A biomarker of aging as a predictor of kidney transplant function

摘要 在等待名单上的肾移植候选人人数每年继续增加，而 肾脏捐赠数量仍然停滞不前。持续的供体短缺迫使临床医生使用肾脏 边际捐助者，称为扩大标准捐助者（ECD）。ECD肾脏，主要来自 年龄较大的供体有更高的移植物功能延迟和移植物丢失的风险。尽管ECD肾脏被认为 回顾性研究表明，现有的评估肾脏质量的系统具有较低的风险， 预测能力导致ECD移植物功能和相关患者存活率的较大变异性。 识别出可以评估ECD移植物质量和预测移植物功能的新因素，将允许扩展 供体库，并在不影响患者结果的情况下最大限度地减少器官丢弃。复制能力的下降 某些自我更新细胞的能力和衰老细胞的积累似乎广泛地有助于 组织老化衰老细胞缺乏复制能力，因此不能有助于组织修复， 体内平衡组织再生潜力的这种缺陷进一步被与组织再生相关的应力加速。 肾移植手术，导致早期移植失败。此外，衰老细胞在代谢过程中 激活并分泌大量促炎细胞因子，导致组织炎症。因此，我们认为， 已经建议测量体内衰老细胞的积累以提供测量 “分子老化”。2004年，Sharpless实验室提出使用p16 INK 4a的表达，p16 INK 4a是细胞凋亡的关键效应子。 衰老，作为人类分子衰老的体内标志物。围绕该标记的知识产权是 2012年发布，是HealthSpan Diagnostics的核心技术。p16 INK 4a标记物，在 血液，已经在超过1,000名人类患者的许多临床情况下进行了评估， 与其他测量体内衰老的方法相比，具有几个显著的技术优势。p16INK4a 诊断在肾移植评估中可能特别有用，因为在移植时肾脏中的p16 INK 4a水平是 器官收获是术后6个月至1年移植肾功能的最佳预测因素。的 发现肾脏p16 INK 4a表达比供体年龄更能预测移植肾功能，进一步支持了我们的研究。 p16 INK 4a诊断可以极大地改善移植评估，并允许老年患者捐献 肾脏移植，显着扩大供体库和减少器官丢弃。在这 我们将确定p16 INK 4a血液检测是否与肾p16 INK 4a类似地与移植物功能相关 表情廉价，易于使用的血液测试的可用性将增加采用的机会， 诊所完成这一第一阶段的建议将使我们能够寻求第二阶段的资金，以进行大规模的临床 试验，并进一步开发我们的p16 INK 4a测定用于商业化。

ABSTRACT The number of kidney transplant candidates on the waiting list continues to increase each year, while the number of kidney donations remains stagnant. The enduring donor shortage compels clinicians to use kidneys from marginal donors, referred to as expanded criteria donors (ECD). ECD kidneys, obtained primarily from older donors, have a higher risk of delayed graft function and graft loss. While ECD kidneys are thought to carry increased risks, retrospective studies suggest that the existing system to evaluate kidney quality has low predictive power resulting in a large variability in ECD graft functions and the associated patient survival. Identification of new factors that can assess ECD graft quality and predict graft function, would allow to expand donor pool and to minimize organ discard without compromising patient outcomes. A decline in the replicative capacity of certain self-renewing cells and accumulation of senescent cells appears to broadly contribute to tissue aging. Senescent cells lack replicative capacity and, therefore, cannot contribute to tissue repair and homeostasis. This defect in tissue regenerative potential is further accelerated by stresses associated with kidney transplant surgeries, leading to an earlier graft failure. Moreover, senescent cells remain metabolically active and secrete a myriad of pro-inflammatory cytokines, contributing to tissue inflammation. Therefore, measuring the accumulation of senescent cells in vivo has been suggested to provide a means of measuring 'molecular aging'. In 2004, the Sharpless lab proposed using expression of p16INK4a, a key effector of cellular senescence, as an in vivo marker of molecular aging in humans. Intellectual property around this marker was issued in 2012 and is the core technology of HealthSpan Diagnostics. The p16INK4a marker, measured in blood, has been evaluated in a number of clinical scenarios in >1,000 human patients and appears to offer several significant technical advantages over other approaches to measuring senescence in vivo. The p16INK4a diagnostic could be especially useful in kidney graft assessment as p16INK4a levels in the kidney at the time of organ harvest are the best known predictor of renal allograft function 6 months to 1 year after surgery. The finding that renal p16INK4a expression is a better predictor of graft function than donor age further supports our theory that p16INK4a diagnostic could greatly improve graft assessment and allow older patients to donate kidneys for transplantation, markedly expanding the donor pool and decreasing organ discard. In this proposal, we will determine if p16INK4a blood test correlates with graft function similarly to kidney p16INK4a expression. The availability of inexpensive, easy to use blood test would increase chances of adoption into the clinic. Completion of this Phase I proposal will allow us to seek Phase II funding to conduct large scale clinical trials and further develop our p16INK4a assay for commercialization.