composite score models to predict long-term kidney transplant outcomes; and SA3: Validate biomarkers predicting short- and long-term outcomes and derive a composite scoring system for clinical application in a point of care test platform. The current approach will evaluate clinical applicability and benefit of adding molecular markers to currently available scoring systems for predicting graft outcomes by (1) accurate assessment of donor organ quality using a systems biology approach, (2) biomarker/score discovery and validation using a multicenter retrospective cohort of prospectively evaluated patients with already available outcomes and mRNA profiles, and (3) independent replication of biomarkers/scores using clinically usable reactions. This study will yield markers and scoring systems for organ quality evaluation that could be tested prospectively in a large study.