Intra Hemodialytic Oral Protein and Exercise (IHOPE)

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Intradialytic Protein Supplementation & Exercise Training in Dialysis Patients.

Conditions
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Kidney Diseases

Intervention / Treatment
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* Dietary Supplement: Control
* Dietary Supplement: Protein
* Behavioral: Protein + Exercise


Participation Criteria
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Eligibility Criteria
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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).

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Sham Comparator: Control<br>This group of patients will receive a non-nutritive beverage, and no exercise. | Dietary Supplement: Control<br>* A placebo non-nutritive beverage will be administered before dialysis sessions 3 times per week.<br>|
| Active Comparator: Protein<br>This group of patients will ingest 30 grams of a liquid whey protein supplement during the first hour of their dialysis session | Dietary Supplement: Protein<br>* A whey protein beverage will be administered before dialysis sessions 3 times per week.<br>|
| Active Comparator: Protein + Exercise<br>This group will ingest 30 grams of a liquid whey protein supplement as well as exercise for 30-45 minutes during their dialysis treatment | Behavioral: Protein + Exercise<br>* A whey protein beverage will be administered before dialysis sessions 3 times per week. Patients will also exercise by stationary bicycle during dialysis sessions 3 times per week.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Examine the effects of intradialytic oral protein supplementation and exercise training on physical function. | 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. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Examine the effects of intradialytic oral protein supplementation and exercise training on CVD risk. | 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. | 12 months | 
| Examine the effects of intradialytic oral protein supplementation and exercise training on bone health as determined by bone mineral density (BMD). | 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. | 12 months |