Mechanisms of Muscle Blood Flow Dysregulation and Exercise Intolerance in Chronic Kidney Disease

Study Overview
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Brief Summary
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Patients with chronic kidney disease (CKD) experience fatigue and exercise intolerance. Increased oxidative stress in CKD may be a contributing factor. The role of impaired muscle blood flow regulation has not been fully explored. The investigators hypothesize that functional sympatholysis is exaggerated in CKD and this is associated with increased oxidative stress. The investigators also hypothesize that exercise training will improve functional sympatholysis and oxidative stress

Detailed Description
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Progressive muscle weakness and premature fatigue are characterize the condition of chronic kidney disease (CKD) which can be very debilitating. Mechanisms underlying exercise intolerance in CKD is not completely understood. Previous studies have demonstrated impaired skeletal muscle vasodilation during exercise in CKD patients, which may contribute to exercise intolerance. Normally, there is blunting of sympathetic mediated vasoconstriction in exercising muscle to allow for steady blood supply to exercising muscles. This phenomenon is called functional sympatholysis. Functional sympatholysis is impaired by increases in reactive oxygen specie and may be impaired in CKD. Experiments will be performed on 2 groups of subjects 1) Normal kidney function (eGFR>90) 2) Stage 2-3 CKD (eGFR 30-89). VAsoactive medications will be held for 72 hours before study. All participants will attend a baseline study visit, which will include a physical examination, a medical history review, vital sign measurements, and blood collection. Muscle nerve activity and muscle oxygenation will be measured while the subjects perform hand grip exercise at 30% maximum voluntary contraction with and without lower body negative pressure (- 20 mmHg). Muscle blood flow will be measured before and after hand grip exercises. CKD subjects will then be randomized to exercise training (to squeeze a tennis ball repeatedly for at least 30 min/day) or no exercise training for 28 days. Procedures in baseline visit will be repeated followed by cross over to alternate group for 28 days followed by repeat of baseline procedures. Blood flow, muscle oxygenation and muscle nerve activity will be compared between CKD and normal subjects as well as before and after exercise training for CKD subjects.

Official Title
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Mechanisms of Muscle Blood Flow Dysregulation and Exercise Intolerance in Chronic Kidney Disease

Conditions
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Chronic Kidney Disease

Intervention / Treatment
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* Behavioral: Forearm exercise training


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Normotensive adults CKD 2-3 Exclusion Criteria: Blood Pressure ≥140/90 eGFR >60ml/min/1.73 m2 or eGFR <30ml/min/1.73 m2 Any evidence of cardiopulmonary disease, left ventricular hypertrophy or systolic dysfunction by echocardiography. Diabetes mellitus or other systemic illness Pregnancy Any history of substance abuse or current cigarette use Any history of psychiatric illness History of malignancy

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Exercise training followed by no exercise training<br>CKD subjects will be randomized to exercise training (to squeeze a tennis ball repeatedly for at least 30 min/day) or no exercise training for 28 days. Procedures in baseline visit will be repeated followed by cross over to alternate group for 28 days followed by repeat of baseline procedures. | Behavioral: Forearm exercise training<br>* Subjects will be asked to squeeze a tennis ball repeatedly for at least 30 min/day for 28 days at an approximate rate of 20 squeezes/min.<br>|
| Experimental: No exercise training followed by exercise training<br>CKD subjects will be randomized to exercise training (to squeeze a tennis ball repeatedly for at least 30 min/day) or no exercise training for 28 days. Procedures in baseline visit will be repeated followed by cross over to alternate group for 28 days followed by repeat of baseline procedures. | Behavioral: Forearm exercise training<br>* Subjects will be asked to squeeze a tennis ball repeatedly for at least 30 min/day for 28 days at an approximate rate of 20 squeezes/min.<br>|
| No Intervention: Normal Control<br>Control subjects without CKD will undergo baseline assessment as above. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in muscle oxygenation | Tissue oxygenation will be recorded using Near-infrared spectroscopy (NIRS) | After 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Forearm vascular conductance (FVC) | Doppler ultrasonography to measure blood flow | After 28 days | 
| Change in plasma isoprostanes | Plasma isoprostanes will be used as a measure of oxidative stress | After 28 days | 
| Change in muscle sympathetic nerve activity (MSNA) | MSNA will be measured using tiny tungsten wire inserted into the common peroneal nerve below fibular head. | After 28 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic Kidney Disease, Functional sympatholysis, Exercise training, Exercise intolerance, Handgrip exercise, Near infrared spectroscopy, Lower body negative pressure