RECRUITINGPhase 2INTERVENTIONAL

Neurovascular Transduction During Exercise in Chronic Kidney Disease

Neurovascular Regulation During Exercise in Humans With Chronic Kidney Disease

About This Trial

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.

Who May Be Eligible (Plain English)

Inclusion Criteria for Chronic Kidney Disease Patients: - Stage III or IV Chronic Kidney Disease, defined as reduction in estimated glomerular filtration rate (eGFR) to 15-59 cc/minute as calculated by the modified Modification of Diet in Renal Disease (MDRD) Study equation or the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation - Stable renal function, with no greater than a 30% reduction in eGFR over the prior 3 months - Does not exercise regularly (defined as exercising less than 20 minutes twice per week) - Willing and able to cooperate with the study protocol Inclusion Criteria for Control Study Participants: - Does not exercise regularly (defined as exercising less than 20 minutes twice per week) - Willing and able to cooperate with the study protocol Who Should NOT Join This Trial: - 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 Always talk to your doctor about whether this trial is right for you.

Original Eligibility Criteria

View original clinical language

Inclusion Criteria for Chronic Kidney Disease Patients: * Stage III or IV Chronic Kidney Disease, defined as reduction in estimated glomerular filtration rate (eGFR) to 15-59 cc/minute as calculated by the modified Modification of Diet in Renal Disease (MDRD) Study equation or the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation * Stable renal function, with no greater than a 30% reduction in eGFR over the prior 3 months * Does not exercise regularly (defined as exercising less than 20 minutes twice per week) * Willing and able to cooperate with the study protocol Inclusion Criteria for Control Study Participants: * Does not exercise regularly (defined as exercising less than 20 minutes twice per week) * Willing and able to cooperate with the study protocol 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

Treatments Being Tested

DRUG

6R-BH4

Participants will receive 200 mg of 6R-BH4 twice daily for 12 weeks. Study pills are dissolved in water or apple juice, and taken with food.

OTHER

6R-BH4 placebo

Participants will receive a placebo that is identical to 200 mg of 6R-BH4. The placebo will be taken twice daily for 12 weeks. Study pills are dissolved in water or apple juice, and taken with food.

DIETARY_SUPPLEMENT

Folic acid

Participants will take 1 mg of folic acid daily for 12 weeks. Folic acid is given because it enhances the binding affinity of BH4 to nitric oxide synthase (NOS), and also enhances the regeneration of BH4 from inactive BH2

OTHER

Exercise training

Participants will exercise 3 times a week on a stationary ergometer. Exercise intensity will begin at low levels (50% of maximal heart rate reserve) calculated utilizing the Karvonen method. Briefly, target exercise heart rate (HR) is calculated by subtracting the persons age from 220. Resting heart rate is then subtracted from this number. The answer is then multiplied by the target percent (50% for example) and the product is added back to resting heart rate to provide the target exercise session heart rate. Intensity will be increased by 5% every week (as tolerated by the participant) to a maximum of 80% of maximal heart rate. Exercise time will progress from an initial 20 minutes per session to a maximum of 45 minutes by increasing 5 minutes each week.

OTHER

Stretching

Participants randomized to 'No Exercise Training' group will instead of aerobic exercise, undergo progressive whole body stretching and toning exercises designed for individuals 65 and older. This type of low intensity activity is designed not to increase heart rate and will serve as the Control group to the Exercise Training group. The Control group will come in for stretching sessions 3 times per week for 20-45 minutes.

DIETARY_SUPPLEMENT

Histidine and beta-alanine supplementation

Histidine and beta-alanine are two over-the-counter supplements commonly used to enhance sports performance in athletes. Participants randomized to this study arm will receive combined histidine (4g/day) and beta-alanine (3.2g/day) supplementation.

OTHER

Histidine and beta-alanine placebo

Participants randomized to this study arm will receive a placebo to match combined histidine (4g/day) and beta-alanine (3.2g/day) supplementation.

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