Exercise Intolerance in Renal Failure

Study Overview
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Brief Summary
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Patients with chronic kidney disease have profound exercise intolerance which contributes to an increased risk of cardiovascular disease. The investigators have found that chronic kidney disease patients have an exaggerated increase in blood pressure during certain forms of exercise that could certainly contribute to exercise dysfunction as well as cardiovascular risk. The investigators will test the mechanisms underlying this exaggerated blood pressure response, as well as the potential benefits of short-term tetrahydrobiopterin (BH4) with folic acid on both exercise dysfunction and cardiovascular risk factors in chronic kidney disease. The investigators will test whether short-term treatment with tetrahydrobiopterin (BH4), a cofactor for nitric oxide, together with folic acid improves inflammation, vascular health, and adrenaline levels, both at rest and during exercise in chronic kidney disease.

Official Title
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The Role of Neurovascular Dysfunction and Oxidative Stress in the Exercise Intolerance of Renal Failure

Conditions
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Kidney Failure, Chronic

Intervention / Treatment
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* Drug: Tetrahydrobiopterin
* Drug: Placebo
* Dietary Supplement: Folate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: chronic kidney disease (CKD) stages I, II, and III and do not regularly exercise 1. CKD Stages I, II, and III will be defined as reduction in estimated glomerular filtration rate (eGFR) to 30-59 cc/minute as calculated by the Modification of Diet in Renal Disease (MDRD) equation, or an eGFR>60 cc/minute with proteinuria greater than 500 mg/g of Creatinine or 500 mg per 24 hours. willing and able to cooperate with the protocol CKD patients must have stable renal function (no greater than a 20% reduction in eGFR over the prior 3 months) controls will be matched for age, gender, race, and hypertensive status. Exclusion Criteria: severe CKD (eGFR<30 cc/minute) drug or alcohol abuse diabetes any serious systemic disease that might influence survival severe anemia with hgb level <10 g/dL clinical evidence of congestive heart failure or ejection fraction below 35% any history of past myocardial infarction or cerebrovascular accident symptomatic heart disease determined by electrocardiogram, stress test, and/or history treatment with central alpha agonists uncontrolled hypertension with BP greater than 160/90 mm Hg low blood pressure with BP less than 110/60 history of nephrolithiasis pregnancy or plans to become pregnant treatment with vitamin C within the past 3 months hepatic enzyme concentrations greater than 2 times the upper limit of normal HIV infection surgery within the past 3 months previous treatment with BH4 known hypersensitivity to BH4 any condition that places the participant at high risk of poor adherence or poor follow-up patients must be willing to use an acceptable method of contraception if of childbearing age

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tetrahydrobiopterin + Folate<br>Male subjects with hypertension and chronic kidney disease stage 2 or 3 will receive Tetrahydrobiopterin (6R-BH4) 200 mg twice daily and folic acid 1 mg daily | Drug: Tetrahydrobiopterin<br>* Tetrahydrobiopterin (BH4) 200 mg PO BID for 12 weeks<br>* Other names: Kuvan;Dietary Supplement: Folate<br>* Folate 1 mg daily for 12 weeks<br>* Other names: Folic Acid;|
| Placebo Comparator: Placebo + Folate<br>Male subjects with hypertension and chronic kidney disease stage 2 or 3 will receive 2 placebo pills twice daily and folic acid 1 mg daily | Drug: Placebo<br>* 2 placebo pills PO BID for12 weeks<br>Dietary Supplement: Folate<br>* Folate 1 mg daily for 12 weeks<br>* Other names: Folic Acid;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Resting Muscle Sympathetic Nerve Activity (MSNA) |  | Baseline, 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Mean Central Augmentation Index (AIx) | The augmentation index (AIx) is a measure of systemic arterial stiffness, and is defined as the ratio of augmentation (Δ P) to central pulse pressure and expressed as percent. AIx = (ΔP/PP) x 100, where P = pressure and PP = Pulse Pressure. The mean AIx for each group was estimated as an average and expressed as a change from baseline to 12 weeks. | Baseline, 12 weeks | 
| Change in Heart-rate-corrected Augmentation Index (AIx) | The augmentation index (AIx) is a measure of systemic arterial stiffness, and is defined as the ratio of augmented aortic pressure (Δ P) to central pulse pressure expressed as a percent. AIx = (ΔP/PP) x 100, where P = pressure and PP = Pulse Pressure. Because heart rate (HR) affects AIx, AIx was corrected to a HR of 75 beats per minute (bpm) as follows: HR-corrected AIx = -0.39 x (75 - HR) + AIx. The mean AIx for each group was estimated as an average and expressed as a change from baseline to 12 weeks. | Baseline, 12 weeks |