Mediators & prognostic value of muscle mass & function in chronic kidney disease

调解员

• 批准号: 8853857
• 负责人: FRANCIS PERRY WILSON
• 金额: $ 17.93万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-15 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8853857
• 关键词: Accounting; Acidosis; Acquired Immunodeficiency Syndrome; Activin Receptor; Address; Affect; Age; Aging; Agonist; American; Anemia; Anemia due to Chronic Disorder; Area; Award; Biolectric Impedance; Biometry; Biostatistics Core; Blood specimen; Board Certification; Body Composition; Budgets; Cardiovascular system; Cessation of life; Chronic; Chronic Kidney Failure; Chronic Kidney Insufficiency; Clinical; Clinical Trials Design; Cohort Studies; Congestive Heart Failure; Creatinine; Cross-Sectional Studies; Data; Death Rate; Dialysis procedure; Disease; Disease Progression; Dual-Energy X-Ray Absorptiometry; Enrollment; Environment; Epidemiologist; Epidemiology; Extramural Activities; Faculty; Functional disorder; Funding; Future; Gender; Generations; Goals; Individual; Internal Medicine; Intervention; Intervention Trial; Kidney; Kidney Diseases; Knowledge; Lead; Ligands; Malignant Neoplasms; Master of Science; Measurement; Measures; Mediating; Mediator of activation protein; Modeling; Morbidity - disease rate; Multicenter Studies; Muscle; Muscle function; Names; National Institute of Diabetes and Digestive and Kidney Diseases; Nephrology; Nested Case-Control Study; Organ; Outcome; Participant; Pathologic Processes; Pathway interactions; Patients; Pennsylvania; Physical Function; Physical activity; Physiological; Population; Postdoctoral Fellow; Prevalence; Proxy; Publications; Race; Relative (related person); Renal function; Reproducibility; Research; Research Infrastructure; Research Personnel; Resources; Risk; Risk Factors; Role; Serum; Severities; Site; Staging; Testing; Time; Training; Translating; Universities; Urine; Variant; Western Blotting; X-Ray Computed Tomography; activin A; adverse outcome; aged; base; clinical epidemiology; clinical practice; cohort; experience; grasp; improved; inflammatory marker; member; mortality; muscle form; myostatin; nutrition; originality; post gamma-globulins; prognostic; prognostic value; protein intake; public health relevance; statistics; stem; therapeutic target; wasting

DESCRIPTION (provided by applicant): Candidate: Dr. Wilson is currently a post-doctoral researcher with Internal Medicine and Nephrology board certification. He was awarded a Master of Science of Clinical Epidemiology (MSCE) degree in August of 2012. He has demonstrated significant originality of research with several first-author publications to his name. His immediate goals include pursuing more advanced coursework in epidemiology and biostatistics and pursuing research into the clinical aspects of muscle mass and function in the setting of chronic kidney disease. In the long-term, through more advanced training in clinical trial design and analysis, he will pursue interventional trials targeting improved outcomes in patients with CKD. Environment: The studies described in this application will be pursued at the University of Pennsylvania in the Center for Clinical Epidemiology and Biostatistics (CCEB). The CCEB core faculty includes 33 clinician epidemiologists, 11 non-clinician epidemiologists, and 28 biostatisticians (these totals exclude 116 affiliated faculty members). More than 200 full-time research, administrative, and clerical staff support the activities of the faculty. CCEB research currently receives over $38M/year in extramural support. Its total budget is approximately $58M. Research: Low muscle mass and function have been established as robust and powerful predictors of mortality in aging and a variety of chronic conditions including AIDS, cancer and congestive heart failure. Cross-sectional studies suggest correlations between low muscle mass and eGFR in patients with CKD, but the prognostic value of these findings has yet to be elucidated. The assessment of muscle - a dynamic, functional, and metabolically active organ - may augment our ability to risk-stratify patients with CKD, and offer potential targets for intervention. Utilizing data from the Chronic Renal Insufficiency Cohort (CRIC), we will leverage multiple measures of muscle mass and function to characterize the prevalence, predictors, and impact of muscle loss and muscle dysfunction in a broad and diverse CKD population. These findings will be directly applicable to future intervention trials targeting muscle wasting in chroic kidney disease. Aim 1: Assess the value of surrogates of muscle mass and muscle function in predicting all-cause mortality in the setting of CKD. Using data collected in the Chronic Renal Insufficiency Cohort (CRIC), we will analyze the predictive ability of various proxies of muscle mass and function with all-cause mortality primarily using Cox regression. We will assess the discriminant ability of these measures using C-statistics. Secondary analyses will examine cardiovascular mortality and kidney-specific outcomes such as initiation of dialysis. Aim 2: To characterize the within-individual reproducibility and reliability of grip strength dynamometry and bioelectrical impedance analysis (BIA) at the UPenn CRIC site. The candidate will prospectively validate these measures performed by study coordinators to determine inter- rater and within-individual consistency of measurement in order to confirm that translating these measurements into routine clinical practice is feasible. Analyses will utilize Pearson's correlation coefficient and Bland-Altman plots to assess bias in measurement. Aim 3: Assess the degree to which the decline of muscle mass and function in CRIC participants is associated with modifiable factors. Anemia, acidosis, decreased protein intake, and decreased physical activity may associate with greater declines in muscle mass over time in patients with CKD. We will explore these relationships in order to inform hypotheses regarding causal pathways that mediate decline of muscle mass in CKD and to suggest future therapeutic targets. Aim 4: Assess the role of ligands of the activin receptor 2b (ActRIIB) as mediators of loss of muscle mass over time in a subset of patients enrolled in the CRIC Study Baseline serum concentrations of myostatin, GDF-11, and activin A, along with their key modulators, will be assessed via western blot in a 256 patient nested case-control study within CRIC. Cases will be defined as patients in the highest quintile of longitudinal muscle loss as assessed by slope of creatinine generation rate over time. Controls will be matched based upon age, race, gender eGFR, and baseline muscle mass but be selected from the lowest quintile. The primary analysis will use mixed-effects models clustered at the matched-pair level.

描述（由申请人提供）： 候选人：Wilson 博士目前是一名拥有内科和肾脏病学委员会认证的博士后研究员。他于 2012 年 8 月获得临床流行病学理学硕士学位 (MSCE)。他以第一作者的名义发表了多篇论文，展示了研究的显着原创性。他的近期目标包括学习流行病学和生物统计学方面的更高级课程，以及对慢性肾脏疾病背景下肌肉质量和功能的临床方面进行研究。从长远来看，通过临床试验设计和分析方面更高级的培训，他将开展旨在改善 CKD 患者预后的介入试验。环境：本申请中描述的研究将在宾夕法尼亚大学临床流行病学和生物统计学中心 (CCEB) 进行。 CCEB 核心教职人员包括 33 名临床流行病学家、11 名非临床流行病学家和 28 名生物统计学家（这些总数不包括 116 名附属教职人员）。超过 200 名全职研究、行政和文员人员为学院的活动提供支持。 CCEB 研究目前每年获得超过 3800 万美元的外部支持。其总预算约为 5800 万美元。研究：低肌肉质量和功能已被确定为衰老和各种慢性疾病（包括艾滋病、癌症和充血性心力衰竭）死亡率的有力预测因素。横断面研究表明 CKD 患者的低肌肉质量与 eGFR 之间存在相关性，但这些研究结果的预后价值尚未阐明。对肌肉（一种动态的、功能性的、代谢活跃的器官）的评估可能会增强我们对 CKD 患者进行风险分层的能力，并提供潜在的干预目标。 利用慢性肾功能不全队列 (CRIC) 的数据，我们将利用多种肌肉质量和功能测量指标来描述广泛且多样化的 CKD 人群中肌肉损失和肌肉功能障碍的患病率、预测因素和影响。这些发现将直接适用于未来针对慢性肾病肌肉萎缩的干预试验。目标 1：评估肌肉质量和肌肉功能的替代指标在预测 CKD 情况下全因死亡率方面的价值。使用慢性肾功能不全队列 (CRIC) 中收集的数据，我们将主要使用 Cox 回归分析各种肌肉质量和功能指标对全因死亡率的预测能力。我们将使用 C 统计量评估这些措施的判别能力。二次分析将检查心血管死亡率和肾脏特异性结果，例如开始透析。目标 2：表征握力测力的个体内再现性和可靠性 宾夕法尼亚大学 CRIC 站点的生物电阻抗分析 (BIA)。候选人将前瞻性地验证研究协调员执行的这些测量，以确定测量者间和个体内部的一致性，以确认将这些测量转化为常规临床实践是可行的。分析将利用 Pearson 相关系数和 Bland-Altman 图来评估测量偏差。目标 3：评估 CRIC 参与者肌肉质量和功能下降与可改变因素的相关程度。贫血、酸中毒、蛋白质摄入量减少和体力活动减少可能与 CKD 患者的肌肉质量随着时间的推移出现更大的下降有关。我们将探索这些关系，以便为有关介导 CKD 肌肉质量下降的因果途径的假设提供信息，并提出未来的治疗目标。目标 4：在参加 CRIC 研究的一部分患者中，评估激活素受体 2b (ActRIIB) 配体作为随时间推移肌肉质量损失的介质的作用。肌肉生长抑制素、GDF-11 和激活素 A 的基线血清浓度，以及及其关键调节剂，将在 CRIC 内的 256 名患者巢式病例对照研究中通过蛋白质印迹进行评估。病例将被定义为纵向肌肉损失最高五分位数的患者，通过肌酐生成率随时间的斜率进行评估。对照将根据年龄、种族、性别 eGFR 和基线肌肉质量进行匹配，但从最低的五分之一中选择。主要分析将使用在配对水平上聚集的混合效应模型。