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Uric acid extrarenal excretion: the gut microbiome as an evident yet understated factor in gout development.
Méndez-Salazar, EO, Martínez-Nava, GA
Rheumatology international. 2022;(3):403-412
Abstract
Humans do not produce uricase, an enzyme responsible for degrading uric acid. However, some bacteria residing in the gut can degrade one-third of the dietary and endogenous uric acid generated daily. New insights based on metagenomic and metabolomic approaches provide a new interest in exploring the involvement of gut microbiota in gout. Nevertheless, the exact mechanisms underlying this association are complex and have not been widely discussed. In this study, we aimed to review the evidence that suggests uric acid extrarenal excretion and gut microbiome are potential risk factors for developing gout. A literature search was performed in PubMed, Web of Science, and Google Scholar using several keywords, including "gut microbiome AND gout". A remarkable intestinal dysbiosis and shifts in abundance of certain bacterial taxa in gout patients have been consistently reported among different studies. Under this condition, bacteria might have developed adaptive mechanisms for de novo biosynthesis and salvage of purines, and thus, a concomitant alteration in uric acid metabolism. Moreover, gut microbiota can produce substrates that might cross the portal vein so the liver can generate de novo purinogenic amino acids, as well as uric acid. Therefore, the extrarenal excretion of uric acid needs to be considered as a factor in gout development. Nevertheless, further studies are needed to fully understand the role of gut microbiome in uric acid production and its extrarenal excretion, and to point out possible bacteria or bacterial enzymes that could be used as probiotic coadjutant treatment in gout patients.
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Serum uric acid level and all-cause and cardiovascular mortality in peritoneal dialysis patients: A systematic review and dose-response meta-analysis of cohort studies.
Kang, T, Hu, Y, Huang, X, Amoah, AN, Lyu, Q
PloS one. 2022;(2):e0264340
Abstract
BACKGROUND The association between serum uric acid (SUA) and all-cause and cardiovascular disease (CVD) mortality in peritoneal dialysis (PD) patients is controversial. Therefore, we aimed to determine the relationship between SUA and all-cause and CVD mortality in PD patients. METHOD Web of Science, EMBASE, PubMed and the Cochrane Library databases were searched from their inception to 7 April 2021. Effect estimates were presented as hazard ratios (HRs) with 95% confidence intervals (95% CIs) and pooled using random effects model. RESULT Thirteen cohort studies with 22418 patients were included in this systematic review, of which 9 were included in the meta-analysis. Before switching the reference group, pooled result for the highest SUA category was significantly greater than the median for all-cause mortality (HR = 2.41, 95% CI: 1.37-4.26). After switching the reference group, the highest SUA category did not demonstrate an increased all-cause (HR = 1.40, 95% CI: 0.95-2.05) or CVD (HR = 1.30, 95% CI: 0.72-2.34) mortality compared with the lowest SUA category. Dose-response analysis suggested a nonlinear association between SUA and all-cause mortality risk (Pnonlinearity = 0.002). CONCLUSION This meta-analysis didn't find the relationship between SUA levels and all-cause and CVD mortality risk in PD patients. More rigorously designed studies are warranted in the future.
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Factors Influencing Change in Serum Uric Acid After Administration of the Sodium-Glucose Cotransporter 2 Inhibitor Luseogliflozin in Patients With Type 2 Diabetes Mellitus.
Chino, Y, Kuwabara, M, Hisatome, I
Journal of clinical pharmacology. 2022;(3):366-375
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Abstract
Although sodium-glucose cotransporter 2 (SGLT2) inhibitors lower serum uric acid, their long-term effect on uric acid metabolism is not well understood. We analyzed pooled data from studies wherein patients with type 2 diabetes mellitus received luseogliflozin, an SGLT2 inhibitor. Upon stratifying patients by baseline glycated hemoglobin (HbA1c ) or serum uric acid, lower HbA1c or higher serum uric acid level was associated with a greater reduction in serum uric acid after treatment. At week 12 of treatment, significant increases in urinary glucose/creatinine (Cr) ratio and urinary uric acid clearance/Cr clearance ratio (CUA /CCr ratio) and a significant reduction in serum uric acid were observed. Comparison of the subgroups of patients with a reduction or an increase in serum uric acid showed that the increase subgroup had a higher estimated glomerular filtration rate (eGFR) at baseline, and the eGFR was significantly reduced, associated with a significant reduction in the CUA /CCr ratio. Multiple regression analysis showed that the reduction in serum uric acid in the luseogliflozin group was strongly associated with baseline high serum uric acid, low HbA1c levels, and an increase in eGFR. Luseogliflozin was shown to reduce serum uric acid by enhancing urinary uric acid excretion in association with increased urinary glucose. Treatment with luseogliflozin resulted in increased serum uric acid in some patients, which may be due to reduced glomerular filtration of uric acid via the tubuloglomerular feedback. SGLT2 inhibitors reduced serum uric acid desirably in patients with type 2 diabetes mellitus with low HbA1c and high serum uric acid.
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Impacts of Sodium/Glucose Cotransporter-2 Inhibitors on Circulating Uric Acid Concentrations: A Systematic Review and Meta-Analysis.
Akbari, A, Rafiee, M, Sathyapalan, T, Sahebkar, A
Journal of diabetes research. 2022;:7520632
Abstract
BACKGROUND Several trials have assessed the antihyperglycemic effects of sodium/glucose cotransporter-2 inhibitors (SGLT2i) in patients with type 2 diabetes mellitus (T2DM). We conducted a quantitative analysis to assess the impact of SGLT2is on serum uric acid (SUA) in patients with T2DM. METHODS Placebo-controlled trials published before 13 August 2021 were identified by searching PubMed, Embase, Web of Science, and Scopus. The intervention group received SGLT2i as monotherapy or add-on treatment, and the control group received a placebo that was replaced with SGLT2i. Clinical trials providing changes in SUA were included. The mean change of SUA, glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), and body weight were calculated (PROSPERO CRD42021287019). RESULTS After screening of 1172 papers, 59 papers were included in the systematic review. A total of 55 trials (122 groups) of 7 types of SGLT2i on patients with T2DM were eligible for meta-analysis. All SGLT2is significantly decreased SUA levels compared with the placebo groups: empagliflozin mean difference (MD) = -40.98 μmol/L, 95% CI [-47.63, -34.32], dapagliflozin MD = -35.17 μmol/L, 95% CI [-39.68, -30.66], canagliflozin MD = -36.27 μmol/L, 95% CI [-41.62, -30.93], luseogliflozin MD = -24.269 μmol/L, 95% CI [-33.31, -15.22], tofogliflozin MD = -19.47 μmol/L, 95% CI [-27.40, -11.55], and ipragliflozin MD = -18.85 μmol/L, 95% CI [-27.20, -10.49]. SGLT2i also decreased FPG, body weight, and HbA1c levels. SUA reduction persisted during long-term treatment with SGLT2i (except for empagliflozin), while the SUA reduction was affected by the duration of diabetes. CONCLUSIONS SGLT2i can be a valid therapeutic strategy for patients with T2DM and comorbid hyperuricemia. Besides reducing FPG, body weight, and HbA1c, SGLT2i can significantly decrease SUA levels compared to placebo (Total MD = -34.07 μmol/L, 95% CI [-37.00, -31.14]).
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Serum Uric Acid Level Is Positively Associated With Higher Bone Mineral Density at Multiple Skeletal Sites Among Healthy Qataris.
Ibrahim, WN, Younes, N, Shi, Z, Abu-Madi, MA
Frontiers in endocrinology. 2021;:653685
Abstract
BACKGROUND Oxidative stress has been implicated as a fundamental mechanism in the decline of bone mass. Although serum uric acid (SUA) has potent antioxidant properties, the findings of many epidemiological and experimental studies couldn't draw a clear conclusion on the relation between SUA and bone health. We aim to investigate the association between SUA and bone mineral density (BMD) at different skeletal sites among healthy Qataris. METHODOLOGY A cross-sectional analysis including total-body and site-specific bone mineral density scores and other serological markers of 2981 healthy Qatari adults (36.4 ± 11.1 years) from the Qatar biobank database was conducted. The study participants were divided into quartiles based on the level of SUA, and the BMD was measured using dual-energy X-ray absorptiometry (DXA). Multiple regression analyses were applied to investigate the association between SUA and BMD adjusting for multiple confounding factors. RESULTS High levels of SUA were significantly associated with the increased bone mineral density of the total body and at site-specific skeletal locations after adjusting for age and gender (p-value < 0.001). Further adjustment for body mass index (BMI), smoking, vitamin D, alkaline phosphatase, and estimated glomerular filtration rate (eGFR) levels attenuated the association but the association remained significant for individuals with high SUA levels (p-value ≤ 0.01).The association between SUA and BMD was not significant in non-obese, females, young adults, and smokers. However, no interaction was found between SUA and age, gender, BMI and smoking. CONCLUSION Higher SUA levels are associated with a high bone density among healthy Qatari adults. However, such observation demands further investigations to outline the underlying mechanisms.
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A Randomized Pilot Study of DASH Patterned Groceries on Serum Urate in Individuals with Gout.
Juraschek, SP, Miller, ER, Wu, B, White, K, Charleston, J, Gelber, AC, Rai, SK, Carson, KA, Appel, LJ, Choi, HK
Nutrients. 2021;(2)
Abstract
The Dietary Approaches to Stop Hypertension (DASH) diet reduces serum urate (SU); however, the impact of the DASH diet has not been previously evaluated among patients with gout. We conducted a randomized, controlled, crossover pilot study to test the effects of ~$105/week ($15/day) of dietitian-directed groceries (DDG), patterned after the DASH diet, on SU, compared with self-directed grocery shopping (SDG). Participants had gout and were not taking urate lowering therapy. Each intervention period lasted 4 weeks; crossover occurred without a washout period. The primary endpoint was SU. Compliance was assessed by end-of-period fasting spot urine potassium and sodium measurements and self-reported consumption of daily servings of fruit and vegetables. We randomized 43 participants (19% women, 49% black, mean age 59 years) with 100% follow-up. Mean baseline SU was 8.1 mg/dL (SD, 0.8). During Period 1, DDG lowered SU by 0.55 mg/dL (95% CI: 0.07, 1.04) compared to SDG by 0.0 mg/dL (95% CI: -0.44, 0.44). However, after crossover (Period 2), the SU difference between groups was the opposite: SDG reduced SU by -0.48 mg/dL (95% CI: -0.98, 0.01) compared to DDG by -0.05 mg/dL (95% CI: -0.48, 0.38; P for interaction by period = 0.11). Nevertheless, DDG improved self-reported intake of fruit and vegetables (3.1 servings/day; 95% CI: 1.5, 4.8) and significantly reduced total spot urine sodium excretion by 22 percentage points (95% CI: -34.0, -8.6). Though relatively small in scale, this pilot study suggests that dietitian-directed, DASH-patterned groceries may lower SU among gout patients not on urate-lowering drugs. However, behavior intervention crossover trials without a washout period are likely vulnerable to strong carryover effects. Definitive evaluation of the DASH diet as a treatment for gout will require a controlled feeding trial, ideally with a parallel-design.
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Higher Serum Uric Acid Levels Are Associated With an Increased Risk of Vision-Threatening Diabetic Retinopathy in Type 2 Diabetes Patients.
Hu, Y, Chan, Z, Li, C, Shi, Y, She, X, Gu, C, Wang, Y, Zhou, C, Zhao, S, Zheng, Z, et al
Investigative ophthalmology & visual science. 2021;(4):23
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Abstract
PURPOSE To investigate the association between serum uric acid (SUA) levels and vision-threatening diabetic retinopathy (VTDR) in patients with type 2 diabetes. METHODS This cross-sectional study evaluated 3481 patients with type 2 diabetes from four communities in China between 2016 and 2019. VTDR was defined as severe nonproliferative, proliferative diabetic retinopathy, or clinically significant macular edema evaluated by fundus photography and optical coherence tomography. Potential association between SUA and VTDR was examined using multivariable logistic regression. Sub-group analyses based on sex were constructed. RESULTS A total of 305 participants had VTDR. Both higher SUA (odds ratio [OR], 1.22 per 100 µmol/L; 95% confidence interval [CI], 1.04-1.44; P = 0.013) and hyperuricemia (OR, 1.47; 95% CI, 1.07-2.04; P = 0.019) were positively associated with VTDR after adjustment for relevant covariates. Compared with those in the lowest SUA quartile, participants in the third (OR, 1.60; 95% CI, 1.07-2.39; P = 0.022) and fourth (OR, 2.05; 95% CI, 1.37-3.08; P = 0.001) sex-specific SUA quartiles showed a significantly increased risk of VTDR after adjustment. No sex-related difference was observed. CONCLUSIONS Higher SUA levels were associated with an increased risk of VTDR in patients with type 2 diabetes in both sexes, although females seemed to be more sensitive to high SUA than males. Prospective cohort studies are needed to verify SUA as a biomarker for predicting the risk of VTDR. Whether decreased SUA levels could decrease the risk of VTDR also requires further investigation.
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Effect of a high fructose diet on metabolic parameters in carriers for hereditary fructose intolerance.
Debray, FG, Seyssel, K, Fadeur, M, Tappy, L, Paquot, N, Tran, C
Clinical nutrition (Edinburgh, Scotland). 2021;(6):4246-4254
Abstract
BACKGROUND & AIMS Hyperuricemia is an independent risk factor for the metabolic syndrome and cardiovascular disease. We hypothesized that asymptomatic carriers for hereditary fructose intolerance (OMIM 22960) would have increased uric acid and altered component of the metabolic syndrome when exposed to fructose overfeeding. METHODS Six heterozygotes for HFI (hHFI) and 6 controls (Ctrl) were studied in a randomized, controlled, crossover trial. Participants ingested two identical test meals containing 0.7 g kg-1 glucose and 0.7 g kg-1 fructose according to a cross-over design, once after a 7-day on a low fructose diet (LoFruD, <10 g/d) and on another occasion after 7 days on a high fructose diet (HiFruD, 1.4 g kg-1 day-1 fructose + 0.1 g kg-1 day-1 glucose). Uric acid, glucose, and insulin concentrations were monitored in fasting conditions and over 2 h postprandial, and insulin resistance indexes were calculated. RESULTS HiFruD increased fasting uric acid (p < 0.05) and reduced fasting insulin sensitivity estimated by the homeostasis model assessment (HOMA) for insulin resistance (p < 0.05), in both groups. Postprandial glucose concentrations were not different between hHFI and Ctrl. However HiFruD increased postprandial plasma uric acid, insulin and hepatic insulin resistance index (HIRI) in hHFI only (all p < 0.05). CONCLUSIONS Seven days of HiFruD increased fasting uric acid and slightly reduced fasting HOMA index in both groups. In contrast, HiFruD increased postprandial uric acid, insulin concentration and HIRI in hHFI only, suggesting that heterozygosity for pathogenic Aldolase B variants may confer an increased susceptibility to the effects of dietary fructose on uric acid and hepatic insulin sensitivity. This trial was registered at the U.S. Clinical Trials Registry as NCT03545581.
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Effect of Urate-Elevating Inosine on Early Parkinson Disease Progression: The SURE-PD3 Randomized Clinical Trial.
, , Schwarzschild, MA, Ascherio, A, Casaceli, C, Curhan, GC, Fitzgerald, R, Kamp, C, Lungu, C, Macklin, EA, Marek, K, et al
JAMA. 2021;(10):926-939
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Abstract
IMPORTANCE Urate elevation, despite associations with crystallopathic, cardiovascular, and metabolic disorders, has been pursued as a potential disease-modifying strategy for Parkinson disease (PD) based on convergent biological, epidemiological, and clinical data. OBJECTIVE To determine whether sustained urate-elevating treatment with the urate precursor inosine slows early PD progression. DESIGN, PARTICIPANTS, AND SETTING Randomized, double-blind, placebo-controlled, phase 3 trial of oral inosine treatment in early PD. A total of 587 individuals consented, and 298 with PD not yet requiring dopaminergic medication, striatal dopamine transporter deficiency, and serum urate below the population median concentration (<5.8 mg/dL) were randomized between August 2016 and December 2017 at 58 US sites, and were followed up through June 2019. INTERVENTIONS Inosine, dosed by blinded titration to increase serum urate concentrations to 7.1-8.0 mg/dL (n = 149) or matching placebo (n = 149) for up to 2 years. MAIN OUTCOMES AND MEASURES The primary outcome was rate of change in the Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS; parts I-III) total score (range, 0-236; higher scores indicate greater disability; minimum clinically important difference of 6.3 points) prior to dopaminergic drug therapy initiation. Secondary outcomes included serum urate to measure target engagement, adverse events to measure safety, and 29 efficacy measures of disability, quality of life, cognition, mood, autonomic function, and striatal dopamine transporter binding as a biomarker of neuronal integrity. RESULTS Based on a prespecified interim futility analysis, the study closed early, with 273 (92%) of the randomized participants (49% women; mean age, 63 years) completing the study. Clinical progression rates were not significantly different between participants randomized to inosine (MDS-UPDRS score, 11.1 [95% CI, 9.7-12.6] points per year) and placebo (MDS-UPDRS score, 9.9 [95% CI, 8.4-11.3] points per year; difference, 1.26 [95% CI, -0.59 to 3.11] points per year; P = .18). Sustained elevation of serum urate by 2.03 mg/dL (from a baseline level of 4.6 mg/dL; 44% increase) occurred in the inosine group vs a 0.01-mg/dL change in serum urate in the placebo group (difference, 2.02 mg/dL [95% CI, 1.85-2.19 mg/dL]; P<.001). There were no significant differences for secondary efficacy outcomes including dopamine transporter binding loss. Participants randomized to inosine, compared with placebo, experienced fewer serious adverse events (7.4 vs 13.1 per 100 patient-years) but more kidney stones (7.0 vs 1.4 stones per 100 patient-years). CONCLUSIONS AND RELEVANCE Among patients recently diagnosed as having PD, treatment with inosine, compared with placebo, did not result in a significant difference in the rate of clinical disease progression. The findings do not support the use of inosine as a treatment for early PD. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02642393.
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Association between baseline serum uric acid and development of LDL-C level in patients with first acute myocardial infarction.
Chen, Y, Ding, C, Hu, L, Ruan, Y, Zou, K, Dai, C, Liao, Y, Liao, H, Xia, Y, Zhao, Y, et al
BMC cardiovascular disorders. 2021;(1):572
Abstract
BACKGROUND Data on the relationship of baseline serum uric acid (SUA) with development of low-density lipoprotein cholesterol (LDL-C) level in patients with first acute myocardial infarction (AMI) are limited. The present study is to evaluate whether elevated SUA predicts the development of LDL-C in the first AMI. METHODS This is a retrospective 6-month cohort study of 475 hospitalized Chinese patients who underwent first AMI between January 2015 and December 2019 and were reevaluated half a year later at the Department of Cardiology, the Second Affiliated Hospital of Nanchang University, Jiangxi Province, China. The associations of baseline SUA with the percentage decrease of LDL-C (%) and LDL-C control were analyzed by using logistic regression analyses, multivariate linear regression analyses and the restricted cubic spline. RESULTS Over the 6-month follow-up, baseline SUA was independently and positively associated with the percentage decrease of LDL-C (%) and LDL-C control in a dose response fashion. After multivariable adjustment, per SD increment of baseline SUA (120.58 μmol/L) was associated with 3.96% higher percentage decrease of LDL-C(%). The adjusted OR (95% CI) for LDL-C control was 5.62 (2.05, 15.36) when comparing the highest tertile (SUA ≥ 437.0 μmol/L) to the lowest tertile (< 341.7 μmol/L) of baseline SUA. CONCLUSIONS Among Chinese patients with first AMI, higher baseline SUA was associated with higher LDL-C deduction percentage (%), and higher rate of LDL-C control in the short-term follow-up, respectively. SUA acquired when AMI occurred was prone to be profitable in predicting the risk stratification of uncontrolled LDL-C and dyslipidemia management.