Assessment of Donor Quality for Improving Kidney Transplant Outcomes

评估捐献者质量以改善肾移植结果

• 批准号: 9262665
• 负责人: Kellie J. Archer
• 金额: $ 53.68万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-01 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9262665
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Age; Bedside Testings; Biological; Biological Assay; Biological Markers; Biology; Biopsy; Chronic; Clinical; Clinical Markers; Clinical Trials; Comorbidity; Data; Data Set; Dialysis procedure; End stage renal failure; Ensure; Equilibrium; Evaluation; Functional disorder; Gender; Histologic; Histopathology; Injury; Institution; Kidney; Kidney Transplantation; Lead; Manitoba; Medicine; Messenger RNA; Methods; Modeling; Molecular; Molecular Profiling; Online Systems; Organ; Organ Donor; Outcome; Pathologic; Pathway interactions; Patients; Performance; Phenotype; Predictive Value; Process; Prospective cohort; Quality of life; Race; Reaction; Recovery of Function; Reperfusion Injury; Reperfusion Therapy; Reporting; Retrospective cohort; Risk; Sampling; Statistical Methods; System; Systems Biology; Testing; Time; Training; Transplantation; United States National Institutes of Health; Universities; Validation; Waiting Lists; base; body system; clinical application; cohort; college; epigenome; follow-up; graft failure; graft function; improved; kidney allograft; molecular marker; outcome forecast; outcome prediction; phenotypic data; predictive marker; preimplantation; prospective; prospective test; screening; tool; transcriptome; web-accessible

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.

对于大多数末期肾脏疾病（ESRD）患者，成功的肾脏移植（KT）提供了更长的时间 生存和更好的生活质量比透析。不幸的是，器官接收之间保持一致的平衡 鉴于缺乏评估捐助者的精确工具，在采购后丢弃费率很难实现 肾脏质量和预后。具体而言，正如最近报道的那样，已将死者的供体（DD）肾脏取回 移植越来越被丢弃，丢弃孩子的最常见原因是 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 无法预测移植后的结果，并且可能导致劝阻肾脏的使用 适用于移植。这些发现表明在加权时需要其他方法 移植DD肾脏。评估移植时间的器官质量，作为移植性能的预测指标， 是影响对器官接受的关键临床挑战，以及移植后的个性化 管理。尽管如此，发现KT时的临床分数和基于组织病理学的评估是 KT后结局的预测因素不佳。当前，没有与器官生物学特别相关的标记 可以将其包括在捐助者风险评分中。一个独特的匹配捐赠者/收件人队列，包括298 DD初级 肾脏接受者的随访4.1±0.8年，植入前的移植活检，重新灌注后和后 - KT和相关的表型数据可用于拟议的研究。另外，匹配的捐助者/收件人 提供来自3个不同机构的250个DD主要KT接收者的队列（包括培训，包括培训， 验证和复制集）。因此，我们假设添加了生物特定于特定于生物学的筛选 评估DD器官质量和功能的分子生物标志物在预测肾脏移植物方面更为准确 结果比仅基于临床病理病理学的评估。具体目的（SA）包括： SA1：开发一个复合分数模型，以评估肾脏移植时间的器官质量并预测 短期结局； SA2：开发复合分数模型来预测长期的肾脏移植结果；和 SA3：验证生物标志物预测短期和长期结果并得出复合评分 在护理测试平台中的临床应用系统。 当前的方法将评估临床适用性和将分子标记添加到当前的好处 可用的评分系统，可通过（1）准确评估供体器官质量 使用系统生物学方法，（2）使用多中心的生物标志物/得分发现和验证 回顾性的对象的前瞻性评估患者，具有可用的结果和mRNA概况， （3）使用临床上可用反应独立复制生物标志物/评分。这项研究将产生 可以在一项大型研究中前瞻性测试的器官质量评估的标记和评分系统。