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1.  Serum Uric Acid Level and Endothelial Dysfunction in Patients with Nondiabetic Chronic Kidney Disease 
American Journal of Nephrology  2011;33(4):298-304.
Background
An elevated serum uric acid level is strongly associated with endothelial dysfunction and inflammation, both of which are common in chronic kidney disease (CKD). We hypothesized that endothelial dysfunction in subjects with CKD would correlate with uric acid levels.
Materials and Methods
We evaluated the association between serum uric acid level and ultrasonographic flow-mediated dilatation (FMD) in 263 of 486 patients with recently diagnosed CKD (stage 3–5) (48% male, age 52 ± 12 years). To minimize confounding, 233 patients were excluded because they were diabetic, had established cardiovascular complications or were taking drugs (renin-angiotensin system blockers, statins) interfering with vascular function.
Results
Serum uric acid level was significantly increased in all stages of CKD and strongly correlated with estimated glomerular filtration rate (eGFR-MDRD); FMD was inversely associated with serum uric acid (r = −0.49, p < 0.001). The association of serum uric acid with FMD remained after adjustment for age, gender, smoking, LDL cholesterol, eGFR, high-sensitivity C-reactive protein, systolic blood pressure, proteinuria, and homeostatic model assessment index (β = −0.27, p < 0.001).
Conclusion
Increased serum uric acid is an independent predictor of endothelial dysfunction in subjects with CKD.
doi:10.1159/000324847
PMCID: PMC3064939  PMID: 21389694
Chronic kidney disease; Uric acid; Endothelial dysfunction
2.  Serum Uric Acid and Chronic Kidney Disease: The Role of Hypertension 
PLoS ONE  2013;8(11):e76827.
Background
There are inconsistent findings on the role of hyperuricemia as an independent risk factor for chronic kidney disease (CKD). Hypertension has been implicated as a factor influencing the association between serum uric acid and CKD. In this population-based study we investigated the association between serum uric acid and decline in renal function and tested whether hypertension moderates this association.
Methods
We included 2601 subjects aged 55 years and over from the Rotterdam Study. Serum uric acid and estimated glomerular filtration rate (eGFR) were assessed at baseline. After average 6.5 years of follow-up, second eGFR was assessed. CKD was defined as eGFR<60 ml/min/1.73 m2. All associations were corrected for socio-demographic and cardiovascular factors.
Results
Each unit (mg/dL) increase in serum uric acid was associated with 0.19 ml/min per 1.73 m2 faster annual decline in eGFR. While the association between serum uric acid and incidence of CKD was not significant in our study population (Hazard Ratio: 1.12, 95% confidence interval [CI]: 0.98–1.28), incorporating our results in a meta-analysis with eleven published studies revealed a significant association (Relative Risk: 1.18, 95%CI: 1.15–1.22). In the stratified analyses, we observed that the associations of serum uric acid with eGFR decline and incident CKD were stronger in hypertensive subjects (P for interaction = 0.046 and 0.024, respectively).
Conclusions
Our findings suggest that hyperuricemia is independently associated with a decline in renal function. Stronger association in hypertensive individuals may indicate that hypertension mediates the association between serum uric acid and CKD.
doi:10.1371/journal.pone.0076827
PMCID: PMC3827035  PMID: 24265674
3.  Uric Acid and Pentraxin-3 Levels Are Independently Associated with Coronary Artery Disease Risk in Patients with Stage 2 and 3 Kidney Disease 
American Journal of Nephrology  2011;33(4):325-331.
Background and Objectives
Cardiovascular disease is prevalent in chronic kidney disease (CKD). Uric acid is increased in subjects with CKD and has been linked with cardiovascular mortality in this population. However, no study has evaluated the relationship of uric acid with angiographically proven coronary artery disease (CAD) in this population. We therefore investigated the link between serum uric acid (SUA) levels and (i) extent of CAD assessed by the Gensini score and (ii) inflammatory parameters, including C-reactive protein (CRP) and pentraxin-3, in patients with mild-to-moderate CKD.
Material and Methods
In an unselected population of 130 patients with estimated glomerular filtration rate (eGFR) between 90 and 30 ml/min/1.73 m2, we measured SUA, serum pentraxin-3, CRP, urinary protein-to-creatinine ratio, lipid parameters and the severity of CAD as assessed by coronary angiography and quantified by the Gensini lesion severity score.
Results
The mean serum values for SUA, pentraxin-3 and CRP in the entire study population were 5.5 ± 1.5 mg/dl, 6.4 ± 3.4 ng/ml and 3.5 ± 2.6 mg/dl, respectively. The Gensini scores significantly correlated in univariate analysis with gender (R = −0.379, p = 0.02), uric acid (R = 0.42, p = 0.001), pentraxin-3 (R = 0.54, p = 0.001), CRP (R = 0.29, p = 0.006) levels, eGFR (R = −0.33, p = 0.02), proteinuria (R = 0.21, p = 0.01), and presence of hypertension (R = 0.37, p = 0.001), but not with smoking status, diabetes mellitus, and lipid parameters. After adjustments for traditional cardiovascular risk factors, only uric acid (R = 0.21, p = 0.02) and pentraxin-3 (R = 0.28, p = 0.01) remained significant predictors of the Gensini score.
Conclusions
SUA and pentraxin-3 levels are independent determinants of severity of CAD in patients with mild-to-moderate CKD. We recommend a clinical trial to determine whether lowering uric acid could prevent progression of CAD in patients with CKD.
doi:10.1159/000324916
PMCID: PMC3064941  PMID: 21389698
Chronic kidney disease; Coronary artery disease; Uric acid; Pentraxin-3
4.  Uric Acid, Hypertension, and CKD among Alaska Eskimos—the Genetics of Coronary Artery Disease in Alaska Natives (GOCADAN) Study 
It is unknown what role uric acid may play in the increasing cardiovascular disease (CVD) among Alaska Eskimos. Uric acid is associated with both hypertension (HTN) and chronic kidney disease (CKD). We analyzed 1078 Genetics of Coronary Artery Disease in Alaska Natives (GOCADAN) participants. Estimated glomerular filtration rate (eGFR) was calculated from serum creatinine measures using the MDRD equation. CKD was defined by an eGFR of <60ml/min/1.73m2. We adjusted for age, sex, education, diabetes, hypertension (or eGFR), obesity, lipids, and smoking status; 7% (n=75) had prevalent CKD. eGFR decreased with increasing tertiles of serum uric acid. (p<0.001) Uric acid was independently associated with prevalent CKD (Adjusted Odds Ratio [OR] and 95% confidence interval [CI] of 2.04 (1.62–2.56), respectively). 21% (n=230) had prevalent HTN; Uric acid was independently associated with prevalent HTN (Adjusted OR 1.2, 95% CI 1.1–1.5). Uric acid is independently associated with prevalent CKD and HTN in this population.
doi:10.1111/j.1751-7176.2011.00574.x
PMCID: PMC3507473  PMID: 22277138
Alaska Eskimos; chronic kidney disease; epidemiology; hypertension; uric acid
5.  Associations of serum uric acid with cardiovascular events and mortality in moderate chronic kidney disease 
Nephrology Dialysis Transplantation  2008;24(4):1260-1266.
Background. It is unclear whether the presence of kidney disease modifies the associations of uric acid with cardiovascular events and death.
Methods. In the limited access, public use Atherosclerosis Risk In Communities (ARIC) database, associations of serum uric acid levels with cardiovascular events and death were analysed using a parametric proportional hazards model and the modification of these associations by the presence of CKD was assessed using a likelihood ratio test.
Results. Of the 15 366 ARIC participants included in this analysis, 461 had CKD (eGFR <60 ml/min/1.73 m2). In both non-CKD and CKD sub-groups, participants with hyperuricaemia (≥ 7 mg/dl in men and ≥ 6 mg/dl in women) compared to those with normal serum uric acid levels had higher waist circumference and fasting serum insulin levels. In the entire cohort, in a multivariate parametric proportional hazards model, each mg/dl increase in serum uric acid was associated with an increased hazard of cardiovascular events (HR 1.09, 95% CI 1.05–1.12) and death. A multiplicative interaction term of serum uric acid and CKD when added to the above models was significant (P < 0.001). The likelihood ratio test of the models with and without the interaction term was also significant (P < 0.001). In the non-CKD population, a multivariate analysis after adjusting for comorbidities and metabolic syndrome showed a significant association between hyperuricaemia and mortality (HR 1.18, 95% CI 1.04–1.33) but not for cardiovascular events (HR 1.07, 95% CI 0.96–1.19). In the CKD population, the association was not significant for both mortality and cardiovascular events.
Conclusion. We conclude that hyperuricaemia is associated with insulin resistance and mortality in the non-CKD population. The presence of CKD attenuates the associations of uric acid with mortality. Interventional studies are warranted to establish the biological role of hyperuricaemia in mortality in non-CKD and CKD populations.
doi:10.1093/ndt/gfn621
PMCID: PMC2721426  PMID: 19033255
cardiovascular events; chronic kidney disease; insulin resistance; mortality; uric acid
6.  Uric acid - a novel mediator and marker of risk in chronic kidney disease? 
Purpose of Review
To assess the current data suggesting that uric acid lowering therapy may be useful in the prevention or mitigation of chronic kidney disease (CKD).
Recent Findings
Eleven observational studies assessing the potential role of serum uric acid in the prevalence and progression of CKD have been published in the last 2 years. Seven suggest an association, 4 do not. Recent experimental models and clinical trials have mechanistically linked serum uric acid and hypertension, an established risk factor for CKD.
Summary
Elevated serum uric acid is a marker for decreased renal function, may have a mechanistic role in the incidence and progression of renal functional decline and likely has a causal role in hypertension and vascular disease. Clinical trials are needed to determine if uric acid lowering therapy will be effective in preventing CKD.
doi:10.1097/MNH.0b013e328330d9d0
PMCID: PMC2885828  PMID: 19654543
Uric acid; CKD; Hypertension; diuretics; metabolic syndrome; cardiovascular disease
7.  Effects of uric acid on endothelial dysfunction in early chronic kidney disease and its mechanisms 
Background
An increase in serum uric acid (UA) occurs during the early and middle stages of chronic kidney disease (CKD) and aggravates the deterioration of kidney function. This study aims to explore the relation between UA and endothelial dysfunction in early CKD and its mechanisms in a murine model.
Methods
The experimental animals were randomly divided into three groups (n = 10): sham-operation group (control group), right nephrectomy only group (CKD group) and right nephrectomy with oxonic potassium group (CKD with hyperuricemia group). Furthermore, we analyzed the relation between UA and endothelial dysfunction indices in early CKD as well as its mechanisms.
Results
Linear regression analysis showed that the level of serum UA had a significant positive correlation with serum endothelin-1 and the percentage of collagen I positive area, but a negative correlation with serum nitric oxide (NO) and NO/endothelin-1 ratio. In addition, the level of serum UA had significant positive correlations with serum malonaldehyde, serum C-reactive protein, serum oxidatively-modified low-density lipoprotein and serum low-density lipoprotein, but a negative correlation with serum superoxide dismutase.
Conclusions
Endothelial dysfunction in the CKD group was significant and had a positive correlation with the level of serum UA. Endothelial dysfunction in early CKD with hyperuricemia is perhaps related to oxidative stress, micro-inflammation and lipid oxidation.
doi:10.1186/2047-783X-18-26
PMCID: PMC3750429  PMID: 23895583
Early chronic kidney disease; Endothelial dysfunction; Lipid oxidation; Micro-inflammation; Oxidative stress; Uric acid
8.  Association between Serum Uric Acid Levels and Diabetes Mellitus 
Serum uric acid has been shown to be associated with cardiovascular disease, hypertension, and chronic kidney disease in previous studies. However, few studies have examined the association between serum uric acid and diabetes mellitus and their findings are not consistent. Therefore, we examined the association between serum uric acid levels and diabetes mellitus in participants from the third National Health and Nutrition Examination Survey (n = 18, 825, 52.5% women). Serum uric acid levels were categorized into quartiles. Diabetes mellitus was defined as fasting glucose ≥126 mg/dL, nonfasting glucose ≥200 mg/dL, or use of oral hypoglycemic medication or insulin (n = 395). In multivariable logistic regression models, we found that higher serum uric acid levels were inversely associated with diabetes mellitus after adjusting for age, sex, race/ethnicity, education, smoking, alcohol intake, body mass index, hypertension, and serum cholesterol. Compared to quartile 1 of serum uric acid, the odds ratio (95% confidence interval) of diabetes mellitus was 0.48 (0.35–0.66; P trend <0.0001). The results were consistent in subgroup analysis by gender and hypertension status. Higher serum uric acid levels were inversely associated with diabetes mellitus in a representative sample of US adults.
doi:10.1155/2011/604715
PMCID: PMC3216382  PMID: 22114591
9.  Perfluoroalkyl chemicals and elevated serum uric acid in US adults 
Clinical Epidemiology  2011;3:251-258.
Background:
Perfluoroalkyl chemicals, including perfluorooctanoic acid and perfluorooctane sulfonate, are man-made chemicals that have been detected in the blood of over 98% of the US population. Serum uric acid is a novel biomarker, even mild elevations of which has been implicated in the development of hypertension, diabetes mellitus, cardiovascular disease, and chronic kidney disease. We examined the relationship of serum perfluoroalkyl chemicals, including perfluorooctanoic acid and perfluorooctane sulfonate, and elevated uric acid levels in a representative sample of US adults.
Methods:
We examined 3883 participants from the 1999–2000 and 2003–2006 National Health and Nutritional Examination Surveys, a representative, multiethnic population-based survey of noninstitutionalized US adults. Serum perfluorooctanoic acid and perfluorooctane sulfonate were analyzed as quartiles. The main outcome was hyperuricemia.
Results:
We found that serum levels of perfluoroalkyl chemicals, including perfluorooctanoic acid and perfluorooctane sulfonate, were positively associated with hyperuricemia. This association appeared to be independent of confounders such as age, gender, race-ethnicity, body mass index, diabetes, hypertension, and serum cholesterol. Compared with subjects in quartile 1 (referent), the multivariate odds ratio for hyperuricemia among subjects in quartile 4 was 1.97 (95% confidence interval 1.44–2.70, P < 0.0001) for perfluorooctanoic acid and 1.48% (95% confidence interval 0.99–2.22, P = 0.0433) for perfluorooctane sulfonate. This observed association persisted in subgroup analysis by gender and body mass index.
Conclusion:
Our results demonstrate that elevated levels of perfluoroalkyl chemicals are associated with hyperuricemia even at low perfluoroalkyl chemical exposure levels as seen in the US general population.
doi:10.2147/CLEP.S21677
PMCID: PMC3191115  PMID: 22003309
perfluoroalkyl chemicals; perfluorooctanoic acid; perfluorooctane sulfonate; uric acid
10.  Uric Acid and Long-term Outcomes in CKD 
Background
Hyperuricemia is prevalent in chronic kidney disease (CKD); however data are limited on the relationship of uric acid levels with long term outcomes in this patient population.
Study Design
Cohort Study
Setting & Participants
The Modification of Diet in Renal Disease (MDRD) Study was a randomized controlled trial (N=840), conducted 1989–1993, to examine the effects of strict blood pressure control and dietary protein restriction on progression of stage 3–4 CKD. This analysis included 838 patients.
Predictor
Uric acid
Outcomes & Measurements
The study evaluated the association of baseline uric acid levels with all-cause mortality, cardiovascular (CVD) mortality, and kidney failure.
Results
Mean (SD) age was 52 (12) years, glomerular filtration rate was 33 (12) ml/min/1.73m2, and uric acid was 7.63 (1.66) mg/dl. During a median follow-up of 10 years, 208 (25%) participants died of any cause, 127 (15%) from CVD, and 553 (66%) reached kidney failure. In multivariate models, the highest tertile of uric acid was associated with increased risk of all-cause (HR, 1.57 [95% CI, 1.07–2.32]) mortality, a trend towards CVD mortality (HR, 1.47 [95% CI, 0.90–2.39]) and no association with kidney failure (HR, 1.20 [95% CI, 0.95–1.51), compared to the lowest tertile. In continuous analyses, a 1-mg/dl higher uric acid was associated with 17% increased risk of all-cause (HR, 1.17 [95% CI, 1.05–1.30]), and 16% increased risk of CVD mortality (HR, 1.16 [95% CI, 1.01–1.33]), but was not associated with kidney failure (HR, 1.02 [95% CI, 0.97–1.07]).
Limitations
Primary analyses were based on single measurement of uric acid. The results are primarily generalizable to relatively young white patients with predominantly non-diabetic CKD.
Conclusions
In stage 3–4 CKD, hyperuricemia appears to be an independent risk factor for all-cause and CVD mortality but not kidney failure.
doi:10.1053/j.ajkd.2008.12.021
PMCID: PMC2691553  PMID: 19303683
11.  Serum Uric Acid Levels and Incident Chronic Kidney Disease in Patients With Type 2 Diabetes and Preserved Kidney Function 
Diabetes Care  2011;35(1):99-104.
OBJECTIVE
Recent studies have suggested an association between hyperuricemia and adverse renal outcomes in nondiabetic populations. Data on the relationship between hyperuricemia and the risk of incident chronic kidney disease (CKD) in type 2 diabetic patients with normal or near-normal kidney function are lacking. We determined whether baseline serum uric acid levels predict the subsequent development of CKD in patients with type 2 diabetes.
RESEARCH DESIGN AND METHODS
We followed 1,449 type 2 diabetic patients with normal kidney function and without overt proteinuria for 5 years for the occurrence of incident CKD (defined as overt proteinuria or estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2).
RESULTS
During a 5-year follow-up period, 194 (13.4%) patients developed incident CKD. The cumulative incidence of CKD was significantly greater in patients with hyperuricemia than in those without hyperuricemia (29.5 vs. 11.4%, P < 0.001). In univariate logistic regression analysis, the presence of hyperuricemia roughly doubled the risk of developing CKD (odds ratio [OR] 2.55 [95% CI 1.71–3.85], P < 0.001). After adjusting for age, sex, BMI, smoking status, diabetes duration, systolic blood pressure, antihypertensive treatment, insulin therapy, HbA1c, eGFR, and albuminuria, hyperuricemia was associated with an increased risk of incident CKD (adjusted OR 2.10 [1.16–3.76], P < 0.01). In continuous analyses, a 1-SD increment in the serum uric acid level was significantly associated with a 21% increased risk of CKD.
CONCLUSIONS
In type 2 diabetic individuals with preserved kidney function, hyperuricemia seems to be an independent risk factor for the development of incident CKD.
doi:10.2337/dc11-1346
PMCID: PMC3241303  PMID: 22028277
12.  Uric Acid – Key Ingredient in the Recipe for Cardiorenal Metabolic Syndrome 
Cardiorenal Medicine  2013;3(3):208-220.
Elevated serum uric acid levels are a frequent finding in persons with obesity, hypertension, cardiovascular and kidney disease as well as in those with the cardiorenal metabolic syndrome (CRS). The increased consumption of a fructose-rich Western diet has contributed to the increasing incidence of the CRS, obesity and diabetes especially in industrialized populations. There is also increasing evidence that supports a causal role of high dietary fructose driving elevations in uric acid in association with the CRS. Animal and epidemiological studies support the notion that elevated serum uric acid levels play an important role in promoting insulin resistance and hypertension and suggest potential pathophysiological mechanisms that contribute to the development of the CRS and associated cardiovascular disease and chronic kidney disease. To this point, elevated serum levels of uric acid appear to contribute to impaired nitric oxide production/endothelial dysfunction, increased vascular stiffness, inappropriate activation of the renin-angiotensin-aldosterone system, enhanced oxidative stress, and maladaptive immune and inflammatory responses. These abnormalities, in turn, promote vascular, cardiac and renal fibrosis as well as associated functional abnormalities. Small clinical trials have suggested that uric acid-lowering therapies may be beneficial in such patients; however, a consensus on the treatment of asymptomatic hyperuricemia is lacking. Larger randomized controlled trials need to be performed in order to critically evaluate the beneficial effect of lowering serum uric acid in patients with the CRS and those with diabetes and/or hypertension.
doi:10.1159/000355405
PMCID: PMC3884201  PMID: 24454316
Uric acid; Fructose; Cardiorenal metabolic syndrome; Chronic kidney disease

13.  Sugar-sweetened soda consumption, hyperuricemia, and kidney disease 
Kidney International  2009;77(7):609-616.
The metabolism of high-fructose corn syrup used to sweeten soda drinks may lead to elevations in uric acid levels. Here we determined whether soda drinking is associated with hyperuricemia and, as a potential consequence, reduced kidney function. At baseline, 15,745 patients in the Atherosclerosis Risk in Communities Study completed a dietary questionnaire and had measurements of their serum creatinine and uric acid. After 3 and 9 years of follow-up, multivariate odds ratios from logistic regressions for binary outcome of hyperuricemia and chronic kidney disease (eGFR less than 60 ml/min per 1.73 m2) were evaluated. Compared to participants who drank less, consumption of over one soda per day was associated with increased odds of prevalent hyperuricemia and chronic kidney disease. The odds ratio for chronic kidney disease significantly increased to 2.59 among participants who drank more than one soda per day and had a serum uric acid level over 9.0 mg/dl. In longitudinal analyses, however, drinking more than one soda per day was not associated with hyperuricemia or chronic kidney disease. Neither preexistent hyperuricemia nor development of hyperuricemia modified the lack of association between soda drinking and incident chronic kidney disease. Thus our study shows that high consumption of sugar-sweetened soda was associated with prevalent but not incident hyperuricemia and chronic kidney disease.
doi:10.1038/ki.2009.500
PMCID: PMC3299001  PMID: 20032963
chronic kidney disease; epidemiology; fructose; soda; uric acid
14.  Serum uric acid, kidney volume and progression in autosomal-dominant polycystic kidney disease 
Background
Hyperuricemia has been implicated in the development and progression of chronic kidney disease, both in animal experiments and in clinical studies. As a potentially modifiable risk factor, we examined whether serum uric acid levels correlate with early hypertension, kidney volume and progression to end-stage renal disease (ESRD) in autosomal-dominant polycystic kidney disease (ADPKD).
Methods
Retrospective analysis of a prospective observational study of the natural history of ADPKD, conducted at the University of Colorado between 1985 and 2005. Included are 680 ADPKD adults who provided data on blood pressure, renal volume, renal function, uric acid, age at the onset of ESRD or last known age without ESRD. Serum uric acid levels were examined as a continuous variable and as gender-specific quartiles. The main outcome of interest was age at the onset of ESRD; secondary outcomes were hypertension onset before age 30 years and total kidney volume (TKV) at the study visit.
Results
Subjects with early-onset hypertension had higher age-adjusted serum uric acid levels than those with no or late-onset hypertension despite similar creatinine clearance. After adjusting for age, gender and creatinine clearance, there was a 5.8% increase in TKV and 4.1% increase in TKV/body surface area for every 1 mg/dL increase in uric acid (P = 0.007). The multivariate-adjusted Cox regression demonstrated a greater hazard ratio for ESRD for subjects in the 4th and 3rd quartiles of uric acid compared with the 1st [4.8 (2.6–8.9; P < 0.001) and 2.9 (1.6–5.3; P < 0.001)].
Conclusions
Higher serum uric acid levels are associated with earlier onset of hypertension, larger kidney volume and increased hazard for ESRD in ADPKD independent of gender, body mass index and renal function at the study visit. Randomized interventional studies will be necessary to examine whether treating hyperuricemia has a protective role in ADPKD.
doi:10.1093/ndt/gfs417
PMCID: PMC3616764  PMID: 23222419
autosomal-dominant polycystic kidney disease; end-stage renal disease; hypertension; kidney volume; uric acid
15.  Impact of serum uric acid on renal function and cardiovascular events in hypertensive patients treated with losartan 
Hypertension Research  2012;35(8):867-873.
High serum uric acid level (SUA) and chronic kidney disease (CKD) are risk factors for cardiovascular events (CVEs). However, their interactions as cardiovascular risk factors remain unknown. This subanalysis of the Japan Hypertension Evaluation with Angiotensin II Antagonist Losartan Therapy (J-HEALTH) study included 7629 patients, in whom the serum creatinine level was measured at least twice. The study examined the impact of hyperuricemia (SUA ⩾7 mg dl−1) on CVE according to the level of renal dysfunction and whether early changes in SUA predicted future glomerular filtration rates (GFRs). The mean follow-up period was 3.1 years. The patients were divided into three groups according to the baseline estimated GFR (eGFR): groups A, B and C with eGFR <45, 45–59 and ⩾60 ml min−1 per 1.73 m2, respectively. eGFR increased from 38.1 to 57.6, from 52.8 to 67.5 and from 74.7 to 80.7 ml min−1 per 1.73 m2 in groups A, B and C, respectively. In non-hyperuricemic patients, the CVE rate was 10.83, 4.98 and 4.21/1000 person-years in groups A, B and C, respectively, while in hyperuricemic patients, the corresponding values were 14.18, 17.02 and 5.93. Thus, hyperuricemia increased the risk of CVE only in group B (relative risk (RR) 3.43 (95% confidence interval (CI) 1.55 to 7.60); P<0.002). The final change in the eGFR was negatively correlated with the change in SUA from baseline to year 1 (P<0.001). CVEs were more frequent in those with a decrease in eGFR. Hyperuricemia may be a major determinant of increased cardiovascular risk in CKD stage 3A, and SUA may be involved in the progression of CKD. Changes in the GFR influence the rate of CVE.
doi:10.1038/hr.2012.59
PMCID: PMC3419971  PMID: 22573200
cardiovascular disease; chronic kidney disease; glomerular filtration rate; uric acid
16.  Hyperuricaemia, chronic kidney disease, and outcomes in heart failure: potential mechanistic insights from epidemiological data 
European Heart Journal  2011;32(6):712-720.
Aim
To determine if the association between hyperuricaemia and poor outcomes in heart failure (HF) varies by chronic kidney disease (CKD).
Methods and results
Of the 2645 systolic HF patients in the Beta-Blocker Evaluation of Survival Trial with data on baseline serum uric acid, 1422 had hyperuricaemia (uric acid ≥6 mg/dL for women and ≥8 mg/dL for men). Propensity scores for hyperuricaemia, estimated for each patient, were used to assemble a matched cohort of 630 pairs of patients with and without hyperuricaemia who were balanced on 75 baseline characteristics. Associations of hyperuricaemia with outcomes during 25 months of median follow-up were examined in all patients and in those with and without CKD (estimated glomerular filtration rate of <60 mL/min/1.73 m2). Hyperuricaemia-associated hazard ratios (HRs) and 95% confidence intervals (CI) for all-cause mortality and HF hospitalization were 1.44 (1.12–1.85, P = 0.005) and 1.27 (1.02–1.58, P = 0.031), respectively. Hazard ratios (95% CIs) for all-cause mortality among those with and without CKD were 0.96 (0.70–1.31, P = 0.792) and 1.40 (1.08–1.82, P = 0.011), respectively (P for interaction, 0.071), and those for HF hospitalization among those with and without CKD were 0.99 (0.74–1.33, P = 0.942) and 1.49 (1.19–1.86, P = 0.001), respectively (P for interaction, 0.033).
Conclusion
Hyperuricaemia has a significant association with poor outcomes in HF patients without CKD but not in those with CKD, suggesting that hyperuricaemia may predict poor outcomes when it is primarily a marker of increased xanthine oxidase activity, but not when it is primarily due to impaired renal excretion of uric acid.
doi:10.1093/eurheartj/ehq473
PMCID: PMC3056205  PMID: 21199831
Heart failure; Hyperuricaemia; Chronic kidney disease; Outcomes
17.  The relationship between serum uric acid and chronic kidney disease among Appalachian adults 
Nephrology Dialysis Transplantation  2010;25(11):3593-3599.
Background. Higher serum uric acid (SUA) levels have been shown to be associated with cardiovascular disease. SUA levels are also associated with hypertension, a strong risk factor for chronic kidney disease (CKD). However, it is unclear whether SUA is independently associated with CKD. We examined the hypothesis that higher SUA levels are positively associated with CKD.
Methods. We analysed data from the C8 Health Study, a population-based study of Appalachian adults aged ≥18 years and free of cardiovascular disease (n = 49,295, 53% women). SUA was examined as gender-specific quartiles. The outcome of interest was CKD (n = 2,980), defined as an estimated glomerular filtration rate of <60 mL/min/1.73 m2 from serum creatinine.
Results. Overall, we observed a clear positive association between increasing quartiles of SUA and CKD, independent of confounders. Compared with the lowest quartile of SUA (referent), the multivariable odds ratios (95% confidence interval) for quartiles 2–4, respectively, of CKD were 1.53 (1.31, 1.78), 2.16 (1.86 2.50) and 4.67 (4.07, 5.36); P-trend < 0.0001. This observed positive association persisted in separate analysis among men (P-trend < 0.0001) and women (P-trend < 0.0001).
Conclusions. In conclusion, higher SUA levels are positively associated with CKD, suggesting that at least part of the reported association between SUA and cardiovascular disease may be mediated by CKD.
doi:10.1093/ndt/gfq262
PMCID: PMC2980994  PMID: 20501458
Appalachian; chronic kidney disease; creatinine serum; glomerular filtration rate; serum uric acid
18.  The Association between Uric Acid and Chronic Kidney Disease in Korean Men: A 4-Year Follow-up Study 
Journal of Korean Medical Science  2013;28(6):855-860.
There have been many studies between serum uric acid (UA) and chronic kidney disease (CKD). However, as far as we know, little research has been done to examine the prospective association between serum UA and development of CKD in Korean men. This prospective cohort study was performed using 18,778 men who participated in a health checkup program both on January, 2005 and on December, 2009. CKD was defined as an estimated glomerular filtration rate < 60 mL/min per 1.73 m2. The odds ratio (OR) from binary logistic regressions for the development of CKD was determined with respect to the quintiles grouping based on serum UA. During 74,821.4 person-years of follow-up, 110 men were found to develop CKD. The OR for the development of CKD increased as the quintiles for baseline serum UA levels increased from the first to fifth quintiles (1.00 vs 1.22, 1.19, 2.59, and 3.03, respectively, p for linear trend < 0.001) after adjusting for covariates. The adjusted OR comparing those participants with hyperuricemia ( ≥ 7.0 mg/dL) to those with normouricemia ( < 7.0 mg/dL) was 1.96 (1.28-2.99). Elevated serum UA levels were independently associated with increased likelihood for the development of CKD in Korean men (IRB number: KBC10034).
doi:10.3346/jkms.2013.28.6.855
PMCID: PMC3678001  PMID: 23772149
Uric Acid; Kidney Failure, Chronic
19.  A population-based survey of Chronic REnal Disease In Turkey—the CREDIT study 
Nephrology Dialysis Transplantation  2010;26(6):1862-1871.
Background. Chronic kidney disease (CKD) is a growing health problem worldwide that leads to end-stage kidney failure and cardiovascular complications. We aimed to determine the prevalence of CKD in Turkey, and to evaluate relationships between CKD and cardiovascular risk factors in a population-based survey.
Methods. Medical data were collected through home visits and interviews. Serum creatinine, blood glucose, total cholesterol, triglycerides, HDL, LDL and uric acid were determined from 12-h fasting blood samples, and spot urine tests were performed for subjects who gave consent to laboratory evaluation.
Results. A total of 10 872 participants were included in the study. The final analysis was performed on 10 748 subjects (mean age 40.5 ± 16.3 years; 55.7% women) and excluded 124 pregnant women. A low glomerular filtration rate (GFR) (< 60 mL/min/1.73 m2) was present in 5.2% of the subjects who were evaluated for GFR, while microalbuminuria and macroalbuminuria were observed in 10.2% and 2% of the subjects, respectively. The presence of CKD was assessed in subjects who gave consent for urinary albumin excretion measurement (n = 8765). The overall prevalence of CKD was 15.7%; it was higher in women than men (18.4% vs. 12.8%, P < 0.001) and increased with increasing age of the subjects. The prevalence of hypertension (32.7% in the general population), diabetes (12.7%), dyslipidaemia (76.3%), obesity (20.1%) and metabolic syndrome (31.3%) was significantly higher in subjects with CKD than subjects without CKD (P < 0.001 for all).
Conclusions. The prevalence of CKD in Turkey is 15.7%. Cardiovascular risk factors were significantly more prevalent in CKD patients.
doi:10.1093/ndt/gfq656
PMCID: PMC3107767  PMID: 21051501
chronic kidney disease; epidemiology and outcomes; risk factors
20.  Uric Acid as a Pathogenic Factor in Preeclampsia 
Placenta  2008;29(Suppl A):S67-S72.
Hyperuricemia is a common finding in preeclamptic pregnancies evident from early pregnancy. Despite the fact that elevated uric acid often pre-dates the onset of clinical manifestations of preeclampsia, hyperuricemia is usually considered secondary to altered kidney function. Increased serum uric acid is associated with hypertension, renal disease and adverse cardiovascular events in the non-pregnant population and with adverse fetal outcomes in hypertensive pregnancies. We hypothesize that an elevated concentration of uric acid in preeclamptic women is not simply a marker of disease severity but rather contributes directly to the pathogenesis of the disorder. Using epidemiological and experimental evidence, gained largely outside of pregnancy, we will propose pathogenic roles for uric acid in preeclamptic pregnancies. Uric acid's ability to promote inflammation, oxidative stress and endothelial dysfunction will be highlighted with discussions of the potential impact on placental development and function and maternal vascular health.
doi:10.1016/j.placenta.2007.11.001
PMCID: PMC3319018  PMID: 18093648
21.  Association of Renal Manifestations with Serum Uric Acid in Korean Adults with Normal Uric Acid Levels 
Journal of Korean Medical Science  2010;25(12):1766-1770.
Several studies have reported that hyperuricemia is associated with the development of hypertension and cardiovascular disease. Increasing evidences also suggest that hyperuricemia may have a pathogenic role in the progression of renal disease. Paradoxically, uric acid is also widely accepted to have antioxidant activity in experimental studies. We aimed to investigate the association between glomerular filtration rate (GFR) and uric acid in healthy individuals with a normal serum level of uric acid. We examined renal function determined by GFR and uric acid in 3,376 subjects (1,896 men; 1,480 women; aged 20-80 yr) who underwent medical examinations at Gangnam Severance Hospital from November 2006 to June 2007. Determinants for renal function and uric acid levels were also investigated. In both men and women, GFR was negatively correlated with systolic and diastolic blood pressures, fasting plasma glucose, total cholesterol, uric acid, log transformed C reactive protein, and log transformed triglycerides. In multivariate regression analysis, total uric acid was found to be an independent factor associated with estimated GFR in both men and women. This result suggests that uric acid appears to contribute to renal impairment in subjects with normal serum level of uric acid.
doi:10.3346/jkms.2010.25.12.1766
PMCID: PMC2995231  PMID: 21165292
Glomerular Filtration Rate; Uric Acid; Antioxidants
22.  Community-based study on CKD subjects and the associated risk factors 
Nephrology Dialysis Transplantation  2009;24(7):2117-2123.
Background. The study was performed to investigate the prevalence, awareness and the risk factors of chronic kidney disease (CKD) in the community population in Shanghai, China.
Methods. A total of 2596 residents were randomly recruited from the community population in Shanghai, China. All were screened for albuminuria, haematuria, morning spot urine albumin-to-creatinine ratio and renal function. Serum creatinine, uric acid, cholesterol, triglyceride and haemoglobin were assessed. A simplified MDRD equation was used to estimate the glomerular filtration rate (eGFR). All studied subjects were screened by kidney ultrasound. Haematuria, if present in the morning spot urine dipstick test, was confirmed by microscopy. The associations among the demographic characteristics, health characteristics and indicators of kidney damage were examined.
Results. Two thousand five hundred and fifty-four residents (n = 2554), after giving informed consent and with complete data, were entered into this study. Albuminuria and haematuria were detected in 6.3% and 1.2% of all the studied subjects, respectively, whereas decreased kidney function was found in 5.8% of all studied subjects. Approximately 11.8% of subjects had at least one indicator of kidney damage. The rate of awareness of CKD was 8.2%. The logistic regression model showed that age, central obesity, hypertension, diabetes, anaemia, hyperuricaemia and nephrolithiasis each contributed to the development of CKD.
Conclusion. This is the first Shanghai community-based epidemiological study data on Chinese CKD patients. The prevalence of CKD in the community population in Shanghai is 11.8%, and the rate of awareness of CKD is 8.2%. All the factors including age, central obesity, hypertension, diabetes, anaemia, hyperuricaemia and nephrolithiasis are positively correlated with the development of CKD in our studied subjects.
doi:10.1093/ndt/gfn767
PMCID: PMC2698090  PMID: 19193736
awareness; chronic kidney disease; epidemiology; prevalence; risk factors
23.  IMproving the imPlemEntation of cuRrent guidelines for the mAnagement of major coronary hearT disease rIsk factors by multifactorial interVEntion. The IMPERATIVE renal analysis 
Introduction
The short-term effects of multifactorial intervention for cardiovascular disease (CVD) prevention on renal function and serum uric acid (SUA) levels in patients with stage 3 chronic kidney disease (CKD) and multiple CVD risk factors are unclear. The aim of the study was to prospectively assess these effects.
Material and methods
This post hoc analysis of 5 "best practice" studies involved patients with multiple CVD risk factors. Estimated glomerular filtration rate (eGFR) was assessed using the Modification of Diet in Renal Disease (MDRD) formula. Among the 4,153 patients, 1,235 (29.7%) had stage 3 CKD (eGFR between 30 and 59 ml/min/1.73 m2). A baseline visit was followed by a concerted effort from previously trained physicians to improve adherence to lifestyle advice and optimize drug treatment, including a statin, for all vascular risk factors. After 6 months eGFR and SUA levels were re-evaluated.
Results
The intervention improved compliance to lifestyle measures and increased the use of evidence-based medication, including a statin. There was also a 5.6% increase in eGFR (p < 0.001) in patients with stage 3 CKD and a 6.1% reduction in SUA levels (p < 0.001). Among patients with stage 3 CKD, 127 (10.3%) improved to stage 2 CKD and 9 (0.7%) advanced to stage 4 CKD by the end of the 6-month study period. There were no major side-effects.
Conclusions
Multitargeted intervention, including a statin, may improve renal function and reduce SUA levels within 6 months, thus offsetting 2 potential CVD risk factors in high-risk patients.
doi:10.5114/aoms.2011.26610
PMCID: PMC3264990  PMID: 22328881
renal function; uric acid; dyslipidaemia; diabetes mellitus; hypertension; metabolic syndrome; multifactorial intervention; statin
24.  Serum Uric Acid as a Predictor for the Development of Nonalcoholic Fatty Liver Disease in Apparently Healthy Subjects: A 5-Year Retrospective Cohort Study 
Gut and Liver  2010;4(3):378-383.
Background/Aims
This study evaluated the relationship between hyperuricemia and nonalcoholic fatty liver disease (NAFLD) by comparing the incidence rates of NAFLD in relation to serum uric acid levels in apparently healthy subjects during a 5-year period.
Methods
Among 15,638 healthy Korean subjects who participated in a health-screening program in 2003 and 2008, respectively, 4954 subjects without other risk factors were enrolled in this study. We compared the incidence rates of NAFLD in 2008 with respect to baseline uric acid levels.
Results
In 2003, serum uric acid levels were categorized into the following quartiles: 0.6-3.9, 3.9-4.8, 4.8-5.9, and 5.9-12.6 mg/dL. The incidence of NAFLD in 2008 increased with the level of baseline uric acid (5.6%, 9.8%, 16.2%, and 20.9%, respectively; p<0.05). Multiple logistic regression analysis demonstrated that hyperuricemia was associated with the development of NAFLD. When compared to the subjects in quartile 1, the odds ratio (OR) for the incidence of NAFLD for quartiles 2, 3, and 4 were 1.53 (95% confidence interval [CI], 1.09-2.16; p=0.014], 1.69 (95% CI, 1.17-2.44; p=0.005), and 1.84 (95% CI, 1.25-2.71; p=0.002), respectively.
Conclusions
High serum uric acid levels appear to be associated with an increased risk of the development of NAFLD.
doi:10.5009/gnl.2010.4.3.378
PMCID: PMC2956352  PMID: 20981217
Non-alcoholic fatty liver disease; Uric acid; Metabolic syndrome
25.  High Serum Uric Acid Increases the Risk for Nonalcoholic Fatty Liver Disease: A Prospective Observational Study 
PLoS ONE  2010;5(7):e11578.
Nonalcoholic fatty liver disease (NAFLD) is a common form of chronic liver disease, and serum uric acid is observed to be significantly elevated in NAFLD patients. However, whether this elevation is causal, a bystander, or a consequence of NAFLD remains unclear. We performed a population-based prospective study among the employees of Zhenhai Refining & Chemical Company Ltd., Ningbo, China to investigate whether the elevation of serum uric acid has a casual role for NAFLD. A total of 6890 initially NAFLD-free subjects were followed up for 3 years. Overall, 11.80% (813/6890) subjects developed NAFLD over 3 years of follow-up. The cumulative incidence of NAFLD increased with progressively higher baseline serum uric acid levels (the cumulative incidence was 7.2%, 9.5%, 11.5%, 13.8%, and 17.2% in quintile 1, quintile 2, 3, 4 and 5, respectively; P value for trend <0.001). Cox proportional hazards regression analyses showed that serum uric acid levels were independently and positively associated with the risk for incident NAFLD; the age-, gender- and metabolic syndrome adjusted hazard ratio (95% CI) for the subjects in quintile 2, 3, 4 and 5 versus quintile 1 was 1.18 (0.91–1.54), 1.32 (1.03–1.70), 1.39 (1.09–1.78) and 1.50 (1.18–1.92), respectively. Taken together, our prospective observational study showed that elevation of serum uric acid levels independently predicts increase risk for incident NAFLD.
doi:10.1371/journal.pone.0011578
PMCID: PMC2904389  PMID: 20644649

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