Exercise to Prevent Muscle Mass and Functional Loss in Elderly Dialysis Patients

Elderly patients comprising half the end-stage renal disease (ESRD) population, are
especially 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 exercise (EX), including endurance, resistance or combined, can counteract the
loss of muscle mass and function. However most studies have not specifically targeted the
elderly, involved small numbers or lacked controls and the impact on long-term outcome is
unknown. Nevertheless, despite substantial evidence indicating that EX is beneficial and low
cost, EX is not part of the routine care of MHD patients. In contrast EX is regarded as
standard of care for the wasted elderly and also cardiac patients. 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 (PS) and also directly
activate the mTOR signaling pathway stimulating PS. In normal subjects if AA are ingested at
the time of resistance EX, anabolic signaling and PS is enhanced and this leads to increases
in muscle mass. Whether the EX and AA stimulated signaling response is intact in elderly MHD
patients is unknown and there is little information about the cellular processes invoked.
Taking this all together, the investigators plan to test the hypothesis that a home-based EX
program, effective in cardiac patients, will improve cardiopulmonary function and muscle mass
and function in elderly MHD patients. Also, in a pilot study the investigators will examine
whether a protein supplement acutely enhances EX stimulated anabolic signaling. Functionally
impaired MHD subjects aged 65-80 yrs are randomized into 2 groups of 30 each, one undergoing
EX and the other usual care. After 3 months, half in each group receive a one-time
protein-calorie supplement or placebo during an acute bout of EX and muscle biopsied for
examining the signaling response. Assays at baseline and at 3 months include cardiopulmonary
function, muscle strength and function, body composition by DEXA, thigh muscle volume and
composition by CT, quality of life (QOL) and cognitive function, and nutritional,
inflammatory, lipid and biochemical status and morphologic and molecular analysis of biopsied
muscle. The investigators anticipate that home-based EX will counteract muscle wasting,
enhance cardiopulmonary and muscle function and QOL, and reduce surrogate markers of
long-term outcome. New insights into the mechanisms whereby EX and nutrients induce an
anabolic response in muscle of elderly uremics will be provided and may serve as a basis for
devising strategies to counteract loss of muscle mass and function. Finally, the
investigators anticipate that the EX program will be "user friendly" and may thus form a part
of the routine care of elderly and perhaps younger MHD patients. If short-term benefits are
evident from this study in elderly MHD patients, it could form the basis for a comprehensive
long-term outcomes study.

Inclusion Criteria:

- Males and females aged 55-80 years undergoing maintenance hemodialysis (MHD) for at
least three months and without other active/uncontrolled disease will be studied.

- Exercise and usual care groups will be matched by age, body mass index (BMI), MHD
duration, and protein intake using a stratified randomization approach.

- Subjects will be required to be in the peak VO2 range of 10 to 20 ml/kg/min,
equivalent to moderate functional impairment in patients with heart failure.

- Subjects will be required to have dialysis treatment for >3 months with an average
Kt/V 1.2, and be able to perform exercise safely.

Exclusion Criteria:

- Current activity > 2 hrs/wk of moderate intensity exercise, temporary vascular access,
uncontrolled diabetes mellitus, active vasculitis, active autoimmune disease,
malignancy, severe obesity (BMI > 35), alcoholism or other recreational drug use,
unstable cardiac disease (abnormal exercise test, angina, uncontrolled arrhythmias or
myocardial infarction within three months), peripheral vascular disease (claudication
with exercise), lung, liver or intestinal disease, those who are medically unstable
and subjects who have received anabolic, catabolic or cytotoxic medications in the
past 3 months.

- The investigators will also exclude subjects with excessive previous exposure to
radiation.