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1.  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
2.  Cystatin C and asymptomatic coronary artery disease in patients with metabolic syndrome and normal glomerular filtration rate 
Background
All of the components of Metabolic syndrome (MetS) have been regarded as risk factors for coronary artery disease (CAD). Early detection of CAD in asymptomatic patients with MetS remains a challenge. Cystatin C,which has been proposed as a novel marker of renal dysfunction,is correlated with mortality in CAD, The purpose of the study was to evaluate whether cystatin C is a potential marker of asymptomatic CAD in MetS patients with normal kidney function.
Methods
A total of 211asymptomatic MetS patients without prior history of CAD patients were included in a cross-sectional study. Patients were divided into MetS with asymptomatic CAD (n = 136) and MetS without CAD (n = 75) groups according to coronary angiograph results. Serum cystatin C levels were measured using particle enhanced immunonephelometric assays. We first assessed whether there is an independent association of cystatin C with the presence and severity of asymptomatic CAD. Then, we investigated the association between cystatin C and other biochemical risk factors for atherosclerosis.
Results
Serum cystatin C levels in patients with asymptomatic CAD were significantly higher than those without CAD (P = 0.004). A multiple logistic regression analysis demonstrated cystatin C was independently associated with the presence of asymptomatic CAD (OR = 1.326, 95%CI: 1.086-1.619). On receiver operating characteristics (ROC) analysis, the area under the curve (AUC) was 0.622 (95 % CI: 0543–0.701, P = 0.003), and cystatin C showed a moderate predictive value. Furthermore, cystatin C was independently correlated with Gensini score (standardized β = 0.183, P = 0.007), and serum cystatin C levels increased with the increasing of number of disease vessels (P = 0.005). In a multiple stepwise regression analysis, uric acid (UA)(P < 0.001), body mass index (BMI)(P = 0.002), triglyceride(TG)(P = 0.03), estimated glomerular filtration rate (eGFR)(P < 0.001), and fibrinogen(P = 0.001) were independently associated with cystatin C.
Conclusions
Serum cystatin C in our study was significantly associated with the presence and severity of asymptomatic CAD in MetS patients with normal kidney function, suggesting that cystatin C is probably more than a marker of glomerular filtration rate.
doi:10.1186/1475-2840-11-108
PMCID: PMC3473246  PMID: 22978689
Cystatin C; Gensini score; Metabolic syndrome; Asymptomatic coronary artery disease
3.  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
4.  Relationship between Inflammatory Cytokines and Uric Acid Levels with Adverse Cardiovascular Outcomes in Patients with Stable Coronary Heart Disease 
PLoS ONE  2012;7(9):e45907.
Background
So far it is unclear whether the association between serum uric acid (SUA), inflammatory cytokines and risk of atherosclerosis is causal or an epiphenomenon. The aim of the project is to investigate the independent prognostic relationship of inflammatory markers and SUA levels with adverse cardiovascular outcomes in a patient population with stable coronary heart disease (CHD).
Methods
SUA, C-reactive protein (CRP) and interleukin (IL)-6 were measured at baseline in a cohort of 1,056 patients aged 30–70 years with CHD. Cox proportional hazards model was used to determine the prognostic value of these markers on a combined CVD endpoint during eight year follow-up after adjustment for covariates.
Results
For 1,056 patients with stable coronary heart disease aged 30–70 years (mean age 58.9 years, SD 8.0) follow-up information and serum measurements were complete and n = 151 patients (incidence 21.1 per 1000 patients years) experienced a fatal or non-fatal CVD event during follow-up (p-value = 0.05 for quartiles of SUA, p = 0.002 for quartiles of CRP, p = 0.13 for quartiles of IL-6 in Kaplan-Meier analysis). After adjustment for age, gender and hospital site the hazard ratio (HR) for SUA increased from 1.37 to 1.65 and 2.27 in the second, third, and top quartile, when compared to the bottom one (p for trend <0.0005). The HR for CRP increased from 0.85 to 0.98 and 1.64 in the respective quartiles (p for trend 0.02). After further adjustment for covariates SUA still showed a clear statistically significant relationship with the outcome (p for trend 0.045), whereas CRP did not (p for trend 0.10).
Conclusion
The data suggest that compared to inflammatory markers such as CRP and IL-6 serum uric acid levels may predict future CVD risk in patients with stable CHD with a risk increase even at levels considered normal.
doi:10.1371/journal.pone.0045907
PMCID: PMC3448711  PMID: 23029307
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.  Relationship of Serum Uric Acid Level and Angiographic Severity of Coronary Artery Disease in Male Patients with Acute Coronary Syndrome 
Pakistan Journal of Medical Sciences  2013;29(5):1137-1141.
Background and objective: The association between serum uric acid and ischemic heart disease remains controversial and it has not yet been established as cardiovascular risk factor. Our objective was to study the association of serum uric acid level with angiographic severity of coronary artery disease in men with acute coronary syndrome (ACS).
Methods : This cross-sectional study was conducted on 100 consecutive male patients presenting with ACS at Punjab Institute of Cardiology. Hyperuricemia was defined as serum uric acid level > 6.5 mg/dl. Severity of ischemic heart disease was assessed on the basis of Gensini score, number of diseased vessels, critical lesions and total occlusions on coronary angiogram.
Results: Mean age of normouricemic group (n=59) was 52.62 ± 9.46 years and mean age of hyperuricemic group (n=41) was 50.52 ± 9.40 years (p=0.273). Mean uric acid level; normouricemic group (4.75 ± 1.05), hyperuricemic group (7.61 ± 1.24), p<0.001. Mean Gensini score; normouricemic group (22.15 ± 21.52), hyperuricemic group (35.69 ± 26.80). Mann Whitney U test was applied to compare the Gensini score of two groups and it showed statistically significant difference (p value <0.006). Critical lesions, total occlusions and multi-vessel disease were more frequent in hyperuricemic group but statistically significant difference was found only for total occlusions (p=0.013) and critical lesions (p=0.046).
Conclusions : Hyeruricemia is associated with higher Gensini score and more frequent total occlusions and critical lesions in men presenting with acute coronary syndrome.
PMCID: PMC3858930  PMID: 24353707
Acute coronary syndrome; CVD risk factors; Gensini score; Serum uric acid
7.  Variation in High-Sensitivity C-Reactive Protein Levels over 24 Hours in Patients with Stable Coronary Artery Disease 
Texas Heart Institute Journal  2010;37(1):42-48.
Limited, controversial data exist regarding changes in high-sensitivity C-reactive protein (hs-CRP) levels over short times and the importance of detecting these changes in patients who have coronary artery disease (CAD). We investigated the variation of hs-CRP levels and their association with the severity of CAD in patients with stable CAD.
We measured morning, midday, evening, and midnight hs-CRP levels in 124 patients (94 with CAD, 30 with normal coronary arteries), who were evaluated via coronary angiography and Gensini scoring. Patients were divided into 3 groups (normal coronary arteries, mild CAD, or severe CAD) according to Gensini score.
Temporal hs-CRP levels varied significantly—the highest mean concentrations were found in the morning, and the lowest concentrations at midday (P <0.001). All temporal hs-CRP measurements and the absolute increase in hs-CRP levels were significantly higher in patients with severe CAD (both P <0.001). The most significant predictors of CAD severity were age (P=0.005), midday hs-CRP level (P <0.001), and brain natriuretic peptide level (P=0.045). Receiver operating characteristic curve analysis showed that cutoff values of hs-CRP taken at different times predicted severe CAD with similar sensitivity and specificity. Different cutoff values for temporal hs-CRP levels correlated with the severity of CAD. Serum levels of hs-CRP varied over 24 hours, whether patients had CAD or normal coronary arteries.
PMCID: PMC2829811  PMID: 20200626
Analysis of variance; biological markers/ blood; C-reactive protein/analysis; coronary artery disease/blood; coronary stenosis; predictive value of tests; reference values; time factors
8.  A Comparative Study of Serum Uric Acid levels and Lipid Ratios in Coronary Artery Disease Patients 
Introduction:
Coronary Artery Disease (CAD) appears to be common in the Indian population of different geographical origins, religions and languages. Measurement of lipid fractions and ratios are widely recommended for risk assessment. A few studies have shown that serum uric acid plays a role in the development of cardiovascular morbidity. Very few reports are cited linking serum uric acid with the lipid fraction in CAD
Objectives:
To find the significance of non-HDL cholesterol, LDL-c/HDL-c ratio, TC/HDL ratio and serum uric acid level in CAD patients
Subjects and Methodology:
In this study, we included fifty CAD patients as subjects and an equal number of controls. Both subjects and controls were assessed for anthropometric, physiological and biochemical parameters
Results:
The present study showed significant increased levels of total cholesterol (p=0.002), TAGs (p<0.001), HDL (p=0.005), LDL (p<0.006) and non-HDL cholesterol (p<0.001). LDL-c/HDL-c ratio (p<0.001) and TC/HDL ratio (p<0.001) in CAD patients (subjects) were also significant when compared to controls. Uric acid level in CAD patients was increased (p<0.001).
Conclusion:
Serum Uric Acid, TC/HDL and LDL/HDL ratios could be regarded as objective markers, in association with existing atherogenic dyslipidemia in patients with CAD.
PMCID: PMC4092080  PMID: 25018681
Coronary Artery Disease; Serum Uric Acid; Lipid Ratio
9.  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
10.  Association of glycemic variability and the presence and severity of coronary artery disease in patients with type 2 diabetes 
Background
Glucose variability is one of components of the dysglycemia in diabetes and may play an important role in development of diabetic vascular complications. The objective of this study was to assess the relationship between glycemic variability determined by a continuous glucose monitoring (CGM) system and the presence and severity of coronary artery disease (CAD) in patients with type 2 diabetes mellitus (T2DM).
Methods
In 344 T2DM patients with chest pain, coronary angiography revealed CAD (coronary stenosis ≥ 50% luminal diameter narrowing) in 252 patients and 92 patients without CAD. Gensini score was used to assess the severity of CAD. All participants' CGM parameters and biochemical characteristics were measured at baseline.
Results
Diabetic patients with CAD were older, and more were male and cigarette smokers compared with the controls. Levels of the mean amplitude of glycemic excursions (MAGE) (3.7 ± 1.4 mmol/L vs. 3.2 ± 1.2 mmol/L, p < 0.001), postprandial glucose excursion (PPGE) (3.9 ± 1.6 mmol/L vs. 3.6 ± 1.4 mmol/L, p = 0.036), serum high-sensitive C-reactive protein (hs-CRP) (10.7 ± 12.4 mg/L vs. 5.8 ± 6.7 mg/L, p < 0.001) and creatinine (Cr) (87 ± 23 mmol/L vs. 77 ± 14 mmol/L, p < 0.001) were significantly higher in patients with CAD than in patients without CAD. Gensini score closely correlated with age, MAGE, PPGE, hemoglobin A1c (HbA1c), hs-CRP and total cholesterol (TC). Multivariate analysis indicated that age (p < 0.001), MAGE (p < 0.001), serum levels of HbA1c (p = 0.022) and hs-CRP (p = 0.005) were independent determinants for Gensini score. Logistic regression analysis revealed that MAGE ≥ 3.4 mmol/L was an independent predictor for CAD. The area under the receiver-operating characteristic curve for MAGE (0.618, p = 0.001) was superior to that for HbA1c (0.554, p = 0.129).
Conclusions
The intraday glycemic variability is associated with the presence and severity of CAD in patients with T2DM. Effects of glycemic excursions on vascular complications should not be neglected in diabetes.
doi:10.1186/1475-2840-10-19
PMCID: PMC3056765  PMID: 21349201
11.  Effects of irbesartan on serum uric acid levels in patients with hypertension and diabetes 
Background
Hyperuricemia has been proposed to be a risk factor for cardiovascular disease and chronic kidney disease. Since diabetes is often complicated by hypertension and hyperuricemia, efficient therapeutic strategy against these two complications is very important in diabetic treatment. It has been reported that the antihypertensive drug, irbesartan, inhibits the renal uric acid reabsorptive transporters, URAT1 and GLUT9; this result suggests that irbesartan decreases serum uric acid level (SUA).
Subjects and methods
A retrospective study of 107 patients with hypertension and diabetes was performed to analyze the effects of irbesartan on blood pressure, estimated glomerular filtration rate (eGFR), and SUA. The follow-up period was 6–12 months. Seventy percent of the patients were diagnosed with diabetic nephropathy stage II–IV. We excluded patients treated with drugs that influenced SUA. The multiple logistic regression analysis was introduced to identify the relative factors for SUA decline. The time-dependent SUA changes were examined in a mixed-linear model.
Results
Irbesartan reduced blood pressure significantly after 1, 6, and 12 months’ treatment. No subject showed significant change in eGFR from baseline level throughout the period. The multiple logistic regression analysis revealed that SUA baseline significantly influenced SUA decline after 6–12 months. In patients whose SUA baseline was ≥5.9 mg/dL, the SUA was significantly decreased from 6.6±0.16 mg/dL to 6.2±0.16 mg/dL (P=0.010), after 12 months’ irbesartan treatment. In the SUA baseline <5.9 mg/dL group, the SUA did not show significant change over the monitoring period.
Conclusion
Our results demonstrate that irbesartan reduces the risk of hyperuricemia. No decline in renal function was observed after the initiation of irbesartan treatment. The present report determines the criteria of SUA baseline for introducing an antihyperuricemic effect using irbesartan. Its antihypertensive effect coupled with SUA decline would be effective for the treatment of hypertension complicated by hyperuricemia.
doi:10.2147/CPAA.S61462
PMCID: PMC4014383  PMID: 24833923
angiotensin-receptor blocker; diabetes; hypertension; hyperuricemia; serum 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.
doi:10.1111/j.1751-7176.2011.00574.x
PMCID: PMC3507473  PMID: 22277138
Alaska Eskimos; chronic kidney disease; epidemiology; hypertension; uric acid
13.  Association of Maximum Weight with Hyperuricemia Risk: A Retrospective Study of 21,414 Chinese People 
PLoS ONE  2012;7(11):e51186.
Background
Obesity has been demonstrated to be associated with increased serum uric acid (SUA); however, little is known regarding the relationship between maximum weight, or maximum weight fluctuation, and uric acid concentration. Through retrospective means, we determined the association of maximum weight with SUA risk.
Methods
Data of 21,414 participants (8,630 males and 12,784 females) from the 2007-8 China National Diabetes and Metabolic Disorders Study were analyzed for parameters including lifestyle habits, biochemical blood analysis and self-reported maximum weight.
Results
Elevated SUA subjects shared a cluster of demographic features. After adjustment for age, gender, education, smoking, drinking, physical activity, WHR, height, eGFR(evaluate glomerular filtration rate), and diuretic usage, multivariate logistic regression models demonstrated maximum weight was associated with increased risk of elevated SUA level (P<0.001). Duration of maximum weight was related with decreased risk of elevated SUA level (P<0.001). There was a significant correlation between time of weight loss and risk of increased SUA level reduction (P<0.001). Furthermore, our data indicated that the degree of weight loss from maximum weight was another important factor for the risk of increased SUA level reduction (P<0.001). Finally, ROC curve analysis revealed area under the curve was 0.661 (95% CI, 0.647-0.674), statistically significant for maximum weight association with hyperuricemia (P<0.001).
Conclusions
Maximum weight is a strong risk factor for increased uric acid level in the Chinese population, which might serve as a novel clinical indicator suggesting hyperuricemia. Controlling maximum weight, keeping weight to the appropriate range, and maintaining the stable weight may be conducive for decreasing risk of hyperuricemia.
doi:10.1371/journal.pone.0051186
PMCID: PMC3511391  PMID: 23226486
14.  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
15.  Elevated Serum Uric Acid Is Associated with High Circulating Inflammatory Cytokines in the Population-Based Colaus Study 
PLoS ONE  2011;6(5):e19901.
Background
The relation of serum uric acid (SUA) with systemic inflammation has been little explored in humans and results have been inconsistent. We analyzed the association between SUA and circulating levels of interleukin-6 (IL-6), interleukin-1β (IL-1β), tumor necrosis factor- α (TNF-α) and C-reactive protein (CRP).
Methods and Findings
This cross-sectional population-based study conducted in Lausanne, Switzerland, included 6085 participants aged 35 to 75 years. SUA was measured using uricase-PAP method. Plasma TNF-α, IL-1β and IL-6 were measured by a multiplexed particle-based flow cytometric assay and hs-CRP by an immunometric assay. The median levels of SUA, IL-6, TNF-α, CRP and IL-1β were 355 µmol/L, 1.46 pg/mL, 3.04 pg/mL, 1.2 mg/L and 0.34 pg/mL in men and 262 µmol/L, 1.21 pg/mL, 2.74 pg/mL, 1.3 mg/L and 0.45 pg/mL in women, respectively. SUA correlated positively with IL-6, TNF-α and CRP and negatively with IL-1β (Spearman r: 0.04, 0.07, 0.20 and 0.05 in men, and 0.09, 0.13, 0.30 and 0.07 in women, respectively, P<0.05). In multivariable analyses, SUA was associated positively with CRP (β coefficient ± SE = 0.35±0.02, P<0.001), TNF-α (0.08±0.02, P<0.001) and IL-6 (0.10±0.03, P<0.001), and negatively with IL-1β (−0.07±0.03, P = 0.027). Upon further adjustment for body mass index, these associations were substantially attenuated.
Conclusions
SUA was associated positively with IL-6, CRP and TNF-α and negatively with IL-1β, particularly in women. These results suggest that uric acid contributes to systemic inflammation in humans and are in line with experimental data showing that uric acid triggers sterile inflammation.
doi:10.1371/journal.pone.0019901
PMCID: PMC3098830  PMID: 21625475
16.  Impaired renal function is a major determinant of left ventricular diastolic dysfunction: assessment by stress myocardial perfusion imaging 
Annals of Nuclear Medicine  2013;27:729-736.
Objective
Relationships between myocardial scintigraphic parameters and renal function have not been fully determined. We investigated correlations between estimated glomerular filtration rate (eGFR) and left ventricular (LV) diastolic function using stress electrocardiographic (ECG)-gated myocardial single photon emission computed tomography (SPECT).
Methods
We enrolled 136 consecutive patients with suspected coronary artery disease (CAD) who were assessed using technetium-99m stress ECG-gated myocardial SPECT. We evaluated SPECT images using 17-segment defect scores graded on a 5-point scale, summed stress score, summed rest score and summed difference score (SDS). The parameters for assessing LV diastolic function were peak filling rate (PFR), 1/3 mean filling rate and time to peak filling. The CAD was defined as SDS ≥2. Chronic kidney disease (CKD) was defined as eGFR <60 mL/min/1.73 m2. Patients were assigned to the following four groups (no CAD/no CKD: control group, n = 68; CAD/no CKD: CAD group, n = 24; no CAD/CKD: CKD group, n = 34; CAD/CKD: CAD + CKD group, n = 10).
Results
The PFR was significantly impaired after stress in the CKD and CAD + CKD groups compared with controls (p < 0.001 for both). Furthermore, PFR at rest positively correlated with eGFR (r = 0.29, p < 0.001) and inversely correlated with SDS (r = −0.18, p < 0.05). Multivariate stepwise regression analysis independently associated eGFR with PFR (β coefficient = 0.260, p = 0.002).
Conclusions
Our data suggest that impaired renal function is a significant determinant of LV diastolic dysfunction in patients with suspected CAD.
doi:10.1007/s12149-013-0739-z
PMCID: PMC3824632  PMID: 23712332
Chronic kidney disease; Estimated glomerular filtration rate; Coronary artery disease; Left ventricular diastolic function; Gated SPECT
17.  Elevated serum adipocyte fatty acid-binding protein concentrations are independently associated with renal dysfunction in patients with stable angina pectoris 
Background
Chronic kidney disease (CKD) is associated with cardiovascular events. Adipocyte fatty acid-binding protein (A-FABP) plays an important role in atherosclerosis. We investigated whether plasma A-FABP is involved in renal function in patients with stable angina pectoris.
Methods
A total of 221 patients with significant coronary artery stenosis were enrolled after coronary angiography. CKD was defined as an estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m2. The severity of coronary stenosis was assessed using a modified Gensini score and coronary angiography. Serum A-FABP levels were determined by enzyme-linked immunosorbent assay.
Results
Serum A-FABP levels were significantly correlated with both eGFR (r = -0.41, p < 0.01) and the severity of coronary artery stenosis (r = 0.16, p = 0.02), and these relationships remained significant after adjusting for confounding factors. The prevalence of CKD and multi-vessel disease was significantly higher among patients with serum A-FABP levels above the median value of 20.3 ng/ml than among patients with serum A-FABP levels below the median value (57% vs. 27%, p < 0.01 and 64% vs. 48%, p = 0.02, respectively). Multivariate analysis revealed that the presence of three-vessel disease in comparison with single-vessel disease was independently associated with the higher A-FABP (per doubling) (odds ratio; 2.26, 95% confidential interval; 1.28-3.98, p < 0.01) and tended to be associated with the lower eGFR (p = 0.06).
Conclusion
Serum A-FABP may have a significant role in the interplay between renal dysfunction and coronary atherosclerosis.
doi:10.1186/1475-2840-11-26
PMCID: PMC3353231  PMID: 22433902
Adipocyte; Fatty acid-binding protein; Renal dysfunction; Coronary artery disease
18.  Clinical Value of Serum Uric Acid in Patients with Suspected Coronary Artery Disease 
Background/Aims
Although increased serum uric acid (SUA) concentrations are commonly encountered in patients with risk factors for coronary artery disease (CAD), the clinical value of SUA has not been established.
Methods
The study group comprised 687 consecutive patients with suspected CAD who had undergone coronary angiography. CAD was defined as stenosis ≥ 50% of the luminal diameter. CAD severity was expressed as 1-, 2-, or 3-vessel disease. Metabolic syndrome (MS) was defined according to National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATP III) criteria, and aortofemoral pulse wave velocity (PWV) was obtained by arterial catheterization invasively.
Results
In total, 395 patients had CAD. SUA was higher in patients with CAD as compared to those without CAD (5.5 ± 1.0 vs. 5.2 ± 1.0 mg/dL, p = 0.004). In addition, SUA was significantly associated with the severity of CAD (p = 0.002). However, after adjusting for significant confounding factors including age, diabetes, smoking, cholesterol, MS, and PWV, SUA was not an independent risk factor for CAD (p = 0.151). Based on a subgroup analysis, SUA was more closely associated with CAD in women than in men, and in the highest quartile (≥ 6.4 mg/dL) than in the first quartile (< 4.8 mg/dL); however, these results were not significant (p = 0.062, p = 0.075, respectively). In a multivariate regression analysis, the most important determinant of SUA was MS (i.e., insulin resistance syndrome), which is strongly associated with CAD.
Conclusions
In patients with suspected CAD, SUA was not an independent risk factor for CAD and may be merely a marker of insulin resistance.
doi:10.3904/kjim.2010.25.1.21
PMCID: PMC2829412  PMID: 20195399
Coronary artery disease; Insulin resistance; Uric acid
19.  Decreased Renal Function Is an Independent Predictor of Severity of Coronary Artery Disease: An Application of Gensini Score 
Journal of Korean Medical Science  2013;28(11):1615-1621.
Coronary artery disease (CAD) is the leading cause of death in patients with chronic kidney disease (CKD).Although many studies have shown a higher prevalence of CAD among these patients, the association between the spectrum of renal dysfunction and severity of CAD remains unclear. In this study, we investigate the association between renal function and the severity of CAD. We retrospectively reviewed the medical records of 1,192 patients who underwent elective coronary angiography (CAG). The severity of CAD was evaluated by Gensini score according to the degree of luminal narrowing and location(s) of obstruction in the involved main coronary artery. In all patients, the estimated glomerular filtration rate (eGFR) was independently associated with Gensini score (β=-0.27, P < 0.001) in addition to diabetes mellitus (β=0.07, P = 0.02), hypertension (β=0.12, P < 0.001), low density lipoprotein (LDL)-cholesterol (β=0.08, P = 0.003), and hemoglobin (β=-0.07, P = 0.03) after controlling for other confounding factors. The result of this study demonstrates that decreased renal function is associated not only with the prevalence, but also the severity, of CAD.
doi:10.3346/jkms.2013.28.11.1615
PMCID: PMC3835503  PMID: 24265524
Coronary Artery Disease; Kidney Failure, Chronic; Gensini Score; Glomerular Filtration Rate
20.  Usefulness of metabolic syndrome score in the prediction of angiographic coronary artery disease severity according to the presence of diabetes mellitus: relation with inflammatory markers and adipokines 
Background
It is a matter of debate whether metabolic syndrome (MS) improves cardiovascular risk prediction beyond the risk associated with its individual components. The present study examined the association of MS score with high sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), resistin, adiponectin, and angiographic coronary artery disease (CAD) severity according to the presence of DM. In addition, the predictive value of various clinical and biochemical parameters were analyzed, including the MS score for angiographic CAD.
Methods
The study enrolled 363 consecutive patients (196 men, 62 ± 11 years of age) who underwent coronary angiography for evaluation of chest pain. Blood samples were taken prior to elective coronary angiography. MS was defined by the National Cholesterol Education Program criteria, with MS score defined as the numbers of MS components. CAD was defined as > 50% luminal diameter stenosis of at least one major epicardial coronary artery. CAD severity was assessed using the Gensini score.
Results
Of the 363 patients studied, 174 (48%) had CAD and 178 (49%) were diagnosed with MS. When the patients were divided into 4 subgroups according to MS score (0–1, 2, 3, 4–5), IL-6 levels and the CAD severity as assessed by the Gensini score increased as MS scores increased. In contrast, adiponectin levels decreased significantly as MS scores increased. When subjects were divided into two groups according to the presence of DM, the relationships between MS score and IL-6, adiponectin, and Gensini score were maintained only in patients without DM. Age, smoking, DM, MS score, and adiponectin independently predicted angiographic CAD in the whole population. However, age is the only predictor for angiographic CAD in patients with DM.
Conclusions
In the presence of DM, neither adipokines nor MS score predicted angiographic CAD. However, in non-diabetic patients, IL-6 and adiponectin showed progressive changes according to MS score, and MS score was an independent predictor of CAD in patients without DM.
doi:10.1186/1475-2840-12-140
PMCID: PMC3850730  PMID: 24088407
Metabolic syndrome; Adipokines; Coronary artery disease; Diabetes mellitus
21.  Relationship between Uric Acid and Subtle Cognitive Dysfunction in Chronic Kidney Disease 
American Journal of Nephrology  2011;34(1):49-54.
Background
Elevated serum uric acid has been associated with cognitive dysfunction and vascular cognitive impairment in the elderly. Serum uric acid is also commonly elevated in chronic kidney disease (CKD), but its relationship with cognitive function in these patients has not been addressed.
Methods
Subjects with CKD (defined as eGFR <60/ml/min/1.73 m2) were evaluated for cognitive dysfunction using the validated Standardized Mini-Mental State Examination (SMMSE). Individuals with dementia, depression or other psychiatric disorders were excluded, as were subjects on uric acid-lowering therapy or with serious illnesses such as severe anemia or active or ongoing cardiovascular or cerebrovascular disease.
Results
247 subjects were enrolled. SMMSE scores showed stepwise deterioration with increasing quartile of serum uric acid (26.4; 26.1; 25.5; 25.3, score range 20–30, p = 0.019). Post-hoc analysis demonstrated that there was no linear trend and only groups 1 and 4 were different with respect to SMMSE scores (p = 0.025). Stepwise multivariate linear regression revealed that age, educational status, presence of cerebrovascular disease, and serum uric acid were independently related to SMMSE scores.
Conclusion
Serum uric acid levels are independently and inversely associated with mild cognitive dysfunction in subjects with CKD.
doi:10.1159/000329097
PMCID: PMC3121541  PMID: 21659739
Cognitive function; Chronic kidney disease; Uric acid
22.  Value of serum glycated albumin and high-sensitivity C-reactive protein levels in the prediction of presence of coronary artery disease in patients with type 2 diabetes 
Background
Coronary artery disease (CAD) is a major vascular complication of diabetes mellitus and reveals high mortality. Up to 30% of diabetic patients with myocardial ischemia remain asymptomatic and are associated with worse prognosis compared to non-diabetic counterpart, which warrants routine screening for CAD in diabetic population. The purpose of this study was to evaluate the clinical value of serum glycated albumin and high-sensitivity C-reactive protein (hs-CRP) levels in predicting the presence of CAD in patients with type 2 diabetes.
Methods
Three hundred and twenty-four patients with type 2 diabetes were divided into two groups based on presence (CAD group, n = 241) or absence (control group, n = 83) of angiographically-documented CAD (lumen diameter narrowing ≥70%). Serum levels of glycated albumin and hs-CRP as well as serum concentrations of glucose, lipids, creatinine, blood urea nitrogen and uric acid were measured in both groups. Predictors of CAD were determined using multivariate logistic regression model and receiver-operating characteristic (ROC) curves.
Results
Serum glycated albumin and hs-CRP levels were significantly increased in diabetic patients with CAD. Multivariate regression analysis revealed that male gender, age, serum levels of glycated albumin, hs-CRP, creatinine and lipoprotein (a) were independent predictors for CAD. Areas under the curve of glycated albumin and hs-CRP and for regression model were 0.654 (95%CI 0.579–0.730, P < 0.001), 0.721 (95%CI 0.658–0.785, P < 0.001) and 0.824 (95% CI 0.768–0.879, P < 0.001), respectively. The optimal values of cut-off point were 18.7% (sensitivity 67.9%, specificity 60.0%) for glycated albumin and 5.2 mg/l (sensitivity 72.2%, specificity 60.0%) for hs-CRP to predict CAD. Logistic regression model was defined as: P/(1-P) = EXP(-1.5 + 1.265 gender + 0.812 age + 1.24 glycated albumin + 0.953 hs-CRP + 0.902 lipoprotein(a) + 1.918 creatinine). The optimal probability value for predicting CAD in type 2 diabetic patients was 0.648 (sensitivity 82.3%, specificity 68.6%).
Conclusion
Serum glycated albumin and hs-CRP levels were significantly elevated in patients with type 2 diabetes and CAD. The logistic regression model incorporating with glycated albumin, hs-CRP and other major risk factors of atherosclerosis may be useful for screening CAD in patients with type 2 diabetes.
doi:10.1186/1475-2840-5-27
PMCID: PMC1764721  PMID: 17178005
23.  Hyperuricemia and deterioration of renal function in autosomal dominant polycystic kidney disease 
BMC Nephrology  2014;15:63.
Background
The role of hyperuricemia in disease progression of autosomal dominant polycystic kidney disease (ADPKD) has not been defined well. We investigated the association of serum uric acid (sUA) with renal function and the effect of hypouricemic treatment on the rate of renal function decline.
Methods
This is a single-center, retrospective, observational cohort study. A total of 365 patients with ADPKD who had estimated glomerular filtration rate (eGFR) ≥ 15 mL/min/1.73 m2 and who were followed up for > 1 year were included in our analysis. Hyperuricemia was defined by a sUA level of ≥ 7.0 mg/dL in male and ≥ 6.0 mg/dL in female or when hypouricemic medications were prescribed.
Results
Hyperuricemia was associated with reduced initial eGFR, independent of age, sex, hypertension, albuminuria, and total kidney volume. During a median follow-up period of over 6 years, patients with hyperuricemia showed a faster annual decline in eGFR (−6.3% per year vs. −0.9% per year, p = 0.008). However, after adjusting for age, sex, hypertension and initial eGFR, sUA was no longer associated with either annual eGFR decline or the development of ESRD. Among 53 patients who received hypouricemic treatment, the annual eGFR decline appeared to be attenuated after hypouricemic treatment (pretreatment vs. posttreatment: −5.3 ± 8. 2 vs. 0.2 ± 6.2 mL/min/1.73 m2 per year, p = 0.001 by Wilcoxon signed-rank test).
Conclusions
Although hyperuricemia was associated with reduced eGFR, it was not an independent factor for renal progression in ADPKD. However, the correction of hyperuricemia may attenuate renal function decline in some patients with mild renal insufficiency.
doi:10.1186/1471-2369-15-63
PMCID: PMC4021172  PMID: 24739095
Glomerular filtration rate; Hyperuricemia; Polycystic kidney; Autosomal dominant; Uric acid
24.  Value of coronary artery calcium score to predict severity or complexity of coronary artery disease 
Arquivos Brasileiros de Cardiologia  2014;102(2):120-127.
Background
Prediction of severity or complexity of coronary artery disease (CAD) is valuable owing to increased risk for cardiovascular events. Although the association between total coronary artery calcium (CAC) score and severity of CAD, Gensini score was not used, it has been previously demonstrated. There is no information about the association between total CAC score and complexity of CAD.
Objectives
To investigate the association between severity or complexity of coronary artery disease (CAD) assessed by Gensini score and SYNTAX score (SS), respectively, and coronary artery calcium (CAC) score, which is a noninvasive method for CAD evaluation in symptomatic patients with accompanying significant CAD.
Methods
Two-hundred-fourteen patients were enrolled. Total CAC score was obtained before angiography. Severity and complexity of CAD was assessed by Gensini score and SS, respectively. Associations between clinical and angiographic parameters and total CAC score were analyzed.
Results
Median total CAC score was 192 (23.0-729.8), and this was positively correlated with both Gensini score (r: 0.299, p<0.001) and SS (r: 0.577, p<0.001). At multivariate analysis, it was independently associated with age (ß: 0.154, p: 0.027), male gender (ß: 0.126, p: 0.035) and SS (ß: 0.481, p< 0.001). Receiver-operating characteristic (ROC) curve analysis revealed a cut-off value > 809 for SS >32 (high SS tertile).
Conclusion
In symptomatic patients with accompanying significant CAD, total CAC score was independently associated with SS and patients with SS >32 may be detected through high Agatston score.
doi:10.5935/abc.20130241
PMCID: PMC3987334  PMID: 24676367
Total coronary calcium score; Gensini score; SYNTAX score; Coronary artery disease
25.  Relationship Between MMP-1, MMP-9, TIMP-1, IL-6 and Risk Factors, Clinical Presentation, Extent and Severity of Atherosclerotic Coronary Artery Disease 
Background:
Matrix metalloproteinases (MMPs) and Tissue Inhibitor of Matrix Metalloproteinases (TIMPs) may be associated with atherogenesis and plaque rupture. We evaluated the relationship between MMP-1, MMP-9, TIMP-1 and IL-6 levels and risk factors, presentation, extent and severity of atherosclerotic coronary artery disease (CAD).
Methods:
Consecutive patients who underwent coronary angiography were randomly included. The serum concentrations of MMP-1, MMP-9, TIMP-1 and IL-6 were analyzed with ELISA method in 134 patients. Participants were divided into 5 groups; stable angina pectoris (SAP; n= 34), unstable angina pectoris (USAP; n=29), non-ST elevation myocardial infarction (NSTEMI; n=16), acute ST elevation myocardial infarction (STEMI; n=25) and controls (n=30). Coronary angiographic Gensini score was calculated.
Results:
MMP-1 levels were higher in STEMI and NSTEMI groups compared with USAP, SAP and control groups (STEMI vs USAP p=0.005; STEMI vs SAP p=0.001; STEMI vs control p<0.001; NSTEMI vs USAP p=0.02; NSTEMI vs SAP p=0.027; NSTEMI vs control p<0.001). In STEMI group, MMP-9 levels were higher than USAP and control groups (p=0.002; p<0,001). TIMP-1 levels were not significantly different within all 5 groups. MMP-1 levels were found to be elevated in diabetic patients (p=0.020); whereas MMP-9 levels were higher in smokers (p=0.043). Higher MMP-1, MMP-9 and IL-6 levels were correlated with severe Left Anterior Descending artery (LAD) stenosis and higher angiographic Gensini Score (for severe LAD stenosis; r = 0.671, 0.363, 0.509 p<0.001; for Gensini score; r = 0.717, 0.371, 0.578 p<0.001).
Conclusions:
Serum levels of MMP-1, MMP-9, and IL-6 are elevated in patients with CAD; more so in acute coronary syndromes. MMP-1, MMP-9 and IL-6 are associated with more extensive and severe CAD (as represented by Gensini score).
doi:10.2174/1874192401105010110
PMCID: PMC3136999  PMID: 21772929
Matrix metalloproteinase; Interleukin-6; coronary artery disease; Gensini score.

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