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

简介（由申请人提供）：候选人：Wilson博士目前是一名博士后研究员，拥有内科和肾脏病学委员会认证。2012年8月获临床流行病学硕士学位。他以第一作者的名义发表了几篇论文，证明了他的研究具有重要的原创性。他的近期目标包括在流行病学和生物统计学方面进行更高级的课程学习，并在慢性肾脏疾病的背景下进行肌肉质量和功能的临床研究。从长远来看，通过在临床试验设计和分析方面的更高级培训，他将从事针对改善CKD患者预后的介入性试验。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核心教师包括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名附属教师）。200多名全职研究、行政和文书人员为学院的活动提供支持。CCEB研究目前每年获得超过3800万美元的校外支持。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）死亡率的可靠而有力的预测指标。横断面研究表明CKD患者低肌肉质量和eGFR之间存在相关性，但这些发现的预后价值尚未得到阐明。肌肉是一个动态的、功能性的、代谢活跃的器官，对它的评估可以增强我们对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，我们将利用肌肉质量和功能的多种测量来表征广泛和多样化的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脏疾病肌肉萎缩的干预试验。目的1：评估肌肉质量和肌肉功能替代物在预测CKD全因死亡率中的价值。使用慢性肾功能不全队列（CRIC）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统计来评估这些措施的判别能力。二级分析将检查心血管死亡率和肾脏特异性结局，如开始透析。目的2：表征握力测定仪在个体内的重复性和可靠性

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.