Assessment of Donor Quality for Improving Kidney Transplant Outcomes

对于大多数终末期肾病（ESRD）患者，成功的肾移植（KT） 生存率和生活质量优于透析。不幸的是，器官接受度和 由于缺乏评估捐助者的准确工具， 肾脏质量和预后。具体而言，正如最近报道的那样，死亡供体（DD）肾脏被取回用于 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价， 不能预测移植后的结果，并可能导致劝阻使用肾脏，否则 适合移植。这些发现表明，在衡量是否 移植一个DD肾在移植时评估器官质量，作为移植物性能的预测指标， 是影响器官接受以及移植后个体化的关键临床挑战 管理尽管如此，在KT时的临床评分和基于组织病理学的评估已被发现， KT术后预后的预测因子较差。目前，还没有与器官生物学特别相关的标记物 可以被纳入捐献者风险评分一个独特的匹配供体/受体队列，包括298例DD原发性 肾移植受者，随访4.1 ± 0.8年，植入前、再灌注后和植入后移植物活检， KT和相关表型数据可用于拟定研究。另外，匹配的捐赠者/接受者 来自3个不同机构的250名DD初级KT接受者的队列可用（方法包括培训， 验证和复制集）。因此，我们假设，增加生物特异性筛选， 评价DD器官质量和功能的分子生物标志物在预测肾移植中更准确 结果比单独的临床和基于组织病理学的评估。具体目标（SA）包括： SA 1：开发一个综合评分模型，以评估肾移植时的器官质量，并预测 短期成果; SA 2：开发综合评分模型以预测长期肾移植结局;以及 SA 3：预测短期和长期结局的生物标志物，并得出复合评分 本发明涉及一种用于护理点测试平台中临床应用的系统。 目前的方法将评估临床适用性和增加分子标记物的好处， 通过（1）准确评估供体器官质量 使用系统生物学方法，（2）生物标志物/评分发现和验证，使用多中心 回顾性队列前瞻性评价的患者已经获得的结果和mRNA谱， 和（3）使用临床可用反应的生物标志物/评分的独立复制。这项研究将产生 用于器官质量评价的标记物和评分系统，可以在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.