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Study of Vitamin D and Uric Acid Lowering on Kidney and Blood Vessel Function (MODERATE)

This study has been completed.
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
John P. Forman, Brigham and Women's Hospital Identifier:
First received: March 21, 2011
Last updated: April 1, 2016
Last verified: April 2016
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 (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Basic Science
Official Title: Modifiable Effectors of Renin System Activation: Treatment Evaluation (MODERATE)

Resource links provided by NLM:

Further study details as provided by John P. Forman, Brigham and Women's Hospital:

Primary Outcome Measures:
  • kidney specific renin angiotensin system (RAS) activation [ Time Frame: 8 weeks ]
    measured by the renal plasma flow response to captopril in high sodium balance

  • systemic renin angiotensin system (RAS) activation [ Time Frame: 8 weeks ]
    measured by plasma renin activity and Angiotensin II concentration

Secondary Outcome Measures:
  • endothelial function [ Time Frame: 8 weeks ]
    assessed by endothelium-dependent vasodilation using brachial artery ultrasonography

  • Ambulatory Blood Pressure [ Time Frame: 8 weeks ]
    24-hour mean ambulatory blood pressure

Enrollment: 225
Study Start Date: March 2011
Study Completion Date: June 2015
Primary Completion Date: May 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.

Ages Eligible for Study:   18 Years to 75 Years   (Adult, Senior)
Sexes Eligible for Study:   All
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 Locations
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Please refer to this study by its identifier: NCT01320722

United States, Massachusetts
Brigham and Women's Hospital
Boston, Massachusetts, United States, 02115
Sponsors and Collaborators
Brigham and Women's Hospital
National Heart, Lung, and Blood Institute (NHLBI)
Principal Investigator: John P Forman, MD, MSc Brigham and Women's Hospital
  More Information

Responsible Party: John P. Forman, INSTRUCTOR IN MEDICINE, BRIGHAM AND WOMEN'S HOSPITAL, Brigham and Women's Hospital Identifier: NCT01320722     History of Changes
Other Study ID Numbers: 2010-P-002049
1R01HL105440 ( US NIH Grant/Contract Award Number )
Study First Received: March 21, 2011
Last Updated: April 1, 2016

Keywords provided by John P. Forman, Brigham and Women's Hospital:
renin angiotensin system
vitamin D
uric acid
endothelial function

Additional relevant MeSH terms:
Body Weight
Signs and Symptoms
Vitamin D
Uric Acid
Growth Substances
Physiological Effects of Drugs
Bone Density Conservation Agents
Molecular Mechanisms of Pharmacological Action
Protective Agents
Enzyme Inhibitors
Gout Suppressants
Antirheumatic Agents
Free Radical Scavengers
Uricosuric Agents
Renal Agents processed this record on June 22, 2017