Improving frailty and long-term outcomes after kidney transplantation

项目摘要/摘要 在美国，提高肾移植(KT)的长期存活率是一项国家优先事项。疾病的流行 终末期肾脏疾病正在增加，器官短缺也在加剧。不幸的是，长期的贪污和 自20世纪90年代以来，患者的存活率没有改善。已故供者肾脏的半衰期目前仅为 十五年了。肾移植失败的最常见原因是病人死亡。为了解决这个问题 健康危机，移植社区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征 以生理储备减少为特征，在慢性肾脏疾病(CKD)患者中很常见。 移植前的虚弱与移植后死亡率的增加有关，并已被证明是 在非移植患者中可修改。然而，对于KT后的脆弱性，存在着显著的知识差距， 包括其发生的风险因素，用于识别其的生物标志物，以及用于 改进它。细胞衰老是直接适用于这些缺陷的脆弱研究的一个令人兴奋的新领域。 在衰老过程中，代谢应激源使细胞进入永久性生长停滞状态。 衰老细胞在全身积累，并分泌因子，统称为衰老- 相关分泌表型(SASP)，诱导其他衰老细胞的形成并引起 周围组织受损。细胞衰老是衰老和与年龄相关的疾病的一种机制，如 脆弱。在非移植人群中，SASP的成分可作为脆弱的生物标志物，可能有助于我们 确定KT受者功能衰退和过早死亡的高风险。此外，脆弱的生物标志物可能 最终作为旨在改善脆弱性的临床试验的替代终点。这样做的总体目标是 应用于1)识别肾移植后的脆弱轨迹，2)识别肾移植后脆弱的生物标志物 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申请涉及 使用创新的生物标记物和行为干预来改善KT后的脆弱性和长期结果， NIDDK的优先事项是弥合翻译研究差距，以改善健康和 慢性肾脏病患者的生活质量。候选人有特别的资源可用：a 多学科专家导师团队；接触到大量移植患者；以及出色的职业生涯 发展活动，即统计方法、生物标记物开发方面的正式课程和讲习班； 行为临床试验。这些资源加在一起，将使候选人能够实现她的长期目标 成为生物标志物技术使用方面的独立调查者和国家认可的专家 以及行为干预，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.