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：威尔逊博士目前是内科和肾脏病董事会认证的博士后研究员。他于2012年8月获得临床流行病学科学硕士学位（MSCE）学位。他的近期目标包括在流行病学和生物统计学方面追求更先进的课程，并在慢性肾脏疾病的情况下研究肌肉质量的临床方面和功能。从长远来看，通过在临床试验设计和分析方面进行更先进的培训，他将进行针对CKD患者预后改善的介入试验。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与生物统计学中心（CCEB）的宾夕法尼亚大学进行。 CCEB核心教师包括33位临床医生，11位非临床主义流行病学家和28位生物统计学家（这些总数不包括116名附属教职员工）。 200多个全日制研究，行政和文书人员支持教师的活动。 CCEB研究目前获得超过3800万美元的壁外支持。它的总预算约为5800万美元。研究：低肌肉质量和功能已被确定为衰老中死亡率的强大而有力的预测指标，以及包括艾滋病，癌症和充血性心力衰竭在内的各种慢性病。横断面研究表明，CKD患者低肌肉质量和EGFR之间的相关性，但是这些发现的预后价值尚未阐明。肌肉的评估 - 一种动态，功能性和代谢活性器官 - 可能会增强我们风险分离CKD患者的能力，并提供潜在的干预靶标。 利用来自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的度量来表征广泛多样的CKD种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针对肌肉疾病中肌肉浪费的将来的干预试验。目标1：评估肌肉质量和肌肉功能在CKD环境中预测全因死亡率方面的替代物的价值。使用在慢性肾功能不全队列（CRIC）中收集的数据，我们将分析肌肉质量的各种代理和功能的预测能力，主要使用COX回归。我们将使用C统计数据来评估这些措施的判别能力。次要分析将检查心血管死亡率和肾脏特异性结果，例如透析的启动。目标2：要表征握力强度大量计的个体内部可重复性和可靠性 Upenn 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措施，以确定测量的间和个体内的一致性，以确认将这些测量值转化为常规临床实践是可行的。分析将利用皮尔逊的相关系数和平淡的altman图来评估测量中的偏差。 AIM 3：评估CRIC参与者的肌肉质量和功能下降与可修改因素有关的程度。贫血，酸中毒，蛋白质摄入量减少和体育锻炼的降低可能与CKD患者的肌肉质量下降相关。我们将探索这些关系，以告知有关介导CKD肌肉质量下降并提出未来治疗靶标的因果途径的假设。目标4：评估活化素受体2b（ACTRIIB）的配体作为肌肉质量损失的介体在CRIC研究基线血清，GDF-111和活化素A的基线血清浓度以及关键调节剂中，将在256例患者嵌套的CRIC中评估。病例将被定义为纵向肌肉损失最高五分位数的患者，随着时间的流逝，肌酐发电率评估。控制措施将根据年龄，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。主要分析将使用在匹配的对级别聚类的混合效应模型。