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Abstract-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. Key Words: antioxidants Ⅲ hypertension, essential Ⅲ cardiovascular diseases Ⅲ renin-angiotensin system Ⅲ vascular diseases Ⅲ renal disease U ric acid, a product of purine metabolism, is degraded in most mammals by the hepatic enzyme, urate oxidase (uricase), to allantoin, which is freely excreted in the urine. However, during the Miocene epoch (20 to 5 million years ago), 2 parallel but distinct mutations occurred in early hominoids that rendered the uricase gene nonfunctional. 1 As a consequence, humans and the great apes have higher uric acid levels (Ͼ2 mg/dL) compared with most mammals (Ͻ2 mg/dL).Uric acid levels also vary significantly within humans as the result of factors that increase generation (such as high purine or protein diets, alcohol consumption, conditions with high cell turnover, or enzymatic defects in purine metabolism) or decrease excretion. A reduction in glomerular filtration rate (GFR) increases serum uric acid, although a significant compensatory increase in gastrointestinal excretion occurs. 2 Hyperuricemia also may result from increased net tubular absorption. After filtration, uric acid undergoes both reabsorption and secretion in the proximal tubule, and this process is mediated by a urate/anion exchanger and a voltagesensitive urate channel. 3,4 Organic anions such as lactate decrease urate secretion by competing for urate through the organic anion transporter, whereas several substances, including probenacid and benziodarone, have opposite effects. 5 Hyperuricemia is usually defined as Ͼ6.5 or 7.0 mg/dL in men and Ͼ6.0 mg/dL in women.

The worldwide epidemic of metabolic syndrome correlates with an elevation in serum uric acid as well as a marked increase in total fructose intake (in the form of table sugar and high-fructose corn syrup). Fructose raises uric acid, and the latter inhibits nitric oxide bioavailability. Because insulin requires nitric oxide to stimulate glucose uptake, we hypothesized that fructose-induced hyperuricemia may have a pathogenic role in metabolic syndrome. Four sets of experiments were performed. First, pair-feeding studies showed that fructose, and not dextrose, induced features (hyperinsulinemia, hypertriglyceridemia, and hyperuricemia) of metabolic syndrome. Second, in rats receiving a high-fructose diet, the lowering of uric acid with either allopurinol (a xanthine oxidase inhibitor) or benzbromarone (a uricosuric agent) was able to prevent or reverse features of metabolic syndrome. In particular, the administration of allopurinol prophylactically prevented fructose-induced hyperinsulinemia (272.3 vs.160.8 pmol/l, P < 0.05), systolic hypertension (142 vs. 133 mmHg, P < 0.05), hypertriglyceridemia (233.7 vs. 65.4 mg/dl, P < 0.01), and weight gain (455 vs. 425 g, P < 0.05) at 8 wk. Neither allopurinol nor benzbromarone affected dietary intake of control diet in rats. Finally, uric acid dose dependently inhibited endothelial function as manifested by a reduced vasodilatory response of aortic artery rings to acetylcholine. These data provide the first evidence that uric acid may be a cause of metabolic syndrome, possibly due to its ability to inhibit endothelial function. Fructose may have a major role in the epidemic of metabolic syndrome and obesity due to its ability to raise uric acid.

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Abstract-Experimental animal models suggest that uric acid might have a pathogenic role in the early development of primary hypertension. We hypothesized that serum uric acid is correlated with blood pressure in children with new-onset, untreated, primary hypertension. We evaluated 125 consecutive children referred to the Baylor Pediatric Renal Program for evaluation of hypertension. None of the subjects had previously been evaluated or treated for hypertension. The children ranged in age from 6 to 18 years (mean, 13.4Ϯ3.3) and had normal renal function (creatinine clearance Ͼ80 mL · min Ϫ1 · 1.73 m Ϫ2 ). Sixty-three children had primary hypertension, 40 had secondary hypertension, and 22 had white-coat hypertension. Forty controls with normal blood pressure were recruited from the renal clinic. Uric acid levels were directly correlated with systolic (rϭ0.80, Pϭ0.0002) and diastolic (rϭ0.66, Pϭ0.0006) blood pressure in controls and in subjects with primary hypertension and were independent of renal function. Serum uric acid concentrations Ͼ5.5 mg/dL were found in 89% of subjects with primary hypertension, in 30% with secondary hypertension, in 0% with white-coat hypertension, and in 0% of controls. We conclude that serum uric acid is directly correlated with blood pressure in untreated children and that a serum uric acid value Ͼ5.5 mg/dL in an adolescent being evaluated for hypertension strongly suggests primary hypertension as opposed to white-coat or secondary hypertension. These results are consistent with the hypothesis that uric acid might have a role in the early pathogenesis of primary hypertension. Key Words: uric acid Ⅲ hypertension, essential Ⅲ children Ⅲ renal disease H ypertension, the most common form of cardiovascular disease, is present in nearly 25% of adults and increases in prevalence with age. Hypertension results in increased morbidity and mortality by dramatically escalating the risk of myocardial infarction, congestive heart failure, stroke, peripheral vascular disease, and renal failure. 1,2 Several clinical and laboratory observations are consistent with the hypothesis that uric acid might be important in the development of primary hypertension in humans. An association of gout with hypertension was first noted in 1879. 3 Twenty-five percent to 40% of adult patients with untreated hypertension have hyperuricemia (Ͼ6.5 mg/dL), and many more have a high-normal serum uric acid value (5.0 to 6.5 mg/dL). 4,5 The relation between uric acid and blood pressure (BP) is continuous and is observed in both AfricanAmericans and whites. 6 Furthermore, hyperuricemia predicts the development of, and is an independent risk factor for, hypertension. 7,8 Finally, we demonstrated that hyperuricemic rats develop hypertension 9 followed by preglomerular arteriolopathy. 10 Early hypertension is dependent on the reninangiotensin system and nitric oxide pathways 9 ; however, once preglomerular vascular disease develops, hypertension is driven by the kidney, and lowering uric acid levels is no longer protective. 1...

BACKGROUND Poor lifestyle behaviors are leading causes of preventable diseases globally. Added sugars contribute to a diet that is energy dense but nutrient poor and increase risk of developing obesity, cardiovascular disease, hypertension, obesity-related cancers, and dental caries. METHODS AND RESULTS For this American Heart Association scientific statement, the writing group reviewed and graded the current scientific evidence for studies examining the cardiovascular health effects of added sugars on children. The available literature was subdivided into 5 broad subareas: effects on blood pressure, lipids, insulin resistance and diabetes mellitus, nonalcoholic fatty liver disease, and obesity. CONCLUSIONS Associations between added sugars and increased cardiovascular disease risk factors among US children are present at levels far below current consumption levels. Strong evidence supports the association of added sugars with increased cardiovascular disease risk in children through increased energy intake, increased adiposity, and dyslipidemia. The committee found that it is reasonable to recommend that children consume ≤25 g (100 cal or ≈6 teaspoons) of added sugars per day and to avoid added sugars for children <2 years of age. Although added sugars most likely can be safely consumed in low amounts as part of a healthy diet, few children achieve such levels, making this an important public health target.

Few data exist regarding the long-term sequelae of acute renal failure (ARF), and these studies are limited to a few renal conditions. We aim to assess the 3-5-year survival and incidence of renal injury in children who previously developed ARF of varying causes. We queried parents, physicians, and hospital/state vital statistics records to find patient survival in 174 children who previously had ARF and survived to hospital discharge. We assessed the following in 29 children for residual renal injury: (a) microalbuminuria, (b) glomerular filtration rate (GFR) by Schwartz formula, (c) hypertension, and (d) hematuria. The 3-5-year survival of children with ARF who survived to hospital discharge was 139/174 (79.9%). Most deaths (24/35 (68.5%)) occurred within 12 months after initial hospitalization. Combining those who died during initial hospitalization and in subsequent 3-5 years, the overall survival rate was 139/245 (56.8%). In all, 16 children progressed to end-stage renal disease; thus, renal survival was 127/173 (91%). Those with primary renal/urologic conditions had lower renal survival than others (24/35 (68.6%) vs 134/139 (96.4%); P<0.0001). Among the 29 patients assessed for long-term sequelae at 3-5 years, 17/29 (59%) subjects had at least one sign of renal injury; microalbuminuria (n=9), hyperfiltration (n=9), decreased GFR (n=4), and hypertension (n=6). A pediatric nephrologist was involved in care of only 6/17 (35%) with chronic renal injury. Patients have high risks of ongoing residual renal injury and death after ARF; therefore, periodic evaluation after the initial insult is necessary.

Abstract-Epidemiologic studies, animal models, and preliminary clinical trials in children implicate uric acid in the development of essential hypertension. Controversy remains as to whether the observations indicate a general mechanism or a surrogate phenomenon. We sought to determine whether uric acid is a causative mediator of increased blood pressure (BP) and impaired vascular compliance. We report a randomized, double-blinded, placebo-controlled trial comparing 2 mechanisms of urate reduction with placebo in prehypertensive, obese, adolescents, aged 11 to 17 years. Subjects were randomized to the xanthine oxidase inhibitor, allopurinol, uricosuric, probenecid, or placebo. Subjects treated with urate-lowering therapy experienced a highly significant reduction in BP. In clinic systolic BP fell 10.2 mm Hg and diastolic BP fell 9.0 mm Hg in treated patients compared with a rise of 1.7 mm Hg and 1.6 mm Hg systolic and diastolic BP, respectively in patients on placebo. Urate-lowering therapy also resulted in significant reduction in systemic vascular resistance. These data indicate that, at least in adolescents with prehypertension, uric acid causes increased BP that can be mitigated by urate lowering therapy. (Hypertension. 2012;60:1148-1156.)