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

描述(由申请人提供)：候选人：威尔逊博士目前是内科和肾脏病委员会认证的博士后研究员。2012年8月，他被授予临床流行病学理学硕士学位。他以自己的名字发表了几本第一作者的著作，证明了他的研究具有重大的原创性。他的近期目标包括在流行病学和生物统计学方面攻读更高级的课程，以及在慢性肾脏疾病的背景下对肌肉质量和功能的临床方面进行研究。从长远来看，通过在临床试验设计和分析方面进行更高级的培训，他将进行旨在改善慢性肾脏病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名附属教员)。200多名全职研究、行政和文书工作人员为教员的活动提供支持。CCEB研究目前每年获得超过3800万美元的外部支持。它的总预算约为5800万美元。研究：低肌肉质量和功能已被证实是衰老和各种慢性疾病(包括艾滋病、癌症和充血性心力衰竭)死亡率的有力和有力的预测因素。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，但这些发现的预后价值尚未阐明。对肌肉--一个动态、功能和代谢活跃的器官--的评估可能会增强我们对CKD患者进行风险分层的能力，并为干预提供潜在的靶点。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肌肉丢失和肌肉功能障碍在广泛和多样化的CKD人群中的患病率、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：评价肌肉质量和肌肉功能指标在慢性肾脏病全因死亡率预测中的价值。利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与全因死亡率的预测能力。我们将使用C-统计量来评估这些度量的判别能力。二次分析将检查心血管死亡率和肾脏特有的结果，如开始透析。目的2：评价握力测功的个体内重复性和可靠性。 在宾夕法尼亚大学CRIC站点进行生物电阻抗分析(BIA)。候选人将前瞻性地验证由研究协调员执行的这些测量，以确定评价者之间和个体内测量的一致性，以确认将这些测量转换为常规临床实践是可行的。分析将利用皮尔逊相关系数和Bland-Altman曲线图来评估测量中的偏差。目的3：评估CRIC参与者肌肉质量和功能下降与可调节因素的关系程度。慢性肾脏病患者的贫血、酸中毒、蛋白质摄入量减少和体力活动减少可能与肌肉质量随时间的推移下降幅度更大有关。我们将探索这些关系，以提供关于CKD中调节肌肉质量下降的因果途径的假说，并建议未来的治疗目标。目的4：评估激活素受体2b(ActRIIB)的配体在CRIC研究中登记的一组患者中作为肌肉质量随时间丢失的介体的作用。在CRIC内的256名患者嵌套的病例对照研究中，将通过免疫印迹法评估血清中肌肉生长抑素、GDF-11和激活素A及其关键调节剂的基线浓度。病例将被定义为纵向肌肉损失的最高五分之一的患者，根据随时间变化的肌酐生成率的斜率进行评估。对照组将根据年龄、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。初步分析将使用在配对水平上聚集的混合效应模型。

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.