Daniel I. Feig

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

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.

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

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 > or = 6 mg/dL. Participants were treated at the Pediatric Hypertension Clinic at Texas Childrens 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 < .001). 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.

Hyperuricemia in Childhood Primary Hypertension

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, 13.4±3.3) and had normal renal function (creatinine clearance >80 mL · min−1 · 1.73 m−2). 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 (r =0.80, P =0.0002) and diastolic (r =0.66, P =0.0006) blood pressure in controls and in subjects with primary hypertension and were independent of renal function. Serum uric acid concentrations >5.5 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 >5.5 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.

Hypothesis: could excessive fructose intake and uric acid cause type 2 diabetes?

We propose that excessive fructose intake (>50 g/d) may be one of the underlying etiologies of metabolic syndrome and type 2 diabetes. The primary sources of fructose are sugar (sucrose) and high fructose corn syrup. First, fructose intake correlates closely with the rate of diabetes worldwide. Second, unlike other sugars, the ingestion of excessive fructose induces features of metabolic syndrome in both laboratory animals and humans. Third, fructose appears to mediate the metabolic syndrome in part by raising uric acid, and there are now extensive experimental and clinical data supporting uric acid in the pathogenesis of metabolic syndrome. Fourth, environmental and genetic considerations provide a potential explanation of why certain groups might be more susceptible to developing diabetes. Finally, we discuss the counterarguments associated with the hypothesis and a potential explanation for these findings. If diabetes might result from excessive intake of fructose, then simple public health measures could have a major impact on improving the overall health of our populace.

Uric Acid Reduction Rectifies Prehypertension in Obese Adolescents

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.

Serum Uric Acid: A Risk Factor and a Target for Treatment?

Serum uric acid was first noted to be associated with increased BP by Frederick Mohamed in the 1870s. Although the link was rediscovered periodically over the years, it generally was dismissed as a surrogate marker for decreased renal function that led to increased uric acid and increased risk for hypertension and cardiovascular (CV) disease. Recently, however, several lines of evidence suggest that increased serum uric acid may be a significant modifiable risk factor. Increased serum uric acid is associated with increased risk for future hypertension in several large longitudinal clinical trials as well as an independent risk factor for poor CV prognosis. Animal model experiments demonstrate that increased serum uric acid causes increased BP that initially is reversible but becomes irreversible, salt sensitive, and uric acid independent over time. The mechanisms include the direct action of uric acid on smooth muscle and vascular endothelial cells. Finally, in adolescents with new-onset essential hypertension, the prevalence of elevated serum uric acid is >90%, and preliminary clinical trial evidence suggests that agents that lower serum uric acid may lower BP in this select population. Although the investigations are still preliminary, serum uric acid represents a possible new and intriguing target for the reduction of morbidity and mortality associated with hypertension and CV disease.

Cost-effectiveness of ambulatory blood pressure monitoring in the initial evaluation of hypertension in children.

OBJECTIVE. The goal was to determine the cost-effectiveness of ambulatory blood pressure monitoring in the initial evaluation of stage 1 hypertension. METHODS. Retrospective chart review of data for children referred to Texas Childrens Hospital hypertension clinic between January 2005 and August 2006 was performed. We compared the costs of standard evaluations versus the initial use of ambulatory blood pressure monitoring for children with clinic blood pressure measurements suggesting stage 1 hypertension. Charges for clinic visits, laboratory tests, and imaging were obtained from the Texas Childrens Hospital billing department. RESULTS. A total of 267 children were referred. One hundred thirty-nine children did not receive ambulatory blood pressure monitoring; 54 met clinical indications for ambulatory blood pressure monitoring but did not receive it because it was not a covered expense (44 children) or the family refused the study (10 children). One hundred twenty-six children received clinically indicated ambulatory blood pressure monitoring, paid for either through insurance or by the family. Fifty-eight children (46%) had confirmed white-coat hypertension, 62 (49%) stage 1 hypertension, and 6 (5%) stage 2 hypertension. With the observed prevalence of white-coat hypertension, initial ambulatory blood pressure monitoring use yielded net savings after evaluation of 3 patients, with projected savings of

Inaccuracy in pediatric outpatient blood pressure measurement

2.4 million per 1000 patients. CONCLUSIONS. Ambulatory blood pressure monitoring in the initial evaluation of suspected childhood hypertension is highly cost-effective. Awareness of cost saving potential may increase the availability of ambulatory blood pressure monitoring for evaluation of new-onset hypertension.

Does asymptomatic hyperuricaemia contribute to the development of renal and cardiovascular disease? An old controversy renewed.

OBJECTIVE. Hypertension is common in the pediatric population. There is increasing evidence for early hypertensive target organ damage that may lead to substantial long-term morbidity. Because a critical aspect of any screening program for hypertension is the ability to measure blood pressure accurately, we compared typical blood pressure measurements at a vital sign station with those that were obtained following recommendations set forth in “The Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents.” METHODS. We compared the blood pressure measurements that were obtained with standard practice vital sign station screening with those that were obtained by trained personnel in accordance with Fourth Task Force recommendations. A total of 390 children were evaluated at 580 visits to the Pediatric Hypertension Clinic at Texas Children’s Hospital. RESULTS. Seventy-four percent of the readings were higher at the vital sign station, and only 12% differed by <5 mm Hg for both systolic blood pressure and diastolic blood pressure. The mean difference between vital sign station and examination room was 13.2 ± 8.9 mm Hg for systolic blood pressure and 9.6 ± 7.6 mm Hg for diastolic blood pressure. Multiple regression analyses revealed that age, gender, race, obesity, first versus subsequent visit, essential versus secondary, or white coat hypertension and antihypertensive medications made no statistically significant difference in the lack of correlation of the readings. CONCLUSION. These results suggest that if pediatricians use vital sign station screening for blood pressure, children with elevated initial measurements must be reevaluated in the examination room.

Childhood hypertension is not a silent disease

SUMMARY:  Recent studies in both humans and experimental animals have led to renewed interest in uric acid and its association with hypertension, cardiovascular events and renal disease progression. This has also refuelled a longstanding debate regarding the precise role of this ubiquitous breakdown product of purine metabolism in these disease processes. Various lines of evidence suggest that uric acid may have a direct role in the pathogenesis of hypertension and vascular disease. Regardless of this possibility, it is apparent that serum uric acid levels serve as a powerful ‘biomarker’ or independent predictor of prognosis and outcome in certain renal, cardiovascular and cerebrovascular diseases. Whether these outcomes can be improved by specifically treating asymptomatic hyperuricaemia remains inadequately resolved at this stage. Data from various animal studies suggests that lowering uric acid levels may be of benefit, but the crucial human studies are still lacking. This review will examine some of the recent evidence supporting a causal and contributory role for uric acid in cardiovascular and renal disease. How clarification of the role of uric acid may guide future treatment strategies will also be discussed.