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author:("jala, Diana")
1.  ELEVATED SERUM URIC ACID LEVELS ARE ASSOCIATED WITH NON-ALCOHOLIC FATTY LIVER DISEASE INDEPENDENTLY OF METABOLIC SYNDROME FEATURES IN THE UNITED STATES: LIVER ULTRASOUND DATA FROM THE NATIONAL HEALTH AND NUTRITION EXAMINATION SURVEY 
Objective
Experimental and observational studies suggest a role for uric acid in non-alcoholic fatty liver disease (NAFLD). We examined the association between serum uric acid levels and NAFLD in a large population-based study from the United States.
Materials/Methods
A cross-sectional analysis of 10,732 nondiabetic adults who participated in the National Health and Nutrition Examination Survey 1988–1994. Sex specific uric acid quartiles were defined: ≤5.2, 5.3–6.0, 6.1–6.9, and >6.9 mg/dL for men and ≤3.7, 3.8–4.5, 4.6–5.3, and >5.3 mg/dL for women. NAFLD presence and severity were defined by ultrasonographic detection of steatosis in the absence of other liver diseases. We modeled the probability that more severe NAFLD would be associated with the highest quartiles of uric acid.
Results
Compared to the 1st quartile, the odds ratio for NAFLD was 1.79 (95% C.I. 1.49–2.15, p < 0.001) and 3.14 (95% C.I. 2.63–3.75, p < 0.001) for the 3rd and 4th quartiles, respectively. After adjusting for demographics, hypertension, waist circumference, triglycerides, high-density lipoprotein-cholesterol, homeostasis model assessment-estimated insulin resistance, estimated glomerular filtration rate, and aspartate aminotransferase, uric acid (4th quartile) was significantly associated with NAFLD (odds ratio 1.43; 95% C.I. 1.16–1.76, p < 0.001). Positive parameter estimates suggest increasing uric acid is associated with greater severity of NAFLD.
Conclusions
Elevated uric acid level is independently associated with ultrasound-diagnosed NAFLD in a nationally representative sample of United States nondiabetic adults. Increasing uric acid is associated with increasing severity of NAFLD on ultrasonography. These findings warrant further studies on the role of uric acid in NAFLD.
doi:10.1016/j.metabol.2012.08.013
PMCID: PMC3565047  PMID: 23036645
hyperuricemia; NHANES; metabolic syndrome
2.  Uric Acid as a Target of Therapy in CKD 
The prevalence of chronic kidney disease (CKD) has risen and will continue to rise in the United States and worldwide. This is alarming considering that CKD remains an irreversible condition and patients who progress to chronic kidney failure suffer reduced quality of life and high mortality rates. As such, it is imperative to identify modifiable risk factors to develop strategies to slow CKD progression. One such factor is hyperuricemia. Recent observational studies have associated hyperuricemia with kidney disease. In addition, hyperuricemia is largely prevalent in patients with CKD. Data from experimental studies have revealed several potential mechanisms by which hyperuricemia may contribute to the development and progression of CKD. In this manuscript we offer a critical review of the experimental evidence linking hyperuricemia to CKD, we highlight the gaps in our knowledge on the topic as it stands today, and we review the observational and interventional studies that have examined the potential nephro-protective effect of lowering uric acid in CKD patients . While uric acid may also be linked to cardiovascular disease and mortality in patients with CKD, this review will focus only on uric acid as a potential therapeutic target to prevent kidney disease onset and progression.
doi:10.1053/j.ajkd.2012.07.021
PMCID: PMC3525781  PMID: 23058478
kidney disease progression; uric acid
3.  Association between Non-Alcoholic Liver Disease and Chronic Kidney Disease: An Ultrasound Analysis from NHANES 1988–1994 
American journal of nephrology  2012;36(5):466-471.
Background/ Aims
Non-alcoholic fatty liver disease (NAFLD) has been proposed to contribute to chronic kidney disease (CKD) independently of traditional cardiometabolic risk factors. We hypothesized that NAFLD is associated with CKD and that greater severity of NAFLD is associated with higher odds of CKD.
Methods
A cross-sectional analysis of 11,469 adults who participated in the National Health and Nutrition Examination Survey 1988–1994. NAFLD was defined by ultrasonographic detection of steatosis in the absence of other liver diseases. CKD was defined as an estimated glomerular filtration rate of ≤60 mL/min/1.73 m2 or the presence of albuminuria in subjects with an estimated glomerular filtration rate of >60 mL/min/1.73 m2.
Results
2,891 (25.4%) patients in the cohort had CKD. The prevalence of NAFLD was higher in individuals with CKD compared to those without CKD (42.2% vs. 34.5%, p<0.0001). NAFLD was associated with CKD in unadjusted logistic regression analysis (odds ratio 1.47, 95% confidence interval 1.29–1.67, p<0.0001). Adjustment for demographics and components of metabolic syndrome attenuated this relationship (odds ratio 1.04, 95% confidence interval 0.88–1.23, p=0.64). Moderate and severe NAFLD on ultrasound were increasingly associated with prevalent CKD in unadjusted analysis but not after adjustment for metabolic syndrome components.
Conclusion
After adjusting for features of metabolic syndrome, ultrasound-diagnosed NAFLD is not associated with prevalent CKD among US adults. Aggressive public health efforts are needed to prevent and treat metabolic syndrome.
doi:10.1159/000343885
PMCID: PMC3563287  PMID: 23128368
chronic kidney disease; nonalcoholic fatty liver disease; NHANES
4.  C-reactive protein as a predictor of cardiovascular events in elderly patients with chronic kidney disease 
Journal of nephrology  2012;25(5):719-725.
Background
Few studies have evaluated the relationship between high-sensitivity C-reactive protein (hs-CRP) and vascular events in the elderly with chronic kidney disease (CKD).
Methods
The relationship of hs-CRP with vascular events was examined according to CKD status in 3166 participants of the Intervention Project on Cerebrovascular Diseases and Dementia in the Community of Ebersberg, Bavaria (INVADE study). CKD was defined as a creatinine clearance <60mL/min estimated by the Cockcroft-Gault formula. hs-CRP was used as a binary variable > or < 2.1mg/l (median value). Vascular events were defined as a composite of myocardial infarction, stroke and vascular death.
Results
After 4 years of follow-up, 204 (6.4%) participants experienced a major cardiovascular event. High hs-CRP levels and CKD at baseline were associated with a greater risk of vascular events. Compared to patients with low hs-CRP/non-CKD, the adjusted HR (95% CI) for vascular events was 1.42 (1.11; 2.21) for low hs-CRP/CKD,1.57 (1.21; 2.34) for high hs-CRP/non-CKD, and 1.93 (1.45; 2.89) for high hs-CRP/CKD.
Conclusions
These results suggest that high CRP provides prognostic information in patients with CKD.
doi:10.5301/jn.5000047
PMCID: PMC3704176  PMID: 22038335
C-reactive protein; inflammation; CKD; cardiovascular disease
5.  Clinical Outcome of Hyperuricemia in IgA Nephropathy: A Retrospective Cohort Study and Randomized Controlled Trial 
Kidney & Blood Pressure Research  2011;35(3):153-160.
Background
Hyperuricemia is an independent risk factor for renal progression in IgA nephropathy (IgAN). However, no study has evaluated the effect of allopurinol on the clinical outcome in hyperuricemic IgAN.
Methods
First,a retrospective cohort study of 353 IgAN patients was conducted to explore the relationship between uric acid (UA) and the progression of renal disease over a mean period of 5 years. Then, 40 hyperuricemic IgAN patients were randomized to receive allopurinol (100–300 mg/day) or usual therapy for 6 months. The study outcomes were renal disease progression and/or blood pressure.
Results
Hyperuricemia independently predicted renal survival at 1, 3, and 5 years after adjustment for different baseline estimated glomerular filtration rates. In the randomized controlled trial, allopurinol did not significantly alter renal progression or proteinuria. The antihypertensive drug dosage was reduced in 7 of 9 cases with hypertension in the allopurinol group compared to 0 of 9 cases in the control group (p < 0.01). UA levels correlated with mean arterial pressure in normotensive patients (r = 0.388, p < 0.001).
Conclusion
Hyperuricemia predicts the progression of IgAN independently of baseline estimated glomerular filtration rate. Allopurinol may improve the control of blood pressure. Further studies are required to explore the effects of lowering UA on renal protection in IgAN.
doi:10.1159/000331453
PMCID: PMC3242707  PMID: 22116196
Hyperuricemia; IgA nephropathy; Prognosis; Outcome
6.  Age and Sex Influence Cystatin C in Adolescents With and Without Type 1 Diabetes 
Diabetes Care  2011;34(11):2360-2362.
OBJECTIVE
To compare serum cystatin C levels, a novel biomarker of renal function, in adolescents with and without type 1 diabetes and to determine what factors affect cystatin C levels.
RESEARCH DESIGN AND METHODS
Cystatin C was measured in youth 12–19 years of age with (n = 259, diabetes duration 9 ± 3 years, HbA1c 8.9 ± 1.6%) and without diabetes (n = 78). Data were compared by diabetes status, and linear regression was used to determine factors affecting cystatin C.
RESULTS
Cystatin C (0.698 ± 0.083 vs. 0.688 ± 0.127 mg/L, P = 0.40) was similar by diabetes status. In multiple linear regression, cystatin C was associated with age and serum creatinine in nondiabetic subjects and sex, age, and serum creatinine in subjects with diabetes (P < 0.05).
CONCLUSIONS
These data suggest sex differences and age-related changes in cystatin C in adolescents with type 1 diabetes. An understanding of these changes is needed to determine the potential role of cystatin C as a marker of renal function in this population.
doi:10.2337/dc11-0829
PMCID: PMC3198267  PMID: 21926294
7.  Sucrose induces Fatty Liver and Pancreatic Inflammation in Male Breeder Rats Independent of Excess Energy Intake 
Aims
Fructose induces metabolic syndrome in rats but studies have been criticized for using high concentrations of fructose that are not physiologic, for using only pure fructose, and for not controlling for energy intake. We tested the hypothesis that a 40% sucrose diet (containing 20% fructose) might induce features of metabolic syndrome in male breeder rats independent of excess energy intake.
Methods
Male Sprague-Dawley breeder rats were pair fed 40% sucrose or isocaloric starch diet for 4 months and evaluated for metabolic syndrome and diabetes. In vitro studies were performed in rat insulinoma cells (RIN-m5F) exposed to uric acid and markers of inflammation were assessed.
Results
Rats fed a 40% sucrose diet developed accelerated features of metabolic syndrome with upregulation of fructose-dependent transporter Glut 5 and fructokinase. Fatty liver and low grade pancreatic inflammation also occurred. Uric acid was found to stimulate inflammatory mediators and oxidative stress in islet cells in vitro.
Conclusions
Sucrose, at concentrations ingested by a subset of Americans, can accelerate metabolic syndrome, fatty liver and type 2 diabetes in male breeder rats, and the effects are independent of excess energy intake.
doi:10.1016/j.metabol.2011.01.008
PMCID: PMC3137694  PMID: 21489572
Sucrose; Fructose; Insulin Resistance; Uric acid; Nonalcoholic Fatty Liver Disease
8.  Uric Acid as a Mediator of Diabetic Nephropathy 
Seminars in nephrology  2011;31(5):459-465.
Despite the advances in the management of patients with diabetes, diabetic nephropathy (DN) remains the most common cause of end stage renal disease (ESRD) in the US and worldwide. Inflammation and endothelial dysfunction appear to play a central role in the onset and the progression of DN. Recent evidence has emerged in the last decade to suggest uric acid is an inflammatory factor and may play a role in endothelial dysfunction. This has lead our group and others to explore the role of uric acid in the onset and progression of DN. In this review, we will highlight some of the animal and human studies that implicate uric acid in DN. Based on the evidence we review, we conclude the need for properly planned randomized controlled studies to lower uric acid levels and assess the impact of such therapy on diabetic kidney disease.
doi:10.1016/j.semnephrol.2011.08.011
PMCID: PMC3197214  PMID: 22000654
9.  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
10.  Serum Uric Acid Predicts Progression of Subclinical Coronary Atherosclerosis in Individuals Without Renal Disease 
Diabetes Care  2010;33(11):2471-2473.
OBJECTIVE
To examine uric acid (UA) as a possible predictor of the progression of coronary artery calcification (CAC) using data from the prospective Coronary Artery Calcification in Type 1 Diabetes (CACTI) Study.
RESEARCH DESIGN AND METHODS
CAC was measured by electron beam tomography at the baseline and at a follow-up 6.0 ± 0.5 years later. The study population included 443 participants with type 1 diabetes and 526 control subjects who were free of diagnosed coronary artery disease at baseline. The presence of renal disease was defined by the presence of albuminuria and/or low glomerular filtration rate.
RESULTS
In subjects without renal disease, serum UA predicted CAC progression (odds ratio 1.30 [95% CI 1.07–1.58], P = 0.007) independent of conventional cardiovascular risk factors including diabetes and the presence of metabolic syndrome.
CONCLUSIONS
Serum UA levels predict the progression of coronary atherosclerosis and may be useful in identifying who is at risk for vascular disease in the absence of significant chronic kidney disease.
doi:10.2337/dc10-1007
PMCID: PMC2963516  PMID: 20798338
11.  Serum uric acid levels predict the development of albuminuria over 6 years in patients with type 1 diabetes: Findings from the Coronary Artery Calcification in Type 1 Diabetes study 
Nephrology Dialysis Transplantation  2010;25(6):1865-1869.
Background. Recent studies suggest that uric acid is a mediator of diabetic nephropathy. We hypothesized that elevated serum uric acid levels are a strong predictor of albuminuria in patients with type 1 diabetes.
Methods. We analyzed data from the Coronary Artery Calcification in Type 1 Diabetes study, a prospective observational study. A stepwise logistic regression model was applied to predict the development of micro- or macroalbuminuria after 6 years of follow-up in 324 participants who had no evidence of micro- or macroalbuminuria at baseline. A P-value <0.1 was used as the criteria for entry into and removal from the model.
Results. The following factors were selected in the stepwise multivariate model as predictors of micro- or macroalbuminuria at the 6-year follow-up visit: baseline serum uric acid levels, HbA1c and pre-albuminuria. For every 1-mg/dl increase in serum uric acid levels at baseline, there was an 80% increased risk of developing micro- or macroalbuminuria at 6 years (odds ratio 1.8; 95% confidence interval 1.2, 2.8; P = 0.005). Additional covariates considered in the stepwise model were sex, age, duration of diabetes, angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker treatment, waist circumference, waist/hip ratio, body mass index, systolic and diastolic blood pressure, smoking, serum creatinine, cystatin C, high-density lipoprotein cholesterol and triglycerides.
Conclusion. Elevated serum uric acid levels are a strong predictor of the development of albuminuria in patients with type 1 diabetes.
doi:10.1093/ndt/gfp740
PMCID: PMC2902891  PMID: 20064950
type 1 diabetes; uric acid; albuminuria
12.  Aldosterone-sensitive repression of ENaCα transcription by a histone H3 lysine-79 methyltransferase 
Aldosterone is a major regulator of epithelial Na+ absorption. One of its principal targets is the epithelial Na+ channel α-subunit (ENaCα), principally expressed in the kidney collecting duct, lung, and colon. Models of aldosterone-mediated trans-activation of the ENaCα gene have focused primarily on interactions of liganded nuclear receptors with the ENaCα gene promoter. Herein, we demonstrate that the murine histone H3 lysine-79 methyltransferase, murine disruptor of telomeric silencing alternative splice variant “a” (mDot1a), is a novel component in the aldosterone signaling network controlling transcription of the ENaCα gene. Aldosterone downregulated mDot1a mRNA levels in murine inner medullary collecting ducts cells, which was associated with histone H3 K79 hypomethylation in bulk histones and at specific sites in the ENaCα 5′-flanking region, and trans-activation of ENaCα. Knockdown of mDot1a by RNA interference increased activity of a stably integrated ENaCα promoter-luciferase construct and expression of endogenous ENaCα mRNA. Conversely, overexpression of EGFP-tagged mDot1a resulted in hypermethylation of histone H3 K79 at the endogenous ENaCα promoter, repression of endogenous ENaCα mRNA expression, and decreased activity of the ENaCα promoter-luciferase construct. mDot1a-mediated histone H3 K79 hypermethylation and repression of ENaCα promoter activity was abolished by mDot1a mutations that eliminate its methyltransferase activity. Collectively, our data identify mDot1a as a novel aldosterone-regulated histone modification enzyme, and, through binding the ENaCα promoter and hypermethylating histone H3 K79 associated with the ENaCα promoter, a negative regulator of ENaCα transcription.
doi:10.1152/ajpcell.00431.2005
PMCID: PMC3009459  PMID: 16236820
gene regulation; collecting duct; Na+ transport; chromatin; epigenetic; Dot1
13.  Vascular Endothelial Function Is Not Related to Serum Uric Acid in Healthy Adults 
American Journal of Hypertension  2012;25(4):407-413.
Background
Some experimental evidence suggests that uric acid impairs endothelial function. It is controversial if high uric acid levels and impaired endothelial function are related in healthy adults. In addition, the effect of uric acid on endothelial cells (ECs) of humans is unexplored.
Methods
Data of 107 healthy adult volunteers were analyzed. The association between serum uric acid and endothelial-dependant dilation (EDD) and endothelial-independent dilation (EID) was evaluated by linear regression models. We also examined the relations between uric acid and systemic and cellular markers of inflammation and oxidative stress in all or subsets of participants.
Results
Uric acid levels and EDD were not related in unadjusted or adjusted models. There was a significant negative correlation between uric acid and EID in the pooled sample (r = −0.34, P = 0.005). This correlation remained significant after adjusting for demographics (P = 0.04) and was attenuated after adjusting for other cardiac risk factors (P = 0.12). Higher serum uric acid levels were found to correlate significantly with C-reactive protein (CRP) (r = 0.31, P = 0.002). Serum uric acid levels were not associated with brachial artery EC nuclear factor-κB (NF-κB) p65 or NADPH oxidase p47phox expression or with nitrotyrosine staining, but were inversely associated with EC manganese superoxide dismutase (MnSOD) expression (r = −0.5, P = 0.01, n = 25).
Conclusion
Elevated serum uric acid is not associated with endothelial dysfunction among healthy adults, but is inversely related to EID and EC MnSOD, and positively related to systemic inflammation. These findings may have implications for cardiovascular risk in healthy adults.
doi:10.1038/ajh.2011.237
PMCID: PMC3309158  PMID: 22237152
blood pressure; endothelium; hypertension; inflammation; uric acid

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