Exercise Intolerance in Renal Failure

Phase 2

Completed

Interventions: Drug: Placebo
Drug: Tetrahydrobiopterin
Dietary Supplement: Folate

Brief Summary: 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.

Recruitment & Eligibility

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

Arm && Interventions

Group	Intervention	Description
Placebo + Folate	Folate	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
Tetrahydrobiopterin + Folate	Folate	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
Placebo + Folate	Placebo	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
Tetrahydrobiopterin + Folate	Tetrahydrobiopterin	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

Primary Outcome Measures

Name	Time	Method
Change in Resting Muscle Sympathetic Nerve Activity (MSNA)	Baseline, 12 weeks

Secondary Outcome Measures

Name	Time	Method
Change in Mean Central Augmentation Index (AIx)	Baseline, 12 weeks	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.
Change in Heart-rate-corrected Augmentation Index (AIx)	Baseline, 12 weeks	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.