Plasma Uric Acid Level and Risk for Incident Hypertension

Among Men
John P. Forman,*†§ Hyon Choi,*‡ and Gary C. Curhan*†§
*Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, †Renal
Division, Department of Medicine, Brigham and Women’s Hospital, and §Department of Epidemiology, Harvard School
of Public Health, Boston, Massachusetts; and ‡Division of Rheumatology, Vancouver General Hospital, University of
British Columbia, Vancouver, British Columbia, Canada

Several studies have found that uric acid (UA) level is associated with an increased risk for hypertension, but the association
could be confounded by metabolic factors that were not included in these previous studies. UA level and risk for incident
hypertension was examined prospectively among men who participated in the Health Professionals’ Follow-up Study. From
among men without hypertension at the time blood was collected, 750 participants who developed hypertension during the
subsequent 8 yr and 750 age-matched controls were selected. In addition to adjustment for standard hypertension risk factors
and renal function, adjustments controlled for fasting insulin, triglyceride, and cholesterol levels. The mean age of partici-
pants was 61 yr, and mean plasma UA level was 6.0 mg/dl (SD 1.25 mg/dl). The multivariable relative risk (RR) for a 1-SD
increase in UA was 1.02 (95% confidence interval [CI]0.87 to 1.18); the RR comparing the highest with lowest quartile of UA
was 1.08 (95% CI 0.71 to 1.63). The multivariable RR associated with a 1-SD increase in UA was 1.38 (95% CI 1.05 to 1.81) for
men aged <60 yr and 0.90 (95% CI 0.74 to 1.10) for men >60 yr (P ! 0.04 for interaction). However, further adjustment for
fasting insulin, triglyceride, and cholesterol levels attenuated the results (RR for men <60 yr 1.24; 95% CI 0.93 to 1.66). In
conclusion, no independent association between UA level and risk for incident hypertension was found among older men.
J Am Soc Nephrol 18: 287–292, 2007. doi: 10.1681/ASN.2006080865

E
xpanding animal and human literature supports a role
for plasma uric acid (UA) level in the development of
hypertension (1). A rat model of mild hyperuricemia
that was developed by Johnson and colleagues (2– 4) demon-
strated activation of the renin-angiotensin system (RAS) and
endothelial dysfunction with preglomerular vascular disease.
Nine prospective observational studies have reported that UA
is associated with incident hypertension or an increase in BP
(5–13). These observational studies have varied in population
composition as well as statistical method, with some not con-
trolling for potentially important confounding factors, such as
body mass index (BMI) (5,7), renal function (5,7–11,13), and
certain metabolic derangements such as insulin resistance or
dyslipidemia (5– 8,12,13). Common to each of these nine pro-
spective studies, however, is the relatively young age of the
participants; the mean age of each population was !50 yr,
whereas two thirds of the hypertension disease burden lies
among older individuals (14). We performed a prospective
nested case-control study of 1454 male participants of the
Health Professionals’ Follow-up Study (HPFS) to examine the
independent association between plasma UA and risk for inci
Received August 16, 2006. Accepted October 18, 2006.
Published online ahead of print. Publication date available at www.jasn.org.
Address correspondence to: Dr. John P. Forman, Channing Laboratory 3rd Floor,
181 Longwood Avenue, Boston, MA 02115. Phone: 617-525-2092; Fax: 617-525-
2008; E-mail: jforman@partners.org
This study, although negative, documents the reawakening interest in the
role of uric acid in several disorders of the kidney and vasculature and is
linked to a paper by Ejaz et al. in this month’s issue of CJASN (pp. 16 –12),
which suggests that chronic hyperuricemia is a risk factor for acute renal
failure.
dent hypertension among older men aged 47 to 81 yr and to
explore effect modification by age.
Materials and Methods
Study Sample
The HPFS is an ongoing prospective cohort study of 59,529 male
health professionals that began in 1986 and has been described in detail
elsewhere (15). Follow-up of participants was "90% through 2004. In
1993, 18,025 men contributed blood samples that were stored in liquid
nitrogen (#130°C). We conducted a nested case-control study among
men with available blood samples and without prevalent hypertension
in 1994 (approximately 1 yr after blood samples were collected). Only
men whose BMI in 1994 was !30 kg/m2 and whose blood sample was
drawn after fasting for !8 h were considered. The BMI restriction was
imposed because BMI is a strong predictor of UA level (16,17) and is a
powerful predictor of hypertension and because the association be-
tween UA and hypertension may be modified by BMI (11). Fasting
status was imposed to evaluate possible confounding by fasting insulin,
triglycerides, and cholesterol. We then randomly selected 750 men who
developed a new diagnosis of hypertension from 1994 to 2002 and 750
age-matched controls by risk-set sampling (18). Because risk-set sam-
pling allows that a control may be selected as a case in a subsequent
time period, 713 controls were unique individuals and 37 were selected
later as a case and matched to a new control. Risk-set sampling is

Copyright © 2007 by the American Society of Nephrology ISSN: 1046-6673/1801-0287

288 Journal of the American Society of Nephrology
commonly used for prospective, nested, case-control studies, and the
resulting odds ratio that is derived from logistic regression directly
estimates the relative risk (RR) (18). After the exclusion of nine men
with missing UA information, the total study sample consisted of 1454
unique individuals with 745 matched case-control pairs. The institu-
tional review board at Brigham and Women’s Hospital reviewed and
approved this study.
Ascertainment of UA
UA concentration was determined by oxidization with the specific
enzyme uricase to form allantoin and H2O2 (Roche Diagnostics, India-
napolis, IN) at Boston Children’s Hospital Laboratory (Nader Rifai,
director). The coefficient of variation for this assay using quality control
specimens was 2.7%.
Ascertainment of Hypertension
In biennial mailed questionnaires, we asked participants to report
whether a clinician had made a new diagnosis of hypertension during
the preceding 2 yr. Self-reported hypertension was shown to be highly
reliable in HPFS (19). Among a subset of men who reported hyperten-
sion, 100% had the diagnosis confirmed by medical record review. In
addition, self-reported hypertension was highly predictive of subse-
quent cardiovascular events (19). A participant was considered to have
prevalent hypertension and thus excluded if he reported this diagnosis
on any questionnaire up to and including the 1994 questionnaire.
Therefore, cases included only individuals who first reported hyper-
tension on subsequent questionnaires (1996 to 2002).
Ascertainment of Covariates
Age, BMI (weight in kilograms divided by height in meters squared),
smoking status, physical activity, and alcohol intake were ascertained
from the 1994 questionnaire. Baseline BP was ascertained from the 1992
questionnaire, when participants reported their usual BP in categories,
and were assigned the median of the chosen category. Change in
weight was calculated as the difference between the weight in 1994 and
the subsequent weight when case or control status was defined. Ques-
tionnaire-derived information about these covariates was validated
previously, with correlations of 0.97 for weight compared with direct
measurement, 0.79 for physical activity compared with physical activ-
ity diaries, and 0.90 for alcohol compared with multiple averaged
dietary records (15,20,21). Family history of hypertension was available
on the 1990 questionnaire.
In addition to UA, blood samples were assayed in the same labora-
tory for creatinine using a modified Jaffe method, insulin using a RIA,
triglycerides by a standardized enzymatic assay, and cholesterol by a
standard esterase-oxidase method. The coefficients of variation for
these measurements were 4.0, 4.6, 3.6, and 2.7% respectively. Estimated
GFR (eGFR) was estimated using the Modification of Diet in Renal
Disease (MDRD) equation: 186 $ creatinine#1.154 $ age#0.203 $ 1.212 (if
black) (22).
Statistical Analyses
UA was normally distributed and was examined as a continuous
variable in the principal analyses to calculate the RR for hypertension
for a 1-SD (1.25 mg/dl) increment. In other analyses, we examined UA
in quartiles and by clinically defined hyperuricemia ("7.0 mg/dl)
(23–25). To determine differences in baseline characteristics among UA
quartiles, we log-transformed continuous variables and used one-way
ANOVA; for categorical variables (smoking status and family history of
hypertension), we used "2 tests for trend.
We analyzed the association between UA and hypertension using
J Am Soc Nephrol 18: 287–292, 2007
conditional logistic regression conditioning on the matching factor
(age). Multivariable models were adjusted for BMI, alcohol consump-
tion, change in weight, eGFR, physical activity, smoking status, race,
family history of hypertension, and baseline systolic and diastolic BP.
For all RR, we calculated 95% confidence intervals (CI).
The men in our sample were considerably older than the populations
studied by others; we therefore investigated whether the association
between UA and hypertension varied by age (!60 and !60 yr). Because
Nakanishi et al. (11) found a stronger association among those with
lower BMI, we also examined possible interaction between UA and
BMI (!25 and !25 kg/m2). Effect modification was analyzed by cre-
ating appropriate interaction terms between UA level and either age or
BMI.
Finally, because higher UA levels are correlated with other metabolic
abnormalities such as insulin resistance (16,17,26 –31), higher triglycer-
ide levels (16,28,29,31,32), and higher BMI, some have argued that UA
is a component of the metabolic syndrome (16,29). Its association with
hypertension therefore may be confounded by other metabolic abnor-
malities (33). In an attempt to examine the independent association
between UA and hypertension, we further adjusted our analyses for
fasting insulin, triglyceride, and total cholesterol levels. All statistical
analyses were performed with SAS, version 9.2 (SAS Institute, Cary,
NC).
Results
Baseline Characteristics
The mean plasma UA was 6.0 mg/dl (range 2.4 to 11.5), and
the SD was 1.25 mg/dl. The mean age of the population at
baseline was 61 yr (range 47 to 81), and the mean BMI was 25.0
kg/m2 (range 16.4 to 29.9). The characteristics and laboratory
values of the controls at baseline are shown in Table 1, stratified
by quartile of plasma UA. With increasing quartile of UA, we
observed higher BMI and increasing levels of plasma creatinine
(and decreasing eGFR), fasting insulin, triglycerides, and total
cholesterol.
Overall Analysis
The crude RR of incident hypertension for each 1-SD incre-
ment in plasma UA was 1.02 (95% CI 0.92 to 1.13), and the
multivariable-adjusted RR was 1.02 (95% CI 0.87 to 1.18; Table
2). The multivariable RR for men in the highest compared with
lowest quartile of plasma UA was 1.08 (95% CI 0.71 to 1.63) and
was 0.93 (95% CI 0.64 to 1.33) for hyperuricemic men compared
with those without hyperuricemia. Because diastolic BP may be
a negative confounder in this population of older men, we also
performed multivariable analyses without adjusting for dia-
stolic BP; the results essentially were unchanged.
Effect Modification
The multivariable RR of incident hypertension for each 1-SD
increment in plasma UA varied according to age group (P %
0.04 for interaction; Table 3). Plasma UA level was associated
positively and significantly with risk for incident hypertension
among the men who were younger than 60 yr (RR 1.38; 95% CI
1.04 to 1.81) but not associated among men who were !60 yr of
age (RR 0.90; 95% CI 0.74 to 1.10).
In the quartile analysis, there was a trend toward a positive
association between UA and risk for hypertension among the
younger but not the older men. Comparing participants in the
J Am Soc Nephrol 18: 287–292, 2007 Uric Acid and Risk for Hypertension 289

Table 1. Baseline characteristics and laboratory values according to quartile of plasma UA among controls (n %
745)a
Quartile of Plasma UA (mg/dl; Median &Range')
Characteristic P (Trend)
4.6 (2.4 to 5.1) 5.5 (5.2 to 5.9) 6.3 (6.0 to 6.7) 7.4 (6.8 to 11.5)

Age (yr; median &IQR') 61 (53 to 68) 61 (53 to 68) 60 (53 to 68) 62 (54 to 68) 0.36
BMI (kg/m2; median &IQR') 23.8 (22.2 to 25.1) 24.7 (23.0 to 26.5) 25.1 (23.5 to 26.8) 25.1 (24.0 to 27.1) !0.001
Physical activity (METS; median &IQR') 28.5 (13.6 to 52.0) 27.3 (11.6 to 54.0) 27.4 (12.4 to 52.4) 27.7 (11.0 to 58.1) 0.89
Alcohol intake (g/d; median &IQR') 3.4 (0 to 12.4) 5.9 (0 to 14.8) 7.1 (1.5 to 15.4) 8.4 (1.8 to 21.1) 0.28
Current smoking (%) 5.0 5.0 5.3 2.6 0.29
Family history of hypertension (%) 34.4 34.6 35.1 35.4 0.83
Creatinine (mg/dl; median &IQR') 0.96 (0.86 to 1.07) 0.99 (0.92 to 1.05) 1.01 (0.93 to 1.14) 1.07 (0.98 to 1.18) !0.001
eGFR (ml/min per 1.73 m2; median &IQR') 63.6 (55.4 to 70.1) 61.0 (56.3 to 67.3) 59.2 (52.5 to 67.0) 55.4 (49.3 to 62.0) !0.001
Fasting Insulin (IU/ml; median &IQR') 5.0 (3.4 to 7.4) 6.0 (3.6 to 9.1) 5.9 (4.4 to 8.7) 6.8 (4.6 to 10.4) !0.001
Triglycerides (mg/dl; median &IQR') 95 (71 to 142) 110 (77 to 163) 118 (85 to 155) 130 (88 to 184) !0.001
Total cholesterol (mg/dl; median &IQR') 200 (178 to 230) 208 (184 to 230) 206 (188 to 236) 216 (191 to 243) !0.001
a
Study sample restricted to body mass index (BMI) !30 kg/m2. eGFR, estimated glomerular filtration rate; IQR,
interquartile range; METS, metabolic equivalents; UA, uric acid.

highest UA quartile with those in the lowest, the multivariable
RR were 2.01 (95% CI 0.98 to 4.14; P % 0.08 for trend) for men
who were !60 yr of age and 0.87 (95% CI 0.50 to 1.50) for men
who were !60 yr of age. We did not observe an interaction
between BMI and UA level (P % 0.96 for interaction).
Independence from Other Metabolic Derangements
Further adjustment for fasting insulin, triglycerides, and total
cholesterol significantly attenuated the association between
plasma UA and risk for incident hypertension in the younger
men (Table 3). Among participants who were !60 yr of age, the
multivariable adjusted RR for each 1-SD increment fell to 1.24
(95% CI 0.93 to 1.66) and was no longer statistically significant.
The RR comparing the highest with lowest quartiles also was
substantially reduced and NS (RR 1.57; 95% CI 0.73 to 3.34). The
point estimates among men who were !60 yr of age remained
NS after adjustment for fasting insulin, triglycerides, and total
cholesterol.
Discussion
Plasma UA was not associated with an increased risk for
incident hypertension among older men. Although we ob-
served a significant association in the subgroup of men who
were !60 yr of age, this association was attenuated and no
longer significant after further controlling for fasting insulin,
triglycerides, and total cholesterol.
The most notable difference between our study and previous
ones is the age of the populations. Age is critically important
given that approximately two thirds of the hypertension dis-
ease burden in men lies with older individuals (14). Whereas
the mean age of men in our sample was 61 yr, the next oldest
cohorts were that of Hunt et al. (7) (mean age 50 yr) and
Sundstrom et al. (12) (mean age 48.7 yr) (12). The possible effect
of age on the UA– hypertension association was suggested pre-
viously in the discussion by Sundstrom et al. (12); they noted a
13% increase in risk for each 1.0-mg/dl increment in UA (mean
age 48.7 yr), compared with a 20% increase per 1.0 mg/dl in
Taniguchi et al. (9) (mean age 41 yr) and a 23% increase per 1.0
mg/dl in Josaa et al. (8) (mean age 36 yr). The findings from our
study are consistent with the lack of a relation between UA and
hypertension in older individuals.
A rat model of mild hyperuricemia that was developed by
Johnson and colleagues demonstrates UA-dependent BP eleva-
tion and offers a biologic mechanism whereby UA could lead to
similar BP elevations in humans. First, renal vasoconstriction
occurs by inhibition of the nitric oxide pathway and by activa-
tion of the RAS; the resulting elevation of BP was reversible by

Table 2. RR of incident hypertension per 1 SD and according to quartile of plasma UAa

Per 1-SD Increase Quartile of Plasma UA (mg/dl; Median &Range')
Parameter in Plasma UA
(1.25 mg/dl) 4.6 (2.4 to 5.1) 5.5 (5.2 to 5.9) 6.3 (6.0 to 6.7) 7.4 (6.8 to 11.5) P (Trend)

Unadjusted RR 1.02 (0.92 to 1.13)

Multivariableb RR 1.02 (0.87 to 1.18)
No. of cases 174 188 186 197
Unadjusted RR 1.00 (reference) 0.96 (0.72 to 1.28) 1.12 (0.84 to 1.49) 1.05 (0.79 to 1.40) 0.51
Multivariableb RR 1.00 (reference) 0.88 (0.60 to 1.30) 1.05 (0.71 to 1.57) 1.08 (0.71 to 1.63) 0.54
a
Conditional logistic regression, case-control pairs matched on age. RR, relative risk.
b
Adjusted for BMI, eGFR, alcohol intake, smoking status, interval change in weight, physical activity, race, family history of
hypertension, and baseline systolic and diastolic BP (BP ascertained 1 yr before blood collection).
290 Journal of the American Society of Nephrology
Table 3. Risk for incident hypertension per 1-SD increase in plasma UA, stratified by agea
Per 1-SD Increase in Plasma UA (1.25 mg/dl)
Parameter
Age !60 yr Age !60 yr
No. of cases 325 420
Multivariableb RR 1.38 (1.05 to 1.81) 0.90 (0.74 to 1.10)
Multivariablec RR 1.24 (0.93 to 1.66) 0.94 (0.77 to 1.16)
Age !60 yr
no. of cases
multivariableb RR
multivariablec RR
Age !60 yr
no. of cases
multivariableb RR
multivariablec RR
a
Conditional logistic regression, case-control pairs matched on age.
b
Adjusted for BMI, eGFR, alcohol intake, smoking status, interval change in weight, physical activity, race, family history of
hypertension, and baseline systolic and diastolic BP (BP ascertained 1 yr before blood collection). P % 0.04 for interaction.
c
Adjusted for everything in model b and also for fasting insulin, triglycerides, and total cholesterol levels.
decreasing UA levels (2– 4,34). A recent report demonstrated
that UA level was associated with lower basal renal plasma
flow and blunted renal vasoconstriction that typically is seen
with angiotensin II infusion during high-salt balance, lending
support to the hypothesis that UA may activate the renal RAS
directly (35). Second, vascular smooth muscle cell proliferation
and inflammation as a result of UA may lead to irreversible
damage to small renal vessels, leading to persistence of hyper-
tension and salt sensitivity (36).
This mechanism may be less important when hypertension
develops at an older age, when stiffening of the aorta may be a
principal mechanism (37). Furthermore, because increasing age
is associated with activation of the renal RAS and with renal
vasoconstriction (38,39), it is not surprising that the association
between UA and hypertension may be blunted in older indi-
viduals.
Finally, we adjusted simultaneously for both renal function
and other metabolic derangements, including fasting insulin,
triglyceride, and cholesterol levels. We adjusted for these fac-
tors to assess whether elevated UA might be simply a feature of
a broader metabolic syndrome and not an independent risk
factor for incident hypertension (16,17,26 –33). Further adjust-
ment for these laboratory values substantially attenuated the
positive association that we observed among younger men, and
the association became NS. Conversely, if UA is causal in the
development of the metabolic syndrome, as was suggested in
rat experiments by Nakagawa et al. (40), then adjustment for
these other metabolic derangements may be inappropriate.
Our study has potential limitations that deserve mention.
First, we relied on self-reported hypertension and did not mea-
sure directly the BP of our participants; however, all partici-
pants are health professionals, and hypertension reporting was
shown previously to be highly accurate in this cohort (19).
Second, controls may have been misclassified if they were
unaware of existing hypertension and thus did not report it, but
because we required control subjects to have had a clinician
examination during the study period, this possibility is re-
J Am Soc Nephrol 18: 287–292, 2007
Quartile of Plasma UA (mg/dl; Median &range')
4.6 5.5 6.3 7.4 P
(2.4 to 5.1) (5.2 to 5.9) (6.0 to 6.7) (6.8 to 11.5) (Trend)
71 89 76 89
1.00 (reference) 1.48 (0.78 to 2.80) 1.35 (0.69 to 2.61) 2.01 (0.98 to 4.14) 0.08
1.00 (reference) 1.30 (0.66 to 2.56) 1.07 (0.53 to 2.15) 1.57 (0.73 to 3.34) 0.31
103 99 110 108
1.00 (reference) 0.68 (0.41 to 1.15) 1.04 (0.60 to 1.81) 0.87 (0.50 to 1.50) 0.94
1.00 (reference) 0.72 (0.42 to 1.23) 1.17 (0.67 to 2.05) 0.98 (0.56 to 1.72) 0.68
duced. Third, we purposefully restricted our sample to men
with BMI values !30 kg/m2. Although this limits the general-
izability of our findings to nonobese men, Nakanishi et al. (11)
found that the association between UA and hypertension was
stronger among leaner men. Finally, we may have had insuffi-
cient power to detect an association in the age-stratified anal-
yses; therefore, a true association among younger but not older
men remains possible.
Conclusion
Plasma UA level was not associated with incident hyperten-
sion in older men; the association that was observed among
men who were younger than 60 yr was confounded in fully
adjusted models. We believe that these findings are important
for several reasons. Our study is the first to examine this
association in older men, who shoulder the larger share of the
hypertension disease burden. This study also is the first to
control simultaneously for renal function and metabolic factors,
including insulin resistance and dyslipidemia, in addition to
other confounders. Our findings should be confirmed by sub-
sequent studies in older individuals; moreover, future investi-
gations of the UA– hypertension relation should control for
metabolic factors that may confound this association.
Acknowledgments
This study was supported by TAP Pharmaceuticals and National
Institutes of Health grants HL35464 and CA550750.
Disclosures
TAP Pharmaceuticals helped fund this research.
References
1. Johnson RJ, Feig DI, Herrera-Acosta J, Kang DH: Resurrec-
tion of uric acid as a causal risk factor in essential hyper-
tension. Hypertension 45: 18 –20, 2005
2. Mazzali M, Hughes J, Kim YG, Jefferson JA, Kang DH,
J Am Soc Nephrol 18: 287–292, 2007
Gordon KL, Lan HY, Kivlighn S, Johnson RJ: Elevated uric
acid increases blood pressure in the rat by a novel crystal-
independent mechanism. Hypertension 38: 1101–1106, 2001
3. Kang DH, Nakagawa T, Feng L, Watanabe S, Han L, Maz-
zali M, Truong L, Harris R, Johnson RJ: A role for uric acid
in the progression of renal disease. J Am Soc Nephrol 13:
2888 –2897, 2002
4. Khosla UM, Zharikov S, Finch JL, Nakagawa T, Roncal C,
Mu W, Krotova K, Block ER, Prabhakar S, Johnson RJ:
Hyperuricemia induces endothelial dysfunction. Kidney Int
67: 1739 –1742, 2005
5. Kahn HA, Medalie JH, Neufeld HN, Riss E, Goldbourt U:
The incidence of hypertension and associated factors: The
Israel ischemic heart disease study. Am Heart J 84: 171–182,
1972
6. Selby JV, Friedman GD, Quesenberry CP Jr: Precursors of
essential hypertension: Pulmonary function, heart rate,
uric acid, serum cholesterol, and other serum chemistries.
Am J Epidemiol 131: 1017–1027, 1990
7. Hunt SC, Stephenson SH, Hopkins PN, Williams RR: Pre-
dictors of an increased risk of future hypertension in Utah.
A screening analysis. Hypertension 17: 969 –976, 1991
8. Jossa F, Farinaro E, Panico S, Krogh V, Celentano E, Ga-
lasso R, Mancini M, Trevisan M: Serum uric acid and
hypertension: The Olivetti heart study. J Hum Hypertens 8:
677– 681, 1994
9. Taniguchi Y, Hayashi T, Tsumura K, Endo G, Fujii S,
Okada K: Serum uric acid and the risk for hypertension
and type 2 diabetes in Japanese men: The Osaka Health
Survey. J Hypertens 19: 1209 –1215, 2001
10. Masuo K, Kawaguchi H, Mikami H, Ogihara T, Tuck ML:
Serum uric acid and plasma norepinephrine concentra-
tions predict subsequent weight gain and blood pressure
elevation. Hypertension 42: 474 – 480, 2003
11. Nakanishi N, Okamoto M, Yoshida H, Matsuo Y, Suzuki K,
Tatara K: Serum uric acid and risk for development of
hypertension and impaired fasting glucose or type II dia-
betes in Japanese male office workers. Eur J Epidemiol 18:
523–530, 2003
12. Sundstrom J, Sullivan L, D’Agostino RB, Levy D, Kannel
WB, Vasan RS: Relations of serum uric acid to longitudinal
blood pressure tracking and hypertension incidence. Hy-
pertension 45: 28 –33, 2005
13. Alper AB Jr, Chen W, Yau L, Srinivasan SR, Berenson GS,
Hamm LL: Childhood uric acid predicts adult blood pres-
sure: The Bogalusa Heart Study. Hypertension 45: 34 –38,
2005
14. Fields LE, Burt VL, Cutler JA, Hughes J, Roccella EJ, Sorlie
P: The burden of adult hypertension in the United States
1999 to 2000: A rising tide. Hypertension 44: 398 – 404, 2004
15. Rimm EB, Giovannucci EL, Stampfer MJ, Colditz GA, Litin
LB, Willett WC: Reproducibility and validity of an ex-
panded self-administered semiquantitative food frequency
questionnaire among male health professionals. Am J Epi-
demiol 135: 1114 –1126; discussion 1127–1136, 1992
16. Moriarity JT, Folsom AR, Iribarren C, Nieto FJ, Rosamond
WD: Serum uric acid and risk of coronary heart disease:
Atherosclerosis Risk in Communities (ARIC) Study. Ann
Epidemiol 10: 136 –143, 2000
17. Hoieggen A, Alderman MH, Kjeldsen SE, Julius S, Devereux
RB, De Faire U, Fyhrquist F, Ibsen H, Kristianson K, Leder-
balle-Pedersen O, Lindholm LH, Nieminen MS, Omvik P,
Uric Acid and Risk for Hypertension 291
Oparil S, Wedel H, Chen C, Dahlof B: The impact of serum
uric acid on cardiovascular outcomes in the LIFE study. Kid-
ney Int 65: 1041–1049, 2004
18. Prentice RL, Kalbfleisch JD, Peterson AV Jr, Flournoy N,
Farewell VT, Breslow NE: The analysis of failure times in
the presence of competing risks. Biometrics 34: 541–554,
1978
19. Ascherio A, Rimm EB, Giovannucci EL, Colditz GA, Ros-
ner B, Willett WC, Sacks F, Stampfer MJ: A prospective
study of nutritional factors and hypertension among US
men. Circulation 86: 1475–1484, 1992
20. Wolf AM, Hunter DJ, Colditz GA, Manson JE, Stampfer
MJ, Corsano KA, Rosner B, Kriska A, Willett WC: Repro-
ducibility and validity of a self-administered physical ac-
tivity questionnaire. Int J Epidemiol 23: 991–999, 1994
21. Rimm EB, Stampfer MJ, Colditz GA, Chute CG, Litin LB,
Willett WC: Validity of self-reported waist and hip circum-
ferences in men and women. Epidemiology 1: 466 – 473, 1990
22. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D:
A more accurate method to estimate glomerular filtration
rate from serum creatinine: A new prediction equation.
Modification of Diet in Renal Disease Study Group. Ann
Intern Med 130: 461– 470, 1999
23. Choi HK, Liu S, Curhan G: Intake of purine-rich foods,
protein, and dairy products and relationship to serum
levels of uric acid: The Third National Health and Nutri-
tion Examination Survey. Arthritis Rheum 52: 283–289, 2005
24. Wortmann RL: Recent advances in the management of
gout and hyperuricemia. Curr Opin Rheumatol 17: 319 –324,
2005
25. Krishnan E, Baker JF, Furst DE, Schumacher HR: Gout and
the risk of acute myocardial infarction. Arthritis Rheum 54:
2688 –2696, 2006
26. Modan M, Halkin H, Karasik A, Lusky A: Elevated serum
uric acid: A facet of hyperinsulinaemia. Diabetologia 30:
713–718, 1987
27. Zavaroni I, Bonora E, Pagliara M, Dall’Aglio E, Luchetti L,
Buonanno G, Bonati PA, Bergonzani M, Gnudi L, Passeri
M, et al.: Risk factors for coronary artery disease in healthy
persons with hyperinsulinemia and normal glucose toler-
ance. N Engl J Med 320: 702–706, 1989
28. Zavaroni I, Mazza S, Fantuzzi M, Dall’Aglio E, Bonora E,
Delsignore R, Passeri M, Reaven GM: Changes in insulin
and lipid metabolism in males with asymptomatic hype-
ruricaemia. J Intern Med 234: 25–30, 1993
29. Iribarren C, Folsom AR, Eckfeldt JH, McGovern PG, Nieto
FJ: Correlates of uric acid and its association with asymp-
tomatic carotid atherosclerosis: The ARIC Study. Athero-
sclerosis Risk in Communities. Ann Epidemiol 6: 331–340,
1996
30. Reaven GM: The kidney: An unwilling accomplice in syn-
drome X. Am J Kidney Dis 30: 928 –931, 1997
31. Zanolin ME, Tosi F, Zoppini G, Castello R, Spiazzi G,
Dorizzi R, Muggeo M, Moghetti P: Clustering of cardio-
vascular risk factors associated with the insulin resistance
syndrome: Assessment by principal component analysis in
young hyperandrogenic women. Diabetes Care 29: 372–378,
2006
32. Russo C, Olivieri O, Girelli D, Guarini P, Corrocher R:
Relationships between serum uric acid and lipids in
healthy subjects. Prev Med 25: 611– 616, 1996
292 Journal of the American Society of Nephrology J Am Soc Nephrol 18: 287–292, 2007

33. Schachter M: Uric acid and hypertension. Curr Pharm Des
11: 4139 – 4143, 2005
34. Kang DH, Park SK, Lee IK, Johnson RJ: Uric acid-induced
C-reactive protein expression: Implication on cell prolifer-
ation and nitric oxide production of human vascular cells.
J Am Soc Nephrol 16: 3553–3562, 2005
35. Perlstein TS, Gumieniak O, Hopkins PN, Murphey LJ,
Brown NJ, Williams GH, Hollenberg NK, Fisher ND: Uric
acid and the state of the intrarenal renin-angiotensin sys-
tem in humans. Kidney Int 66: 1465–1470, 2004
36. Watanabe S, Kang DH, Feng L, Nakagawa T, Kanellis J,
Lan H, Mazzali M, Johnson RJ: Uric acid, hominoid evo-
lution, and the pathogenesis of salt-sensitivity. Hyperten-
sion 40: 355–360, 2002
37. Kaplan NM, Opie LH: Controversies in hypertension. Lan-
cet 367: 168 –176, 2006
38. Baylis C, Schmidt R: The aging glomerulus. Semin Nephrol
16: 265–276, 1996
39. Fuiano G, Sund S, Mazza G, Rosa M, Caglioti A, Gallo G,
Natale G, Andreucci M, Memoli B, De Nicola L, Conte G:
Renal hemodynamic response to maximal vasodilating
stimulus in healthy older subjects. Kidney Int 59: 1052–1058,
2001
40. Nakagawa T, Hu H, Zharikov S, Tuttle KR, Short RA,
Glushakova O, Ouyang X, Feig DI, Block ER, Herrera-
Acosta J, Patel JM, Johnson RJ: A causal role for uric acid in
fructose-induced metabolic syndrome. Am J Physiol Renal
Physiol 290: F625–F631, 2006

Access to UpToDate on-line is available for additional clinical information

at http://www.jasn.org/