Feig 2012 The Journal of Clinical Hypertension

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STATE OF THE ART REVIEW PAPER
The Role of Uric Acid in the Pathogenesis of Hypertension in the Young
Daniel I. Feig, MD, PhD
From the Division of Nephrology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL
Uric acid has been suspected to be a risk factor for hyper-
tension since the 1870s. Numerous epidemiological stud-
ies demonstrate an association between uric acid and
both incident and prevalent hypertension in diverse popu-
lations. Studies in elderly patients have had more variable
results, raising the possibility that uric acid may be more
significant to hypertension in the young. Animal models
support a two-phase mechanism for the development of
hyperuricemic hypertension. Initially, uric acid induces
vasoconstriction by activation of the renin-angiotensin sys-
tem and reduction of circulating nitric oxide, which can be
reversed by lowering uric acid. Over time, uric acid uptake
into vascular smooth muscle cells causes cellular prolifera-
tion and secondary arteriolosclerosis that impairs pressure
natriuresis, causing sodium-sensitive hypertension. Consis-
tent with the animal model data, small clinical trials per-
formed in adolescents with newly diagnosed essential
hypertension demonstrate that at least in certain young
patients, reduction of serum uric acid can mitigate blood
pressure elevation. While more research is clearly neces-
sary, the available data suggest that uric acid is likely
causative in some cases of early-onset hypertension.
J Clin Hypertens (Greenwich). 2012; 14:346–352. �2012
Wiley Periodicals, Inc.
The concept that uric acid might be associated with
the development of hypertension is not a new one.
Even in the earliest discussions of hypertension as a
disease entity, uric acid was considered. In the 1870s,
Frederick Mahomed1,2 postulated that the problem of
hypertension resulted from a circulating toxin that
caused an increase in blood pressure (BP) and subse-
quently damaged the vasculature of the heart and kid-
neys. While he suggested several candidate molecules,
he proposed uric acid as an important mediator and
published the first sphymagraph tracings showing a
patient with gout who had increased systemic BP.2 A
few years later, Alexander Haig3 also linked uric acid
with elevated BP and went so far as to write a text-
book that suggested a diet that would lower uric acid
and control BP in the general population. In 1897,
Nathan Davis,4 addressing the American Medical
Association, argued that gout was a major cause of
hypertension that manifested as arteriolar disease,
interstitial renal injury, and myocardial hypertrophy.
Henri Huchard,5a renowned cardiologist, hypothesized
that arteriole sclerosis, the vascular lesion associated
with hypertension, had three causes: uric acid, lead,
and intake of fatty meats, the latter of which also yield
increased uric acid. As early as 1913, experimental
evidence supported a link between uric acid and
hypertension. Injection of uric acid into rabbits was
shown to increase BP.6 In 1915, Urodonal, a drug con-
sisting of theobromine and methenamine, was intro-
duced in France as a treatment to lower uric acid and
control BP; however, it was eventually proven to be
ineffective. Nevertheless, at the end of the 19th
century and the first two decades of the 20th century,
uric acid was already linked with hypertension and
cardiovascular diseases.
The investigation of a link between uric acid and
hypertension made relatively little progress through
much of the 20th century. While some of the cardio-
vascular risk trials measured uric acid and suggested
an association between uric acid and hypertension, or
cardiovascular disease (Table), the lack of plausible
mechanistic evidence linking the two led most investi-
gators to conclude that uric acid was an associated
surrogate marker for more important risk factors such
as obesity, diabetes, and chronic kidney disease
(CKD).7 In the 1980s, uric acid was removed from
some of the common laboratory panels, markedly
reducing the available epidemiologic data on uric acid
in otherwise healthy patients and those with cardiovas-
cular disease. The move was made after the majority
of serious side effects from the urate-lowering drug,
allopurinol, were observed in patients with asymptom-
atic hyperuricemia, not gout.8 The shift to minimize
inadvertent diagnosis of hyperuricemia was thought to
reduce risk of unnecessary medication side effects and
reduced the awareness of the prevalence of hyperurice-
mia in the absence of symptomatic gout.
EPIDEMIOLOGY
Numerous longitudinal cardiovascular risk trials have
evaluated the possible relationship between serum uric
acid and hypertension (Table). As early as 1972, in the
Israeli Heart Trial, an evaluation of the medical data
of young adults inducted into the armed services
demonstrated that the highest tertile of uric acid was
associated with double the risk of incident hyperten-
sion within 5 years.9 The association is robust across
racial groups, with similar findings in African Ameri-
cans noted in the Coronary Artery Revascularization
in Diabetes (CARDIA) trial10 as well as several trials
Address for correspondence: Daniel I. Feig, MD, PhD, 1600 7th
Avenue South, ACC 516, Birmingham, AL 35233
E-mail: dfeig@peds.uab.edu
Manuscript received: March 26, 2012; revised: April 5, 2012;
accepted: April 6, 2012
DOI: 10.1111/j.1751-7176.2012.00662.x
346 The Journal of Clinical Hypertension Vol 14 | No 6 | June 2012 Official Journal of the American Society of Hypertension, Inc.
TABLE. Epidemiology of Uric Acid and Hypertension
Study (Year) Population Relative Risk of Hypertension Reference
Israeli Heart (1972) 10,000 Israeli men, age 17–25 y, enrolled at
military induction
Two-fold risk at 5 y 9
Fessel et al (1973) 224 White men in Western United States, age >35 y Greater increase in systolic blood
pressure at 4 y
60
Gruskin (1985) 55 Adolescents, racially mixed US population Higher uric acid, higher blood pressure 53
Moscow Children’s Study (1985) 145 Caucasian children in Moscow, age 8–17 Uric acid >8 mg ⁄ dL predicts severe
hypertension
17
Brand et al (1986) 4286 Men and women age 35–50 y in the
Framingham cohort
Uric acid, systolic blood pressure rise a
linear relation
61
Hungarian Children’s (1990) 17643 Hungarian children, age 6–19 y Uric acid predicts adolescent
hypertension
16
Kaiser Permanente (1990) 2062 Adult men and women in the Kaiser
Permanente Multiphasic Health Checkup
cohort in Northern California
Two-fold risk at 6 y 62
University of Utah (1991) 1482 Adult men and women in 98 Utah pedigrees Two-fold risk at 7 y 63
NHANES (1993) 6768 Healthy children age 6–17 y Uric acid predicts adolescent
hypertension
18
Olivetti Heart Study (1994) 619 Adult men from Southern Italy Two-fold risk at 12 y 64
CARDIA study (1999) 5115 Black men and women age 18–30 y Increased risk at 10 y 10
Osaka Health Survey (2001) 6356 Japanese men age 35–60 y Two-fold risk at 10 y 15
Hawaii-LA-Hiroshima Study (2001) 140 Japanese American men age 40–69 y 3.5-fold risk at 15 y 11
Feig and Johnson (2003) 175 Racially diverse children, age 6–18 y in Texas Uric acid >5.5 mg ⁄ dL predicts
hypertension
54
Osaka Factory Study (2003) 433 Nonobese Japanese men age 18–40 y 1.0 mg ⁄ dL, increased 27 mm Hg
systolic blood pressure at 5 y
12
Osaka Health Survey (2003) 2310 Male office workers in Japan, age 35–59 y 1.6-fold risk at 6 y 14
Okinawa (2004) 4489 Japanese men and women, age >30 y 1.7-fold risk at 13 y 13
Bogalusa Heart (2005) 577 Black (58%) and white (42%) children
enrolled at age followed until age 18–35 y
Increased risk for diastolic
hypertension at 11 y
22
Framingham (2005) 3329 Men and women in the Framingham cohort 1.6-fold at 4 y 23
Normative Aging Study (2006) 2062 Healthy men age40–60 y at enrollment 1.5-fold at 21 y 65
ARIC (2006) 9104 Mixed race (black and white) men and
women age 45–64 y at enrollment
1.5-fold at 9 y 66
Beaver Dam Survey (2006) 2520 White men (44%) and women (56%) age
43–84 y in Wisconsin
1.65-fold at 10 y 67
Health Professional Followup (2006) 750 Mostly white men in Massachusetts 1.08-fold at 8 y 68
MRFIT (2007) 3073 Men age 35–57 y 1.8-fold at 6 y 69
Nurses Health (2009) 1496 Women, racially diverse, age 32–52 y 1.9-fold at 6 y 70
Qingdao Port Health (2009) 7220 Men (74%) and women (26%) in Quingdoa
China, mean age 37 y
1.39 For men, 1.85 for women at 4 y 71
Jones et al (2009) 141 Children age 7–18 y , 64% men, 71% black 2.1-fold risk in adolescence by
ambulatory blood pressure
monitoring
72
Leite et al (2010) 1410 Men and women in Milan, Italy, young
cohort 42–59 y, older cohort 60–74
Increased risk in middle age,
not elderly
73
Grayson et al (2010) 55,607 Adults, meta-analysis of 18 prospective studies 1.41-fold risk each 1 mg ⁄ dL
uric acid
74
Silverstein et al (2011) 108 Racially diverse children, age 6–18 in Texas
and Washington, DC
Linear association between
systolic blood
pressure and uric acid in
children on renal
replacement therapy
24
GOCADAN (2012) 1078 Alaskan native Americans with chronic kidney
disease II or III
1.2-fold age-adjusted risk 75
Fadrowski (2012) 6036 Adolescents, age 11–17 y, evaluated in the
National Health and Nutrition Examination Survey
Uric acid >5.5 mg ⁄ dL, 2.03-fold risk 76
Official Journal of the American Society of Hypertension, Inc. The Journal of Clinical Hypertension Vol 14 | No 6 | June 2012 347
Role of Uric Acid in Hypertension | Feig
demonstrating the same association in Asians and
Asian Americans.11–15 Several studies in children and
adolescents, particularly the Hungarian Children’s
Study,16 the Moscow Children’s trial,17 and the
National Health and Nutrition Examination Survey
(NHANES)18 in the 1980s and early 1990s demon-
strated a particularly strong association between uric
acid and hypertension despite the much lower inci-
dence in children. Studies specifically of older and
elderly patients have had much more variable
results7,19–21 and led many investigators to conclude
that the association was spurious; however, an alterna-
tive explanation is that if uric acid leads to hyperten-
sion, there may be a preferential effect in the young.
In the past decade, new epidemiological studies have
rekindled an interest in the link between uric acid and
hypertension. Three longitudinal studies in Japanese
patients showed an association between serum uric
acid and incident hypertension. Nakanishi and col-
leagues14 demonstrated a 1.6-fold increased risk of
new hypertension over 6 years in young adult office
workers with serum uric acid in the highest tertile.
Tanaguichi and associates15 demonstrated a 2-fold
increased risk of new hypertension over 10 years asso-
ciated with elevated uric acid in the Osaka Health
Study. Masuo and coworkers12 evaluated the linear
association of serum uric acid and systolic BP, finding
an average increase of 27 mm Hg per 1 mg ⁄dL
increase in serum uric acid among nonobese young
men. In an ethnically diverse population within the
Bogalusa Heart Study, higher childhood and young
adult serum uric acid levels were associated with inci-
dent hypertension and progressive increase in BP even
within the normal range.22 A post hoc analysis from
the Framingham Heart Study also suggested that a
higher serum uric acid level is associated with
increased risk of rising BP.23 Taken together, the pre-
ponderance of evidence supports a close epidemiologic
link between uric acid and hypertension that is robust
across ethnic racial and anthropomorphic categories
but may be attenuated in the elderly. One cautionary
note that should be considered is that the paucity of
recent reports of a lack of an association could be
publication bias against negative studies.
URIC ACID METABOLISM
The causes of mild to moderate hyperuricemia in the
young are not well established; however, many possi-
bilities exist and probably co-exist. Increased uric acid
can result from decreased renal function and in gen-
eral, children with CKD and end-stage renal disease
have higher serum uric acid.24 There are numerous
medications that impair renal clearance of uric acid,
even in the presence of normal glomerular filtration
rate, including loop and thiazide diuretics.25 Genetic
polymorphisms in anion transporters such as uric acid
anion transporter 1 (URAT-1)26 and the SLC2A9 that
encodes for GLUT9, an anion transporter with affinity
for uric acid,27 can lead to hyperuricemia by altering
proximal tubular urate clearance. Approximately 15%
of uric acid clearance is through the GI tract; conse-
quently, small bowel disease can also contribute
increased serum uric acid.28 Diets rich in fatty meats,
seafood, and alcohol increase serum uric acid,29,30 and
obesity confers a 3-fold increased risk of hyperurice-
mia.31 Finally, as uric acid is the end point of the
purine disposal pathway, impairment of the efficiency
of purine recycling metabolism or overwhelming the
recycling pathway with excessive cell death or cell
turnover will increase serum uric acid.32
Serum uric acid levels throughout the population
correlate with sweetener consumption.33 Sweetener
consumption in the United States has dramatically
increased since the introduction of high fructose corn
syrup in the early 1970s.34 Fructose raises uric acid
rapidly via activation of the fructokinase pathway in
hepatocytes.35 Fructokinase consumes ATP, leading to
an increased load of intracellular purines requiring
metabolism and disposal through xanthine oxidase–
mediated metabolism ending in uric acid.35 The
administration of large quantities of fructose to rats,
60% of their caloric intake, resulted in hyperuricema,
elevated BP, the development of preglomerular arte-
riolopathy,36 and features of the metabolic syndrome
(elevated triglycerides, low high-density lipoprotein
cholesterol, abdominal obesity, and insulin resis-
tance).37 Furthermore, lowering uric acid prevents
these changes despite ongoing fructose consumption.34
The requirement for prodigious fructose intake in rats
to raise uric acid may be because rats have uricase, an
enzyme that metabolizes uric acid to allantoin, and is
absent in humans.
Human studies also show that fructose loading leads
to increased serum uric acid levels acutely, and that
chronic increased fructose consumption leads to chron-
ically increased serum uric acid and increases in BP.38
With the nearly universal exposure to sweetened foods
and beverages in the pediatric population, it is very
likely that much of the hyperuricemia, especially that
associated with obesity, is dietary rather than genetic
in origin.39 Consistent with this hypothesis, epidemio-
logical studies have shown a relationship between
fructose and serum uric acid in most but not all stud-
ies.40 One reason some studies may be negative could
reflect the action of fructose, as it tends to increase
uric acid mostly in the postprandial setting and, since
most studies use fasting uric acid levels, it is possible
that an elevation in mean 24-hour uric acid would be
missed.
Jalal and colleagues40 used the data from NHANES
2000–2003, which was a survey of healthy adults in
the United States in which direct BP measurement was
available as well as dietary intake of fructose as deter-
mined by dietary questionnaire. The major finding was
that there was a strong independent relationship of
fructose intake with elevated systolic BP. Interestingly,
the relationship was independent of fasting serum uric
acid. In a different study, Nguyen and colleagues39
348 The Journal of Clinical Hypertension Vol 14 | No 6 | June 2012 Official Journalof the American Society of Hypertension, Inc.
Role of Uric Acid in Hypertension | Feig
also found an independent relationship of sugary soft
drinks with hypertension in adolescents. Perez-Pozo
and coworkers41 administered 200 g of fructose per
day to healthy overweight men with or without allo-
purinol during a 2-week period. In this study, an
increase in serum uric acid was observed in association
with a significant increase in daytime systolic and both
24-hour and daytime diastolic BP. Allopurinol reduced
serum uric acid and blocked the BP rise. While the
dose of fructose was very high, 25% of the NHANES
cohort consumed similar quantities.40
ANIMAL MODELS OF HYPERURICEMIC
HYPERTENSION
While significant epidemiological evidence supported
the hypothesis that uric acid may be associated with
hypertension, it was not until the experiments of John-
son and colleagues in 2001 that a plausible mechanism
could be established using a rat model of hyperurice-
mia. Hyperuricemia results in hypertension within
2 weeks, with systolic BP and diastolic BP elevation
proportional to serum uric acid. This effect can be
ameliorated by uric acid–lowering drugs (allopurinol
or benziodarone). Early hypertension is completely
reversible with urate reduction, but prolonged hyper-
uricemia results in irreversible sodium-sensitive hyper-
tension that becomes uric acid–independent.42,43 Early
hypertension is mediated by increased renal renin and
reduction of circulating plasma nitrates,42,44–46 leading
to a phenotype of excessive vasoconstriction that can
be reversed by reduction of uric acid or renin-angio-
tensin system blockade. The later, irreversible hyper-
tension, is secondary to altered intra-renal vascular
architecture. Uric acid enters vascular smooth muscle
cells via the URAT-1 channel, resulting in activation
of kinases, nuclear transcription factors, cyclo-oxygen-
ase 2 generation, and the production of growth factors
(PDGF), and inflammatory proteins (C-reactive pro-
tein, monocyte chemoattractant protein-1), resulting in
VSCM proliferation, shifted pressure natriuresis, and
sodium-sensitive hypertension47–51 (Figure 1).
These mechanistic studies, as well as the recent epi-
demiologic data described above, have led to a dra-
matic increase in the number of research publications
addressing the link between uric acid and hyperten-
sion. The number had remained relatively constant
from 1970 to 2000, but has been consistently rising
since (Figure 2).
PEDIATRIC CLINICAL TRIALS
In adolescents, there is a close association between ele-
vated serum uric acid and the onset of essential hyper-
tension. The Moscow Children’s Hypertension Study
found hyperuricemia (>8.0 mg ⁄dL) in 9.5% of chil-
dren with normal BP, 49% of children with borderline
hypertension, and 73% of children with moderate and
severe hypertension.52 The Hungarian Children’s
Health Study followed 17,624 children born in Buda-
pest in 1964 over 13 years and found that significant
risk factors for the development of hypertension were
elevated heart rate, early sexual maturity, and hyper-
uricemia.16 These two studies did not separate the
hypertensive children by underlying diagnosis, essential
hypertension vs that caused by renal, cardiac, or endo-
crinologic causes independent of uric acid, so the rela-
tionship between serum uric and hypertension may be
Phase 1: Reversible Vasoconstriction
Uric Acid
Increased renin
Remains uric acid
dependent
Sodium resistant
Phase 2: Arteriolar Wall Thickening
Decreased NO
Uric Acid Becomes uricUric Acid
Vascular smooth
muscle proliferation
acid independent
Sodium sensitive
mediated by PDGF
and MCP-1
FIGURE 1. Animal model data suggest that hyperuricemia leads to
hypertension in a stepwise fashion. The effects of uric acid on the
blood vessel are shown. The first phase is direct, uric acid–dependent
activation of the renin-angiotensin system and down-regulation of the
nitric oxide (NO) production, leading to vasoconstriction. At this stage,
uric acid reduction results in vascular relaxation and improved blood
pressure. The second phase, which develops over time, is uric acid–
mediated arteriolosclerosis. Uric acid uptake into vascular smooth
muscle cells causes the activation and elaboration of production of
growth factor (PDGF) and monocyte chemoattractant protein-1 (MCP-
1). This results in the autocrine stimulation of vascular smooth muscle
cell proliferation, vascular wall thickening, loss of vascular compliance,
and a shift in pressure natriuresis. This process is not reversed by the
late reduction of uric acid and causes permanent sodium-sensitive
hypertension.
FIGURE 2. Number of research articles published per year, 1970–
2011, on the topic of the role of uric acid in hypertension. Articles were
identified on PubMed using search terms uric acid, urate, hyperten-
sion, cardiovascular disease, fructose, sweetened beverages, xanthine
oxidase inhibitors, allopurinol, uricosurics and probenecid. Reviews
were excluded and abstracts were reviewed for relevance.
Official Journal of the American Society of Hypertension, Inc. The Journal of Clinical Hypertension Vol 14 | No 6 | June 2012 349
Role of Uric Acid in Hypertension | Feig
attenuated somewhat. In a small study, Gruskin53
compared adolescents (13 to 18 years) who had essen-
tial hypertension with age-matched healthy controls
with normal BPs. The hypertensive children had both
elevated serum uric acid (mean >6.5 mg ⁄dL) and
higher peripheral renin activity. In a racially diverse
population referred for the evaluation of hypertension,
Feig and Johnson54 observed that the mean serum uric
acid level children with white-coat hypertension was
3.6�0.7 mg ⁄dL, slightly higher in secondary hyperten-
sion (4.3�1.4 mg ⁄dL, P=.008) and significantly
elevated in children with primary hypertension
(6.7�1.3mg ⁄dL, P=.000004). There was a tight linear
correlation between serum uric acid levels and systolic
and diastolic BPs in the population referred for evalua-
tion of hypertension (r=0.8 for systolic BP and r=0.6
for diastolic BP) (Figure 3). Each 1-mg ⁄dL increase in
serum uric acid was associated with an average
increase of 14 mm Hg in systolic BP and 7 mm Hg in
diastolic BP.54 Among patients referred for evaluation
of hypertension, serum uric acid >5.5 mg ⁄dL had an
89% positive predictive value for essential hyperten-
sion, while serum uric acid <5.0 had a negative pre-
dictive value for essential hypertension of 96%.54
The evaluation of a large-referral population of chil-
dren with essential hypertension and elevated uric acid
reveal several observations that are consistent with the
mechanisms of uric acid–mediated hypertension seen
in the animal model. Among 513 children consecu-
tively evaluated for hypertension, children with essen-
tial hypertension (n=206) had higher blood
hemoglobin (14.6�1.3 g ⁄dL) compared with those
with secondary hypertension (n=176, hemoglobin
12.8�1.6) or white-coat hypertension (n=135, hemo-
globin 12.5�1.2 g ⁄dL). In children with serum uric
acid >6 mg ⁄dL, the average hemoglobin is
15.4�1.4 g ⁄dL. While the mechanism is not yet estab-
lished, one possibility is that uric acid–mediated
vasoconstriction and arteriolosclerosis, seen in the rat
model, leads to decreased microvascular perfusion and
increased serum erythropoetin. Polycythemia and
hypertension have been previously described in
patients with hyperuricemia and gout; however, it has
been assumed that the elevation in uric acid was sec-
ondary to the hematopoietic disorder.55,56 In obese
patients with prehypertension and serum uric acid
>5 mg ⁄dL, systemic vascular resistance (measured by
noninvasive bioimpedence) is elevated relative to obese
children with normal uric acid and similar BP (2482�
306 dynesec ⁄ cm5 ⁄m2 vs 1843�291 dynesec ⁄ cm5 ⁄m2).
While these physiologicobservations do not prove that
the effects of increased serum uric acid are the same in
humans as in rats, they are consistent with a vasocon-
strictive effect due to uric acid.
Results from a small pilot study in children suggest
that uric acid may directly contribute to the onset of
hypertension in some humans. Five children, aged 14
to 17 years, with newly diagnosed and untreated
essential hypertension were treated for 1 month with
allopurinol as a solitary pharmacologic agent. All 5
children had a decrease in BP by both casual and
ambulatory monitoring and 4 of the 5 were normoten-
sive at the end of 1 month.57 In a separate study, 30
adolescents with newly diagnosed essential hyperten-
sion were treated in a randomized, double-blinded
crossover trial with allopurinol vs placebo. Sixty-seven
percent of children taking allopurinol and 91% of
children with serum uric acid <5.5 mg ⁄dL on treat-
ment had normal BPs compared with 3% of children
taking placebo.58 While these observations need to be
confirmed in larger and more general populations, if
serum uric acid is indeed directly causing renal arte-
riolopathy, altered regulation of natriuresis, and persis-
tent systemic hypertension, it is a modifiable risk
factor for CKD in the absence of other mechanisms.
FUTURE DIRECTIONS
The combination of epidemiological, animal model,
and clinical trials support a causative role for uric acid
in some patients with elevated BP. The controversy
over its role stems from the lack of a plausible causa-
tive mechanism prior to 2001 and its overlap with
other more conventional risk factors such as renal dis-
ease, diabetes, and obesity. More recent mechanistic
studies, however, support uric acid–mediated activa-
tion of the renin-angiotensin system, a process with
rapid onset that can also be quickly controlled, fol-
lowed by a more gradual alteration of renovascular
geometry and sodium handling that results in chronic
salt-sensitive hypertension. The implications of this
paired mechanism are two-fold. First, it would explain
the greater magnitude of effect seen in younger
patients or at least the attenuation of affect in the
elderly. Second, it may represent a unique opportunity
in newly diagnosed hyperuricemic hypertension, in
which metabolic control may delay or prevent irrevers-
ible vasculopathy and permanent future hypertension.
180
140
160
120
140
100
Serum Uric Acid, mg/dL
Sy
st
ol
ic
 B
lo
od
 P
re
ss
u
re
, m
m
 H
g
80
1 2 3 4 5 6 7 8 9 10
FIGURE 3. Serum uric acid is plotted against systolic blood pressure
for children with normal blood pressure and children with primary
hypertension. Data do not include individuals with secondary hyperten-
sion or white-coat hypertension. The solid and dotted lines represent
the best fit and 95% confidence intervals, respectively, and
demonstrate the linear relation between uric acid and systolic blood
pressure.54
350 The Journal of Clinical Hypertension Vol 14 | No 6 | June 2012 Official Journal of the American Society of Hypertension, Inc.
Role of Uric Acid in Hypertension | Feig
The link between fructose intake and serum uric
acid may also hold important promise; however, while
fructose loading clearly leads to increased serum uric
acid and increased BP in clinical trials, the efficacy of
fructose reduction has not been proven. A post hoc
evaluation for the PRIMIER trial, a large trial of the
efficacy of nonpharmacologic therapy for hypertension
and cardiovascular risk mitigation, demonstrated that
patients with the greatest reduction in sweetener
consumption also had the greatest reduction in BP59;
however, the effect of sweetener intake reduction as
monotherapy for BP has not been formally tested.
CONCLUSIONS
How best to approach mild to moderate hyperurice-
mia remains an open question. The currently available
medications, especially allopurinol, are associated
with significant, even life-threatening, side effects that
preclude its safe use in populations as large as those
at risk for future hypertension. Consequently, the
treatment of asymptomatic hyperuricemia or mild
hypertension in the presence of hyperuricemia should
not be treated with the currently available uric acid–
lowering medications. As there are many classes of
readily available antihypertensive medications with
more optimal safety profiles, direct management of
hypertension is preferable. The caveat to such an
approach is the poor actual control rates in both
adult and pediatric hypertension with current conven-
tional therapies bespeak the need for novel therapeu-
tics. Definitive, large-scale studies, particularly
randomized, double-blinded, placebo-controlled trials
of urate-lowering medications other than allopurinol,
either xanthine oxidase inhibitors or uricosurics, are
needed to prove, or refute, the general utility and
safety of mitigating hypertension through uric acid
control.
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