Clinical trial NCT01320722: Study of Vitamin D and Uric Acid Lowering on Kidney and Blood Vessel Function
Official title: Modifiable Effectors of Renin System Activation: Treatment Evaluation (MODERATE)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Renal Function
Endothelial Function
Blood Pressure
Overweight
Obesity
Keywords: renin angiotensin system
vitamin D
uric acid
allopurinol
probenecid
endothelial function
Lead sponsor: Brigham and Women's Hospital
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2011-03-22
Enrollment: 242
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility 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

Primary outcomes:
measure: Change in Renal Plasma Flow (RPF) in Response to Captopril in High Sodium Balance [Vitamin D]
timeFrame: Week 8 (pre and post captopril)
measure: Plasma Renin Activity (PRA) [Vitamin D]
timeFrame: Week 8
measure: Angiotensin II (ATII) Concentration [Vitamin D]
timeFrame: Week 8
measure: Change in Renal Plasma Flow (RPF) Response to Captopril in High Sodium Balance [Uric Acid]
timeFrame: Week 8 (pre and post captopril)
measure: Plasma Renin Activity (PRA) [Uric Acid]
timeFrame: Week 8
measure: Angiotensin II (ATII) Concentration [Uric Acid]
timeFrame: Week 8
Secondary outcomes:
measure: Change in Endothelium-Dependent Vasodilation (EDV)
timeFrame: Baseline and Week 8 (pre and post ischaemic stimulus)
measure: Mean 24-Hour Ambulatory Blood Pressure (ABP)
timeFrame: Baseline and Week 8
measure: Mean 24-Hour Ambulatory Blood Pressure (ABP) Nocturnal Dipping
timeFrame: Baseline and Week 8
Other outcomes:
Locations:
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
Study officials:
affiliation: Brigham and Women's Hospital
name: John P Forman, MD, MSc
role: PRINCIPAL_INVESTIGATOR
References: