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

Mass General Brigham

Status and phase

Completed

Phase 3

Conditions

Endothelial Function

Overweight

Renal Function

Obesity

Blood Pressure

Treatments

Drug: Allopurinol

Drug: Placebo

Drug: Probenecid

Drug: Vitamin D ergocalciferol

Study type

Interventional

Funder types

Other

NIH

Identifiers

NCT01320722

2010-P-002049

1R01HL105440 (U.S. NIH Grant/Contract)

Details and patient eligibility

About

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.

Full 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.

Enrollment

242 patients

Sex

All

Ages

18 to 75 years old

Volunteers

Accepts Healthy Volunteers

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

Trial design

Primary purpose

Treatment

Allocation

Randomized

Interventional model

Parallel Assignment

Masking

Triple Blind

242 participants in 5 patient groups, including a placebo group

Vitamin D

Experimental group

Description:

Vitamin D ergocalciferol 50,000 unit soft gel capsule once per week for 8 weeks.

Treatment:

Drug: Vitamin D ergocalciferol

Probenecid

Experimental group

Description:

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).

Treatment:

Drug: Probenecid

Allopurinol

Experimental group

Description:

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).

Treatment:

Drug: Allopurinol

Placebo- Vitamin D

Placebo Comparator group

Description:

Placebo soft gel once per week for 8 weeks.