Kidney Failure, Chronic
Conditions
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.
Interventions
Tetrahydrobiopterin (BH4) 200 mg PO BID for 12 weeks
DRUGPlacebo
2 placebo pills PO BID for12 weeks
DIETARY_SUPPLEMENTFolate
Folate 1 mg daily for 12 weeks
Sponsors
National Institutes of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Emory University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Change in Resting Muscle Sympathetic Nerve Activity (MSNA) | Baseline, 12 weeks |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Participant flow
Recruitment details
Subjects were recruited from the Atlanta Veterans Affairs (VA) Medical Center from August 2010 to May 2014.
Pre-assignment details
42 subjects were withdrawn prior to group assignment. 16 were screen failures, 7 subjects withdrew, and 19 subjects were terminated early.
Participants by arm
| Arm | Count |
|---|---|
| Tetrahydrobiopterin + Folate Male subjects with hypertension and chronic kidney disease stage 2 or 3 received Tetrahydrobiopterin (BH4) 200 mg twice daily and folic acid 1 mg daily | 18 |
| Placebo + Folate Male subjects with hypertension and chronic kidney disease stage 2 or 3 received 2 placebo pills twice daily and folic acid 1 mg daily | 14 |
| Total | 32 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 2 |
Baseline characteristics
| Characteristic | Tetrahydrobiopterin + Folate | Placebo + Folate | Total |
|---|---|---|---|
| Age, Continuous | 57.5 years STANDARD_DEVIATION 1.3 | 55.2 years STANDARD_DEVIATION 2.2 | 56.4 years STANDARD_DEVIATION 1.8 |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 18 Participants | 14 Participants | 32 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 2 / 18 | 2 / 14 |
| serious Total, serious adverse events | 0 / 18 | 0 / 14 |
Outcome results
Primary
Change in Resting Muscle Sympathetic Nerve Activity (MSNA)
Time frame: Baseline, 12 weeks
Population: Two subjects withdrawn from each arm due to adverse events. Additionally, two subjects from the treatment group and one subject from the placebo group were not included in this analysis because an adequate MSNA neurogram was unable to be obtained at the end of the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tetrahydrobiopterin + Folate | Change in Resting Muscle Sympathetic Nerve Activity (MSNA) | -7.5 bursts/minute | Standard Error 2.1 |
| Placebo + Folate | Change in Resting Muscle Sympathetic Nerve Activity (MSNA) | 3.2 bursts/minute | Standard Error 1.3 |
Secondary
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.
Time frame: Baseline, 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tetrahydrobiopterin + Folate | Change in Heart-rate-corrected Augmentation Index (AIx) | -3.2 percent | Standard Error 2.1 |
| Placebo + Folate | Change in Heart-rate-corrected Augmentation Index (AIx) | 1.1 percent | Standard Error 1.2 |
Secondary
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.
Time frame: Baseline, 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tetrahydrobiopterin + Folate | Change in Mean Central Augmentation Index (AIx) | -5.8 percent | Standard Error 2 |
| Placebo + Folate | Change in Mean Central Augmentation Index (AIx) | 1.8 percent | Standard Error 1.7 |