Improving frailty and long-term outcomes after kidney transplantation

改善肾移植后的虚弱和长期结果

• 批准号: 10017047
• 负责人: Elizabeth C. Lorenz
• 金额: $ 15.88万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-11 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10017047
• 关键词: Address; Aerobic Exercise; Aging; Animal Model; Aortic Valve Stenosis; Area; Behavior Therapy; Biological Markers; Blood; CCL2 gene; Cell Aging; Cells; Cessation of life; Chronic Kidney Failure; Clinical; Clinical Trials; Clinical Trials Design; Colon Carcinoma; Communities; Coronary Arteriosclerosis; DNA Damage; Data; Development; Diagnosis; Diagnostic; Disease; Educational workshop; End stage renal failure; Exercise; Failure; Fibrosis; Future; GDF15 gene; General Population; Goals; Growth; Half-Life; Health; Immunocompromised Host; Immunosuppression; Inflammation; Intervention; Kidney; Kidney Transplantation; Knowledge; Life; Lung diseases; Mediating; Mental Depression; Mentors; Metabolic; Monitor; Multi-Institutional Clinical Trial; National Institute of Diabetes and Digestive and Kidney Diseases; Organ; Organ Transplantation; Osteoporosis; Outcome; Oxidative Stress; Patients; Phase II Clinical Trials; Phenotype; Physiological; Plague; Plasma; Population; Prevalence; Procedures; Process; Prospective Studies; Proteins; Quality of life; Randomized; Regimen; Research; Research Personnel; Resources; Risk Factors; Role; Savings; Solid; Statistical Methods; Surrogate Endpoint; Survival Rate; Syndrome; Technology; Testing; Therapeutic; Tissues; Translational Research; Transplant Recipients; Transplantation; Urine; Vascular Diseases; activin A; age related; behavioral clinical trial; biomarker development; career development; comorbidity; design; exercise intervention; exercise training; experience; frailty; functional decline; high risk; improved; indexing; innovation; malignant breast neoplasm; modifiable risk; mortality; mortality risk; multidisciplinary; novel strategies; pancreatic cancer patients; patient population; performance based measurement; post-transplant; premature; prognostic; prospective; senescence; strength training; stressor; therapeutic target; transplant centers; transplant survivor; treatment as usual

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.

项目摘要/摘要 改善肾脏移植（KT）的长期生存是美国的国家优先事项。流行率 末期肾脏疾病正在增加，器官短缺正在增长。不幸的是，长期移植物和 自1990年代以来，患者的生存一直没有改善。死者肾脏肾脏的半衰期目前只有 十五年。肾脏移植衰竭的最常见原因是患者死亡。为了解决这个问题 健康危机，移植社区需要专注于患者死亡和其他其他的可修改风险因素 肾脏移植后的不良长期结局，例如脆弱。脆弱是一种临床综合征 其特征是生理储备降低，并且在慢性肾脏疾病（CKD）的患者中很常见。 在KT之前脆弱与移植后死亡率增加有关，已被证明是 在非移植患者中可修改。但是，关于KT之后脆弱的知识差距很大， 包括其开发的风险因素，可以识别的生物标志物以及采取的干预措施 改进它。细胞衰老是直接适用于这些缺陷的脆弱研究的令人兴奋的新领域。 在衰老过程中，代谢压力源会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，分泌因子，共同称为衰老 相关的分泌表型（SASP），诱导其他衰老细胞形成并引起 周围的组织损伤。细胞衰老是衰老和与年龄有关的疾病的机制，例如 脆弱。 SASP的组成部分是非移植人群中脆弱的生物标志物，可能会帮助我们 确定功能下降和过早死亡风险高风险的KT接收者。此外，脆弱的生物标志物可以 最终在旨在改善脆弱性的临床试验中充当替代终点。总体目标 应用是1）识别肾脏移植后脆弱的轨迹，2）确定脆弱的生物标志物 肾脏移植和3）进行II期临床试验，检查初步疗效，可行性和 对移植后脆弱的运动干预的可接受性。拟议的K23申请涉及 使用创新的生物标志物和行为干预措施来改善KT之后的脆弱和长期结果 NIDDK的优先事项，重点是弥合翻译研究差距，以改善健康和 CKD患者的生活质量。候选人有她可用的特殊资源： 多学科专家导师团队；进入大量移植患者；和出色的职业 开发活动，即统计方法，生物标志物开发和 行为临床试验。这些资源将共同使候选人实现她的长期目标 成为独立研究者和全国认可的生物标志物技术的专家 和行为干预措施，以改善KT之后的脆弱和长期结果。