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 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 synthetic GHRS, ghrelin mimetic MK-677 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 hypothesize that MK-677 will effect an increase of IGF-I and have similar effects to exogenous GH and IGF-I in CKD and ESRD. First it must be shown to be effective in the CKD/ESRD population. We propose a pilot study to address this hypothesis. If successful, then large scale studies can be initiated to examine a potential broader effect long term. We propose three specific aims. All would be double blind in nature.
Aim 1 will determine if MK-677 elicits an increase in IGF-I in short term cross-over studies in CKD stage 4/5.
Aim 2 will assess if MK-677 increases IGF-I in ESRD in the same study format as Aim 1.
If Aims 1 and 2 demonstrate an increase in IGF-I, as anticipated, then a one year study to assess the effect of MK-677 on muscle mass in patients with CKD / ESRD will be performed. The primary outcome in Specific Aim 1 and 2 will be IGF-I levels.
For Aim 3, the primary outcome will be muscle mass. Secondary outcomes will be the effects on cytokine levels, nutritional parameters, quality of life, physical function and economic parameters. This is an investigator initiated proposal for which Merck will only supply active MK-677 pills with matching placebo and advice from unpublished data and trials. Bolton, W. Kline 7 Project narrative: Relevance: Chronic kidney disease (CKD) and the need for dialysis, end stage renal disease (ESRD) are major public health issues in the United States. Morbidity and mortality in CKD and ESRD are related to nutritional status with patients having worst nutritional status and having a higher risk for death, hospitalization, and complication of their diseases. There is currently no good treatment of the malnutrition of CKD and ESRD. If this problem could be alleviated or eliminated, this would have a significant financial and societal impact on patients with CKD and ESRD. The present proposal seeks to determine if MK-677, which induces growth hormone in normal subjects with subsequent beneficial effects clinically, can induce similar changes in patients with CKD and ESRD. If it does so, this would decrease the malnutrition in this group of patients and significantly improve their risk for death and complications of kidney disease, and decrease the cost for hospitalization and medical care. ? ? ?

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1-RUS-A (51))
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Eggers, Paul Wayne
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University of Virginia
Internal Medicine/Medicine
Schools of Medicine
United States
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Bhatt, Aadra P; Gunasekara, Dulan B; Speer, Jennifer et al. (2018) Nonsteroidal Anti-Inflammatory Drug-Induced Leaky Gut Modeled Using Polarized Monolayers of Primary Human Intestinal Epithelial Cells. ACS Infect Dis 4:46-52
Campbell, Garland A; Patrie, James T; Gaylinn, Bruce D et al. (2018) Oral ghrelin receptor agonist MK-0677 increases serum insulin-like growth factor 1 in hemodialysis patients: a randomized blinded study. Nephrol Dial Transplant 33:523-530
Gupta, Rohit K; Kuppusamy, Tamil; Patrie, James T et al. (2013) Association of plasma des-acyl ghrelin levels with CKD. Clin J Am Soc Nephrol 8:1098-105