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 1 a/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.
Chronic kidney disease is an exceedingly common condition affecting 17% of Americans aged 20 and older. This project seeks to advance our knowledge of the decline of muscle mass and function as kidney function declines; and to determine if that loss of muscle predicts adverse outcomes such as death and the need for dialysis. This will lead to future interventional trials aimed at altering the course of chronic kidney disease- associated muscle loss.
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