Elderly patients comprise half of the end-stage renal disease (ESRD) population and are particularly vulnerable to loss of muscle mass, strength and function - changes that lead to frailty and increased morbidity and mortality. Many factors contribute to the decline in muscle mass and function in the elderly uremic, and apart from aging and co-morbid conditions, wasting is worsened by inactivity. Studies in maintenance hemodialysis (MHD) patients have shown that regular exercise, including aerobic, resistance or combined modalities, can counteract the loss of muscle mass and function in these patients. However, most studies have not specifically targeted the elderly, have involved small numbers or lacked controls, and the impact on long-term outcomes is unknown. Nevertheless, despite substantial evidence indicating that exercise is beneficial and cost-effective, it is not part of the routine care of MHD patients. In contrast, among patients with cardiovascular disease and other conditions associated with muscle wasting, regular exercise is regarded as standard of care. Some protection against uremic muscle wasting can also be afforded by an adequate protein-calorie intake. Amino acids (AA) from this source serve as substrates for protein synthesis and also directly activate the mTOR signaling pathway which further stimulates protein synthesis. In normal subjects, if AA are ingested at the time of resistance exercise, anabolic signaling and protein synthesis are enhanced and this leads to increased muscle mass. Whether the exercise and AA-stimulated signaling response is intact in elderly MHD patients is unknown, and there is little information regarding the cellular processes invoked. Taking this all together, we plan to test the hypothesis that a home-based exercise program, effective in cardiac patients, will improve cardiopulmonary function and muscle mass and function in elderly MHD patients. In addition, in a pilot study we will examine whether a protein supplement acutely enhances exercise- stimulated anabolic signaling. Functionally impaired MHD subjects aged 65-80 years will be randomized into two groups of 30 each, one undergoing exercise training and the other usual care. After 3 months, half of each group will receive a one-time protein-calorie supplement while the other half will receive placebo during an acute bout of exercise, and muscle will be biopsied for examining the signaling response. Assesments at baseline and 3 months will include cardiopulmonary function, muscle strength and function, thigh muscle volume and composition, whole body composition, quality of life (QOL), cognitive function, nutritional, inflammatory, lipid and biochemical status, and morphologic and molecular analyses of biopsied muscle. We anticipate that home-based exercise will counteract muscle wasting, enhance cardiopulmonary and muscle function and QOL, and reduce surrogate markers of long-term outcome. New insights into mechanisms whereby exercise and nutrient supplementation induce an anabolic response in muscle of elderly MHD patients will be provided, which may serve as a basis for devising strategies to counteract loss of muscle mass and function in these individuals. Finally, we anticipate that our exercise program will be "user-friendly" and may thus form part of routine care of elderly, and perhaps younger MHD patients. If short-term benefits are evident from this study in the elderly, it could form the basis for a broader long-term outcomes study.

Public Health Relevance

Chronic kidney disease (CKD) is a major cause of disability, morbidity, and mortality in the VA, and this condition is expected to increase by 25% over the next decade. Elderly patients comprise half the CKD population and are particularly vulnerable to loss of muscle mass, strength and function - changes common in CKD that lead to increased morbidity and mortality. Studies in maintenance hemodialysis patients show that regular exercise can counteract the loss of muscle mass and function and is low cost. However, most studies have not specifically targeted the elderly and have involved small numbers or lacked controls;in addition, little is known regarding the actual wasting process. The primary aim of this study is to develop an effective user- friendly home-based exercise program that counteracts wasting and loss of muscle function that occurs in elderly dialysis patients. Our second aim is to better understand the processes causing muscle wasting in CKD. Our third aim is to test whether the response to exercise can be enhanced with nutrient supplementation.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
1I01RX000915-01A2
Application #
8586711
Study Section
Musculoskeletal/Orthopedic Rehabilitation (RRD2)
Project Start
2014-02-01
Project End
2018-01-31
Budget Start
2014-02-01
Budget End
2018-01-31
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Veterans Admin Palo Alto Health Care Sys
Department
Type
DUNS #
046017455
City
Palo Alto
State
CA
Country
United States
Zip Code
94304