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

调解员

• 批准号: 8973660
• 负责人: FRANCIS PERRY WILSON
• 金额: $ 15.5万
• 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/8973660
• 关键词: Mediators; prognostic; value; muscle; mass

DESCRIPTION (provided by applicant): Candidate: Dr. Wilson is currently a 3rd year nephrology fellow with Internal Medicine and Nephrology board certification. He is pursuing a master's degree in clinical epidemiology, expected to be awarded in June 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). 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. Despite our growing understanding of multiple risk factors that explain clinical outcomes in the setting of CKD, there remains substantial unexplained variation in the rates of death, renal disease progression and other morbidities. The assessment of muscle -a dynamic, functional, and immunomodulatory organ - may reduce this variation, augmenting our ability to risk-stratify patients with CKD. The studies proposed herein stem from the hypothesis that measures of muscle mass and function serve to integrate multiple discrete pathologic processes to provide a more comprehensive risk profile in patients with CKD. Broadly speaking, we hypothesize that~ 1) measures of muscle mass and function provide prognostic information regarding clinical outcomes in the setting of CKD that augments that provided by previously reported risk factors, and 2) loss of muscle mass and function is mediated by humoral factors that are dysregulated in the setting of CKD. 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 chronic kidney disease. Aim 1a/b: To determine the value of measures of muscle mass and function in predicting a) mortality and b) ESRD in the setting of CKD. Using data collected in the Chronic Renal Insufficiency Cohort (CRIC), we will analyze the association of various proxies of muscle mass and function with these hard outcomes primarily using Cox regression. We will assess the discriminant ability of these measures using C-statistics. Aim 2: To determine the association between level of kidney function, proteinuria, inflammation and measures of muscle mass and function. We will assess these associations cross-sectionally, at CRIC study entry, with a primary focus on the correlation between lower eGFR and measures of muscle mass. These analyses will be performed primarily with linear regression. Aim 3: To determine predictors of loss of muscle mass and function over time in the setting of CKD. We will assess baseline factors including markers of inflammation, renal function, and several biomarkers including myostatin to determine their association with the rate of muscle loss over time leveraging the long- term follow-up and repeated measures of muscle mass and function in the CRIC cohort. The primary analysis will employ generalized estimating equations to account for the inter-subject repeated measures.

描述（由申请人提供）：候选人：Dr. Wilson目前是内科和肾脏病委员会认证的第三年肾病研究员。他正在攻读临床流行病学硕士学位，预计将于2012年6月获得学位。他以第一作者的身份发表了几篇论文，在研究方面具有显著的独创性。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。尽管我们对解释CKD临床结果的多种危险因素的了解越来越多，但在死亡率、肾脏疾病进展和其他发病率方面仍存在大量无法解释的差异。对肌肉——一个动态的、功能性的和免疫调节的器官——的评估可能会减少这种差异，增强我们对CKD患者进行风险分层的能力。本文提出的研究基于这样的假设，即肌肉质量和功能的测量有助于整合多个离散的病理过程，从而为CKD患者提供更全面的风险概况。从广义上讲，我们假设：1)肌肉质量和功能的测量为CKD的临床结果提供了预后信息，增加了先前报道的危险因素提供的信息；2)肌肉质量和功能的损失是由CKD环境中失调的体液因素介导的。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1a/b：确定肌肉质量和功能测量在预测a)死亡率和b)慢性肾病中ESRD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回归分析肌肉质量和功能的各种代理与这些硬结果的关联。我们将使用c统计来评估这些措施的判别能力。目的2：确定肾功能、蛋白尿、炎症水平与肌肉质量和功能测量之间的关系。我们将在CRIC研究开始时对这些关联进行横断面评估，主要关注较低eGFR与肌肉质量测量之间的相关性。这些分析将主要用线性回归进行。目的3：确定CKD患者肌肉质量和功能随时间变化的预测因素。我们将评估基线因素，包括炎症标志物、肾功能和几种生物标志物，包括肌生长抑制素，以确定它们与随着时间的推移肌肉损失率的关系，利用长期随访和重复测量肌肉质量和功能。初步分析将采用广义估计方程来解释主体间的重复测量。