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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.
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.
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).
Increased serum uric acid is an independent predictor of endothelial dysfunction in subjects with CKD.
PMCID: PMC3064939  PMID: 21389694
Chronic kidney disease; Uric acid; Endothelial dysfunction
2.  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.
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.
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.
PMCID: PMC3064941  PMID: 21389698
Chronic kidney disease; Coronary artery disease; Uric acid; Pentraxin-3
3.  Uric Acid Level Has a U-Shaped Association with Loss of Kidney Function in Healthy People: A Prospective Cohort Study 
PLoS ONE  2015;10(2):e0118031.
The relationship between hyperuricemia and chronic kidney disease (CKD) has been found in various observational studies. Although hypouricemia is associated with cardiovascular events, it has not been established as a risk factor for CKD. We investigated the relationship between serum uric acid level and the loss of kidney function and incident CKD in healthy people.
Materials and Methods
Healthy people were enrolled in this community-based prospective cohort study, the Saitama Cardiometabolic Disease and Organ Impairment Study, Japan. The analysis was conducted on 4188 subjects followed up for at least 3 years, 3102 for 6 years and 1052 for 9 years. Their data including glomerular filtration rate (eGFR) decline were examined every three years. The outcome event was incident CKD or the decrease in eGFR by more than 25% in three years. Multivariate statistical models were adjusted for the baseline characteristics.
The following data was obtained: mean±SD age, male, 39.6±10.4 years, female 38.4±10.8 years; eGFR, male, 81.9±16.4 ml/min/1.73m2, female, 82.1±17.5 ml/min/1.73m2; serum uric acid level, male, 5.8±1.2 mg/dl, female, 4.1±0.9 mg/dl. Both low and high serum uric acid levels were associated with the outcome and eGFR decline in males (multivariate logistic additional additive models, linear p = 0.0001, spline p = 0.043; generalized additive models, linear p = 0.0001, spline p = 0.012). In subjects with low serum uric acid levels (male, <5 mg/dl; female, <3.6 mg/dl), multivariate linear mixed models showed that low serum uric acid levels were associated with eGFR decline in a time-dependent manner (male, p = 0.0001; female, p = 0.045).
This study showed that low as well as high levels of uric acid are associated with the loss of kidney function. Hypouricemia is a candidate predictor of kidney function decline in healthy people.
PMCID: PMC4320097  PMID: 25658588
4.  Serum Uric Acid and Chronic Kidney Disease: The Role of Hypertension 
PLoS ONE  2013;8(11):e76827.
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.
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.
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).
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.
PMCID: PMC3827035  PMID: 24265674
5.  Serum Uric Acid Is Associated with Incident Chronic Kidney Disease in Middle-Aged Populations: A Meta-Analysis of 15 Cohort Studies 
PLoS ONE  2014;9(6):e100801.
Mounting evidence indicates that elevated serum uric acid may increase the incidence of chronic kidney disease (CKD). Our goal was to systematically evaluate longitudinal cohort studies for the association of serum uric acid levels and incident CKD.
We searched electronic databases and the reference lists of relevant articles. The primary outcome was incident CKD, which was defined as an eGFR less than 60 mL/min/1.73 m2 at the follow-up examination. Study-specific risk estimates were combined using random-effects models. The included studies were stratified into subgroups, and meta-regression analyses were performed.
Fifteen unique cohorts with a total of 99,205 individuals and 3,492 incident CKD cases were included. The relative risk of CKD was 1.22 (95% CI 1.16–1.28, I2 = 65.9%) per 1 mg/dL serum uric level increment. This positive association was consistently observed in subgroups stratified according to most of the study-level characteristics. The observed positive association was more pronounced among group with a mean age <60 years (RR 1.26, 95% CI 1.21–1.31), and low-level heterogeneity was observed in the findings for this age group (I2 = 46.4%, P = 0.022). However, no association was observed among studies with a mean age≥60 years (RR 1.04, 95% CI 0.96–1.13), and no evidence of heterogeneity was evident among the studies (I2 = 0%, P = 0.409). This mean age-related difference in the association between serum uric acid levels and CKD was significant (P = 0.004). The sensitivity analysis results were consistent when the analyses were restricted to studies that controlled for proteinuria and metabolic syndrome.
Our meta-analysis demonstrated a positive association between serum uric acid levels and risk of CKD in middle-aged patients independent of established metabolic risk factors. Future randomized, high-quality clinical trials are warranted to determine whether lowering uric acid levels is beneficial in CKD.
PMCID: PMC4069173  PMID: 24959886
6.  Correlation Between Serum Uric Acid and Renal Function in Patients With Stable Coronary Artery Disease and Type 2 Diabetes 
The aim of this study was to investigate the relationship between serum uric acid and renal function, expressed as estimated glomerular filtration rate (eGFR), in patients with stable coronary artery disease (CAD) and type 2 diabetes mellitus (T2DM) in China.
Serum levels of uric acid and creatinine were determined in 526 enrolled patients diagnosed with stable CAD and T2DM. To assess renal function, eGFR was calculated using a modified MDRD formula suitable for the Chinese population. Patients’ anthropometric measurements were collected using standardized protocols, and 6-month follow-up results were collected and analyzed. Pearson’s correlation coefficient r was calculated and multivariate analysis was performed to evaluate the relationship between uric acid and renal function. Patients with eGFR < 60 mL/min/1.73 m2 were classified as having reduced renal function or chronic kidney disease (CKD) in this study.
Uric acid levels were negatively associated with eGFR (P = 0.002), especially in patients with CKD (eGFR < 60 mL/min/1.73 m2) (P < 0.001). In patients with reduced renal function, the risk in the highest quartile of uric acid levels was higher than in the lowest quartile (odds ratio 9.18, 95% confidence interval: 4.01 - 21.01, P < 0.001). These associations remained after multiple adjustments for potential confounders and were recapitulated after 6-month follow-up.
Serum uric acid level is negatively associated with renal function, as assessed by eGFR, and serves as an independent predictor for CKD in patients with stable CAD and T2DM.
PMCID: PMC4169086  PMID: 25247018
Stable coronary artery disease; Estimated glomerular filtration rate; Type 2 diabetes mellitus; Uric acid; Follow-up
7.  The relationship between indoleamine 2,3-dioxygenase activity and post-stroke cognitive impairment 
Activation of indoleamine 2,3-dioxygenase (IDO) and higher concentrations of several kynurenine metabolites have been observed post-stroke, where they have been associated with increased mortality. While lower tryptophan or a higher ratio of kynurenine/tryptophan (K/T) in peripheral blood have been associated with dementia and the severity of cognitive symptoms in Alzheimer's disease, the association between K/T ratios and post-stroke cognitive impairment (PSCI) has not been investigated.
Patients were recruited from the acute stroke unit of a general hospital within 1 month post-stroke. Assessments included the Standardized Mini-Mental State Examination (sMMSE) for cognition, the National Institutes of Health Stroke Scale (NIHSS) for stroke severity, and the Center for Epidemiological Studies-Depression Scale (CES-D) for depressive symptoms. Tryptophan and kynurenine concentrations were determined by high-performance liquid chromatography.
A total of 41 patients with ischemic stroke ([mean ± SD] age 72.3 ± 12.2 years, 53.7% male, sMMSE 25.6 ± 4.1, NIHSS 7.27 ± 5.55) were recruited. Higher K/T ratios were associated with lower post-stroke global cognition (i.e. sMMSE scores; β = -.327, P = .037). A backward stepwise elimination linear regression (F1,40=6.15, P=.005, adjusted R2=.205) showed that the highest K/T ratio tertile (β = -.412, P = .006) predicted lower sMMSE scores, controlling for age (β = -.253, p = .081), with NIHSS (β = -.027, P = 0.859), and lesion volume (β = -.066, P = 0.659) removed from the model. In receiver operating characteristic analysis, a K/T ratio of 78.3 μmol/mmol (top tertile) predicted significant cognitive impairment (sMMSE score ≤ 24) with 67% sensitivity and 86% specificity (area under the curve = 0.730, p = .022).
These data suggest an inflammatory response characterized by IDO activation may be relevant to the development of PSCI. Since the neuroactivity of kynurenine metabolites may be amenable to pharmacotherapeutic intervention, the K/T ratio may be a clinically important biomarker.
PMCID: PMC3055827  PMID: 21324164
8.  Is hyperuricemia an independent risk factor for new-onset chronic kidney disease?: a systematic review and meta-analysis based on observational cohort studies 
BMC Nephrology  2014;15:122.
Hyperuricemia has been reported to be associated with chronic kidney disease (CKD). However whether an elevated serum uric acid level is an independent risk factor for new-onset CKD remained controversial.
A systematic review and meta-analysis using a literature search of online databases including PubMed, Embase, Ovid and ISI Web/Web of Science was conducted. Summary adjusted odds ratios with corresponding 95% confidence intervals (95% CI) were calculated to evaluate the risk estimates of hyperuricemia for new-onset CKD.
Thirteen studies containing 190,718 participants were included. A significant positive association was found between elevated serum uric acid levels and new-onset CKD at follow-up (summary OR, 1.15; 95% CI, 1.05–1.25). Hyperuricemia was found be an independent predictor for the development of newly diagnosed CKD in non-CKD patients (summary OR, 2.35; 95% CI, 1.59–3.46). This association increased with increasing length of follow-up. No significant differences were found for risk estimates of the associations between elevated serum uric acid levels and developing CKD between males and females.
With long-term follow-up of non-CKD individuals, elevated serum uric acid levels showed an increased risk for the development of chronic renal dysfunction.
PMCID: PMC4132278  PMID: 25064611
Chronic kidney disease; Hyperuricemia; Uric acid
9.  Uric Acid Level and Erectile Dysfunction In Patients With Coronary Artery Disease 
The journal of sexual medicine  2013;11(1):165-172.
Erectile dysfunction (ED) is a frequent complaint of elderly subjects, and is closely associated with endothelial dysfunction and cardiovascular disease. Uric acid is also associated with endothelial dysfunction, oxidative stress and cardiovascular disease, raising the hypothesis that an increased serum uric acid might predict erectile dysfunction in patients who are at risk for coronary artery disease.
To evaluate the association of serum uric acid levels with presence and severity of ED in patients presenting with chest pain of presumed cardiac origin.
This is a cross-sectional study of 312 adult male patients with suspected coronary artery disease who underwent exercise stress test (EST) for workup of chest pain and completed a sexual health inventory for men (SHIM) survey form to determine the presence and severity of ED. Routine serum biochemistry (and uric acid levels) were measured. Logistic regression analysis was used to assess risk factors for ED.
Main Outcome Measures
The short version of the international index of erectile function (IIEF-5) questionnaire diagnosed ED (cutoff score ≤21). Serum Uric acid levels were determined. Patients with chest pain of suspected cardiac origin underwent an exercise stress test.
149 of 312 (47.7%) male subjects had ED by survey criteria. Patients with ED were older and had more frequent CAD, hypertension, diabetes, and impaired renal function, and also had significantly higher levels of uric acid, fibrinogen, glucose, CRP, triglycerides compared with patients without ED. Uric acid levels were associated with ED by univariate analysis (OR = 1.36, p = 0.002); however, this association was not observed in multivariate analysis adjusted for eGFR.
Subjects presenting with chest pain of presumed cardiac origin are more likely to have ED if they have elevated uric acid levels.
PMCID: PMC3962193  PMID: 24433559
Uric Acid; Erectile Dysfunction; Coronary Artery Disease; Endothelial Dysfunction
10.  Chronic kidney disease in gout in a managed care setting 
BMC Nephrology  2011;12:36.
To study the prevalence of chronic kidney disease (CKD) and its impact on allopurinol dosing and uric acid control among patients with gout.
This was a retrospective study using data from a large US health plan. Claims and laboratory data were analyzed for enrollees from the health plan database from January 2002 through December 2005. Patients with gout were identified from pharmacy and medical claims data based on the presence of codes for gout medication or gout diagnosis. Severity of CKD was determined using the estimated glomerular filtration rate (eGFR). Allopurinol titration was defined as a change in average daily dose from first prescription to last prescription of ≥ 50 mg.
A total of 3,929 patients were identified for inclusion in this study, 39% of whom had CKD (based on having an eGFR < 90 mL/min/1.73 m2). Subjects with CKD were older (p < 0.01) and more likely to be women (p < 0.01), had a greater number of comorbid conditions (p < 0.01), and were more likely to be prescribed allopurinol (p < 0.01) compared to those with no CKD. The average starting dose of allopurinol was lower among those with CKD, and it decreased with worsening kidney function. Among the 3,122 gout patients who used allopurinol, only 25.6% without CKD and 22.2% with CKD achieved a serum uric acid concentration of < 6.0 mg/dL (p = 0.0409). Also, only 15% of allopurinol users had an upward dose titration (by ≥50 mg), but the average increase in dose did not differ significantly between those with and without CKD.
About two out of every five patients with gout in this population had CKD. Allopurinol doses were not adjusted in the majority of CKD patients. Serum uric acid control in gout was poor among patients without CKD and even worse among those with CKD.
PMCID: PMC3174872  PMID: 21812963
11.  Low-fructose diet lowers blood pressure and inflammation in patients with chronic kidney disease 
Fructose has been strongly linked with hypertension, hyperuricemia and inflammation in experimental models and humans. However, the effect of low-fructose diet on inflammation, hyperuricemia and the progression of renal disease has not yet been evaluated in patients with chronic kidney disease (CKD).
Twenty-eight patients (age 59 ± 15 years, 17 males/11 females) with Stages 2 and 3 CKD were switched from a regular (basal) (60.0 g/24 h) to a low (12.0 g/24 h) fructose diet for 6 weeks, followed by a resumption of their regular diet for another 6 weeks. Diet was monitored by a dietician. At the baseline, low- and regular-fructose diet ambulatory blood pressure (BP) was measured and blood sampled for renal function (creatinine), inflammatory markers, fasting glucose and insulin and serum uric acid. Twenty-four-hour urine collections were also obtained for creatinine, uric acid, monocyte chemotatic protein-1, transforming growth factor-beta and N-acetyl-beta-D-glucosaminidase.
The low-fructose diet tended to improve BP for the whole group (n = 28), while significant reduction of BP was only seen in dippers (n = 20) but not in non-dippers (n = 8). No effects on estimated glomerular filtration rate (eGFR) or proteinuria were observed. Serum uric acid was lowered non-significantly with low-fructose diet (7.1 ± 1.3 versus 6.6 ± 1.0 mg/dL, P < 0.1), whereas a significant decrease in fasting serum insulin was observed (11.2 ± 6.1 versus 8.2 ± 2.9 mIU/mL, P < 0.05) and the reduction persisted after return to the regular diet. A slight but not significant reduction in urinary uric acid and fractional uric acid excretion was observed while the patients were on the low fructose diet. The low-fructose diet also decreased high sensitivity C-reactive protein (hsCRP) (4.3 ± 4.9 versus 3.3 ± 4.5 mg/L; P < 0.01) and soluble intercellular adhesion molecule (sICAM) (250.9 ± 59.4 versus 227 ± 50.5 ng/mL; P < 0.05). The hsCRP returned to baseline with resumption of the regular diet, whereas the reduction in sICAM persisted.
Low-fructose diet in subjects with CKD can reduce inflammation with some potential benefits on BP. This pilot study needs to be confirmed by a larger clinical trial to determine the long-term benefit of a low-fructose diet compared to other diets in subjects with CKD.
PMCID: PMC3350341  PMID: 21613382
blood pressure; chronic kidney disease; inflammation; low-fructose diet; uric acid
12.  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.
PMCID: PMC3507473  PMID: 22277138
Alaska Eskimos; chronic kidney disease; epidemiology; hypertension; uric acid
13.  Association between Serum Bilirubin and Estimated Glomerular Filtration Rate among Elderly Persons 
PLoS ONE  2014;9(12):e115294.
Chronic kidney disease (CKD) is a major public health problem. However, few studies have examined the significance of serum bilirubin as a risk factor for the development of CKD in the general Japanese population. The subjects comprised 413 men (mean age: 79±9 years; (range, 60–100 years) and 637 women (mean age: 81±8 years; range, 60–106 years) who visited the medical department of Seiyo Municipal Nomura Hospital. We examined the relationship between increased serum bilirubin and renal function that was evaluated by estimated glomerular filtration rate (eGFR) using CKD-EPI equations modified by a Japanese coefficient. Stepwise multiple regression analysis with eGFR as the objective variable, and adjusted risk factors as the explanatory variables, showed that serum bilirubin (β = 0.11, P<0.001) was significantly and independently associated with eGFR, in addition to gender, age, prevalence of antihypertensive medication, triglycerides, prevalence of antidiabetic medication, and serum uric acid. Compared with stages 1+2 (eGFR ≥60.0 ml/min/1.73 m2), mean multivariate-adjusted odds ratio {95% (confidence interval (CI)} for hypobilirubinemia (first quartile, <0.52 mg/dL) was 3.52 (range: 1.88–6.59). Next, to control potential confounding factors, data were further stratified by gender, age, medication (antihypertensive, antidyslipidemic, and antidiabetic agents), and prevalence of cardiovascular disease. The standardized coefficient for eGFR was significant in both groups, and there was no interaction between the groups. Our data demonstrated an independent positive association between serum bilirubin and eGFR in both genders. Low serum bilirubin level would be useful as a potential risk factor for renal function.
PMCID: PMC4267840  PMID: 25514359
14.  Uric Acid and Long-term Outcomes in CKD 
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.
Uric acid
Outcomes & Measurements
The study evaluated the association of baseline uric acid levels with all-cause mortality, cardiovascular (CVD) mortality, and kidney failure.
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]).
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.
In stage 3–4 CKD, hyperuricemia appears to be an independent risk factor for all-cause and CVD mortality but not kidney failure.
PMCID: PMC2691553  PMID: 19303683
15.  Relationship between serum uric acid levels and ventricular function in patients with idiopathic pulmonary hypertension 
To investigate the relationship between serum uric acid levels and pulmonary hypertension in patients with idiopathic pulmonary artery hypertension (IPAH).
Serum uric acid levels were measured in 86 patients (mean [± SD] age 35.2±12.3 years; 36 men) with IPAH. Pulmonary arterial pressure and ventricular function were assessed using echocardiography. Serum uric acid levels were also measured in 40 healthy subjects (35.9±11.6 years of age; 15 men).
Serum uric acid levels in IPAH patients were higher compared with control subjects (405±130 μmol/L versus 344±96 μmol/L; P<0.05). Fifty-two (60.4%) of the 86 patients with IPAH had elevated serum uric acid levels. The pulmonary systolic pressure and mean pulmonary pressure in the high uric acid group were higher than in the normal uric acid group (P<0.05). The left and right ventricular ejection fractions were lower in the high uric acid group compared with the normal uric acid group (P<0.05). Serum uric acid levels were correlated with the mean pulmonary arterial pressure (r=0.387; P<0.01) and New York Heart Association class (r=0.41; P<0.01). There was also an inverse correlation between uric acid levels and the left (r=−0.550; P<0.01) and right ventricular ejection fractions (r=−0.481; P<0.05).
Serum uric acid levels are associated with IPAH severity and the severity of ventricular dysfunction.
PMCID: PMC3716500  PMID: 24294046
Idiopathic pulmonary artery hypertension; Uric acid; Ventricular function
16.  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.
PMCID: PMC2721426  PMID: 19033255
cardiovascular events; chronic kidney disease; insulin resistance; mortality; uric acid
17.  Correlation between Renal Function and Common Risk Factors for Chronic Kidney Disease in a Healthy Middle-Aged Population: A Prospective Observational 2-Year Study 
PLoS ONE  2014;9(11):e113263.
Age, proteinuria, metabolic syndrome, and hyperuricemia are the reported risk factors for chronic kidney disease (CKD) and cardiovascular disease (CVD). However, the best predictor of changes in renal function in the early stages of renal disease in a healthy middle-aged population is still unknown. Our study evaluated the correlation between changes in renal function and common risk factors to determine such a predictor.
In total, 2,853 healthy persons aged ≤50 years participated in the study. They had no proteinuria and were not on medications for hypertension, diabetes mellitus, hyperlipidemia, or hyperuricemia. Over 2 years, participants underwent annual health screening. The relationship between changes in estimated glomerular filtration rate (eGFR) and changes in risk factors for CKD was evaluated using univariate and multivariate linear regression analyses.
Over 2 years, eGFR showed a significant decrease. Univariate regression analysis revealed that changes in fasting plasma glucose (FPG), total cholesterol, LDL-cholesterol, serum uric acid levels, and hemoglobin showed a significant negative correlation with changes in eGFR. Multiple regression analysis confirmed that changes in FPG, serum uric acid levels, in particular, and hemoglobin had a significant negative correlation with changes in eGFR.
The changes in eGFR and other variables over 2 years were small and could be within expected biologic variation. A longer observational study is needed to elucidate whether FPG, serum uric acid and hemoglobin represent the earliest markers of eGFR decline.
PMCID: PMC4232529  PMID: 25396414
18.  Elevated Blood Pressure and Serum γ -Glutamyltransferase as Significant Characteristics of Smokers With Chronic Kidney Disease 
Nephro-urology Monthly  2014;6(4):e20746.
Smoking is a risk factor for chronic kidney disease (CKD). However, it is speculated that only a small subset of sensitive smokers develop CKD.
We aimed to reveal the characteristics of such smokers sensitive to the renal effects of smoking with respect to cardiovascular (CV) risk factors associated with smoking and/or CKD.
Patients and Methods:
Renal functions and CVD risk factors were assessed in middle-aged male workers. The patients were comprised of 336 nonsmokers, 332 smokers currently smoking up to one pack per day, and 38 who smoked more than one pack per day. CKD was determined by estimated glomerular filtration rate (eGFR) from serum creatinine and urinary albumin to creatinine ratio (ACR). The independent and interactive effects of smoking and CKD on the CVD risk factors adjusted for age, body mass index, alcohol consumption, and physical activity were statistically analyzed.
In comparison to nonsmokers, smokers had significantly higher waist circumference, white blood cells (WBC), serum triglycerides, γ-glutamyltransferase (GGT), and C-reactive protein (CRP) and lower serum high-density lipoprotein cholesterol and uric acid. On the other hand, blood pressure (BP) and WBC tended to be higher in those showing CKD than others. Serum GGT and fasting plasma glucose were significantly higher, and insulin resistance index of homeostatic model assessment (HOMA-IR) tended to be higher in those with CKD. Serum CRP was especially high in those with moderate to severe CKD. A significant interactive effect of smoking and CKD on BP and serum GGT levels was detected, i.e. BP and GGT were not different in the subjects among nonsmokers with and without CKD, but were conspicuously high among smokers with CKD. No significant interactive effect was found on either HOMA-IR or serum CRP.
Smokers with a higher BP and/or serum GGT may be at a higher risk of developing CKD. The associations of BP and serum GGT with CKD in smokers are not entirely mediated by increased insulin resistance or chronic inflammation caused by smoking.
PMCID: PMC4317723
Smoking; Chronic Kidney Disease; Blood Pressure; Serum gamma-glutamyltransferase; Insulin resistance; Inflammation
19.  Effect of pegloticase on renal function in patients with chronic kidney disease: a post hoc subgroup analysis of 2 randomized, placebo-controlled, phase 3 clinical trials 
BMC Research Notes  2014;7:54.
Pegloticase is approved in the US for treatment of refractory chronic gout. Since chronic kidney disease (CKD) is common in these patients, we conducted a post-hoc analysis of 2 replicate phase 3 trials and the subsequent open-label extension study to determine the effects of pegloticase on renal function in patients with CKD stages 3 and 4, as well as the effects of renal dysfunction on pegloticase efficacy and safety.
Patients with renal insufficiency were randomized to pegloticase 8 mg every 2 weeks (n = 42), pegloticase 8 mg every 4 weeks (n = 41), or placebo (n = 20) for 6 months as defined by the study protocols. Renal function was assessed by estimated glomerular filtration rate (eGFR). All patients completing the randomized trials could participate in an open-label extension study for a further 2.5 years. Uric acid response, the primary end point in the trials, was plasma uric acid <6.0 mg/dl for 80% of months 3 and 6.
Mean eGFR in both pegloticase dosing cohorts remained constant over the randomized treatment phase and long-term open-label extension study. The number of patients achieving uric acid response was similar across CKD stages (32% stage 1, 23% stage 2, 35% stage 3, and 39% stage 4, respectively, P = 0.3). There was no difference in the pegloticase safety profile based on CKD stage.
Pegloticase treatment does not impact eGFR in CKD patients and response to pegloticase is independent of CKD stage.
Trial registration
Clinical trial identifier: NCT00325195
PMCID: PMC3937145  PMID: 24447425
Refractory chronic gout; Uric acid; Kidney; Renal function
20.  A delta-aminolevulinic acid dehydratase (ALAD) polymorphism may modify the relationship of low-level lead exposure to uricemia and renal function: the normative aging study. 
Environmental Health Perspectives  2003;111(3):335-341.
In this study we investigated whether a known delta-aminolevulinic acid dehydratase (ALAD) exon 4 polymorphism has a modifying effect on the association of blood or bone lead level with uricemia and indices of renal function among middle-aged and elderly men. We performed a cross-sectional study of subjects who participated between 1991 and 1995 in the Department of Veterans Affairs Normative Aging Study. Information on blood lead levels, bone lead levels (measured by K-shell X-ray fluorescence), serum uric acid, serum creatinine, estimated creatinine clearance, and ALAD polymorphism status was available in 709 subjects. Regression models were constructed to examine the relationships of serum uric acid, serum creatinine, and estimated creatinine clearance to blood or bone lead level, stratified by genotype. We also adjusted for age, body mass index, blood pressure, smoking, alcohol consumption, and ingestion of analgesic medications (n = 638). Of the 709 subjects, 7 (1%) and 107 (15%) were homozygous and heterozygous for the variant (ALAD-2) allele, respectively. The mean (range) serum uric acid and creatinine levels were 6.5 (2.9-10.6) and 1.2 (0.6-2.5) mg/dL. No significant differences were found in serum uric acid, serum creatinine, or estimated creatinine clearance by ALAD genotype. However, after adjusting for other potential confounders, we found a significant linear relationship between serum uric acid and patella bone lead (p = 0.040) among the ALAD 1-2/2-2 genotype individuals above a threshold patellar lead level of 15 micro g/g. In contrast, among the wild-type (ALAD 1-1) individuals, there was a suggestion of a significant linear relationship of serum uric acid with patella bone lead (p = 0.141), but only after a threshold of 101 micro g/g. There was evidence of a significant (p = 0.025) interaction of tibia lead with genotype (ALAD 1-1 vs. ALAD 1-2/2-2) regarding serum creatinine as an outcome, but in the same linear regression model tibia lead alone was not a significant predictor of serum creatinine. Conversely, for estimated creatinine clearance, patella lead, but not the interaction of patella lead with genotype, was a significantly independent predictor (p = 0.026). Our findings suggest that ALAD genotype may modify the effect of lead on the renal excretion of uric acid as well as overall renal function among middle-aged and elderly men who had community (nonoccupational) exposures to lead. Additional research is needed to ascertain whether this constitutes a true gene-environment interaction and, if so, its clinical impact.
PMCID: PMC1241391  PMID: 12611663
21.  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.
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.
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).
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.
In type 2 diabetic individuals with preserved kidney function, hyperuricemia seems to be an independent risk factor for the development of incident CKD.
PMCID: PMC3241303  PMID: 22028277
22.  Uric acid and IGF1 as possible determinants of FGF23 metabolism in children with normal renal function 
Fibroblast growth factor 23 (FGF23) is a phosphaturic hormone and a suppressor of renal 1α hydroxylase. Although circulating values of FGF23 are increased in early chronic kidney disease (CKD), the interplay between FGF23 levels, growth and nutritional biomarkers has not been evaluated in children with normal renal function.
We performed a secondary analysis of the cross-sectional observational INU23 study in 98 children (51 boys, mean age 10.5 ± 3.9 years) with preserved renal function (glomerular filtration rate (GFR) 114 ± 14 ml/min/1.73 m2).
In bivariate analyses, C-terminal FGF23 levels were positively related to phosphorus and uric acid levels. Intact FGF23 levels were positively associated with uric acid and insulin growth factor 1 (IGF1) levels, with similar results for age, body mass index (BMI), and 25OH vitamin D (25(OH) D). By multivariable analyses, 25(OH)D, uric acid, and phosphorus were independent predictors of C-terminal FGF23, while 25(OH)D, uric acid, and IGF1 were independent predictors of intact FGF23.
In children with preserved kidney function, the association between FGF23, uric acid, and IGF1 suggests that FGF23 could be an early nutritional indicator of high protein and phosphate intake. The association between FGF23 and IGF1 also suggests a relationship between FGF23 and growth, and warrants further investigation.
PMCID: PMC3793329  PMID: 22311343
Children; FGF23; Uric acid; IGF1; Inulin clearance; Growth
23.  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.
PMCID: PMC3107767  PMID: 21051501
chronic kidney disease; epidemiology and outcomes; risk factors
24.  The Value of Serum Uric Acid as a Mortality Prediction in Critically Ill Children 
Iranian Journal of Pediatrics  2010;20(3):323-329.
The role of initial serum uric acid on admission in critically ill patients is controversial; we presumed that uric acid level can predict the mortality of the admitted patients to intensive care unit as a simple test.
Totally, 220 consecutively admitted children (96 girls, 124 boys) with mean age 3.5 years, who were at least 24 hours in pediatric intensive care unit (PICU), were enrolled in a prospective cohort study during January 2006 to December 2007. The subsequent PICU admission in the same hospitalization, those who were discharged from the hospital and then re-admitted to the PICU during the observation period, and the patients with chronic renal failure were excluded. Serum uric acid level was measured during the first day of PICU admission. Death or transfer from PICU was considered as final outcome. The statistical analysis was done by using linear regression analysis, ROC curve, Student t-test, and Chi- square. P value less than 0.05 was considered significant.
From 44 patients who had serum uric acid level more than 8 mg/dl, 17 cases died showing with a higher relative risk of 1.88, higher mortality (P<0.05). The relative risk of death in patients who had serum uric acid >8 mg/dl and needed vasopressor was 1.04, and in those under mechanical ventilation 1.33. In patients who scored pediatric risk of mortality of >38 it was 1.4, and in septic cases 4 (P<0.05). Stepwise linear regression analysis showed that mainly the need for mechanical ventilation (P=0.001) and vasopressor had statistically significant correlation with the poor outcome (P=0.001).
Uric acid level during the first day of intensive critical care admission is not an independent risk of mortality in PICU. Need for mechanical ventilation or inotropic agents was associated with poor outcome and only higher uric acid level in sepsis played an additive risk factor role.
PMCID: PMC3446040  PMID: 23056724
Uric Acid; Mortality; Intensive care; Death; Pediatrics; Sepsis; Hyperuricemia
25.  Relation between serum uric acid and lower limb blood flow in patients with chronic heart failure. 
Heart  1997;78(1):39-43.
OBJECTIVE: To determine whether lower limb blood flow is related to serum uric acid concentrations in patients with chronic heart failure, taking into account the hyperuricaemic effects of diuretic treatment and insulin resistance. DESIGN: Lower limb blood flow was measured at rest and after maximum exercise followed by a five minute period of ischaemia (maximum blood flow) using strain gauge venous occlusion plethysmography. All patients underwent a metabolic assessment, which included an intravenous glucose tolerance test (IVGTT)-to obtain an index of insulin sensitivity- and measurement of serum uric acid. SETTING: University and hospital departments specialising in cardiology and metabolic medicine. SUBJECTS: 22 patients with chronic heart failure. RESULTS: Mean (SEM) resting and maximum blood flow values were 2.87 (0.23) and 24.00 (1.83) ml/100 ml/min, respectively. Patients in the upper tertile of serum uric acid had lower maximum blood flow than those in the lowest tertile (15.6 (2.2) v 31.0 (2.1) ml/100 ml/min, P = 0.003). Serum uric acid correlated with maximum blood flow (r = -0.86, P < 0.001), but not with resting blood flow. In stepwise regression analysis, uric acid emerged as the only predictor of maximum blood flow (standardised coefficient = -0.83 (P < 0.001), R2 = 0.68 (P < 0.001)), independently of diuretic dose, age, body mass index, plasma creatinine, fasting and IVGTT glucose and insulin, insulin sensitivity, maximum oxygen uptake and exercise time during the treadmill exercise test, and alcohol intake. CONCLUSIONS: There is a strong inverse relation between serum uric acid concentrations and maximum leg blood flow in patients with chronic heart failure. Further studies are needed to determine whether serum uric acid can be used as an index of vascular function in cardiovascular diseases.
PMCID: PMC484862  PMID: 9290400

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