Study of Vitamin D and Uric Acid Lowering on Kidney and Blood Vessel Function (MODERATE)
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Purpose
The investigators hypothesize that, among non-hypertensive overweight and obese individuals, treatment of vitamin D deficiency and lowering uric acid concentrations (by either xanthine oxidase inhibition or increased renal excretion) will attenuate renin angiotensin system (RAS) activation, improve endothelial function, and lower blood pressure.
| Condition | Intervention |
|---|---|
|
Renal Function Endothelial Function Blood Pressure Overweight Obesity |
Drug: Vitamin D ergocalciferol Drug: Probenecid Drug: Allopurinol Drug: Placebo |
| Study Type: | Interventional |
| Study Design: | Allocation: Randomized Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Investigator, Outcomes Assessor) Primary Purpose: Basic Science |
| Official Title: | Modifiable Effectors of Renin System Activation: Treatment Evaluation (MODERATE) |
- kidney specific renin angiotensin system (RAS) activation [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]measured by the renal plasma flow response to captopril in high sodium balance
- systemic renin angiotensin system (RAS) activation [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]measured by plasma renin activity and Angiotensin II concentration
- endothelial function [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]assessed by endothelium-dependent vasodilation using brachial artery ultrasonography
- Ambulatory Blood Pressure [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]24-hour mean ambulatory blood pressure
| Estimated Enrollment: | 225 |
| Study Start Date: | March 2011 |
| Estimated Study Completion Date: | June 2015 |
| Estimated Primary Completion Date: | April 2015 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
| Experimental: Vitamin D |
Drug: Vitamin D ergocalciferol
50,000 unit soft gel capsule once per week for 8 weeks
Other Name: Vitamin D
|
| Experimental: Probenecid |
Drug: Probenecid
500 mg tablet once per day for 4 weeks, then either 500 mg tablet once per day for 4 weeks or 1000 mg once per day for 4 weeks (8 weeks total)
|
| Experimental: Allopurinol |
Drug: Allopurinol
300 mg tablet once per day for 4 weeks then either 300 mg once per day or 600 mg once per day for 4 weeks (8 weeks total)
|
| Placebo Comparator: Placebo- vitamin D |
Drug: Placebo
Placebo soft gel once per week for 8 weeks
|
| Placebo Comparator: Placebo- uric acid |
Drug: Placebo
Placebo tablet once per day for 4 weeks then twice per day for 4 weeks (eight weeks total)
|
Detailed Description:
We have demonstrated that lower levels of 25-hydroxyvitamin D (25[OH]D) and higher concentrations of uric acid are both potentially modifiable factors that are independently associated with an increased risk of developing hypertension (high blood pressure) in humans. Other investigators have shown that vitamin D supplementation, or lowering uric acid with allopurinol, may reduce blood pressure. Animal experiments suggest that activation of both the systemic and local kidney-specific renin angiotensin systems (RAS) may be the principal mechanism linking 25(OH)D and uric acid with hypertension. In human parallels to these animal studies, we have shown in cross-sectional analyses that non-hypertensive individuals with lower 25(OH)D and higher uric acid levels have increased activation of their systemic and kidney-specific RAS, independent of other factors. However, whether vitamin D supplementation or uric acid lowering attenuates RAS activation has never been demonstrated in humans. Both lower 25(OH)D and higher uric acid concentrations are also associated with endothelial dysfunction in humans, and endothelial function may modulate the RAS and provide an alternate mechanism for the development of hypertension. It remains unclear, however, whether an intervention to increase 25(OH)D or decrease uric acid levels among non-hypertensive adults improves endothelial function; furthermore, it is unknown whether treatment of these individuals would lower blood pressure. Determining whether treatment of 25(OH)D and uric acid concentrations, per se, can attenuate RAS activation, improve endothelial function, and lower blood pressure among nonhypertensive individuals is critically important, with implications stretching beyond hypertension prevention, since RAS activation, endothelial dysfunction, and blood pressure are also implicated in the pathology of cardiovascular and chronic kidney disease. Individuals who are overweight and obese (two-thirds of US adults) represent an important population who are known to have lower 25(OH)D levels, higher uric acid concentrations, activation of the RAS, endothelial dysfunction, and an increased risk of hypertension, cardiovascular disease, and chronic kidney disease. Interestingly, our preliminary data demonstrate that among overweight and obese individuals with normal 25(OH)D or low uric acid levels, adiposity is no longer associated with activation of the RAS, suggesting that low 25(OH)D and high uric acid concentrations might be mediators of the adverse consequences of overweight and obesity.
Eligibility| Ages Eligible for Study: | 18 Years to 75 Years |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | Yes |
Inclusion Criteria:
- 25(OH)D < 20 ng/mL OR Uric acid ≥ 5 mg/dL
- Age ≥ 18, ≤ 75 years
- BMI ≥ 25
Exclusion Criteria:
- Hypertension, or on BP-lowering medicine
- Diabetes
- Coronary Heart Disease
- estimated glomerular filtration rate (EGFR) <60 mL/min
- Kidney stones
- Active cancer (except non-melanoma skin cancer)
- Pregnant
- Taking vitamin D supplements and unwilling to stop
- Osteoporosis
- Hypo- or hypercalcemia
- Hypo- or hyperphosphatemia
- Known allergy to ACE-inhibitors
- Taking medication for hyperuricemia
- Gout, anemia, cirrhosis, active/chronic hepatitis, abnormal aspartate aminotransferase (AST), alanine aminotransferase (ALT) or total bilirubin levels, or anemia
- Known allergy to either allopurinol or probenecid
- Current use of didanosine, azothioprine, methotrexate, ketoprofen, ketorolac, mycophenolate, or ACE-inhibitors
Contacts and LocationsPlease refer to this study by its ClinicalTrials.gov identifier: NCT01320722
| Contact: Ann L Wohlhueter, BA | 617 264 3071 | AWOHLHUETER@PARTNERS.ORG |
| United States, Massachusetts | |
| Brigham and Women's Hospital | Recruiting |
| Boston, Massachusetts, United States, 02115 | |
| Contact: Ann L Wohlhueter, BA 617-264-3071 awohlhueter@partners.org | |
| Principal Investigator: John P Forman, MD, MSc | |
| Principal Investigator: | John P Forman, MD, MSc | Brigham and Women's Hospital |
More Information
No publications provided
| Responsible Party: | John P. Forman, INSTRUCTOR IN MEDICINE, BRIGHAM AND WOMEN'S HOSPITAL, Brigham and Women's Hospital |
| ClinicalTrials.gov Identifier: | NCT01320722 History of Changes |
| Other Study ID Numbers: | 2010-P-002049, 1R01HL105440 |
| Study First Received: | March 21, 2011 |
| Last Updated: | June 27, 2014 |
| Health Authority: | United States: Institutional Review Board United States: Federal Government |
Keywords provided by Brigham and Women's Hospital:
|
renin angiotensin system vitamin D uric acid |
allopurinol probenecid endothelial function |
Additional relevant MeSH terms:
|
Overweight Body Weight Signs and Symptoms Allopurinol Ergocalciferols Probenecid Uric Acid Vitamin D Vitamins Antimetabolites Antioxidants Antirheumatic Agents Bone Density Conservation Agents |
Enzyme Inhibitors Free Radical Scavengers Gout Suppressants Growth Substances Micronutrients Molecular Mechanisms of Pharmacological Action Pharmacologic Actions Physiological Effects of Drugs Protective Agents Renal Agents Therapeutic Uses Uricosuric Agents |
ClinicalTrials.gov processed this record on February 25, 2015