Intra Hemodialytic Oral Protein and Exercise (IHOPE)

Chronic kidney disease (CKD) patients receiving hemodialysis treatment (CKD stage 5) suffer
from a variety of co-morbid diseases, many of which may be mechanistically linked. Protein
malnutrition, muscle catabolism and wasting are especially common, and these lead to reduced
muscle strength, declines in physical function, and low levels of physical activity. Physical
inactivity exacerbates these functional declines, and also promotes cardiovascular disease
(CVD) and bone disorders. This cycle of disease and disability greatly reduces quality of
life (QOL) and increases mortality rates in dialysis patients.

Many factors contribute to the development of these co-morbidities. Chronic inflammation is
believed to be a cause and a consequence of the protein malnutrition, CVD and bone disorders
in dialysis patients. In addition, abnormalities in mineral metabolism resulting from the
deficit in kidney function promote the loss of mineral from bone and the deposition of
mineral in the vasculature, a process termed vascular calcification (VC). VC is associated
with a variety of CVD-related disorders, including arterial stiffness, increases in arterial
wall intima-media thickness (IMT), left ventricular hypertrophy (LVH), and declines in
cardiac function. As a result of these abnormalities, cardiovascular events are 10 to 30
times greater in dialysis patients than in age- and sex-matched subjects in the general
population.

A variety of pharmacological therapies are commonly used to help prevent or attenuate the
progression of CKD co-morbidities; however, morbidity and mortality in this population remain
extremely high, indicating that additional therapeutic strategies that may improve the health
and QOL in this population are needed. Recently, the National Kidney Foundation recommended
that dialysis patients increase their protein intake to 1.2 g/kg/day to help prevent protein
malnutrition; however, little is known about the efficacy of this recommendation.
Intradialytic (during dialysis) protein supplementation has been shown to increase serum
albumin levels11, and also increases amino acid uptake into skeletal muscle, an effect that
is potentiated by both resistance and endurance exercise. However, the individual and
combined effects of intradialytic protein supplementation and exercise training on lean mass,
muscle strength, and physical function is unknown. Furthermore, intradialytic protein
supplementation and exercise training improve many risk factors associated with CVD and renal
bone disease (e.g., plasma lipids, inflammatory variables), but their effect on functional
CVD outcomes (e.g., arterial stiffness, VC, IMT, LVH, myocardial performance) and bone health
in dialysis patients is unknown.

The primary objective of the proposed research is to evaluate the efficacy of intradialytic
oral protein supplementation, with and without concomitant intradialytic endurance exercise
training (cycling), on physical function, CVD risk, and bone health. We will also examine
potential mechanisms for these effects, and determine if improvements in these factors lead
to improvements in QOL. Hemodialysis patients will be randomized to the following groups for
12 months: 1) usual care/control (CON); 2) intradialytic protein supplementation (PRO); or 3)
intradialytic protein supplementation + exercise training (PRO+EX).

Primary Aim #1: Examine the effects of intradialytic oral protein supplementation and
exercise training on physical function.

Hypothesis #1: Physical function, as assessed by a shuttle walk test, will improve in PRO+EX
and PRO, compared to CON, and the magnitude of improvements will be greatest in PRO+EX. In
secondary analyses, we also will examine the effects of our interventions on other variables
related to physical function, including lean body mass, muscle strength, and activities of
daily living (ADL) assessments.

Primary Aim #2: Examine the effects of intradialytic oral protein supplementation and
exercise training on CVD risk.

Hypothesis #2: CVD risk, as assessed by carotid artery stiffness, will improve in PRO+EX and
PRO, compared to CON, and the magnitude of improvements will be greatest in PRO+EX. In
secondary analyses, we also will examine the effects of our interventions on other factors
related to CVD risk, including carotid IMT, myocardial performance, LVH, aortic
calcification, and epicardial fat levels.

Primary Aim #3: Examine the effects of intradialytic oral protein supplementation and
exercise training on bone health as determined by bone mineral density (BMD).

Hypothesis #3: BMD will be reduced significantly more in CON than in PRO+EX or PRO. We
anticipate that BMD will remain stable in PRO+EX or PRO. Because the exercise is not bone
loading (i.e., invoking ground or joint reaction forces), we do not expect additive effects
of PRO+EX on BMD.

Inclusion Criteria:

- Must receive hemodialysis treatment at least 3 days per week.

- Must be ≥ 30 years of age.

- Must be willing to be randomized to the control or intervention groups.

- Must be physically able to exercise (e.g., no orthopedic problems that would preclude
them from cycling during dialysis).

- Must receive medical clearance from their primary care physician to participate.

- Must be on phosphate binders to control calcium levels.

Exclusion Criteria:

- Persistent hemoglobin levels < 10g/dl.

- Weight greater than 300 pounds.

- Currently receiving any form of intradialytic protein supplementation (oral, enteral,
or parenteral) or participating in any form of intradialytic exercise training.

- Chronic obstructive pulmonary disease (COPD) and decompensated chronic heart failure
(CHF).

- On dialysis treatment for < 3 months (or enrollment may be postponed).