GROWTH HORMONE SECRETAGOGUE MK-677 THERAPY EFFECT ON IGF-1 LEVELS IN CKD & ESRD

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. With development and progression of chronic kidney disease (CKD) to end stage renal disease (ESRD), malnutrition becomes an increasingly severe problem. This is thought to occur from two mechanisms: decreased appetite secondary to uremia and development of a catabolic inflammatory milieu. Patients experience decreased muscle mass and functional activity associated with increased morbidity and mortality. Many therapies to improve poor nutritional state have been used with little success. Growth hormone (GH) and insulin like growth hormone (IGF-I) improve muscle mass, quality of life, nutritional parameters, immune and physical functions but must be given parentally and are limited by expense and patient compliance. Recently, the endogenous GH receptor secretagogue (GHRS) ghrelin has been shown to raise endogenous GH and improve food intake but must be given parentally and is not available. The experimental drug, MK-0677, a synthetic GHRS, ghrelin mimetic which is given orally, has recently been shown to increase IGF-I and muscle mass in the elderly. Its effects in CKD and ESRD are unknown. We will study the effects of MK-0677 on renal patients. Specifically, we hope to show that the drug increases IGF-1 in renal patients and has similar effects to exogenous GH and IGF-1. Subjects will have CKD stage 4/5 or be ESRD hemodialysis patients. This protocol is an investigator-initiated, randomized, double-blind crossover, placebo-controlled pilot study. The study's primary outcome is IGF-1 levels for subjects. Secondary outcomes will be levels of cytokines, leptin, insulin, ghrelin, TNF- alpha, CRPs, IL-1, IL-6 IL-10.We hope to follow this short trial with a larger phase 2b study. The phase 2b study will include renal patients, too, and have broader goals including: MK-0677's effects on muscle mass, nutrition, appetite, physical function, quality of life and economic impact.