Longitudinal Assessment of Skeletal Muscle Physiology in Dialysis Patients

 工作描述(申请人提供)：职业发展计划：我在慢性肾脏疾病(CKD)相关肌肉骨骼并发症的证据审查和流行病学方面拥有丰富的背景，在通过对终末期肾病(ESRD)患者的运动研究进行体能评估方面拥有丰富经验，并有设计和分析针对CKD患者的试点试验以确定其肌肉骨骼健康状况的经验。在这项K23中，我将在一项队列研究中前瞻性地研究肌肉丢失(肌萎缩症)，以确定其临床指标和新接受透析的患者的生物标记物。我将在一项前瞻性队列研究中进行评估，并通过流行病学和生物统计学技术、生物标记物测量的基本工具和临床试验设计方面的高级课程来加强实践培训。我将出席全国肌肉骨骼健康和肾脏病会议。我有一个多学科的指导团队，由肌肉骨骼生理学、肌肉质量和身体性能评估、生物标记物以及CKD临床试验的科学家组成。我的主要导师Sharon Moe博士有令人羡慕的记录，他成功地指导了初级教员在肾脏病和CKD肌肉骨骼疾病的翻译研究中的校外支持。印第安纳大学(IU)在这一领域拥有丰富的研究资源：1)多个系和学校的肌肉骨骼疾病领域的研究人员；2)专业研究生水平的课程和期刊俱乐部；3)高质量设备和设施的可用性。我得到了系主任的承诺，我75%的时间都用于研究事业。研究计划摘要：透析患者有明显的骨质疏松症，这与住院和死亡率的增加有关。我的总体假设是，接受透析的患者骨骼肌再生受损，导致进行性活动障碍和/或死亡。我将进行性活动障碍定义为步态速度在一年内下降0.1m/S。为了验证这一点，我将利用100名患者的数据，这些患者参加了一项正在进行的多中心透析患者研究，名为“Lucid”。在目标1中，我将评估肌肉质量和力量测量，以确定发生进行性活动障碍的透析患者的亚组，以及这种关系的关键协变量和混杂因素。在目标2中，我将研究骨骼肌再生的循环生物标志物与i)骨骼肌减少和ii)进行性活动障碍之间的关系。在目标3中，我将利用整个美国清醒队列(n=750)，并确定肌肉再生的循环标志物水平在结合使用时是否会增加预测透析患者死亡率的能力 已知的风险因素。这些转化性研究将增强我对骨质疏松症的病理生理学的理解，并量化其临床变化，以确定将从我计划进行的针对骨质疏松症的未来介入试验中受益的患者。我的长期目标是改善肾病患者的肌肉骨骼健康。

 DESCRIPTION (provided by applicant): Career Development Plan: I have a background in evidence review as well as in epidemiology of Chronic Kidney Disease (CKD) associated musculoskeletal complications, experience in the assessment of physical performance through my work on a study of exercise in end-stage renal disease (ESRD) patients, and experience in designing and analyzing pilot trials in CKD patients to characterize their musculoskeletal health. In this K23 I will prospectively study muscle loss (sarcopenia) in a cohort study in order to identify its clinical indicators and biomarkers in patients new to dialysis. I will perform assessments in a prospective cohort study and augment this hands-on-training with advanced coursework in epidemiology and biostatistics techniques, basic tools for biomarker measurements and clinical trial design. I will attend national meetings on Musculoskeletal Health and Nephrology. I have a multidisciplinary mentoring team made of scientists in musculoskeletal physiology, muscle mass and physical performance assessment, biomarkers and in the conduct of clinical trials in CKD. Dr. Sharon Moe, my primary mentor has an enviable track record of successfully mentoring junior faculty in nephrology and extramural support in translational research in musculoskeletal disease in CKD. Indiana University (IU) has a wealth of resources for research in this field: 1) investigators in the field of musculoskeletal disease i multiple departments and schools 2) specialized graduate level courses and journal clubs, and 3) the availability of high quality equipment and facilities. I have a commitment from the Chairman of the Department to protect 75% of my time for research career. Research Plan Summary: Dialysis patients have significant sarcopenia which is associated with increased hospitalizations and mortality. My global hypothesis is that patients undergoing dialysis have impaired skeletal muscle regeneration that leads to progressive mobility impairment and/or mortality. I define progressive mobility impairment as a decrease in gait speed of 0.1 m/s over 1 year. To test this, I will utilize data from 100 patients enrolled in the IU cohort of an ongoing, multi-center study of incident dialysis patients, called "LUCID". In Aim 1, I will evaluate muscle mass and strength measures that identify the subset of dialysis patients that develop progressive mobility impairment and key covariates and confounders of that relationship. In Aim 2, I will study the relationship between circulating biomarkers of skeletal muscle regeneration and i) sarcopenia and ii) progressive mobility impairment. In Aim 3 I will utilize the entire US LUCID cohort (n=750) and determine whether levels of circulating markers of muscle regeneration increase the ability to predict mortality in incident dialysis patients, when combined with known risk factors. These translational research studies will enhance my understanding of the pathophysiology of sarcopenia and quantify its clinical changes to identify patients that will benefit from future interventional trials, targeting sarcopenia that I plan to conduct. My long ter goal is to improve musculoskeletal health in patients with kidney disease.