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

描述（由申请人提供）：候选人：威尔逊博士目前是一名博士后研究员，拥有内科和肾脏病委员会认证。他于2012年8月获得临床流行病学（MSCE）硕士学位。他以自己的名字发表了几篇第一作者的论文，证明了他的研究具有重要的原创性。他的近期目标包括追求更先进的流行病学和生物统计学课程，并追求在慢性肾脏疾病的设置肌肉质量和功能的临床方面的研究。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，他将追求针对CKD患者改善结局的干预性试验。工作环境：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，行政和文书工作人员支持教师的活动。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。调研：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）死亡率的可靠和有力的预测指标。横断面研究表明，CKD患者的低肌肉质量和eGFR之间存在相关性，但这些结果的预后价值尚未阐明。肌肉是一个动态的、功能性的、代谢活跃的器官，对肌肉的评估可以增强我们对CKD患者进行风险分层的能力，并为干预提供潜在的靶点。 利用来自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指标来表征广泛多样的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。目的1：评估肌肉质量和肌肉功能替代物在预测CKD患者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，我们将主要使用考克斯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。次要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：描述握力测力法的个体内重现性和可靠性， 生物电阻抗分析（BIA）在UPenn CRIC网站。候选人将前瞻性验证研究协调员执行的这些测量，以确定评估者间和个体内测量的一致性，从而确认将这些测量转化为常规临床实践是可行的。分析将使用Pearson相关系数和Bland-Altman图评估测量偏倚。目标3：评估审评委参与者肌肉质量和功能下降与可改变因素的关联程度。贫血、酸中毒、蛋白质摄入量减少和体力活动减少可能与CKD患者肌肉质量随时间推移的更大下降相关。我们将探讨这些关系，以告知有关因果途径的假设，介导的肌肉质量下降，在CKD和建议未来的治疗目标。目标4：评估激活素受体2b（ActRIIB）的配体作为CRIC研究中招募的患者亚组中肌肉质量随时间损失的介质的作用肌生长抑制素、GDF-11和激活素A的基线血清浓度以及它们的关键调节剂沿着将在CRIC内的256名患者巢式病例对照研究中通过蛋白质印迹评估。病例将定义为通过肌酐生成率随时间的斜率评估的纵向肌肉损失最高五分位数的患者。对照组将根据年龄、人种、性别eGFR和基线肌肉质量进行匹配，但从最低的五分位数中选择。主要分析将使用在配对水平上聚类的混合效应模型。

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.