Both lower 25-hydroxyvitamin D (25[OH]D) and higher uric acid levels are associated with activation of the renin angiotensin system, endothelial dysfunction, and elevation of blood pressure in humans. Furthermore, lower 25(OH)D and higher uric acid levels are associated with overweight and obesity, and may be potential mediators of the adverse effects of adiposity on renin angiotensin system activation, endothelial dysfunction, and blood pressure. However, the effects of vitamin D supplementation and uric acid lowering on these underlying mechanisms of hypertension, cardiovascular and chronic kidney disease are unknown. The MODERATE (MODififable Effectors of Renin system Activation: Treatment Evaluation) study is a randomized, double blind, placebo controlled, clinical trial comparing 50,000 units/week of vitamin D supplementation to placebo for 8 weeks, or comparing uric acid lowering with either allopurinol 300 mg/day or probenecid 500 mg/day (both with a dose titration at 4 weeks to 600 mg/day or 1000 mg/day, respectively) to placebo for 8 weeks. Overweight or obese adults with vitamin D deficiency or uric acid levels e 5 mg/dL will be enrolled, and the primary endpoint will be the activation state of the renin angiotensin system, as determined by the plasma renin activity, angiotensin II concentration, and the renal plasma flow response to infused angiotensin II with individuals in high-sodium balance. The secondary endpoint will be endothelial dependent dilation measured by reactive hyperemia with high resolution ultrasound, and the tertiary endpoint will mean 24 hour systolic and diastolic blood pressure measured with an ambulatory blood pressure device. From a scientific standpoint, this trial will provide the first experimental human data regarding the effects of 25(OH)D and uric acid on renin angiotensin system activation and endothelial function, which are two critical mechanisms of disease. From a public health standpoint, the results of this trial will inform strategies and future trials designed to prevent the incidence of hypertension, cardiovascular and chronic kidney disease.

Public Health Relevance

People with vitamin D deficiency and higher blood levels of a compound called uric acid may be at risk for developing high blood pressure, heart attacks, and kidney disease because their bodies produce inappropriate amounts of certain hormones and because their blood vessels do not function normally. People who are overweight or obese are more likely to have vitamin D deficiency and high levels of uric acid. This study will determine whether giving vitamin D supplements or medication to lower uric acid levels to overweight or obese people can reverse some of the hormone and blood vessel abnormalities that ultimately could cause high blood pressure, heart attacks, and kidney disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL105440-02
Application #
8210813
Study Section
Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
Program Officer
Reid, Diane M
Project Start
2011-01-01
Project End
2015-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
2
Fiscal Year
2012
Total Cost
$700,477
Indirect Cost
$308,053
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Srivastava, Anand; Kaze, Arnaud D; McMullan, Ciaran J et al. (2018) Uric Acid and the Risks of Kidney Failure and Death in Individuals With CKD. Am J Kidney Dis 71:362-370
Borgi, Lea; McMullan, Ciaran; Wohlhueter, Ann et al. (2017) Effect of Uric Acid-Lowering Agents on Endothelial Function: A Randomized, Double-Blind, Placebo-Controlled Trial. Hypertension 69:243-248
Borgi, Lea; McMullan, Ciaran; Wohlhueter, Ann et al. (2017) Effect of Vitamin D on Endothelial Function: A Randomized, Double-Blind, Placebo-Controlled Trial. Am J Hypertens 30:124-129
McMullan, Ciaran J; Borgi, Lea; Fisher, Naomi et al. (2017) Effect of Uric Acid Lowering on Renin-Angiotensin-System Activation and Ambulatory BP: A Randomized Controlled Trial. Clin J Am Soc Nephrol 12:807-816
McMullan, Ciaran J; Borgi, Lea; Curhan, Gary C et al. (2017) The effect of vitamin D on renin-angiotensin system activation and blood pressure: a randomized control trial. J Hypertens 35:822-829
Causland, Finnian R Mc; Sacks, Frank M; Forman, John P (2014) Marital status, dipping and nocturnal blood pressure: results from the Dietary Approaches to Stop Hypertension trial. J Hypertens 32:756-61
Chandler, Paulette D; Scott, Jamil B; Drake, Bettina F et al. (2014) Risk of hypercalcemia in blacks taking hydrochlorothiazide and vitamin D. Am J Med 127:772-8
Mc Causland, Finnian R; McMullan, Ciaran J; Sacks, Frank M et al. (2014) Race, plasma renin activity, and morning blood pressure surge--results from the Dietary Approaches to Stop Hypertension trial. Am J Hypertens 27:530-6
Forman, John P; Scott, Jamil B; Ng, Kimmie et al. (2013) Effect of vitamin D supplementation on blood pressure in blacks. Hypertension 61:779-85
Charytan, David M; Forman, John P (2012) You are what you eat: dietary salt intake and renin-angiotensin blockade in diabetic nephropathy. Kidney Int 82:257-9

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