Improving frailty and long-term outcomes after kidney transplantation

项目概要/摘要 提高肾移植（KT）的长期存活率是美国的国家优先事项。之时尚 终末期肾病正在增加，器官短缺也在加剧。不幸的是，长期的移植和 自20世纪90年代以来，患者存活率没有改善。一个死去的捐赠者肾脏的半衰期目前只有 十五年肾移植失败的最常见原因是患者死亡。为了解决这一 健康危机，移植界需要关注患者死亡和其他可改变的风险因素 肾移植后的长期不良后果，如虚弱。虚弱是一种临床综合症 其特征在于生理储备减少，并且在慢性肾病（CKD）患者中常见。 KT前的虚弱与移植后死亡率增加有关， 在非移植患者中可以改变。然而，在KT后虚弱方面存在重大知识差距， 包括其发展的风险因素，识别它的生物标志物，以及 细胞衰老是一个令人兴奋的新领域的脆弱性研究，直接适用于这些赤字。 在衰老过程中，代谢应激源导致细胞进入永久性生长停滞状态。 衰老细胞在整个身体中积累并分泌统称为衰老的因子- 相关分泌表型（SASP），其诱导其他衰老细胞的形成并引起 周围组织损伤细胞衰老是衰老和年龄相关疾病的一种机制， 脆弱SASP的组成部分作为非移植人群虚弱的生物标志物， 识别处于高功能衰退和过早死亡风险的KT接受者。此外，脆弱的生物标志物可以 最终作为临床试验的替代终点，旨在改善虚弱。本报告的总体目标 本发明的应用是1）鉴定肾移植后的虚弱轨迹，2）鉴定肾移植后虚弱的生物标志物， 肾移植，以及3）进行II期临床试验，检查初步疗效，可行性和 运动干预对移植后虚弱的可接受性。建议的K23应用程序涉及 使用创新的生物标志物和行为干预来改善KT后的虚弱和长期结果， NIDDK的优先事项，重点是弥合转化研究的差距，以改善健康和 CKD患者的生活质量。候选人拥有特殊的资源：a 多学科专家导师团队;接触大量移植患者;以及出色的职业生涯 发展活动，即，统计方法、生物标志物开发和 行为临床试验总之，这些资源将使候选人实现她的长期目标， 成为一名独立的研究者和国家认可的生物标志物技术使用专家 和行为干预，以改善KT后的虚弱和长期结果。

PROJECT SUMMARY/ABSTRACT Improving the long-term survival of kidney transplants (KT) is a national priority in the US. The prevalence of end-stage renal disease is increasing, and the organ shortage is growing. Unfortunately, long-term graft and patient survival has not improved since the 1990s. The half-life of a deceased donor kidney is currently only fifteen years. The most common cause of kidney transplant failure is patient death. In order to address this health crisis, the transplant community needs to focus on modifiable risk factors for patient death and other adverse long-term outcomes after kidney transplantation, such as frailty. Frailty is a clinical syndrome characterized by decreased physiologic reserve and is common in patients with chronic kidney disease (CKD). Frailty prior to KT has been associated with increased post-transplant mortality and has been shown to be modifiable in non-transplant patients. However, there is a significant knowledge gap regarding frailty after KT, including risk factors for its development, biomarkers with which to identify it, and interventions with which to improve it. Cellular senescence is an exciting new area of frailty research that directly applies to these deficits. During the process of senescence, metabolic stressors cause cells to enter a state of permanent growth arrest. Senescent cells accumulate throughout the body and secrete factors collectively called the senescence- associated secretory phenotype (SASP) which induce formation of other senescent cells and cause surrounding tissue damage. Cellular senescence is a mechanism of aging and age-related diseases such as frailty. Components of the SASP serve as biomarkers of frailty in non-transplant populations and may help us identify KT recipients at high risk of functional decline and premature death. In addition, frailty biomarkers could ultimately serve as surrogate endpoints in clinical trials designed to improve frailty. The overall objective of this application is to 1) identify frailty trajectories after kidney transplantation, 2) identify biomarkers of frailty after kidney transplantation, and 3) conduct a phase II clinical trial examining the preliminary efficacy, feasibility and acceptability of an exercise intervention on post-transplant frailty. The proposed K23 application involves the use of innovative biomarkers and behavioral interventions to improve frailty and long-term outcomes after KT, a priority for the NIDDK which focuses on bridging translational research gaps to improve the health and quality of life of patients with CKD. The candidate has exceptional resources available to her: a multidisciplinary team of expert mentors; access to a large volume of transplant patients; and excellent career development activities, i.e., formal courses and workshops in statistical methods, biomarker development, and behavioral clinical trials. Together, these resources will allow the candidate to achieve her long-term goal of becoming an independent investigator and nationally recognized expert on the use of biomarker technology and behavioral interventions to improve frailty and long-term outcomes after KT.