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.

对于大多数终末期肾病 (ESRD) 患者来说，成功的肾移植 (KT) 可以提供更长的时间 不幸的是，器官接受之间存在持续的平衡。 由于缺乏评估捐助者的精确工具，很难实现采购后的废弃率 具体来说，正如最近报道的，已故捐献者 (DD) 肾脏被取出用于治疗。 移植越来越多地被丢弃，丢弃肾脏的最常见原因是 最近的两项研究表明，获取活检的组织学评估是可行的。 不能预测移植后的结果，并可能导致阻止使用其他肾脏 这些发现表明在权衡是否适合移植时需要其他方法。 移植 DD 肾。移植时的器官质量评估，作为移植物性能的预测指标， 是影响器官接受度以及移植后个体化的关键临床挑战 尽管如此，KT 时的临床评分和基于组织病理学的评估仍然存在问题。 目前，尚无与器官生物学专门相关的标记物。 可以包含在捐赠者风险评分中的独特的匹配捐赠者/接受者队列，包括 298 DD 主要参与者。 肾移植受者进行 4.1 ± 0.8 年的随访，在植入前、再灌注后和移植后进行移植活检 KT 和相关表型数据可用于拟议的研究。此外，还提供匹配的供体/受体。 可以使用来自 3 个不同机构的 250 名 DD 主要 KT 接受者（方法包括培训、 在此，我们寻求添加生物学特异性筛选。 评估 DD 器官质量和功能的分子生物标志物在预测肾移植方面更准确 比仅基于临床和组织病理学评估的结果具体目标（SA）包括： SA1：开发综合评分模型来评估肾移植时的器官质量并进行预测 短期结果； SA2：开发综合评分模型来预测长期肾移植结果；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 系统在护理测试平台中的临床应用。 目前的方法将评估临床适用性以及添加分子标记物的益处 可用的评分系统通过 (1) 准确评估供体器官质量来预测移植结果 使用系统生物学方法，(2) 使用多中心发现和验证生物标志物/分数 前瞻性评估患者的回顾性队列，具有已有的结果和 mRNA 概况， (3) 使用临床可用反应独立复制生物标志物/评分。 用于器官质量评估的标记和评分系统可以在大型研究中进行前瞻性测试。