Neurovascular Transduction During Exercise in Chronic Kidney Disease

Phase 2

Recruiting

• Conditions: Renal Insufficiency, Chronic
• Interventions: Other: 6R-BH4 placebo; Drug: 6R-BH4; Dietary Supplement: Folic acid; Dietary Supplement: Histidine and beta-alanine supplementation; Other: Histidine and beta-alanine placebo; Other: Exercise training; Other: Stretching

• Registration Number: NCT02947750
• Lead Sponsor: Emory University

Brief Summary

The purpose of this study is to find out why patients with chronic kidney disease (CKD) have poor exercise capacity and to explore what causes an increase in blood pressure during exercise (i.e. increased adrenaline levels, or decreased ability of blood vessels to dilate). This study will also test whether or not regular exercise on a bicycle and/or treatment with 6R-BH4 (Kuvan) pills, or histidine and beta-alanine supplementation improves these measures during exercise. 6R-BH4 is currently FDA-approved for use in patients with certain forms of a disease called phenylketonuria, but it is not currently FDA approved for blood pressure or exercise capacity in people with CKD.

Detailed Description

The major problem addressed in this study is to understand mechanisms underlying poor exercise capacity in patients with chronic kidney disease (CKD). Prior research has found that CKD patients have an exaggerated increase in blood pressure during certain forms of exercise that could contribute to exercise dysfunction as well as cardiovascular disease. This study will test the mechanisms underlying this exaggerated blood pressure response, as well as the potential benefits of simple measures such as exercise training on a stationary bicycle, and treatment with 6R-BH4, a drug that is currently FDA-approved for the treatment of phenylketonuria, but has been shown to have beneficial effects on vascular health in patients with kidney disease. This study will also examine the effects of exercise with histidine and beta-alanine supplementation. Histidine and beta-alanine are two over-the-counter supplements commonly used to enhance sports performance in athletes.

Prior to the intervention portion of this study, the researchers will measure how much the vein constricts in response to adrenaline in CKD patients versus controls. The study will also measure muscle pH, and muscle oxygenation during exercise in CKD patients and controls.

The intervention portion of the study will test whether aerobic exercise training with and without 6R-BH4, or with and without histidine and beta-alanine supplementation might help muscle pH and adrenaline levels, vascular reactivity, muscle oxygenation, and the exaggerated blood pressure response during exercise in CKD patients. Participants will be randomized using a 2x2 factorial design to exercise training (ET) with 6R-BH4, ET with placebo, stretching (control condition to exercise) with 6R-BH4, and stretching with placebo. Participants will undergo exercise training on a stationary bicycle, or stretching exercises, 3 times per week for 6-14 weeks (depending on availability of the participant).

Study Timeline

• Study Start: 2016-10
• Study First Submitted: 2016-10-17
• Study First Submitted QC: 2016-10-26
• Study First Posted: 2016-10-28
• Status Verified: 2025-02
• Last Update Submitted: 2025-03-03
• Last Update Posted: 2025-03-05
• Primary Completion: 2026-01
• Study Completion: 2026-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 150

Inclusion Criteria

Not provided

Exclusion Criteria

• severe CKD (eGFR<15 cc/minute)
• ongoing drug or alcohol abuse
• diabetic neuropathy
• any serious systemic disease that might influence survival
• severe anemia with hgb level <9 g/dL
• clinical evidence of congestive heart failure or ejection fraction below 35%
• symptomatic heart disease determined by prior electrocardiogram, stress test, and/or history
• treatment with central alpha agonists (clonidine)
• uncontrolled hypertension with BP greater than 170/100 mm Hg
• low blood pressure with BP less than 100/50
• pregnancy or plans to become pregnant
• current treatment with monoamine oxidase (MAO) inhibitors
• inability to exercise on a stationary bicycle

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: FACTORIAL

Arm && Interventions

Group	Intervention	Description
Exercise training + 6R-BH4	Folic acid	Participants randomized to this arm will exercise on a stationary bicycle for 20-45 minutes, 3 times per week, for 6-12 weeks. This arm will also take the study drug 6R-BH4.
Exercise training + 6R-BH4 placebo	6R-BH4 placebo	Participants randomized to this arm will exercise on a stationary bicycle for 20-45 minutes, 3 times per week, for 6-12 weeks. This arm will also take a placebo to match the study drug 6R-BH4.
Exercise training + 6R-BH4	Exercise training	Participants randomized to this arm will exercise on a stationary bicycle for 20-45 minutes, 3 times per week, for 6-12 weeks. This arm will also take the study drug 6R-BH4.
Exercise training + 6R-BH4 placebo	Folic acid	Participants randomized to this arm will exercise on a stationary bicycle for 20-45 minutes, 3 times per week, for 6-12 weeks. This arm will also take a placebo to match the study drug 6R-BH4.
Stretching + placebo	Stretching	Participants randomized to this arm will do muscle stretching and toning for 20-45 minutes, 3 times per week, for 6-12 weeks. This arm will also take a placebo instead of the active study drug.
Exercise training + histidine and beta-alanine placebo	Exercise training	Participants randomized to this arm will exercise on a stationary bicycle for 20-45 minutes, 3 times per week, for 6-12 weeks. This arm will also take a placebo to match the histidine and beta-alanine supplementation.
Exercise training + histidine and beta-alanine	Exercise training	Participants randomized to this arm will exercise on a stationary bicycle for 20-45 minutes, 3 times per week, for 6-12 weeks. This arm will also take histidine and beta-alanine supplementation.
Exercise training + 6R-BH4 placebo	Exercise training	Participants randomized to this arm will exercise on a stationary bicycle for 20-45 minutes, 3 times per week, for 6-12 weeks. This arm will also take a placebo to match the study drug 6R-BH4.
Stretching + placebo	Folic acid	Participants randomized to this arm will do muscle stretching and toning for 20-45 minutes, 3 times per week, for 6-12 weeks. This arm will also take a placebo instead of the active study drug.
Stretching + 6R-BH4	Folic acid	Participants randomized to this arm will do muscle stretching and toning for 20-45 minutes, 3 times per week, for 6-12 weeks. This arm will also take the study drug 6R-BH4.
Stretching + placebo	6R-BH4 placebo	Participants randomized to this arm will do muscle stretching and toning for 20-45 minutes, 3 times per week, for 6-12 weeks. This arm will also take a placebo instead of the active study drug.
Stretching + 6R-BH4	Stretching	Participants randomized to this arm will do muscle stretching and toning for 20-45 minutes, 3 times per week, for 6-12 weeks. This arm will also take the study drug 6R-BH4.
Exercise training + histidine and beta-alanine	Histidine and beta-alanine supplementation	Participants randomized to this arm will exercise on a stationary bicycle for 20-45 minutes, 3 times per week, for 6-12 weeks. This arm will also take histidine and beta-alanine supplementation.
Exercise training + histidine and beta-alanine placebo	Histidine and beta-alanine placebo	Participants randomized to this arm will exercise on a stationary bicycle for 20-45 minutes, 3 times per week, for 6-12 weeks. This arm will also take a placebo to match the histidine and beta-alanine supplementation.
Exercise training + 6R-BH4	6R-BH4	Participants randomized to this arm will exercise on a stationary bicycle for 20-45 minutes, 3 times per week, for 6-12 weeks. This arm will also take the study drug 6R-BH4.
Stretching + 6R-BH4	6R-BH4	Participants randomized to this arm will do muscle stretching and toning for 20-45 minutes, 3 times per week, for 6-12 weeks. This arm will also take the study drug 6R-BH4.

Primary Outcome Measures

Name	Time	Method
Change in functional sympatholysis	Baseline, Week 12	Muscle oxygenation during exercise and sympathoexcitation will be measured.
Change in exaggerated pressor responses during exercise	Baseline, Week 12	Blood pressure and sympathetic responses during exercise will be measured.
Change in vascular alpha 1 adrenergic responsiveness	Baseline, Week 12	Changes in vascular diameter in response to phenylephrine will be measured.

Secondary Outcome Measures

Name	Time	Method
Change in vascular stiffness	Baseline, Week 12	Vascular stiffness using applanation tonometry.
Renal artery resistance during exercise	Baseline, Week 12	Renal artery blood flow will be measured.
Change in endothelial function	Baseline, Week 12	Endothelial function using peripheral arterial tonometry will be measured.

Trial Locations

Locations (3)

Emory University Hospital Midtown; 🇺🇸 Atlanta, Georgia, United States

Emory University Hospital; 🇺🇸 Atlanta, Georgia, United States

Atlanta VA Health Care System; 🇺🇸 Decatur, Georgia, United States