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Uric Acid and Cognitive Function in Older Individuals.
Tana, C, Ticinesi, A, Prati, B, Nouvenne, A, Meschi, T
Nutrients. 2018;(8)
Abstract
Hyperuricemia has been recognized as an independent cardiovascular risk factor in epidemiological studies. However, uric acid can also exert beneficial functions due to its antioxidant properties, which may be particularly relevant in the context of neurodegenerative diseases. In this paper, we critically revise the evidence on the relationship between serum uric acid levels and cognitive function in older individuals, focusing on the etiology of cognitive impairment (Alzheimer's disease, Parkinson's dementia, and vascular dementia) and on the interactive connections between uric acid, dementia, and diet. Despite high heterogeneity in the existing studies, due to different characteristics of studied populations and methods of cognitive dysfunction assessment, we conclude that serum uric acid may modulate cognitive function in a different way according to the etiology of dementia. Current studies indeed demonstrate that uric acid may exert neuroprotective actions in Alzheimer's disease and Parkinson's dementia, with hypouricemia representing a risk factor for a quicker disease progression and a possible marker of malnutrition. Conversely, high serum uric acid may negatively influence the disease course in vascular dementia. Further studies are needed to clarify the physio-pathological role of uric acid in different dementia types, and its clinical-prognostic significance.
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Elevated serum uric acid increases risks for developing high LDL cholesterol and hypertriglyceridemia: A five-year cohort study in Japan.
Kuwabara, M, Borghi, C, Cicero, AFG, Hisatome, I, Niwa, K, Ohno, M, Johnson, RJ, Lanaspa, MA
International journal of cardiology. 2018;:183-188
Abstract
BACKGROUND High serum uric acid (SUA) is associated with the dyslipidemia, but whether hyperuricemia predicts an increase in serum low-density lipoprotein (LDL) cholesterol is unknown. This study is to evaluate whether an elevated SUA predicts the development of high LDL cholesterol as well as hypertriglyceridemia. METHODS This is a retrospective 5-year cohort study of 6476 healthy Japanese adults (age, 45.7 ± 10.1 years; 2.243 men) who underwent health examinations at 2004 and were reevaluated in 2009 at St. Luke's International Hospital, Tokyo, Japan. Subjects were included if at their baseline examination they did not have hypertension, diabetes mellitus, dyslipidemia, chronic kidney disease, or if they were on medication for hyperuricemia and/or gout. The analysis was adjusted for age, body mass index (BMI), smoking and drinking habits, baseline estimated glomerular filtration rate (eGFR), baseline SUA and SUA change over the 5 years. RESULTS High baseline SUA was an independent risk for developing high LDL cholesterol both in men (OR: 1.159 per 1 mg/dL increase, 95% CI:1.009-1.331) and women (OR: 1.215, 95% CI:1.061-1.390). Other risk factors included a higher baseline LDL cholesterol, higher BMI, and higher baseline eGFR (the latter two in women only). Increased SUA over 5 years were also independent risks for developing high LDL cholesterol and hypertriglyceridemia, but not for low high-density lipoprotein (HDL) cholesterol. CONCLUSIONS This is the first study to report that an elevated SUA increases the risk for developing high LDL cholesterol, as well as hypertriglyceridemia. This may shed light into the role of SUA in cardiovascular disease.
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Effects of a Dietary Approach to Stop Hypertension (DASH) Diet Intervention on Serum Uric Acid in African Americans With Hypertension.
Juraschek, SP, White, K, Tang, O, Yeh, HC, Cooper, LA, Miller, ER
Arthritis care & research. 2018;(10):1509-1516
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Abstract
OBJECTIVE To examine whether partial replacement of a diet typical of the average American diet with Dietary Approaches to Stop Hypertension (DASH)-related foods in the home environment lowers the serum uric acid (UA) level in individuals with hypertension. METHODS We conducted an ancillary study of a randomized trial of African American adults with controlled hypertension from an urban clinic. Participants were assigned to either a control group or an intervention (DASH-Plus) group. DASH-Plus participants received coach-directed dietary advice, assistance with purchasing DASH-related foods ($30/week), and home delivery of food via a community supermarket. Participants in the control group received a DASH diet brochure and a debit card account ($30/week) to purchase foods. Serum UA levels were measured at baseline and after 8 weeks. RESULTS Of the original 123 randomized participants, 117 had available serum UA measurements. Seventy percent of the participants were women, the mean ± SD age was 59 ± 9.5 years, and the mean ± SD serum UA level was 6.4 ± 1.7 mg/dl. The DASH-Plus diet did not reduce serum UA levels compared with the control diet (difference in difference -0.01 mg/dl [95% confidence interval -0.39, 0.38]). However, there was a significant trend toward a greater reduction in the serum UA level in participants with higher baseline serum UA levels (P for trend = 0.008). Baseline changes in the serum UA level were inversely associated with changes in systolic blood pressure (P = 0.002), diastolic blood pressure (P = 0.001), and urinary sodium excretion (P = 0.05). CONCLUSION Overall, in African American individuals, partial replacement of a typical diet with DASH foods did not lower serum UA levels compared with a control diet. However, there was a significant trend toward a greater reduction in serum UA levels in subjects with higher baseline serum UA levels. Furthermore, changes in serum UA levels were associated with known correlates, suggesting heterogeneity of effects in the treatment and control arms. Future pragmatic studies of consumption of the DASH diet to lower serum UA levels should optimize replacement strategies and enroll individuals with hyperuricemia or gout.
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Uric acid lowering in relation to HbA1c reductions with the SGLT2 inhibitor tofogliflozin.
Ouchi, M, Oba, K, Kaku, K, Suganami, H, Yoshida, A, Fukunaka, Y, Jutabha, P, Morita, A, Otani, N, Hayashi, K, et al
Diabetes, obesity & metabolism. 2018;(4):1061-1065
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An integrated analysis was performed with data from 4 phase 2 and phase 3 studies of tofogliflozin in which patients with type 2 diabetes mellitus received the sodium-glucose cotransporter 2 inhibitor tofogliflozin for up to 24 weeks. Sex differences, baseline haemoglobin A1c (HbA1c) and serum uric acid (UA) levels, and log10 -transformed urinary N-acetyl-β-D-glucosaminidase ratio were significantly correlated with the reduction in serum UA levels at both 4 and 24 weeks in multivariate analysis (respectively, P < .0001). The decrease in HbA1c levels was greatest in the group with the highest baseline HbA1c level (quartile 4; HbA1c > 8.6%) and lowest in the group with the lowest baseline HbA1c level (quartile 1; HbA1c ≤ 7.4%). The decrease in serum UA levels was greatest in the quartile 1 group and lowest in the quartile 4 group. In most groups, the maximum decrease in serum UA levels was seen in the first 4 weeks, while the maximum decrease in HbA1c was seen at week 24. Thus, serum UA levels were significantly decreased in patients with moderate HbA1c levels.
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Higher serum levels of uric acid are associated with a reduced insulin clearance in non-diabetic individuals.
Fiorentino, TV, Sesti, F, Succurro, E, Pedace, E, Andreozzi, F, Sciacqua, A, Hribal, ML, Perticone, F, Sesti, G
Acta diabetologica. 2018;(8):835-842
Abstract
AIMS: Decreased insulin clearance has been reported to be associated with insulin resistance-related disorders and incident type 2 diabetes. The aim of this study was to evaluate whether higher levels of uric acid (UA), a known risk factor of type 2 diabetes, are associated with a reduced insulin clearance. METHODS 440 non-diabetic individuals were stratified in tertiles according to serum UA levels. Insulin clearance and skeletal muscle insulin sensitivity were assessed by euglycemic hyperinsulinemic clamp. Hepatic insulin resistance was estimated by the liver IR index. RESULTS Subjects with higher levels of UA displayed an unfavorable metabolic phenotype with a worse lipid profile, increased levels of 2-h post-load glucose levels, fasting, and 2-h post-load insulin levels, hsCRP, liver IR index, and lower levels of eGFR and skeletal muscle insulin sensitivity, in comparison to individuals with lower UA levels. Moreover, subjects with higher UA concentrations exhibited decreased levels of insulin clearance even after adjustment for age, gender, BMI, eGFR, and skeletal muscle insulin sensitivity. In a multivariate regression analysis model including several confounding factors, UA concentration was an independent predictor of insulin clearance (β = - 0.145; P = 0.03). However, when liver IR index was included in the model, the independent association between UA levels and insulin clearance was not retained. Accordingly, in a mediation analysis, liver IR index was a mediator of the negative effects of UA levels on insulin clearance (t = - 2.55, P = 0.01). CONCLUSIONS Higher serum levels of UA may affect insulin clearance by impairing hepatic insulin sensitivity.
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Serum uric acid and progression of diabetic nephropathy in type 1 diabetes.
Pilemann-Lyberg, S, Lindhardt, M, Persson, F, Andersen, S, Rossing, P
Journal of diabetes and its complications. 2018;(5):470-473
Abstract
AIMS: Uric acid (UA) is a risk factor for CKD. We evaluated UA in relation to change in GFR in patients with type 1 diabetes. METHODS Post hoc analysis of a trial of losartan in diabetic nephropathy, mean follow-up 3 years (IQR 1.5-3.5). UA was measured at baseline. Primary end-point was change in measured GFR. UA was tested in a linear regression model adjusted for known progression factors (gender, HbA1c, systolic blood pressure, cholesterol, baseline GFR and baseline urinary albumin excretion rate (UAER)). RESULTS Baseline UA was 0.339 mmol/l (SD ±0.107), GFR 87 ml/min/1.73 m2 (±23), geometric mean UAER 1023 mg/24 h (IQR, 631 - 1995). Mean rate of decline in GFR was 4.6 (3.7) ml/min/year. In the upper quartile of baseline UA the mean decline in GFR from baseline to the end of the study was 6.2 (4.9) ml/min/1.73 m2 and 4.1 (3.1) ml/min/1.73 m2 in the three lower quartiles of UA, (p = 0.088). In a linear model including baseline covariates (UAER, GFR, total cholesterol, HDL cholesterol) UA was associated with decline in GFR (r2 = 0.45, p < 0.001). CONCLUSION Uric acid was weakly associated with decline in GFR in type 1 diabetic patients with overt nephropathy.
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Uric acid and incident chronic kidney disease in dyslipidemic individuals.
Barkas, F, Elisaf, M, Liberopoulos, E, Kalaitzidis, R, Liamis, G
Current medical research and opinion. 2018;(7):1193-1199
Abstract
BACKGROUND Elevated uric acid (UA) is a recognized risk factor for chronic kidney disease (CKD). This study aimed to investigate whether this association exists in dyslipidemic patients receiving multifactorial treatment. METHODS An observational study conducted in Greece including 1,269 dyslipidemic individuals followed-up in a lipid clinic for ≥3 years. Estimated glomerular filtration rate (eGFR) was calculated by CKD-EPI equation and CKD was defined as ≤60 mL/min/1.73 m2. The correlation was assessed between UA levels and the CKD risk after adjusting for potential confounding factors, after defining the following UA quartiles: Q1: < 4, Q2: 4-5, Q3: 5-6, and Q4: > 6 mg/dL. RESULTS After excluding patients with baseline eGFR <60 mL/min/1.73 m2, gout and those taking UA-lowering drugs, 1,095 individuals were eligible; of those, 91% and 69% were treated with statins and anti-hypertensive drugs, respectively. During their follow-up (6 years; IQR = 4-10), 11.9% of the subjects developed CKD, whereas the median annual eGFR decline was 0.69 mL/min/1.73 m2 (IQR = 0.45-2.33). Multivariate analysis showed that baseline UA levels (HR = 1.26; 95% CI = 1.09-1.45, p = .001), female gender (HR = 1.74; 95% CI = 1.14-2.65, p = .01), age (HR = 1.10; 95% CI = 1.07-1.12, p < .001), diabetes (HR = 1.67; 95% CI = 1.05-2.65, p = .03), cardiovascular disease (HR = 1.62; 95% CI = 1.02-2.58, p = .04), decreased baseline renal function (eGFR <90 mL/min/1.73 m2) (HR = 2.38; 95% CI = 1.14-4.81, p = .02), and low-density lipoprotein cholesterol reduction (HR = 0.995; 95% CI = 0.991-0.998, p = .01) were associated with incident CKD. Additionally, patients with UA ≥6 mg/dL exhibited a higher risk of incident CKD compared with those in the lowest UA quartile (HR = 2.01; 95% CI = 1.11-3.65, p = .02). CONCLUSION Higher UA levels are correlated with a higher risk of incident CKD in dyslipidemic individuals taking multifactorial treatment.
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Evaluation of the diet wide contribution to serum urate levels: meta-analysis of population based cohorts.
Major, TJ, Topless, RK, Dalbeth, N, Merriman, TR
BMJ (Clinical research ed.). 2018;:k3951
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OBJECTIVE To systematically test dietary components for association with serum urate levels and to evaluate the relative contributions of estimates of diet pattern and inherited genetic variants to population variance in serum urate levels. DESIGN Meta-analysis of cross sectional data from the United States. DATA SOURCES Five cohort studies. REVIEW METHODS 16 760 individuals of European ancestry (8414 men and 8346 women) from the US were included in analyses. Eligible individuals were aged over 18, without kidney disease or gout, and not taking urate lowering or diuretic drugs. All participants had serum urate measurements, dietary survey data, information on potential confounders (sex, age, body mass index, average daily calorie intake, years of education, exercise levels, smoking status, and menopausal status), and genome wide genotypes. The main outcome measures were average serum urate levels and variance in serum urate levels. β values (95% confidence intervals) and Bonferroni corrected P values from multivariable linear regression analyses, along with regression partial R2 values, were used to quantitate associations. RESULTS Seven foods were associated with raised serum urate levels (beer, liquor, wine, potato, poultry, soft drinks, and meat (beef, pork, or lamb)) and eight foods were associated with reduced serum urate levels (eggs, peanuts, cold cereal, skim milk, cheese, brown bread, margarine, and non-citrus fruits) in the male, female, or full cohorts. Three diet scores, constructed on the basis of healthy diet guidelines, were inversely associated with serum urate levels and a fourth, data driven diet pattern positively associated with raised serum urate levels, but each explained ≤0.3% of variance in serum urate. In comparison, 23.9% of variance in serum urate levels was explained by common, genome wide single nucleotide variation. CONCLUSION In contrast with genetic contributions, diet explains very little variation in serum urate levels in the general population.
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Serum uric acid levels are associated with cardiovascular risk score: A post hoc analysis of the EURIKA study.
Borghi, C, Rodriguez-Artalejo, F, De Backer, G, Dallongeville, J, Medina, J, Nuevo, J, Guallar, E, Perk, J, Banegas, JR, Tubach, F, et al
International journal of cardiology. 2018;:167-173
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BACKGROUND Reports are conflicting on whether serum uric acid (sUA) levels are independently associated with increased cardiovascular (CV) death risk. METHODS This post hoc analysis assessed the relationship between sUA levels and CV death risk score in 7531 patients from the cross-sectional, multinational EURIKA study (NCT00882336). Patients had at least one CV risk factor but no clinical CV disease. Ten-year risk of CV death was estimated using SCORE-HDL and SCORE algorithms, categorized as low (<1%), intermediate (1% to <5%), high (≥5% to <10%) or very high (≥10%). RESULTS Mean serum sUA levels increased significantly with increasing CV death risk category in the overall population and in subgroups stratified by diuretics use or renal function (all P<0.0001). Multivariate ordinal logistic regression analyses, adjusted for factors significantly associated with CV death risk in univariate analyses (study country, body mass index, number of CV risk factors and comorbidities, use of lipid lowering therapies, antihypertensives and antidiabetics), showed a significant association between sUA levels and SCORE-HDL category in the overall population (OR: 1.39 [95% CI: 1.34-1.44]) and all subgroups (using diuretics: 1.32 [1.24-1.40]; not using diuretics: 1.46 [1.39-1.53]; estimated glomerular filtration rate [eGFR]<60ml/min/1.73m2: 1.30 [1.22-1.38]; eGFR≥60ml/min/1.73m2: 1.44 [1.38-1.51]; all P<0.0001). Similar results were obtained when using SCORE. CONCLUSIONS Higher sUA levels are associated with progressively higher 10-year CV death risk score in patients with at least one CV risk factor but no CV disease.
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Examining the effects of uric acid-lowering on markers vascular of calcification and CKD-MBD; A post-hoc analysis of a randomized clinical trial.
Andrews, ES, Perrenoud, L, Nowak, KL, You, Z, Pasch, A, Chonchol, M, Kendrick, J, Jalal, D
PloS one. 2018;(10):e0205831
Abstract
BACKGROUND Chronic kidney disease (CKD)-mineral and bone disorder (MBD) is a systemic disorder that leads to vascular calcification and accelerated atherosclerosis. Uric acid has been shown to associate with vascular calcification and with carotid intima-media thickness (CIMT) and to suppress the 1 α-hydroxylase enzyme leading to lower 1,25-dihydroxyvitamin D (1,25(OH)2D) and higher intact parathyroid hormone (iPTH) levels. We hypothesized that lowering serum uric acid would reduce CIMT, calcification propensity, and circulating markers of CKD-MBD in CKD. METHODS This is a post-hoc analysis of a randomized, double-blind study of 80 patients with stage 3 CKD and hyperuricemia who received allopurinol or placebo for 12 weeks. CIMT and T50 were measured as markers of vascular disease and serum calcification propensity, respectively. The following markers of CKD-MBD were measured: serum calcium, phosphorus, vitamin D metabolites, iPTH, and fibroblast growth factor-23 (FGF-23). Expression of extra-renal 1α-hydroxylase was evaluated in endothelial cells of study participants. FINDINGS Allopurinol successfully lowered serum uric acid levels compared to placebo with an estimate of -3.3 mg/dL (95% C.I. -4.1,-2.5; p < 0.0001). After 12 weeks, however, we found no significant change in CIMT or serum T50. There was not a significant change in vitamin D metabolites, iPTH, FGF-23, or the expression of endothelial 1α-hydroxylase. CONCLUSION These data suggest that factors other than uric acid may play a more important role in the regulation of CKD- MBD including vascular calcification and vitamin D metabolism in patients with CKD.