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

Obesity Clinical Trial

— MODERATE  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01320722
• Other study ID #: 2010-P-002049
• Secondary ID: 1R01HL105440
• Status: Completed
• Phase: N/A
• First received: March 21, 2011
• Last updated: April 1, 2016
• Start date: March 2011
• Est. completion date: June 2015

Study information

• Verified date: April 2016
• Source: Brigham and Women's Hospital
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review BoardUnited States: Federal Government
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 225
• Est. completion date: June 2015
• Est. primary completion date: May 2015
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 18 Years to 75 Years

Eligibility

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

Study Design

Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator, Outcomes Assessor), Primary Purpose: Basic Science

Related Conditions & MeSH terms

• Blood Pressure
• Endothelial Function
• Obesity
• Overweight
• Renal Function

Intervention

Drug:
• Vitamin D ergocalciferol
50,000 unit soft gel capsule once per week for 8 weeks
• 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)
• 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
Placebo soft gel once per week for 8 weeks
• Placebo
Placebo tablet once per day for 4 weeks then twice per day for 4 weeks (eight weeks total)

Locations

Country	Name	City	State
United States	Brigham and Women's Hospital	Boston	Massachusetts

Sponsors (2)

Lead Sponsor	Collaborator
Brigham and Women's Hospital	National Heart, Lung, and Blood Institute (NHLBI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	kidney specific renin angiotensin system (RAS) activation	measured by the renal plasma flow response to captopril in high sodium balance	8 weeks	No
Primary	systemic renin angiotensin system (RAS) activation	measured by plasma renin activity and Angiotensin II concentration	8 weeks	No
Secondary	endothelial function	assessed by endothelium-dependent vasodilation using brachial artery ultrasonography	8 weeks	No
Secondary	Ambulatory Blood Pressure	24-hour mean ambulatory blood pressure	8 weeks	No