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Uric acid is associated with cardiovascular disease (CVD) and CVD risk factors in adults, including chronic kidney disease, coronary artery disease, stroke, diabetes, preeclampsia, and hypertension. We examined the association between uric acid and elevated blood pressure in a large, nationally representative cohort of U.S. adolescents, a population with a relatively low prevalence of CVD and CVD risk factors. Among 6,036 adolescents 12-17 years of age examined in the 1999-2006 National Health and Nutrition Examination Survey (NHANES) the mean age was 14.5 years, 17% were obese (body mass index [BMI] ≥95th percentile), and 3.3% had elevated blood pressure. Mean serum uric acid level was 5.0 mg/dL and 34% had a uric acid level ≥5.5 mg/dL. In analyses adjusted for age, sex, race/ethnicity and BMI percentile, the odds ratio of elevated blood pressure, defined as a systolic or diastolic blood pressure ≥95th percentile for age, sex and height, for each 0.1 mg/dL increase in uric acid level was 1.38 (95% confidence interval [CI], 1.16 to 1.65). Compared to <5.5 mg/dL, participants with a uric acid level ≥5.5 mg/dL had a 2.03 times higher odds of having elevated blood pressure (95% CI, 1.38 to 3.00). In conclusion, increasing levels of serum uric acid are associated with elevated blood pressure in healthy U.S. adolescents. Additional prospective studies and clinical trials are needed to determine if uric acid is merely a marker in a complex metabolic pathway, or causal of hypertension and thus a potential screening and therapeutic target.
Hypertension is increasingly prevalent among children and adolescents in the United States.1 In children, hypertension is often attributable to secondary causes such as kidney disease, however, in adolescents, primary or “essential” hypertension is the most common etiology.2 Indeed, primary hypertension in adolescents has become a significant public health issue as it has been associated with the rising prevalence of obesity in the United States and poses significant risks for future cardiovascular disease and target organ damage.1 Given the burden of primary hypertension in both adolescents and adults, further elucidation of mechanisms and potential therapeutic targets is needed.
Elevated serum uric acid levels have been associated with hypertension in multiple large epidemiologic studies in adults.3-8 Controversy remains as to whether uric acid is an independent causal factor, a mediator or merely a marker for the development of hypertension. Proposed mechanisms, primarily based on animal model data, include endothelial damage, vascular inflammation and renin-angiotensin system activation.3 Determining the role of uric acid in hypertension development is complicated by the fact that both serum uric acid level and blood pressure are associated with kidney function and other common metabolic disorders.3, 9, 10 However, a few small clinical trials examining the effect of treating hyperuricemia in hypertensive adults and children support that lowering uric acid can lower blood pressure levels.11-14 The observation that uric acid-lowering therapy improved blood pressure suggests that uric acid may be in the causal pathway in the development of hypertension.
In this study, we examined the association between uric acid level and elevated blood pressure in a large, nationally representative cohort of U.S. adolescents using data from the National Health and Nutrition Examination Survey (NHANES) 1999-2006. Adolescents are an ideal population in which to examine this relationship as it has been hypothesized that uric acid may be most significant in the development of early hypertension before significant vascular damage has occurred, and may have less influence on blood pressure levels once vascular damage is permanent.3, 15 Further, adolescents are less likely to have comorbidities that can make examining this relationship in adults more complex.
The National Center for Health Statistics, within the Centers for Disease Control and Prevention, conducted continuous NHANES two-year cycles from 1999-2006 using a complex multistage sampling design to obtain a representative sample of the U.S. civilian, non-institutionalized population aged 2 months and older.16-19 NHANES 1999-2006 study protocols were approved by the research ethics review board of the National Center for Health Statistics. Written informed consent was obtained from the guardians of participants younger than 18 years of age, and assent was obtained from those aged 12 to 17 years.
Serum for biochemistry analysis, including uric acid level, was collected from those 12 years of age and older. Questionnaire data provided the participants' age, sex and race/ethnicity. Race/ethnicity was categorized into five groups: Mexican American, Other Hispanic, Non-Hispanic White, Non-Hispanic Black, and Other. BMI was calculated as measured weight in kilograms divided by measured height in meters squared, and BMI percentiles were calculated based on the CDC's BMI-for-age sex-specific growth charts.20 BMI categories were defined as follows: “normal,” BMI <85th percentile; “overweight,” BMI ≥85th and <95th percentile; and “obese,” BMI ≥95th percentile.21
In NHANES, serum uric acid was measured on a Roche Hitachi Model 917 or 704 Multichannel Analyzer in 1999-2001 and a Beckman Synchron LX20 in 2002-2006 using a colorimetric method.22-25 Serum creatinine level was measured with the same instruments using the Jaffe kinetic alkaline picrate method.22, 23, 26, 27 Serum creatinine was corrected to standardize to a “gold” standard reference method as recommended by NHANES. 22, 27 Biochemistry measurements were performed by the Coulston Foundation in New Mexico in 1999-2001, and by Collaborative Laboratory Services in Iowa in 2002-2006. The distribution of creatinine and uric acid results from the two laboratories were compared at the time of transition, and no significant differences were observed.28
Estimated glomerular filtration rate (eGFR, milliliters per minute per 1.73 m2) was calculated via the creatinine-based formula of Schwartz: eGFR = k(height in centimeters)/(serum creatinine in milligrams per deciliter), where k is 0.7 in boys and 0.55 in girls.29, 30
In children, blood pressure varies by age, sex and height, and thus blood pressure percentiles are used to standardize measurements and define normal ranges. Blood pressure measurements were obtained by manual auscultation with a mercury-gravity manometer via a standardized protocol by trained physicians. Three blood pressure readings were obtained after the participant had been seated, with feet on the ground and back supported, and resting quietly for at least 5 minutes. Each reading was obtained 30 seconds apart, and a fourth reading was obtained if one or more of the previous readings had been interrupted.31-34 Mean systolic and diastolic blood pressures for each participant were calculated from the recorded readings, and then systolic and diastolic blood pressure percentiles were calculated based on age, sex and height percentile, according to the tables published in The Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents (The Fourth Report).1 Hypertension is defined in The Fourth Report as systolic or diastolic blood pressure ≥95th percentile for age, sex, and height on three consecutive visits.1 Because NHANES obtains blood pressure measurements at a single study visit and thus a formal diagnosis of hypertension is not possible, participants were characterized as having “elevated blood pressure” if the mean systolic and/or diastolic blood pressure percentile was ≥95th percentile, and “normal blood pressure” if the mean systolic and diastolic blood pressure percentile were both <95th percentile.
All statistical analyses were performed using Stata Statistical Software, version 11.35 Survey commands were used to account for the NHANES complex sampling design with a calculated 8-year sample weight. The statistical significance level was set at α=0.05. All statistical analyses were 2-sided.
Bivariate associations between demographic and clinical characteristics of children with elevated blood pressure versus normal blood pressure were compared using t tests and χ2 analyses. Similarly, participant characteristics were compared by uric acid quintile. Statistical differences among quintiles were evaluated using simple regression of the clinical variable on uric acid quintile, with the first quintile as the reference group.
Logistic regression was used to evaluate the association of uric acid with elevated blood pressure. Linear regression was used to evaluate the association of uric acid with blood pressure z-score. As normative blood pressure in children is based on age, sex and height, we examined blood pressure z-scores rather than absolute blood pressure levels as the dependent variable in linear regression analyses. Blood pressure z-scores were also normally distributed in contrast to blood pressure percentile, confirming z-scores as appropriate for linear regression analysis. All regression analyses were adjusted for age, sex, race/ethnicity and BMI percentile. All children had a normal estimated glomerular filtration rate (eGFR), and further adjustment for eGFR resulted in similar results (not shown). Secondary analyses additionally included adjustment for diabetes status, hyperlipidemia, tobacco smoke exposure and household income. Multivariate regression analyses stratified by sex were also examined given the difference in distribution of uric acid levels between males and females. Published uric acid normal reference ranges differ for males and females during adolescence. For males 12-19 years old, serum uric acid levels range 3.0-7.7 mg/dL, and for females 12-19 years old, 2.7-5.7 mg/dL.36
Uric acid levels in logistic and linear regression analyses were modeled in three different ways: 1) continuous (mg/dL); 2) dichotomized as ≥ or <5.5 mg/dL; and 3) quintiles, with the first quintile as the reference group. There is no universally accepted definition of hyperuricemia in children. The cut-off of 5.5 mg/dL was chosen based on a prior observational study which found that a serum uric acid level ≥5.5 mg/dL had a positive predictive value of 82%, a sensitivity of 87% and a specificity of 86% for primary hypertension in otherwise healthy children who were evaluated for hypertension.37
Of eligible adolescents 12-17 years of age, 13 were excluded for not having a documented age in months at the time of examination, necessary for calculation of blood pressure, height, weight and body mass index (BMI) percentiles, and 919 were excluded due to missing uric acid, blood pressure and anthropometric data, resulting in a final sample size of 6,036. 3.3% of participants had elevated blood pressure. Comparing those with elevated versus normal blood pressure, there were no statistically significant differences in age, sex, race/ethnicity, or eGFR. Participants with elevated blood pressure had higher mean weight and BMI percentiles (Table 1). 16% and 17% of the study population was overweight or obese, respectively. Elevated blood pressure was found in 2% of those with a normal BMI, compared to 3% among the overweight and 8% among the obese. Among those with an elevated blood pressure, 44% had a normal BMI percentile, 14% were overweight, and 41% were obese.
Mean uric acid level was 5.0 mg/dL, and 34% had a uric acid level ≥5.5 mg/dL. Six-percent of males and 9% of females had uric acid levels at or above sex-specific published upper limits of normal (7.7 and 5.7 mg/dL for males and females, respectively).36 Participants with elevated blood pressure had a mean uric acid of 5.6 mg/dL, compared to 5.0 mg/dL in the normal blood pressure group (p-value 0.004). Figure 1 shows the distribution of uric acid for those with elevated blood pressure compared to those with normal blood pressure. As uric acid quintile increased, participants were more likely to be older, male, white, have higher weight, height, BMI and systolic blood pressure percentiles, be obese and have elevated blood pressure (please see supplementary table S1, http://hyper.ahajournals.org).
After age, sex, race/ethnicity and BMI adjustment, the odds ratio of having elevated blood pressure for each 0.1 mg/dL increase in uric acid was 1.38 (95% CI, 1.16 to 1.65) (Table 2). Odds ratios and 95% CI for age (per year), sex (female vs. male) and BMI percentile (per 1% increase) in the fully adjusted model were 0.92 (0.83-1.01), 1.45 (0.95-2.19) and 1.01 (1.01-1.02), respectively. Odd ratios and 95% CI for race/ethnicity in the fully adjusted model were 1.02 (0.63-1.65) for Mexican Americans and 1.73 (1.07-2.81) for non-Hispanic Blacks, compared to non-Hispanic Whites. Participants with uric acid level ≥5.5 mg/dL had twice the odds of having elevated blood pressure compared to those with a uric acid level <5.5 mg/dL. Compared to the lowest uric acid quintile, participants in the highest quintile had a three-fold higher odds of elevated blood pressure. The results were similar for the association of uric acid levels with systolic and diastolic blood pressure z-score, although the multivariable adjusted models were not statistically significant (Table 3).
In stratified analysis, the odds ratio for elevated blood pressure for each 0.1 mg/dL increase in uric acid levels was 1.45 (95% CI, 1.17-1.80) in males and 1.17 (95% CI, 0.84-1.61) in females (Table 4). The corresponding odds ratios of elevated blood pressure for uric acid level ≥5.5 mg/dL were 2.23 (95% CI, 1.16-4.31) in males and 1.73 (95% CI, 0.95-3.13) in females. Statistical testing for effect modification of uric acid on elevated blood pressure by sex was not significant (p-value 0.28). Inclusion of diabetes, hyperlipidemia, tobacco exposure and annual household income in logistic and linear regression analyses did not change the relationship of uric acid with blood pressure (results not shown).
In this large, nationally representative sample of adolescents in the U.S., serum uric acid was associated with elevated blood pressure. Blood pressure and serum uric acid levels are known to be impacted by chronic kidney disease (CKD) and obesity.3, 38, 39 This cohort had normal kidney function as would be expected given the low prevalence of CKD in children,40, 41 making it a desirable population in which to independently assess the association of uric acid and blood pressure. As previously reported, the prevalence of overweight and obesity in this sample of U.S. teenagers was high.42 However, the association between uric acid and blood pressure persisted after adjustment for BMI. Finally, the association between uric acid levels and elevated blood pressure was stronger in boys compared to girls, although we did not find evidence for effect modification of the association between uric acid and elevated blood pressure by sex.
This study expands the evidence presented by a previous study which found a positive association between blood pressure and serum uric acid level after adjusting for age, sex, race, height, weight and sexual maturity rating among 6,768 adolescents in NHANES III.43 However, this earlier study did not examine the association between elevated blood pressure and uric acid using blood pressure percentiles, which is the standard of care for defining normotension and hypertension in children. In linear regression models, we used blood pressure z-score as the dependent variable rather than raw blood pressure in order to fully account for variations in blood pressure in children by age, sex, and height. Given that hyperuricemia may also be associated with the metabolic syndrome and obesity, we improved upon the adjustment for obesity by using sex- and age-specific BMI percentile rather than raw height and weight in regression analyses, and secondary analyses found no impact on the association when adjusted for diabetes or hyperlipidemia.3, 9, 39 Similar to the study using NHANES III raw blood pressure values, we found an association between blood pressure z-score and serum uric acid level in linear regression analyses, although statistical significance was not achieved with adjustment for other variables. However, in contrast to the NHANES III study, we showed that uric acid was associated with elevated blood pressure in fully adjusted logistic regression analyses. The lack of significance observed with the linear regression analyses may be due to the lack of a linear association between uric acid level and blood pressure, or because this analysis was underpowered to detect it.
Normative values of uric acid are higher in males and may be affected by onset of puberty, body mass differences, and hormonal effects.44, 45 As significant differences in uric acid levels between male and female adolescents were noted in this and previous studies, the association between uric acid level and elevated blood pressure was examined stratified by sex.44-47 Males had a higher odds than females of having an elevated blood pressure with increasing uric acid level. It is likely that the lower uric acid levels observed in females in the cohort may be diluting the association with elevated blood pressure, as an interaction between uric acid and sex was not statistically significant. Also, small clinical studies in adolescents have not demonstrated a difference in effect based on sex.11, 37
A recent meta-analysis of prospective cohort studies examining incident hypertension and uric acid levels in adults reported a pooled risk ratio of 1.13 for incident hypertension for each 1 mg/dL increase in uric acid (95% CI 1.06-1.20).15 The risk was larger in younger age groups, further supporting the importance of evaluating the pathogenic role of uric acid in young people. A few clinical trials have examined the impact of uric acid on cardiovascular disease by evaluating the effect of uric acid-reduction pharmacotherapy. Two studies found no significant difference in blood pressure between allopurinol and control groups, but did find that allopurinol therapy (100-300 mg/day over 12-24 months) was associated with a decrease in progression of chronic kidney disease.48, 49 In a prospective study of 48 hyperuricemic adults (uric acid >7 mg/dL) treated with 300 mg/day of allopurinol compared to 21 normouricemic age- and sex-matched controls over a 3 month follow-up period, the mean systolic and diastolic blood pressure decreased by 3.9 and 1.9 mmHg, respectively.12 Other adult trials have shown improvement in various measures of endothelial function and cardiac function in patients with significant cardiovascular disease treated with allopurinol.50-52 Each of these adult studies was small and patients had significant comorbidities, including diabetes, chronic kidney disease and extended duration of hypertension, as well as concomitant use of antihypertensive and lipid-lowering therapies.
The only clinical trial in children to date was a randomized, double-blind, placebo-controlled, cross-over trial of 30 adolescents with newly diagnosed primary hypertension and uric acid levels ≥6 mg/dL treated with 400 mg/day allopurinol versus placebo for four weeks.11 No other antihypertensive medications were used in the study. This trial demonstrated a mean change in casual systolic blood pressure of −6.9 mmHg during allopurinol treatment compared to −2.0 mmHg during placebo (p-value 0.009), and a mean change in 24-hour ambulatory systolic blood pressure of −6.3 mmHg for allopurinol and −0.8 mmHg for placebo (p-value 0.001).11 Twenty of 30 participants achieved normal blood pressure levels during the allopurinol phase compared to 1 of 30 during the placebo phase.11
There are some limitations to our study. First, the data is cross-sectional, and therefore it is not possible to establish that relatively higher uric acid levels preceded or caused elevated blood pressure. Second, the definition of elevated blood pressure is based on a single physical exam visit, and does not necessarily signify that the participant has hypertension. However, elevated blood pressure may be indicative of a pre-hypertensive state, and it is known that prehypertension is a risk factor for the development of hypertension in children and other cardiovascular outcomes in adulthood.53, 54 The prevalence of elevated blood pressure in this population is 3.3%, which correlates well with the estimated prevalence of hypertension in the U.S. pediatric population of about 3-5%.55 Despite the low prevalence, we still found a significant association between elevated blood pressure and uric acid level.
This study benefits from the high quality standardized protocol by which blood pressure was measured in NHANES 1999-2006. Another strength of the study includes the large and nationally representative study population that makes the results very generalizable. Finally, these adolescents had no evidence of chronic kidney disease, which is very prevalent in adults and may confound the relationship between uric acid and hypertension.
Among adolescents 12-17 years of age, serum uric acid levels are associated with elevated blood pressure. This study contributes to the accumulating evidence linking uric acid and hypertension. Additional prospective studies and clinical trials are needed to determine if uric acid is merely a marker in a complex metabolic pathway, or causal of hypertension and thus a potential screening and therapeutic target. Given the burden of chronic hypertension, cardiovascular disease, and chronic kidney disease in adulthood, identifying novel ways to intervene in the prevention and early treatment of hypertension is a priority.
Sources of Funding: This work is supported by grant 5T32DK007732-17 from the National Institute of Diabetes and Digestive and Kidney Diseases (Dr. Loeffler), grant 1R01HL090863 from the National Heart, Lung and Blood Institute (Dr. Navas-Acien), grant 5KL2RR025006 from the National Institutes of Health/Johns Hopkins Institute for Clinical and Translational Research (Dr. Brady), and grant K23ES016514 from the National Institute of Environmental Health Science (Dr. Fadrowski).
Conflicts of Interest/Disclosures:None.