NIH Public Access: Author Manuscript

NIH Public Access
Author Manuscript
Arthritis Rheum. Author manuscript; available in PMC 2010 July 15.
Published in final edited form as:
NIH-PA Author Manuscript
Arthritis Rheum. 2009 July 15; 61(7): 885–892. doi:10.1002/art.24612.
Hyperuricemia and Risk of Stroke: A Systematic Review and

Meta-analysis
Seo Young Kim, MD1,2, James P Guevara, MD, MPH2,3, Kyoung Mi Kim, MD4, Hyon K Choi,
MD, DrPH5, Daniel F. Heitjan, PhD2,6, and Daniel A Albert, MD7
1Division of Rheumatology, Department of Medicine, University of Pennsylvania
2Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania

3Division of General Pediatrics, Department of Pediatrics, Children’s Hospital of Philadelphia
4Pusan National University, Pusan, South Korea
5Division
of Rheumatology, Department of Medicine, University of British Columbia, Vancouver,
BC, Canada
6Department of Biostatistics and Epidemiology, University of Pennsylvania

7Division of Rheumatology, Dartmouth Hitchcock Medical Center, Lebanon, NH
Abstract
BACKGROUND—Hyperuricemia is hypothesized to be a risk factor for stroke and other
cardiovascular disease, but to date results from observational studies are conflicting.
METHODS—We conducted a systematic review and meta-analysis to assess the association
between hyperuricemia and risk of stroke incidence and mortality. Studies were identified by
searching major electronic databases using the Medical Subject Headings and keywords without
restriction in languages. Only prospective cohort studies were included if they had data on stroke
incidences or mortalities related to serum uric acid levels in adults. Pooled risk ratios (RRs) for the
association of stroke incidence and mortality with serum uric acid levels were calculated.
RESULTS—A total of 16 studies including 238,449 adults were eligible and abstracted.
Hyperuricemia was associated with a significantly higher risk of both stroke incidence [N=6
studies, RR 1.41, 95% confidence interval (CI): 1.05–1.76] and mortality [N=6 studies, RR 1.36,
95% CI: 1.03–1.69] in our meta-analyses of unadjusted study estimates. Subgroup analyses of
studies adjusting for known risk factors such as age, hypertension, diabetes, and cholesterol still
showed that hyperuricemia was significantly associated with both stroke incidence [N=4 studies,
RR 1.47, 95% CI: 1.19–1.76] and mortality [N=6 studies, RR 1.26, 95% CI: 1.12–1.39]. The
pooled estimate of multivariate RRs did not differ much by gender.
CONCLUSION—Our study suggests that hyperuricemia may modestly increase the risks of both
stroke incidence and mortality. Future research is needed to determine whether lowering uric acid
level has any beneficial effects on stroke.
Corresponding author and Reprint requests: Seo Young Kim, M.D., Division of Rheumatology, University of Pennsylvania, 504
Maloney, 3600 Spruce Street, Philadelphia PA 19104, Tel) 215-662-2350, Fax) 215-615-4312, E-mail: seo.kim@uphs.upenn.edu.
Financial supports or conflicts disclosure
S Kim - NIH T32 (AR07442) Training Program in Rheumatic Disease
HK Choi - Holds the Mary Pack Arthritis Society of Canada Chair in Rheumatology, served on the advisory board for TAP and
Savient Pharmaceuticals
JP Guevara and DA Albert – None
Kim et al. Page 2
Keywords
hyperuricemia; stroke; systematic review; meta-analysis
INTRODUCTION
Uric acid is the end-product of purine metabolism in humans. There is no universally
accepted definition for hyperuricemia, but it is usually defined as serum urate concentration
in excess of 6.8 mg/dL, which is the limit of urate solubility in serum 1, 2. Currently, no
urate-lowering therapy is indicated in asymptomatic hyperuricemia 3. High serum uric acid
level with or without gout is associated with cardiovascular diseases such as hypertension,
coronary heart disease, peripheral vascular disease, and stroke 4–10. However, the role of
high serum uric acid level as an independent risk factor for cardiovascular disease including
stroke has been controversial 11–16. Several patho-physiological mechanisms through
endothelial dysfunction, oxidative metabolism, platelet adhesiveness and aggregation,
related to hyperuricemia in cardiovascular disease have been suggested 17–19. According to
a recent report 20, about 780,000 Americans experience a new or recurrent stroke each year,
on average, one stroke every 40 seconds. Preliminary data from 2005 indicate that stroke
accounted for about 1 of every 17 deaths in the United States 20. If asymptomatic
hyperuricemia has a deleterious effect on serious morbidity and mortality related to stroke,
hyperuricemia may become a new target for more comprehensive risk factor management in
the primary prevention of stroke. Accordingly, we conducted a meta-analysis of prospective
cohort studies to determine the association between hyperuricemia and the risk of stroke.
METHODS
Data Sources
We searched three major electronic databases — MEDLINE (1950-July 2008), EMBASE
(1980-July 2008), and the Cochrane library — for studies of the association between serum
uric acid levels and stroke incidence and/or mortality. We also searched bibliographies of
identified reports and review articles for additional references. Our search strategy is
described in Figure 1.
Study Eligibility
To be eligible for inclusion, we only considered (1) prospective cohort studies of adult
patients, (2) longer than one year of follow-up, (3) with sample size of at least fifty subjects,
and (4) inception cohort free of stroke. We imposed no geographic or language restrictions.
Studies reporting interventional and secondary prevention trials were excluded.
Selection of Studies
Two authors (S. Kim and K. Kim) independently screened each of the potential titles,
abstracts, and/or full-texts to determine inclusion. Areas of disagreement or uncertainty were
resolved by consensus. When multiple articles were published from a single study, we
selected the report that contained the most complete and relevant data on the association
between hyperuricemia and stroke. The electronic search retrieved 566 potentially relevant
studies. Non-electronic search identified 3 additional studies. On initial screening, 504 were
excluded based on title. Of the 65 screened abstracts, 22 studies were retrieved for detailed
evaluation. Of those, two studies were based on the same patient population, so they were
considered as one study in the meta-analysis 21, 22. One study was excluded because it
reported insufficient data on stroke outcome 23. Four studies that reported data on carotid

Kim et al. Page 3
intima-media thickness only were excluded 24–27. Eventually 16 studies were included in
this meta-analysis (Figure 2).
Data Abstraction and Quality Assessment

All data were independently abstracted in duplicate by two authors (S. Kim and K. Kim)
using a data abstraction form. Discrepancies were resolved by consensus. When necessary,
the original authors were contacted for additional information. Data on the study
characteristics such as author name, year of publication, language, sample size, mean age,
uric acid level and number of outcome were collected. The Newcastle–Ottawa Scale was
used to assess the quality of studies 28 (Table 1). A quality score was calculated on the basis
of three major components: selection of the study groups (0–4 points), quality of the
adjustment for confounding (0–2 points) and ascertainment of the outcome of interest in the
cohorts (0–3 points). A higher score represents better methodological quality. Adjustment
for known stroke risk factors, duration of follow-up of at least 5 years, and adequate follow-
up rate were criteria of higher quality.
Statistical Analysis
Some studies included in our meta-analysis used the International system (SI) of units (µmol
per liter) to report levels of serum uric acid. We therefore converted those to the
conventional units (milligram per deciliter), using a conversion rate of 16.81 (1 mg/dL =
59.48 µmol/L) 29. Pooled estimates of risk ratios (RRs) were calculated using the
DerSimonian and Laird random effects model 30, 31 for stroke incidence and mortality.
This statistical technique weighs individual studies by sample size and variance (both
within- and between-study variance) and yields a pooled point estimate and a 95%
confidence interval. The DerSimonian and Laird technique was considered an appropriate
pooling technique because of the relative heterogeneity of the source population in each
study. We also evaluated the presence of heterogeneity across trials by using the I2 statistic,
which quantifies the percentage of variability that can be attributed to between-study
differences 32. To assess the potential for publication bias, we performed the Begg’s test
and the Egger’s test and constructed funnel plots to visualize a possible asymmetry 33. All
the statistical analyses were done in Stata 10 (Stata Corp, College Station, TX). We followed
the Meta-analyses of Observational Studies in Epidemiology (MOOSE) guidelines 34 in the
report of this meta-analysis.
RESULTS
Study Characteristics
Sixteen prospective cohort studies representing data from 238,449 participants were
included in the meta-analysis. The characteristics of the studies and of their participants are
presented in Table 2. Of the 16 trials, 2 were conducted primarily in the United States
although the study by Kagan et al 35 was based on a Hawaiian Japanese cohort. Eight
studies were done in Asian countries and six studies were from European countries. The
number of participants ranged from 153 in a study by Tofuku et al 36 to 83,683 in the
Vorarlberg Health Monitoring and Promotion Program cohort study by Strasak et al 37.
Nine studies 14, 15, 21, 22, 36, 38–42 included both men and women. Four studies used a
lower cut-off value to define hyperuricemia for women compared to men 39, 40, 42, 43. Six
studies 35, 37, 44–47 included only men, and one study 43 only women. Seven studies 35,
37, 39, 41, 43–45 reported gender-specific outcome for ischemic stroke. Six studies 15, 35,
37, 39, 41, 43 provided only adjusted risk estimates.

Kim et al. Page 4
Hyperuricemia and Stroke Incidence

The pooled estimate of unadjusted RRs for stroke based on six studies 14, 36, 38–40, 46 was
1.41 (95% CI: 1.05–1.76) among subjects with hyperuricemia, compared with those with
normouricemia. The heterogeneity test was not significant (I2 =23.8%, p=0.25). The pooled
multivariate RR based on four studies14, 39–41 fully adjusting for known risk factors of
stroke was 1.47 (95% CI: 1.19–1.76). The heterogeneity test for this analysis was not
significant (I2=0.0%, p=0.96).
The pooled estimate of unadjusted RRs among men based on two studies 40, 46 was 1.82,
(95% CI: 0.84–2.80), whereas only one study reported unadjusted RR of 2.55 among women
(95% CI: 0.84–4.27)40. The pooled estimate of multivariate RRs based on three studies39–
41 was 1.42 (95% CI: 1.03–1.80) among women and 1.42 among men (95% CI: 0.94–1.90).
The forest plot of multivariate RRs and 95% CIs for stroke incidence and hyperuricemia are
shown in Figure 3 (top).
Hyperuricemia and Stroke Mortality

The pooled estimate of unadjusted RR based on 6 studies 21, 22, 36, 42, 44, 45, 47 was 1.36
(95% CI: 1.03–1.69) for patients with hyperuricemia, compared with those with
normouricemia. There was no statistically significant heterogeneity among the studies (I2=
0.0%, p=0.62). The pooled multivariate RR based on six studies 15, 37, 42–44 fully
adjusting for known risk factors of stroke was 1.26 (95% CI: 1.12–1.39) with a non-
significant heterogeneity test (I2= 0.0%, p=0.50).
The pooled estimate of unadjusted RRs among men based on 5 studies 21, 42, 44, 45, 47
was 1.34 (95% CI: 1.01–1.67). The pooled unadjusted RR among women based on only two
studies 21, 42 was 4.75, but it was not statistically significant (95% CI: 0.53–8.98).
The pooled multivariate RRs were significantly higher for both men [N=4 studies 37, 42, 44,
45, RR 1.20, 95% CI: 1.05–1.35] and women [N=2 studies 42, 43, RR 1.35, 95% CI: 1.04–
1.66], compared to those with normouricemia. The forest plot of multivariate RRs and 95%
CIs for stroke mortality and hyperuricemia are shown in Figure 3 (bottom).
Publication Bias Assessment

The funnel plots for both stroke incidence and mortality were visually examined (Figure 4).
There was no statistical evidence of publication bias among studies for stroke incidence or
mortality by using Egger’s (p=0.80; 0.25 respectively) and Begg’s (p=0.70; 0.48
respectively) tests.
Sensitivity Analyses
Meta-regression was performed to further investigate the effect of three study-level
characteristics (year of publication, race, and gender) on the risk of stroke. None of the
regression coefficients was statistically significant (Appendix 1). A linear regression model
(Appendix 2) showed that studies that adjusted for more confounding variables had lower
risk estimates than studies that adjusted for fewer or no potentially confounding variables.
For both stroke outcomes, the risk estimates remained above 1 even after adjusting for more
than ten potential risk factors although the confidence intervals crossed 1.
DISCUSSION
Our systematic review and meta-analysis of 16 prospective cohort studies finds that the
elevated serum uric acid level in adults is associated with a modest but statistically
significant increased risk of stroke incidence and mortality.

Kim et al. Page 5
There has been considerable debate whether uric acid is neuro-protective as an antioxidant
or neuro-toxic as a pro-oxidant 12, 48, 49. A pathogenetic role for uric acid in
cardiovascular disease also remains to be elucidated, although recent experimental studies
have shown that hyperuricemia is associated with endothelial dysfunction, local oxidant
generation, elevated circulating levels of systemic inflammatory mediators such as
monocyte chemoattractant protein-1, NF-κB, interleukin-1β, interleukin-6, and tumor
necrosis factor-α, and vascular smooth muscle proliferation 18, 19, 50–53. Hypertension,
one of the most common causes of stroke, is closely related to hyperuricemia 19. Several
experimental animal models showed the development of systemic hypertension in
hyperuricemic rats 54–57. In a recent randomized, placebo-controlled, crossover trial 58
involving 30 hyperuricemic adolescents with newly diagnosed hypertension, allopurinol
treatment was associated with significant reductions in casual and 24-hour ambulatory blood
pressure compared to placebo. More clinical trials with longer follow-up periods are needed
to determine the safety and the generalizability of urate-lowering therapy such as allopurinol
in hypertension.
Interestingly, many previous studies that investigated the role of the uric acid level on either
cardiovascular disease or all-cause mortality observed a J-curve relationship 11, 16, 59–61.
Similar results were noted in some of the studies included in our analysis 14, 15, 35, 42, 44.
It has been postulated that a low uric acid level is associated with a higher mortality because
uric acid may play an antioxidant role 19.
The limitations of this meta-analysis fall into two categories: those attributable to the data
available for analysis and those attributable to the techniques generally used to perform the
meta-analysis. Our analysis is based on observational studies which are subject to
confounding and other biases and cannot prove causality. Randomized clinical trials were,
however, neither generally useful to evaluate etiological hypotheses over a long period of
follow-up 31, nor available in the literature to examine our study questions. We selected
only large prospective studies with inception cohort free of disease, which helped increase
precision of estimates while minimizing heterogeneity. There were different definitions of
hyperuricemia across the studies; therefore, we chose the category nearest to 6.8 mg/dl in
each study for the hyperuricemia group. Although studies differed by geographic location,
age, race, sex distribution and size, meta-regression analysis did not reveal any significant
association with these factors. Nonetheless, we cannot rule out other potential sources for
heterogeneity such as clinical features.
All meta-analyses are inherently vulnerable to publication bias. We attempted to minimize

this bias by searching three major electronic databases with no language restriction. Three
different statistical tests to examine the issue of publication bias were performed revealing
no statistical evidence for significant publication bias. Lastly, because we did not have
access to the raw data on adjustments in each study, we utilized the best adjusted RRs per
individual study. The use of medications such as diuretics was adjusted for in only a few
studies 14, 39, 41, 42. For the stroke outcome data, there is a possibility of misclassification
bias because most of the papers we included used death certificates or diagnostic codes to
define their outcomes.
Our study has several important strengths. This meta-analysis is based on large prospective
cohort studies over a long follow-up period in many different countries. To our knowledge,
this is the first systematic review and meta-analysis on hyperuricemia and the risk of stroke.
We assessed the quality of individual studies using the Newcastle–Ottawa Scale 28. The
majority of the included studies had adequate sizes, follow-up lengths, and adjustments for
other risk factors. We furthermore performed subgroup analyses of the studies with full

Kim et al. Page 6
adjustments for known stroke risk factors as the degree of adjustments for potential
confounders was still different in each study.
In conclusion, our meta-analysis of published prospective studies suggests that high serum
uric acid levels may modestly increase the risk of stroke incidence and mortality. Future
research should focus on confirming the pathogenetic mechanisms of hyperuricemia as well
as examining the role of urate-lowering therapy in stroke.
Acknowledgments
Seo Young Kim is funded, in part, by a National Institutes of Health T32 training grant for training program in
rheumatic disease.
Appendix 1
Effect of study variables by meta-regression
Stroke Incidence Stroke Mortality
Coefficient 95 % CI Coefficient 95 % CI
Gender −0.09 −0.33-0.14 0.21 −0.11-0.53
−0.02-0.03 −0.06 −0.12-0.01

Year 0.003
Race 0.25 −0.14-0.65 0.27 −0.14-0.69
CI; confidence interval
Appendix 2
Linear regression plot for the relative risks (RR) of stroke against the number of adjusted
risk factors in each study
CI: confidence interval
REFERENCES
1. Wilcox W, Khalaf A, Weinberger A, et al. Solubility of uric acid and monosodium urate. Med Biol
Eng. 1972; 10:522–531. [PubMed: 5074854]
2. Becker M, Schumacher HJ, Wortmann R, et al. Febuxostat compared with allopurinol in patients
with hyperuricemia and gout. N Engl J Med. 2005 December.353:2450–2461. [PubMed: 16339094]

Kim et al. Page 7
3. Wortmann R. Gout and hyperuricemia. Curr Opin Rheumatol. 2002; 14:281–286. [PubMed:
11981327]
4. Baker J, Krishnan E, Chen L, et al. Serum uric acid and cardiovascular disease: recent
developments, where do they leave us? Am J Med. 2005; 118:816–826. [PubMed: 16084170]
5. Becker M, Jolly M. Hyperuricemia and associated diseases. Rheum Dis Clin N Am. 2006; 32:275–
293.
6. Wannamethee S. Serum uric acid and risk of coronary heart disease. Curr Pharm Des. 2005;
11:4125–4132. [PubMed: 16375733]
7. Tseng C. Independent association of uric acid levels with peripheral arterial disease in Taiwanese
patients with Type 2 diabetes. Diabet Med. 2004; 21:724–729. [PubMed: 15209765]
8. Baker J, Schumacher H, Krishnan E. Serum uric acid level and risk for peripheral arterial disease:
analysis of data from the multiple risk factor intervention trial. Angiology. 2007; 58(4):450–457.
[PubMed: 17875958]
9. Kim S, De Vera M, Choi H. Gout and mortality. Clin Exp Rheumatol. 2008; 26 Suppl. 51(5):S115–
S119. [PubMed: 19026153]
10. Feig D, Kang D-H, Johnson R. Uric Acid and Cardiovascular Risk. NEJM. 2008 October; 359(17):
1811–1821. [PubMed: 18946066]
11. Culleton B, Larson M, Kannel W, et al. Serum uric acid and risk of cardiovascular disease and
mortality: the Framingham Heart Study. Ann Intern Med. 1999; 31:7–13. [PubMed: 10391820]
12. Kanellis J, Johnson R. Elevated uric acid and ischemic stroke: accumulating evidence that it is
injurious and not neuroprotective. Stroke. 2003; 34:1956–1958. [PubMed: 12843345]
13. Weir C, Muir S, Walters M, et al. Serum urate as an independent predictor of poor outcome and
future vascular events after acute stroke. Stroke. 2003; 34:1951–1957. [PubMed: 12843346]
14. Lehto S, Niskanen L, Ronnemaa T, et al. Serum uric acid is a strong predictor of stroke in patients
with non- insulin-dependent diabetes mellitus. Stroke. 1998 Mar; 29(3):635–639. [PubMed:
9506605]
15. Mazza A, Pessina A, Pavei A, et al. Predictors of stroke mortality in elderly people from the
general population: The CArdiovascular STudy in the ELderly. European J Epidemiol. 2002;
17(12):1097–1104. [PubMed: 12530768]
16. Fang J, Alderman M. Serum uric acid and cardiovascular mortality: the NHANES I epidemiologic
follow-up study, 1971–1992. JAMA. 2000; 283:2404–2410. [PubMed: 10815083]
17. Butler R, Morris A, Belch J, et al. Allopurinol normalizes endothelial dysfunction in type 2
diabetics with mild hypertension. Hypertension. 2000; 35:746–751. [PubMed: 10720589]
18. Kang D, Nakagawa T, Feng L, et al. A role for uric acid in the progression of renal disease. J Am
Soc Nephrol. 2002; 13(12):2888–2897. [PubMed: 12444207]
19. Johnson R, Kang D, Feig D, et al. Is there a pathogenetic role for uric acid in hypertension and
cardiovascular and renal disease? Hypertension. 2003; 41(6):1183–1189. [PubMed: 12707287]
20. Rosamond W, Flegal K, Furie K, et al. Heart Disease and Stroke Statistics—2008 Update.
Circulation. 2008 January; 117(4):e25–e27. [PubMed: 18086926]
21. Bae J, Hyun D, Kwon T, et al. Serum uric acid is associated with cardiovascular events in patients
with coronary artery disease. Korean Circ J. 2007 Apr; 37(4):161–166.
22. Hyun D, Kim K, Yoon H, et al. Gender differences in the role of serum uric acid for predicting
cardiovascular events in patients with coronary artery disease. Korean Circ J. 2007 May; 37(5):
196–201.
23. Longo-Mbenza B, Luila E, Mbete P. Is hyperuricemia a risk factor of stroke and coronary heart
disease among Africans? Int J Cardiol. 1999 Sep 30; 71(1):17–22. [PubMed: 10522560]
24. Joensuu T, Salonen R, Winblad I, et al. Determinants of femoral and carotid artery atherosclerosis.
J Intern Med. 1994; 236(1):79–84. [PubMed: 8021577]
25. Viazzi F, Parodi D, Leoncini G, et al. Serum uric acid and target organ damage in primary
hypertension. Hypertension. 2005 May; 45(5):991–996. [PubMed: 15781669]
26. Iribarren C, Folsom A, Eckfeldt J, et al. Correlates of uric acid and its association with
asymptomatic carotid atherosclerosis: the ARIC Study. Atherosclerosis Risk in Communities. Ann
Epidemiol. 1996 Jul; 6(4):331–340. [PubMed: 8876844]

Kim et al. Page 8
27. Kawamoto R, Tomita H, Oka Y, et al. Association between uric acid and carotid atherosclerosis in
elderly persons. Intern Med. 2005 Aug; 44(8):787–793. [PubMed: 16157974]
28. Wells, G.; Shea, A.; O'Connell, D., et al. The Newcastle-Ottawa Scale (NOS) for Assessing the
Quality of Nonrandomised Studies in Meta-Analyses. 2008.

http://www.ohri.ca/programs/clinical_epidemiology/oxford.htm
29. Young, D.; Huth, E. SI Units for Clinical Measurement. Philadelphia, Pa: American College of
Physicians. 1st ed.. Philadelphia: American College of Physicians; 1998.
30. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986; 7(3):177–188.
[PubMed: 3802833]
31. Egger, M.; Smith, G.; Altman, D. Systematic reviews in health care. Second ed.. London: BMJ
Publishing Group; 2001.
32. Higgins J, Thompson S. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002; 21:1539–
1558. [PubMed: 12111919]
33. Sterne J, Egger M. Funnel plots for detecting bias in meta-analysis: Guidelines on choice of axis. J
Clin Epidemiol. 2001; 54:1046–1055. [PubMed: 11576817]
34. Stroup DF, Berlin JA, Morton SC, et al. Meta-analysis of Observational Studies in Epidemiology:
A Proposal for Reporting. JAMA. 2000; 283(15):2008–2012. [PubMed: 10789670]
35. Kagan A, Popper JS, Rhoads GG, et al. Dietary and other risk factors for stroke in Hawaiian
Japanese men. Stroke. 1985 May–Jun; 16(3):390–396. [PubMed: 4002255]
36. Tofuku Y, Kuroda M, Takeda R. Hyperuricemia associated with hypertension. A 4-year follow-up
study of hyperuricemic hypertensives. Jpn Circ J. 1978 Jul; 42(7):871–879. [PubMed: 713025]
37. Strasak A, Ruttmann E, Brant L, et al. Serum uric acid and risk of cardiovascular mortality: A
prospective long-term study of 83 683 Austrian men. Clin Chem. 2008 Feb; 54(2):273–284.
[PubMed: 18039719]
38. Baba T, Amasaki Y, Soda M, et al. Fatty liver and uric acid levels predict incident coronary heart
disease but not stroke among atomic bomb survivors in Nagasaki. Hypertens Res. 2007 Sep; 30(9):
823–829. [PubMed: 18037775]
39. Bos MJ, Koudstaal PJ, Hofman A, et al. Uric acid is a risk factor for myocardial infarction and
stroke: The Rotterdam Study. Stroke. 2006 Jun; 37(6):1503–1507. [PubMed: 16675740]
40. Chien KL, Hsu HC, Sung FC, et al. Hyperuricemia as a risk factor on cardiovascular events in
Taiwan: The Chin-Shan Community Cardiovascular Cohort Study. Atherosclerosis. 2005 Nov;
183(1):147–155. [PubMed: 16154134]
41. Hozawa A, Folsom AR, Ibrahim H, et al. Serum uric acid and risk of ischemic stroke: the ARIC
Study. Atherosclerosis. 2006 Aug; 187(2):401–407. [PubMed: 16239005]
42. Sakata K, Hashimoto T, Ueshima H, et al. Absence of an association between serum uric acid and
mortality from cardiovascular disease: NIPPON DATA 80, 1980–1994. Eur J Epidemiol. 2001;
17(5):461–468. [PubMed: 11855580]
43. Strasak A, Kelleher C, Brant L, et al. Serum uric acid is an independent predictor for all major
forms of cardiovascular death in 28,613 elderly women: A prospective 21-year follow-up study.
Int J Cardiol. 2008 Apr; 125(2):232–239. [PubMed: 18237790]

44. Gerber Y, Tanne D, Medalie J, et al. Serum uric acid and long-term mortality from stroke,
coronary heart disease and all causes. Eur J Cardiovasc Prev Rehabil. 2006 Apr; 13(2):193–198.
[PubMed: 16575272]
45. Jee SH, Lee SY, Kim MT. Serum uric acid and risk of death from cancer, cardiovascular disease or
all causes in men. Eur J Cardiovasc Prev Rehabil. 2004 Jun; 11(3):185–191. [PubMed: 15179098]
46. Takagi M. Serum uric acid as a risk factor for stroke in a fishing village of rural southern Japan.
Jpn Circ J. 1982 Feb; 46(2):131–136. [PubMed: 7057612]
47. Tomita M, Mizuno S, Yamanaka H, et al. Does hyperuricemia affect mortality? A prospective
cohort study of Japanese male workers. J Epidemiol. 2000; 10(6):403–409. [PubMed: 11210110]
48. Cutler R. Urate and ascorbate: their possible roles as antioxidants in determining longevity of
mammalian species. Arch Gerontol Geriatr. 1984; 3:321–348. [PubMed: 6532339]
49. Proctor P. Uric acid: neuroprotective or neurotoxic? Stroke. 2008; 39:e88. [PubMed: 18369163]

Kim et al. Page 9
50. Kanellis J, Feig D, Johnson R. Does asymptomatic hyperuricaemia contribute to the development
of renal and cardiovascular disease? An old controversy renewed. Nephrology (Carlton). 2004;
9(6):394–399. [PubMed: 15663643]
51. Kanellis J, Watanabe S, Li J, et al. Uric acid stimulates monocyte chemoattractant protein-1
production in vascular smooth muscle cells via mitogen-activated protein kinase and
cyclooxygenase-2. Hypertension. 2003; 41(6):1287–1293. [PubMed: 12743010]
52. Kang D, Han L, Ouyang X, et al. Uric acid causes vascular smooth muscle cell proliferation by
entering cells via a functional urate transporter. Am J Nephrol. 2005; 25(5):425–433. [PubMed:
16113518]
53. Rao G, Corson M, Berk B. Uric acid stimulates vascular smooth muscle cell proliferation by
increasing platelet-derived growth factor A-chain expression. J Bio Chem. 1991; 266(13):8604–
8608. [PubMed: 2022672]
54. Mazzali M, Kanellis J, Han L, et al. Hyperuricemia induces a primary arteriolopathy in rats by a
blood pressure-independent mechanism. Am J Physiol Renal Physiol. 2002; 282:F991–F997.
[PubMed: 11997315]
55. Watanabe S, Kang D, Feng L, et al. Uric acid, hominoid evolution, and the pathogenesis salt-
sensitivity. Hypertension. 2002; 40:355–356. [PubMed: 12215479]
56. Mazzali M, Hughes J, Kim Y, et al. Elevated uric acid increases blood pressure in the rat by a
novel crystal-independent mechanism. Hypertension. 2001; 38:1101–1106. [PubMed: 11711505]
57. Sanchez-Lozada L, Tapia E, Avila-Casado C, et al. Mild hyperuricemia induces glomerular
hypertension in normal rats. Am J Physiol Renal Physiol. 2002; 283:F1105–F1110. [PubMed:
12372787]
58. Feig D, Soletsky B, Johnson R. Effect of Allopurinol on Blood Pressure of Adolescents With
Newly Diagnosed Essential Hypertension. JAMA. 2008; 300(8):924–932. [PubMed: 18728266]
59. Hsu S-P, Pai M-F, Peng Y-S, et al. Serum uric acid levels show a ‘J-shaped’ association with all-
cause mortality in haemodialysis patients. Nephrol Dial Transplant. 2004; 19(2):457–462.
[PubMed: 14736974]
60. Mazza A, Zamboni S, Rizzato E, et al. Serum uric acid shows a J-shaped trend with coronary
mortality in non-insulin-dependent diabetic elderly people. The CArdiovascular STudy in the
ELderly (CASTEL). Acta Diabetol. 2007; 44(3):99–105. [PubMed: 17721747]
61. Suliman M, Johnson R, García-López E, et al. J-shaped mortality relationship for uric acid in
CKD. Am J Kidney Dis. 2006; 48(5):761–771. [PubMed: 17059995]

Kim et al. Page 10
Figure 1.
Search strategy

Kim et al. Page 11
Figure 2.
Selection of studies included in the analysis.

Kim et al. Page 12
Figure 3.
Random effects analysis of fully adjusted studies for the association between hyperuricemia
and stroke
Points (dot) and overall (diamond) estimates are given as risk ratios (RR) with 95% CI. The
size of each box represents the weight of the corresponding study in our meta-analysis;
Combined: studies which did not have gender specific data, ES: effect size, CI: confidence
interval.

Kim et al. Page 13
Figure 4.
Begg’s funnel plot for publication bias in studies for stroke incidence and mortality
RR; risk ratio, s.e.; standard error

Kim et al. Page 14
Table 1
Quality assessment of included studies based on Newcastle-Ottawa Scale
Author Selection Comparability Outcome
Tofuku 36 3 0 2
Takagi 46 4 0 3
Kagan 35 4 1 3
Lehto 14 3 2 3
Chien 40 4 2 3
Bos 39 4 2 3
Hozawa 41 4 2 3
Baba 38 3 0 3
Tomita 47 4 1 3
Sakata 42 4 2 3
Mazza 15 4 2 3
Jee 45 4 2 3
Gerber 44 4 2 3
Bae/Hyun 21, 22 3 0 2
Strasak 37 4 2 3
Strasak 43 4 2 3

NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
Table 2
Characteristics of included cohort studies.
Author, year of Participants (% male) Age Follow-up (yr) Hyperuric No. of total Outcome definition Variables controlled
Kim et al.
publication, country range emia outcomes

or definition
mean (mg/dl)
(yr)
STROKE INIDENCE
Tofuku*36 1978 Japan 153 hypertensive patients (75) 16–77 3.7 ≥ 7 (C) 4 Any stroke --
Takagi 46 1982 Japan 314 men in the fishing village 50–79 8 ≥ 7.5 (C) 30 Any stroke --
(100)
Kagan 35 1985 USA 7,895 Japanese Hawaiian men 45–68 10 ≥ 7.2 (M) 163 (79 All stroke, ischemic, and Age
(100) ischemic, 65 hemorrhagic stroke based on
hemorrhagic and hospital records
19 unknown)
Lehto 14 1998 Finland 1,017 subjects with NIDDM 45–64 7.2 ≥ 5 (C) 114 Any stroke except Age, gender, smoking,
(54) subarachnoid hemorrhage cholesterol, HTN, BMI, total
based on ICD-9 codes and triglycerides, HDL, glucose,
hospital records use of diuretics, duration of
DM, and historical stroke †
Chien 40 2005 Taiwan 3,602 subjects in the Chin- 35+ 11 ≥ 7.7 (M) 155 Any type of stroke based on Age, SBP, BMI, LDL, HDL,
Shan Community (47) ≥ 6.6 (W) clinical manifestation, hospital smoking, alcohol intake, LVH,
records, and death certificates and AF
Bos 39 2006 Netherlands 4,385 subjects in the 63–76 8.4 ≥ 6.4 (M) 381 (205 All stroke, ischemic and Age, sex, SBP, cholesterol,
Rotterdam study (35) ≥ 5.4 (W) ischemic, 46 hemorrhagic stroke based on HDL, DM, smoking, use of
hemorrhagic, hospital records and CT/MRI diuretics, and waist/hip ratio
and 130
unknown)
Hozawa 412006 USA 13,413 subjects in the ARIC 45–64 12.6 ≥ 6.9 (M) 381 Ischemic stroke based on Age, sex, race, education, SBP,
study (46) ≥ 6.9 (W) ICD-9 codes and CT/MRI DM, anti-HTN meds, smoking,

alcohol intake, serum albumin,
vWF, and HDL
Baba 38 2007 Japan 2,024 atomic bomb survivors 63 8 ≥ 7 (C) 84 (63 ischemic Any type of stroke based on --
(39) and 21 clinical presentation and CT/
hemorrhagic) MRI
STROKE MORTALITY
Tomita 47 2000 Japan 49,413 male railroad workers 25–60 5.4 ≥ 8.5 (M) 127 Any type of stroke based on Age
(100) ICD-9 codes
Sakata 42 2001 Japan 8,172 subjects in the National 50 13.3 ≥ 6.5 (M) 174 Any type of stroke based on Age, BMI, SBP, anti- HTN
Cardiovascular study (44) ≥ 5.0 (W) ICD-9 codes meds, cholesterol, serum
creatinine, glucose, smoking,
alcohol intake, LVH
Page 15
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
Author, year of Participants (% male) Age Follow-up (yr) Hyperuric No. of total Outcome definition Variables controlled
publication, country range emia outcomes
or definition
mean (mg/dl)
(yr)
Kim et al.
Mazza 15 2002 Italy 3,282 elderly subjects (39) 65+ 14 ≥ 6.4 (C) 170 Any type of stroke based on Age, historical stroke †, CAD,
ICD-9 codes HTN, SBP, pulse pressure, AF,
LVH, smoking, serum
potassium and sodium
Jee 45 2004 Korea 22,698 subjects in the KMIC 30–77 6.5 ≥ 7.01(M) 192 Any type of stroke based on Age, DM, HTN, cholesterol,
(100) hospital records and ICD-9 and smoking
codes
Gerber 44 2006 Israel 9,125 middle-aged male 49 23 ≥ 5.6 (M) 292 Any type of stroke based on Age, BMI, SBP, DM,
workers (100) ICD-9 codes cholesterol, smoking, and LVH
Bae/Hyun 21, 22 2007 660 subjects with coronary 59 2.3 ≥ 6.1 (M) 12 Any type of stroke based on -
Korea artery disease (57) ≥ 5.1 (W) hospital records
Strasak 37 2008 Austria 83,683 men in the risk factor 41.6 12.4 ≥ 6.7 (M) 645 (147 All stroke, ischemic, and Age, BMI, SBP, DBP,
surveillance program (100) ischemic, 147 hemorrhagic stroke based on cholesterol, triglycerides, GGT,
hemorrhagic, ICD-9 codes and autopsy glucose, smoking, and year of
and 351 examination
unknown)
Strasak 43 2008 Austria 28,613 women in the risk 62.3 13.6 ≥ 5.4 (W) 776 (211 All stroke, ischemic, and Age, BMI, SBP, DBP,
factor surveillance program (0) ischemic, 114 hemorrhagic stroke based on cholesterol, triglycerides, GGT,
hemorrhagic, ICD-9 codes and autopsy glucose, smoking, occupation,
and 451 and year of examination
unknown)
*
Included for both stroke mortality and incidence; C: combined; M: men; W: women; -- : unadjusted; SBP: systolic blood pressure; DBP: diastolic blood pressure; DM: diabetes mellitus; HTN:
hypertension; vWF, von Willebrand factor; HDL: high density lipoprotein; LDL: low density lipoprotein;
†
previous stroke in less than 10 % of the study population; CAD: coronary artery disease; AF: atrial fibrillation; LVH: left ventricular hypertrophy; BMI: body mass index; NIDDDM: non-insulin dependent
diabetes mellitus; ARIC: Atherosclerosis Risk in Communities study; KMIC: Korea Medical Insurance Corporation

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Arthritis Rheum. 2009 July 15; 61(7): 885–892. doi:10.1002/art.24612.

Hyperuricemia and Risk of Stroke: A Systematic Review and

2Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania

6Department of Biostatistics and Epidemiology, University of Pennsylvania

Studies reporting interventional and secondary prevention trials were excluded.

Arthritis Rheum. Author manuscript; available in PMC 2010 July 15.

Data Abstraction and Quality Assessment

Arthritis Rheum. Author manuscript; available in PMC 2010 July 15.

Hyperuricemia and Stroke Incidence

Hyperuricemia and Stroke Mortality

Publication Bias Assessment

Arthritis Rheum. Author manuscript; available in PMC 2010 July 15.

All meta-analyses are inherently vulnerable to publication bias. We attempted to minimize

Arthritis Rheum. Author manuscript; available in PMC 2010 July 15.

Effect of study variables by meta-regression

Stroke Incidence Stroke Mortality

Gender −0.09 −0.33-0.14 0.21 −0.11-0.53

−0.02-0.03 −0.06 −0.12-0.01

Race 0.25 −0.14-0.65 0.27 −0.14-0.69

CI; confidence interval

CI: confidence interval

Arthritis Rheum. Author manuscript; available in PMC 2010 July 15.

Arthritis Rheum. Author manuscript; available in PMC 2010 July 15.

Quality of Nonrandomised Studies in Meta-Analyses. 2008.

Int J Cardiol. 2008 Apr; 125(2):232–239. [PubMed: 18237790]

Arthritis Rheum. Author manuscript; available in PMC 2010 July 15.

Arthritis Rheum. Author manuscript; available in PMC 2010 July 15.

Arthritis Rheum. Author manuscript; available in PMC 2010 July 15.

Arthritis Rheum. Author manuscript; available in PMC 2010 July 15.

Arthritis Rheum. Author manuscript; available in PMC 2010 July 15.

Arthritis Rheum. Author manuscript; available in PMC 2010 July 15.

Author Selection Comparability Outcome

Arthritis Rheum. Author manuscript; available in PMC 2010 July 15.

publication, country range emia outcomes

Arthritis Rheum. Author manuscript; available in PMC 2010 July 15.

Arthritis Rheum. Author manuscript; available in PMC 2010 July 15.

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