Modifiable Effectors of Renin System Activation: Treatment Evaluation (MODERATE)
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 242
- 试验地点
- 1
- 主要终点
- Change in Renal Plasma Flow (RPF) in Response to Captopril in High Sodium Balance [Vitamin D]
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •25(OH)D < 20 ng/mL OR Uric acid ≥ 5 mg/dL
- •Age ≥ 18, ≤ 75 years
- •Body Mass Index (BMI) ≥ 25 kg/m^2
排除标准
- •Hypertension, or on BP-lowering medicine
- •Coronary Heart Disease
- •estimated glomerular filtration rate (EGFR) <60 mL/min
- •Kidney stones
- •Active cancer (except non-melanoma skin cancer)
- •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
研究组 & 干预措施
Vitamin D
Vitamin D ergocalciferol 50,000 unit soft gel capsule once per week for 8 weeks.
干预措施: Vitamin D ergocalciferol (Drug)
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).
干预措施: Probenecid (Drug)
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).
干预措施: Allopurinol (Drug)
Placebo- Vitamin D
Placebo soft gel once per week for 8 weeks.
干预措施: Placebo (Drug)
Placebo- Uric Acid
Placebo tablet once per day for 4 weeks then twice per day for 4 weeks (eight weeks total).
干预措施: Placebo (Drug)
结局指标
主要结局
Change in Renal Plasma Flow (RPF) in Response to Captopril in High Sodium Balance [Vitamin D]
时间窗: 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.
Plasma Renin Activity (PRA) [Vitamin D]
时间窗: 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.
Angiotensin II (ATII) Concentration [Vitamin D]
时间窗: 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.
Change in Renal Plasma Flow (RPF) Response to Captopril in High Sodium Balance [Uric Acid]
时间窗: 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.
Plasma Renin Activity (PRA) [Uric Acid]
时间窗: 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.
Angiotensin II (ATII) Concentration [Uric Acid]
时间窗: 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.
次要结局
- Change in Endothelium-Dependent Vasodilation (EDV)(Baseline and Week 8 (pre and post ischaemic stimulus))
- Mean 24-Hour Ambulatory Blood Pressure (ABP)(Baseline and Week 8)
- Mean 24-Hour Ambulatory Blood Pressure (ABP) Nocturnal Dipping(Baseline and Week 8)
研究者
John P. Forman
INSTRUCTOR IN MEDICINE, BRIGHAM AND WOMEN'S HOSPITAL
Brigham and Women's Hospital