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

Modifiable Effectors of Renin System Activation: Treatment Evaluation (MODERATE)

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.

Study Overview

• Status: Completed
• Conditions: Obesity; Overweight; Blood Pressure; Renal Function; Endothelial Function
• Intervention / Treatment: Drug: Vitamin D ergocalciferol; Drug: Probenecid; Drug: Allopurinol; Drug: Placebo; Drug: Placebo

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 Type: Interventional
• Enrollment (Actual): 242
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

5

Arms and Interventions

Participant Group / 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 Names: 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; Drug: Placebo; Placebo tablet once per day for 4 weeks then twice per day for 4 weeks (eight weeks total)
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 soft gel once per week for 8 weeks; Drug: Placebo; Placebo tablet once per day for 4 weeks then twice per day for 4 weeks (eight weeks total)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Renal Plasma Flow (RPF) in Response to Captopril in High Sodium Balance [Vitamin D]	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.	Week 8 (pre and post captopril)
Plasma Renin Activity (PRA) [Vitamin D]	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.	Week 8
Angiotensin II (ATII) Concentration [Vitamin D]	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.	Week 8
Change in Renal Plasma Flow (RPF) Response to Captopril in High Sodium Balance [Uric Acid]	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.	Week 8 (pre and post captopril)
Plasma Renin Activity (PRA) [Uric Acid]	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.	Week 8
Angiotensin II (ATII) Concentration [Uric Acid]	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.	Week 8

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Endothelium-Dependent Vasodilation (EDV)	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.	Baseline and Week 8 (pre and post ischaemic stimulus)
Mean 24-Hour Ambulatory Blood Pressure (ABP)	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.	Baseline and Week 8
Mean 24-Hour Ambulatory Blood Pressure (ABP) Nocturnal Dipping	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.	Baseline and Week 8

Collaborators and Investigators

• Sponsor: Brigham and Women's Hospital
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: John P Forman, MD, MSc, Brigham and Women's Hospital

Study record dates

Study Major Dates

• Study Start: March 1, 2011
• Primary Completion (Actual): May 1, 2015
• Study Completion (Actual): June 1, 2015

Study Registration Dates

• First Submitted: March 21, 2011
• First Submitted That Met QC Criteria: March 21, 2011
• First Posted (Estimate): March 22, 2011

Study Record Updates

• Last Update Posted (Actual): June 29, 2017
• Last Update Submitted That Met QC Criteria: May 31, 2017
• Last Verified: May 1, 2017

More Information

Terms related to this study

• Keywords: vitamin D; allopurinol; uric acid; endothelial function; renin angiotensin system; probenecid
• Additional Relevant MeSH Terms: Body Weight; Overweight; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites; Protective Agents; Micronutrients; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents; Antioxidants; Free Radical Scavengers; Gout Suppressants; Renal Agents; Uricosuric Agents; Vitamin D; Cholecalciferol; Vitamins; Ergocalciferols; Allopurinol; Probenecid
• Other Study ID Numbers: 2010-P-002049; 1R01HL105440 (U.S. NIH Grant/Contract)