This review summarizes relevant studies concerning uric acid and possible links to hypertension, renal disease, and cardiovascular disease. Whether uric acid is an independent risk factor for such diseases is still a point of debate. Current evidence is presented.

Uric acid and cardiovascular risk.

Hyperuricemia is associated with hypertension, vascular disease, renal disease, and cardiovascular events. In this report, we review the epidemiologic evidence and potential mechanisms for this association. We also summarize experimental studies that demonstrate that uric acid is not inert but may have both beneficial functions (acting as an antioxidant) as well as detrimental actions (to stimulate vascular smooth muscle cell proliferation and induce endothelial dysfunction). A recently developed experimental model of mild hyperuricemia also provides the first provocative evidence that uric acid may have a pathogenic role in the development of hypertension, vascular disease, and renal disease. Thus, it is time to reevaluate the role of uric acid as a risk factor for cardiovascular disease and hypertension and to design human studies to address this controversy.

Is There a Pathogenetic Role for Uric Acid in Hypertension and Cardiovascular and Renal Disease

. Hyperuricemia is associated with renal disease, but it is usually considered a marker of renal dysfunction rather than a risk factor for progression. Recent studies have reported that mild hyperuricemia in normal rats induced by the uricase inhibitor, oxonic acid (OA), results in hypertension, intrarenal vascular disease, and renal injury. This led to the hypothesis that uric acid may contribute to progressive renal disease. To examine the effect of hyperuricemia on renal disease progression, rats were fed 2% OA for 6 wk after 5/6 remnant kidney (RK) surgery with or without the xanthine oxidase inhibitor, allopurinol, or the uricosuric agent, benziodarone. Renal function and histologic studies were performed at 6 wk. Given observations that uric acid induces vascular disease, the effect of uric acid on vascular smooth muscle cells in culture was also examined. RK rats developed transient hyperuricemia (2.7 mg/dl at week 2), but then levels returned to baseline by week 6 (1.4 mg/dl). In contrast, RK+OA rats developed higher and more persistent hyperuricemia (6 wk, 3.2 mg/dl). Hyperuricemic rats demonstrated higher BP, greater proteinuria, and higher serum creatinine than RK rats. Hyperuricemic RK rats had more renal hypertrophy and greater glomerulosclerosis (24.2 ± 2.5 versus 17.5 ± 3.4%; P versus 1.52 ± 0.47; P in vitro studies, cultured vascular smooth muscle cells incubated with uric acid also generated COX-2 with time-dependent proliferation, which was prevented by either a COX-2 or TXA-2 receptor inhihbitor. Hyperuricemia accelerates renal progression in the RK model via a mechanism linked to high systemic BP and COX-2-mediated, thromboxane-induced vascular disease. These studies provide direct evidence that uric acid may be a true mediator of renal disease and progression.

A Role for Uric Acid in the Progression of Renal Disease

http://www.omega3galil.com/wp-content/uploads/2013/10/Potential-role-of-sugar-fructose-in-the-epidemic-of-hypertension-obesity-diabetes-kidney-disease-and-cv-disease.pdf

Potential role of sugar (fructose) in the epidemic of hypertension, obesity and the metabolic syndrome, diabetes, kidney disease, and cardiovascular disease

Context Hyperuricemia is a predictor for the development of hypertension and is commonly present in new-onset essential hypertension. Experimentally increasing uric acid levels using a uricase inhibitor causes systemic hypertension in animal models. Objective To determine whether lowering uric acid lowers blood pressure (BP) in hyperuricemic adolescents with newly diagnosed hypertension. Design, Setting, and Patients Randomized, double-blind, placebo-controlled, crossover trial (September 2004-March 2007) involving 30 adolescents (aged 11-17 years) who had newly diagnosed, never-treated stage 1 essential hypertension and serum uric acid levels ≥6 mg/dL. Participants were treated at the Pediatric Hypertension Clinic at Texas Children's Hospital in Houston. Patients were excluded if they had stage 2 hypertension or known renal, cardiovascular, gastrointestinal tract, hepatic, or endocrine disease. Intervention Allopurinol, 200 mg twice daily for 4 weeks, and placebo, twice daily for 4 weeks, with a 2-week washout period between treatments. The order of the treatments was randomized. Main Outcome Measures Change in casual and ambulatory blood pressure. Results For casual BP, the mean change in systolic BP for allopurinol was −6.9 mm Hg (95% confidence interval [CI], −4.5 to −9.3 mm Hg) vs −2.0 mm Hg (95% CI, 0.3 to −4.3 mm Hg; P = .009) for placebo, and the mean change in diastolic BP for allopurinol was −5.1 mm Hg (95% CI, −2.5 to −7.8 mm Hg) vs −2.4 (95% CI, 0.2 to −4.1; P = .05) for placebo. Mean change in mean 24-hour ambulatory systolic BP for allopurinol was −6.3 mm Hg (95% CI, −3.8 to −8.9 mm Hg) vs 0.8 mm Hg (95% CI, 3.4 to −2.9 mm Hg; P = .001) for placebo and mean 24-hour ambulatory diastolic BP for allopurinol was −4.6 mm Hg (−2.4 to −6.8 mm Hg) vs −0.3 mm Hg (95% CI, 2.3 to −2.1 mm Hg; P = .004) for placebo. Twenty of the 30 participants achieved normal BP by casual and ambulatory criteria while taking allopurinol vs 1 participant while taking placebo (P  Conclusions In this short-term, crossover study of adolescents with newly diagnosed hypertension, treatment with allopurinol resulted in reduction of BP. The results represent a new potential therapeutic approach, although not a fully developed therapeutic strategy due to potential adverse effects. These preliminary findings require confirmation in larger clinical trials. Trial Registration clinicaltrials.gov Identifier: NCT00288184

https://jamanetwork.com/journals/jama/articlepdf/182461/jpc80008_924_932.pdf

Effect of Allopurinol on Blood Pressure of Adolescents With Newly Diagnosed Essential Hypertension: A Randomized Trial

Hyperuricemia is associated with hypertension and vascular disease, but whether this represents a causal relationship or an epiphenomenon remains unknown. We recently reported a model of mild hyper...

https://www.physiology.org/doi/pdf/10.1152/ajprenal.00283.2001

Qiang Chen

Papers

Hyperuricemia induces a primary renal arteriolopathy in rats by a blood pressure-independent mechanism

rats by a blood pressure-independent mechanism Hyperuricemia induces a primary renal arteriolopathy in