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1.
The Association of Longitudinal Serum Uric Acid and All-Cause Mortality in Incident Peritoneal Dialysis Patients.
Chang, W, Zhang, W, Wang, X, Liu, Y, Han, Y, Tu, Y, Uchida, S
Blood purification. 2019;(1-3):185-192
Abstract
BACKGROUND Time-averaged uric acid (TA-UA) value was calculated to investigate the association of longitudinal UA and all-cause mortality in incident peritoneal dialysis (PD) patients. METHODS Three hundred PD patients were divided into 3 groups based on the serum TA-UA level (Group 1: < 6 mg/dL; Group 2: 6-8 mg/dL; Group 3: ≥8 mg/dL). Hazards ratio (HR) of all-cause mortality was calculated. Logistic regression was conducted to identify the associated clinical factors of lower and higher TA-UA level. RESULTS Increased HRs for death existed in Group 1 and Group 3 compared with Group 2 (HR 3.24, 95% CI 1.25-8.39, p = 0.016; HR 4.69, 95% CI 1.24-17.72, p = 0.023). Lower residual renal function, lower albumin, and higher high-density lipoprotein cholesterol were related to the lower serum TA-UA. Higher body mass index and higher C-reactive protein were associated with higher serum TA-UA in PD patients. CONCLUSION Both TA-UA < 6 and ≥8 mg/dL increased the all-cause mortality in incident PD patients.
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Sex differences by design and outcome in the Safety of Urate Elevation in PD (SURE-PD) trial.
Schwarzschild, MA, Macklin, EA, Bakshi, R, Battacharyya, S, Logan, R, Espay, AJ, Hung, AY, Bwala, G, Goetz, CG, Russell, DS, et al
Neurology. 2019;(14):e1328-e1338
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Abstract
OBJECTIVE To investigate whether women and men with Parkinson disease (PD) differ in their biochemical and clinical responses to long-term treatment with inosine. METHODS The Safety of Urate Elevation in Parkinson's Disease (SURE-PD) trial enrolled 75 people with early PD and baseline serum urate below 6 mg/dL and randomized them to 3 double-blinded treatment arms: oral placebo or inosine titrated to produce mild (6.1-7.0 mg/dL) or moderate (7.1-8.0 mg/dL) serum urate elevation for up to 2 years. Parkinsonism, serum urate, and plasma antioxidant capacity were measured at baseline and repeatedly on treatment; CSF urate was assessed once, at 3 months. Here in secondary analyses results are stratified by sex. RESULTS Inosine produced an absolute increase in average serum urate from baseline that was 50% greater in women (3.0 mg/dL) than in men (2.0 mg/dL), consistent with expected lower baseline levels in women. Similarly, only among women was CSF urate significantly greater on mild or moderate inosine (+87% [p < 0.001] and +98% [p < 0.001], respectively) than on placebo (in contrast to men: +10% [p = 0.6] and +14% [p = 0.4], respectively). Women in the higher inosine dosing group showed a 7.0 Unified Parkinson's Disease Rating Scale (UPDRS) points/year lower rate of decline vs placebo (p = 0.01). In women, slower rates of UPDRS change were associated with greater increases in serum urate (r = -0.52; p = 0.001), and with greater increases in plasma antioxidant capacity (r = -0.44; p = 0.006). No significant associations were observed in men. CONCLUSIONS Inosine produced greater increases in serum and CSF urate in women compared to men in the SURE-PD trial, consistent with the study's design and with preliminary evidence for slower clinical decline in early PD among women treated with urate-elevating doses of inosine. CLINICALTRIALSGOV IDENTIFIER NCT00833690. CLASSIFICATION OF EVIDENCE This study provides Class II evidence that inosine produced greater urate elevation in women than men and may slow PD progression in women.
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Serum uric acid and risk of cardiovascular mortality: a systematic review and dose-response meta-analysis of cohort studies of over a million participants.
Rahimi-Sakak, F, Maroofi, M, Rahmani, J, Bellissimo, N, Hekmatdoost, A
BMC cardiovascular disorders. 2019;(1):218
Abstract
BACKGROUND Cardiovascular disease (CVD) is the leading cause of death worldwide. Some studies have suggested anassociation between serum uric acid levels and cardiovascular mortality; however, the results have not been summarized in a meta-analysis. METHODS A comprehensive search of all related studies until April 2018was performed in MEDLINE/PubMed and Scopus databases DerSimonianand Laird random-effects models were used to combine hazard ratios (HRs) with 95% confidence intervals (CIs). Dose-response analysis was also carried out. RESULTS Thirty-two studies containing forty-four arms with 1,134,073 participants reported association between uric acid and risk of CVD mortality were included in our analysis. Pooled results showed a significant positive association between uric acid levels and risk of CVD mortality (HR 1.45, 95% CI 1.33-1.58, I2 = 79%). Sub-group analysis showed this relationshipwasstronger in women compared to men. Moreover, there was a significant non-linear association between uric acid levels and the risk of CVD mortality (r = 0.0709, p = 0.001). CONCLUSION Our analysis indicates a positive dose-response association between SUA and CVD mortality risk.
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The role of uric acid in mineral bone disorders in chronic kidney disease.
Afsar, B, Sag, AA, Oztosun, C, Kuwabara, M, Cozzolino, M, Covic, A, Kanbay, M
Journal of nephrology. 2019;(5):709-717
Abstract
Increasing survival in the chronic kidney disease (CKD) population exposes the bone to the cumulative detrimental sequelae of CKD, now defined physiologically and histopathologically as chronic kidney disease mineral bone disorder (CKD-BMD). This disorder is increasingly recognized as a "nontraditional" driver of morbidity and mortality and presents an opportunity to improve CKD outcomes via research. However, recent advances in the literature on this topic have not yet been collected into a single review. Therefore, this report aims to discuss the disordered renal-bone axis in CKD-BMD, molecular and hormonal drivers, novel treatment strategies, and forthcoming research in a clinician-directed format. A key novel topic will be the unique impact of uric acid on CKD-BMD, which is poised to apply extensive existing research in the uric acid domain to benefit the CKD-BMD population.
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Association of serum uric acid change with mortality, renal function and diuretic dose administered in treatment of acute heart failure.
Zhou, HB, Xu, TY, Liu, SR, Bai, YJ, Huang, XF, Zhan, Q, Zeng, QC, Xu, DL
Nutrition, metabolism, and cardiovascular diseases : NMCD. 2019;(4):351-359
Abstract
BACKGROUND AND AIMS Hyperuricemia is reportedly associated with poor outcome in acute heart failure (AHF). The association between changes in Uric acid (UA) levels with renal function change, diuretic doses, and mortality in patients with AHF were studied. METHODS AND RESULTS Consecutive patients hospitalized with AHF were reviewed (n = 535). UA levels were measured at admission and either at discharge or on approximately the seventh day of admission. Patients with an UA change in the top tertile were defined as having an increase (UA-increase) and were compared to those outside the top tertile (non-UA-increase). The endpoint was all-cause mortality, with a mean follow-up duration of 22.2 months. Patients in the UA-increase group presented with greater creatine increase (P < 0.001), and were administered a higher average daily dose of loop diuretic (P = 0.016) compared with the non-UA-increase group. In-hospital UA-increase was associated with higher risk of mortality even after adjusting for confounding variables including creatine change and diuretic dosage [harzard ratio (HR) 1.53, 95% confidence interval (CI) 1.02-2.30, P = 0.042]. In patients with hyperuricemia on admission, UA-increase was associated with increased mortality (adjusted HR 2.21, 95% CI 1.38-3.52, P = 0.001). Whereas, in those without admission hyperuricemia, UA-increase had no significant association with mortality. CONCLUSIONS An increase in UA during in-hospital treatment is associated with an increase in creatine levels and daily diuretic dose. Mortality associated with increased UA is restricted to patients who already have hyperuricemia at admission. A combination of UA levels at admission and UA changes on serial assessment during hospitalization may be additional value in the risk stratification of AHF patients.
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Effects of Food and Antacids on Pharmacokinetics and Pharmacodynamics of Lesinurad, a Selective Urate Reabsorption Inhibitor.
Shen, Z, Lee, CA, Valdez, S, Yang, X, Wilson, DM, Flanagan, T, Gillen, M
Clinical pharmacology in drug development. 2019;(5):647-656
Abstract
Two clinical studies were performed in healthy volunteers to investigate food and antacid effects on lesinurad, a novel selective uric acid reabsorption inhibitor approved for treatment of hyperuricemia associated with gout in combination with xanthine oxidase inhibitors. Study 1 evaluated a high-fat, high-calorie meal or high doses of antacids (3000 mg calcium carbonate or 1600 mg magnesium hydroxide/1600 mg aluminum hydroxide) on the pharmacokinetics (PK) and pharmacodynamics (PD) of 400 mg oral lesinurad. Study 2 evaluated low doses of antacids (1250 mg calcium carbonate or 800 mg magnesium hydroxide/800 mg aluminum hydroxide) on the PK and PD of 400 mg lesinurad. Food did not alter the plasma AUC of lesinurad and only reduced its Cmax by 18%. In the fasted conditions, high-dose calcium carbonate reduced the Cmax and AUC of lesinurad by 54% and 38%, respectively, whereas high-dose magnesium hydroxide/aluminum hydroxide reduced Cmax and AUC by 36% and 31%, respectively. Food enhanced the maximum serum urate (sUA)-lowering effect of lesinurad by approximately 20% despite reducing the Cmax of lesinurad. High-dose calcium carbonate decreased the urate-lowering effect approximately 20% in the first 6 hours, whereas high-dose magnesium hydroxide/aluminum hydroxide reduced the effect by 26%. Low-dose calcium carbonate or magnesium hydroxide/aluminum hydroxide in the presence of food did not significantly affect plasma lesinurad Cmax and AUC or the sUA lowering and renal handling of uric acid. In summary, study results suggest food did not meaningfully alter lesinurad PK and PD. High doses of antacids reduced lesinurad AUC up to 40% and reduced the lesinurad uric acid-lowering effect.
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A nanocomposite prepared from silver nanoparticles and carbon dots with peroxidase mimicking activity for colorimetric and SERS-based determination of uric acid.
Wang, A, Guan, C, Shan, G, Chen, Y, Wang, C, Liu, Y
Mikrochimica acta. 2019;(9):644
Abstract
Silver-carbon dots (Ag-CDs) nanocomposites with excellent peroxidase-like and surface-enhanced Raman scattering (SERS) activities were fabricated by reducing silver ion with carbon dots. The formation of the core-shell structure was demonstrated by transmission electron microscopy. The Ag-CD nanocomposite catalyzes the oxidation of 3,3',5,5'-tetramethylbenzidine (TMB) in the presence of H2O2 to form oxidized TMB (oxTMB) that has a blue color with an absorption maximum at 652 nm. The catalytic activity originates from the fact that the electrons of CDs are transferred to H2O2 and decompose H2O2 into hydroxy radicals. The nanocomposites can be used for uric acid (UA) detection because UA can reduce oxTMB to form colorless TMB. The absorbance drops as the concentration of UA increases from 1 to 500 μM. The SERS signal of oxTMB can be detected (at 1605 cm-1) using the Ag-CD nanocomposites as SERS substrate. The intensity of the SERS signal decreases when the concentration of UA ranges from 0.01 to 500 μM. Graphical abstract Schematic representation of the fabrication of silver-carbon dots (Ag-CDs). The Ag-CDs catalyze the oxidation of 3,3',5,5'-tetramethylbenzidine (TMB) by H2O2 to form blue-colored oxidized TMB (oxTMB). UA reduces oxTMB to form colorless TMB. This process is monitored by surface-enhanced Raman scattering (SERS) spectra for UA detection.
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Empagliflozin reduces blood pressure and uric acid in patients with type 2 diabetes mellitus: a systematic review and meta-analysis.
Zhao, D, Liu, H, Dong, P
Journal of human hypertension. 2019;(4):327-339
Abstract
The antidiabetic effect of empagliflozin in patients with type 2 diabetes mellitus has been explored in several trials. We performed this meta-analysis determining the effects of empagliflozin on blood pressure, uric acid, estimated glomerular filtration rate, blood lipids, blood glucose, and body weight in patients with type 2 diabetes mellitus. We searched three electronic databases (Pubmed, Web of Science, and Cochrane Central) for all published articles evaluating the effects of empagliflozin on blood glucose or blood pressure in subjects with type 2 diabetes mellitus. Total 5781 patients were included in 12 randomized controlled trials with a follow-up of 28 ± 22 weeks. Empagliflozin 10 or 25 mg reduced systolic and diastolic blood pressure, uric acid, hemoglobin A1c, fasting plasma glucose, and body weight in patients with type 2 diabetes mellitus (all p < 0.001). There were no differences for changes of estimated glomerular filtration rate between empagliflozin 10 or 25 mg and placebo in these patients (all p > 0.05). In conclusion, empagliflozin reduces systolic and diastolic blood pressure, uric acid, hemoglobin A1c, fasting plasma glucose, and body weight. These data suggest the beneficial effects of empagliflozin on these cardiovascular risk factors in patients with type 2 diabetes mellitus.
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Association of Uric Acid with Incident Metabolic Syndrome in a Japanese General Population.
Sumiyoshi, H, Ohyama, Y, Imai, K, Kurabayashi, M, Saito, Y, Nakamura, T
International heart journal. 2019;(4):830-835
Abstract
Uric acid is associated with cardiovascular disease (CVD) and its risk factors. Here, we examined the association between the serum uric acid level and incident metabolic syndrome in a Japanese general population. This retrospective, observational study was based on data obtained from an annual health checkup program in Gunma Prefecture, Japan. We evaluated 14,793 participants who did not use antihypertensive or antidiabetic medications and did not present with CVD or metabolic syndrome at the study baseline in 2009. Metabolic syndrome was defined as per the Japanese diagnostic criteria. A discrete proportional hazards regression model was used to evaluate the association between the serum uric acid level at baseline and the incident metabolic syndrome through 2012 and was adjusted for age, gender, waist circumference, systolic and diastolic blood pressure, fasting blood glucose, high-density lipoprotein cholesterol, and triglyceride. At baseline, the average age of the participants was 48.9 years, who were comprised of 40% women. The mean serum uric acid level at baseline was 5.3 ± 1.4 mg/dL. During the three-year follow-up, 7% of the cohort (n = 1,031) developed metabolic syndrome. The uric acid level was strongly associated with incident metabolic syndrome in the multivariable model (adjusted hazard ratio: 1.10; 95% confidence interval, 1.04-1.17; P < 0.01 per 1 mg/dL increase for uric acid). Higher uric acid levels were independently associated with a greater risk of incident metabolic syndrome in a Japanese general population.
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Plasma urate concentrations and possible REM sleep behavior disorder.
Shen, Y, Li, J, Schwarzschild, M, Pavlova, M, He, S, Ascherio, A, Wu, S, Cui, L, Gao, X
Annals of clinical and translational neurology. 2019;(12):2368-2376
Abstract
OBJECTIVE To examine how urate concentrations are related to the risk of having possible REM sleep behavior disorder (pRBD) in a community-based cohort. METHODS The study included 12,923 Chinese adults of the Kailuan Study, free of Parkinson disease (PD) and dementia. Plasma urate concentrations were measured in 2006, 2008, and 2010. Cumulative average urate concentration was used as primary exposure. In 2012, we determined pRBD status using a validated RBD questionnaire-Hong Kong (RBDQ-HK). Logistic regression analysis was performed to estimate the association between urate concentrations during 2006-2010 and odds of having pRBD in 2012 or pRBD case with symptom onset within 1 year. RESULTS Higher average urate concentrations were associated with a lower odds of pRBD (P-trend <0.001). The adjusted odds ratio (OR), for the highest versus lowest urate quintiles, was 0.43 (95% confidence intervals (CIs) 0.32-0.57). Significant association was consistently observed when we examined the association of a single urate assessment (2006 or 2010) or the rate of change in urate concentrations during 2006-2010 with pRBD (P-trend <0.001 for all). However, restricting to pRBD onset during 2011-2012, we observed a nonsignificant trend between high urate concentration and high odds of pRBD (P-trend = 0.09). INTERPRETATION Higher average urate concentrations were associated with a lower likelihood of having pRBD, but not new-onset pRBD. Because of its observational study design, the result should be interpreted with caution due to the possibility of residual confounding.