Neurovascular Transduction During Exercise in Chronic Kidney Disease (NeurovEx)

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.

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).

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.

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.

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.

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.

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.

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.

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.

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.

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

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.

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.

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.

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

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