Exercise Intolerance in Renal Failure
Condition: Kidney Failure, Chronic
MeSH terms: Renal Insufficiency; Kidney Failure, Chronic
Intervention: Tetrahydrobiopterin; Placebo; Folate
Intervention description: Tetrahydrobiopterin (BH4) 200 mg PO BID for 12 weeks; 2 placebo pills PO BID for12 weeks; Folate 1 mg daily for 12 weeks
Intervention MeSH terms: Folic Acid
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 74.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: Accepts Healthy Volunteers

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.
    

Eligibility criteria:

        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