A biomarker of aging as a predictor of kidney transplant function

摘要 候补名单上的肾移植患者人数每年都在继续增加，而 肾脏捐赠的数量仍然停滞不前。长期的供体短缺迫使临床医生使用肾脏 来自边缘捐助者，称为扩展标准捐助者(ECD)。ECD肾脏，主要来自 年龄较大的供者，移植物功能延迟和移植物丢失的风险更高。而ECD肾脏被认为是 风险增加，回顾研究表明，现有的评估肾脏质量的系统很低 预测能力导致ECD移植物功能和相关患者存活率的很大变异性。 识别可以评估ECD移植物质量和预测移植物功能的新因素，将允许扩大 并在不影响患者预后的情况下最大限度地减少器官丢弃。复制型的衰落 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，因此不能促进组织修复和 动态平衡。组织再生潜力的这种缺陷由于与以下因素相关的压力而进一步加速 肾移植手术，导致较早的移植失败。此外，衰老的细胞保持新陈代谢。 活跃并分泌大量促炎细胞因子，促进组织炎症。因此， 测量体内衰老细胞的积累被认为提供了一种测量方法 “分子老化”。2004年，夏普莱斯实验室提出使用p16INK4a的表达，p16INK4a是细胞的关键效应因子 衰老，作为人类分子衰老的体内标志。围绕这一标志的知识产权是 发布于2012年，是Health Span诊断的核心技术。P16INK4a标记，单位为 血液，已经在1,000名人类患者的许多临床场景中进行了评估，似乎可以提供 与其他方法相比，在活体测量衰老方面有几个显著的技术优势。P16INK4A 诊断可能在肾移植评估中特别有用，因为此时肾脏中的p16INK4a水平 器官采集是术后6个月至1年内预测移植肾功能的最好指标。这个 研究发现，肾脏p16INK4a的表达比供者年龄更能预测移植肾的功能 P16INK4a诊断可以极大地改善移植物评估并允许老年患者捐献 供移植的肾脏，显著扩大了供体库，减少了器官丢弃。在这 建议，我们将确定p16INK4a血液测试与移植肾功能的相关性是否类似于肾脏p16INK4a 表情。廉价、易用的血液检测将增加被采纳为 诊所。完成这项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 试验并进一步发展我们的p16INK4a检测方法以实现商业化。

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.