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

Study Description

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Brief Summary:

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 or disease	Intervention/treatment	Phase
Renal Function; Endothelial Function; Blood Pressure; Overweight; Obesity	Drug: Vitamin D ergocalciferol; Drug: Probenecid; Drug: Allopurinol; Drug: Placebo	Phase 3

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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	242 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose:	Treatment
Official Title:	Modifiable Effectors of Renin System Activation: Treatment Evaluation (MODERATE)
Study Start Date :	March 2011
Actual Primary Completion Date :	May 2015
Actual Study Completion Date :	June 2015

Arms and Interventions

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Arm	Intervention/treatment
Experimental: Vitamin D; Vitamin D ergocalciferol 50,000 unit soft gel capsule once per week for 8 weeks.	Drug: Vitamin D ergocalciferol; 50,000 unit soft gel capsule once per week for 8 weeks; Other Name: Vitamin D
Experimental: Probenecid; 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).	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; 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).	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; Placebo soft gel once per week for 8 weeks.	Drug: Placebo; Placebo soft gel once per week for 8 weeks
Placebo Comparator: Placebo- Uric Acid; Placebo tablet once per day for 4 weeks then twice per day for 4 weeks (eight weeks total).	Drug: Placebo; Placebo tablet once per day for 4 weeks then twice per day for 4 weeks (eight weeks total)

Outcome Measures

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Primary Outcome Measures :

1. Change in Renal Plasma Flow (RPF) in Response to Captopril in High Sodium Balance [Vitamin D] [ Time Frame: Week 8 (pre and post captopril) ]
   Change in RPF in response to captopril is a measure of the vasodilator effect from inhibiting angiotensin II (AngII)- mediated vascular tone and therefore the degree of kidney specific Renin Angiotensin System (RAS) activity. Participants consumed a high sodium diet 3 days prior to the test. Following an 8 hour fast, participants remained in a supine (lying down) position and had an intravenous (IV) catheter inserted in each arm, one for infusion and one for blood collection. An 8 milligrams (mg)/kilogram(kg) loading dose of para-aminohippuric acid (PAH) was given, immediately followed by a continuous PAH infusion at 12 mg/minute. After 60 minutes a single dose of 25 mg of captopril was administered. Three pre-captopril measurements and three post-captopril measurements of RPF were made. RPF was normalized to body surface area of 1.73 meters squared (m^2). The change in RPF was calculated as post-captopril RPF- pre-captopril RPF.
2. Plasma Renin Activity (PRA) [Vitamin D] [ Time Frame: Week 8 ]
   PRA is a measure of systemic renin angiotensin system (RAS) activation. Blood was collected and plasma PRA was analyzed using a competitive binding radioimmunoassay (RIA) laboratory test.
3. Angiotensin II (ATII) Concentration [Vitamin D] [ Time Frame: Week 8 ]
   ATII concentration is a measure of systemic renin angiotensin system (RAS) activation. Blood was collected and plasma ATII was analyzed using a double-antibody radioimmunoassay (RIA) laboratory test.
4. Change in Renal Plasma Flow (RPF) Response to Captopril in High Sodium Balance [Uric Acid] [ Time Frame: Week 8 (pre and post captopril) ]
   RPF in response to captopril iis a measure of the vasodilator effect from inhibiting angiotensin II (AngII)- mediated vascular tone and therefore the degree of kidney specific Renin Angiotensin System (RAS) activity. Participants consumed a high sodium diet 3 days prior to the test. Following an 8 hour fast, participants remained in a supine (lying down) position and had an intravenous (IV) catheter inserted in each arm, one for infusion and one for blood collection. An 8 milligrams (mg)/kilogram(kg) loading dose of para-aminohippuric acid (PAH) was given, immediately followed by a continuous PAH infusion at 12 mg/minute. After 60 minutes a single dose of 25 mg of captopril was administered. Three pre-captopril measurements and three post-captopril measurements of RPF were made. RPF was normalized to body surface area of 1.73 meters squared (m^2). The change in RPF was calculated as post-captopril RPF- pre-captopril RPF.
5. Plasma Renin Activity (PRA) [Uric Acid] [ Time Frame: Week 8 ]
   PRA is a measure of systemic renin angiotensin system (RAS) activation. Blood was collected and plasma PRA was analyzed using a competitive binding radioimmunoassay (RIA) laboratory test.
6. Angiotensin II (ATII) Concentration [Uric Acid] [ Time Frame: Week 8 ]
   ATII concentration is a measure of systemic renin angiotensin system (RAS) activation. Blood was collected and plasma ATII was analyzed using a double-antibody radioimmunoassay (RIA) laboratory test.

Secondary Outcome Measures :

1. Change in Endothelium-Dependent Vasodilation (EDV) [ Time Frame: Baseline and Week 8 (pre and post ischaemic stimulus) ]
   Endothelial function was assessed by EDV using brachial artery ultrasonography. Measurements of brachial artery diameter were made under basal conditions and reactive hyperemia following ischaemic stimulus. A blood pressure cuff on the forearm was pumped up for 5 minutes then released. Images were taken at baseline and after reactive hyperemia (increased blood flow). The maximum diameter was determined by the investigator. Change in EDV was expressed as a percent of brachial luminal diameter calculated as post-ischaemic brachial artery diameter - pre-ischaemic brachial artery diameter/pre-ischaemic brachial artery diameter * 100.
2. Mean 24-Hour Ambulatory Blood Pressure (ABP) [ Time Frame: Baseline and Week 8 ]
   A 24-hour mean ambulatory blood pressure was monitored using a 24 hour ABP device. The ABP device is a small box that is worn on the belt or pant/skirt line with a line that connect under the clothing to the cuff on the upper arm. Blood Pressure was recorded every 30 minutes during the day and every 60 minutes during the night for 24 hours.
3. Mean 24-Hour Ambulatory Blood Pressure (ABP) Nocturnal Dipping [ Time Frame: Baseline and Week 8 ]
   A 24-hour mean ambulatory blood pressure was monitored using a 24 hour ABP device. The ABP device is a small box that is worn on the belt or pant/skirt line with a line that connect under the clothing to the cuff on the upper arm. Blood Pressure was recorded every 30 minutes during the day and every 60 minutes during the night for 24 hours. Nocturnal dipping is the percent change lower between the daytime and nighttime values.

Eligibility Criteria

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Ages Eligible for Study:	18 Years to 75 Years (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	Yes

Criteria

Inclusion Criteria:

• 25(OH)D < 20 ng/mL OR Uric acid ≥ 5 mg/dL
• Age ≥ 18, ≤ 75 years
• Body Mass Index (BMI) ≥ 25 kg/m^2

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 angiotensin-converting enzyme (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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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Locations

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)

Investigators

Principal Investigator:	John P Forman, MD, MSc	Brigham and Women's Hospital

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

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 ( U.S. NIH Grant/Contract )
First Posted:	March 22, 2011
Results First Posted:	June 29, 2017
Last Update Posted:	June 29, 2017
Last Verified:	May 2017

Keywords provided by John P. Forman, 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; Vitamins; Vitamin D; Ergocalciferols; Allopurinol; Probenecid; Uric Acid; Micronutrients; Growth Substances; Physiological Effects of Drugs	Bone Density Conservation Agents; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Gout Suppressants; Antirheumatic Agents; Free Radical Scavengers; Antioxidants; Protective Agents; Uricosuric Agents; Renal Agents