Prothrombotic effects of high uric acid in mice activation of MEF2C-dependent NF-κB pathway by upregulating let-7c.
Aging
Serum uric acid is reportedly associated with thrombosis development. However, still unclear is the mechanism of high uric acid in thrombosis with the involvement of let-7c. In an aim to fill this void, we conducted this study by treating mice and human umbilical vein endothelial cells with high uric acid. Analysis indicated that let-7c was upregulated in hyperuricemia patients as well as in mice and human umbilical vein endothelial cells treated with high uric acid. Furthermore, high uric acid inhibited myocyte enhancer factor-2C, but activated nuclear factor-kappa B pathway in human umbilical vein endothelial cells. Then the targeting relationship between let-7c and myocyte enhancer factor-2C was verified. On the one hand, high uric acid shortened activated partial thromboplastin time and prothrombin time of mice and declined tissue plasminogen activator level. Additionally, the treatment prolonged thrombin time and elevated the levels of thrombosis related molecules or proteins such as Fibrinogen and D-dimer. Nevertheless, these alternations could be reversed by inhibition of let-7c and nuclear factor-kappa B pathway or overexpressing myocyte enhancer factor-2C. To sum up, our results uncovered the pro-thrombotic effect of high uric acid in mice by activating myocyte enhancer factor-2C-dependent nuclear factor-kappa B pathway let-7c upregulation.
10.18632/aging.103540
Hyperuricemia is associated with metabolic syndrome in the community very elderly in Chengdu.
Huang Gang,Xu Junbo,Zhang Tingjie,Cai Lin,Liu Hanxiong,Yu Xiuqiong,Wu Jing
Scientific reports
Hyperuricemia is a risk factor for cardiovascular metabolic diseases. However, in the very elderly, the relationship between hyperuricemia and the metabolic syndrome (MetS) is not yet clear. This study was aimed to investigate the potential association between hyperuricemia and MetS in community very elderly in Chengdu. In this cross-sectional study, 1056 very elderly in the community were enrolled. Serum uric acid (SUA), fast plasma glucose, triglycerides and high-density lipoprotein cholesterol were measured, and then MetS components were calculated. Logistic regression models were used to explore risk factors for MetS in the very elderly. Finally, 1035 participants were included in analysis whose ages ranged between 80 and 100 with a mean age of 83.6 ± 3.4 years. The mean SUA level was 356.2 ± 95.0 µmol/L. The estimated prevalence of MetS in the very elderly was 25.0% vs. 21.6% (international diabetes federation (IDF) criteria vs. Chinese guideline), which was significantly higher for women (IDF criteria:17.3% in men vs 33.6% in women, p < 0.001). Logistic regression has found that participants with hyperuricemia (SUA level > 416 µmol/L in men and > 357 µmol/L in women) had a higher risk (IDF criteria: odds ratio (OR): 2.136, 95% confidence interval(CI): 1.525-2.993, p < 0.001. Chinese guideline: OR: 1.769, 95%CI: 1.249-2.503, p = 0.001) of MetS in very elderly Chinese. MetS is common in the community of very elderly Chinese in Chengdu. Hyperuricemia is associated with MetS in general very elderly and lifestyle changing should also be considered in the very elderly.
10.1038/s41598-020-65605-w
Sex Differences in Association of Elevated Blood Pressure with Variables Characterizing Cardiometabolic Risk in Young Subjects with or Without Metabolic Abnormalities.
Šebeková Katarína,Gurecká Radana,Csongová Melinda,Koborová Ivana,Šebek Jozef
International journal of environmental research and public health
Males present higher blood pressure (BP) values, higher prevalence of elevated BP, and a different prevalence of cardiometabolic risk factors when compared with females. We assumed that the trends of risk markers across BP categories (normotension, high normal BP, and hypertension) differ in young males and females, and between subjects without metabolic abnormalities (without obesity, insulin resistance, atherogenic dyslipidemia, hyperuricemia, or microinflammation) and those presenting them. Data from 2543 subjects (48% males) aged from 16 to 23 years were analyzed. The findings showed that 15% of males and 4% of females presented high normal BP while 9% and 1%, respectively, had hypertension. In males, variables characterizing obesity status, insulin sensitivity, atherogenic dyslipidemia, uric acid, adiponectin, a soluble receptor for advanced glycation end-products, and leukocyte counts showed worsening trends across BP categories. Females presented significant trends only for obesity measures, LDL-cholesterol, and non-HDL-cholesterol. Across BP categories, trends of variables characterizing cardiometabolic risk differed among abnormalities-free and presenting males. The multivariate model selected measures of central obesity, atherogenic dyslipidemia, insulin resistance, and uric acid as significant predictors of BP in both genders, and C-reactive protein in females. Sex differences in measures of cardiovascular health in juveniles may remain undiscovered unless two sexes are analyzed separately. These differences may have implications for sex-specific disease risk in adulthood.
10.3390/ijerph17103612
Uric Acid and Hypertension: An Update With Recommendations.
American journal of hypertension
The association between increased serum urate and hypertension has been a subject of intense controversy. Extracellular uric acid drives uric acid deposition in gout, kidney stones, and possibly vascular calcification. Mendelian randomization studies, however, indicate that serum urate is likely not the causal factor in hypertension although it does increase the risk for sudden cardiac death and diabetic vascular disease. Nevertheless, experimental evidence strongly suggests that an increase in intracellular urate is a key factor in the pathogenesis of primary hypertension. Pilot clinical trials show beneficial effect of lowering serum urate in hyperuricemic individuals who are young, hypertensive, and have preserved kidney function. Some evidence suggest that activation of the renin-angiotensin system (RAS) occurs in hyperuricemia and blocking the RAS may mimic the effects of xanthine oxidase inhibitors. A reduction in intracellular urate may be achieved by lowering serum urate concentration or by suppressing intracellular urate production with dietary measures that include reducing sugar, fructose, and salt intake. We suggest that these elements in the western diet may play a major role in the pathogenesis of primary hypertension. Studies are necessary to better define the interrelation between uric acid concentrations inside and outside the cell. In addition, large-scale clinical trials are needed to determine if extracellular and intracellular urate reduction can provide benefit hypertension and cardiometabolic disease.
10.1093/ajh/hpaa044
Identification of the Uric Acid Thresholds Predicting an Increased Total and Cardiovascular Mortality Over 20 Years.
Virdis Agostino,Masi Stefano,Casiglia Edoardo,Tikhonoff Valerie,Cicero Arrigo F G,Ungar Andrea,Rivasi Giulia,Salvetti Massimo,Barbagallo Carlo M,Bombelli Michele,Dell'Oro Raffaella,Bruno Berardino,Lippa Luciano,D'Elia Lanfranco,Verdecchia Paolo,Mallamaci Francesca,Cirillo Massimo,Rattazzi Marcello,Cirillo Pietro,Gesualdo Loreto,Mazza Alberto,Giannattasio Cristina,Maloberti Alessandro,Volpe Massimo,Tocci Giuliano,Georgiopoulos Georgios,Iaccarino Guido,Nazzaro Pietro,Parati Gianfranco,Palatini Paolo,Galletti Ferruccio,Ferri Claudio,Desideri Giovambattista,Viazzi Francesca,Pontremoli Roberto,Muiesan Maria Lorenza,Grassi Guido,Borghi Claudio,
Hypertension (Dallas, Tex. : 1979)
Serum uric acid (SUA) levels discriminating across the different strata of cardiovascular risk is still unknown. By utilizing a large population-based database, we assessed the threshold of SUA that increases the risk of total mortality and cardiovascular mortality (CVM). The URRAH study (Uric Acid Right for Heart Health) is a multicentre retrospective, observational study, which collected data from several large population-based longitudinal studies in Italy and subjects recruited in the hypertension clinics of the Italian Society of Hypertension. Total mortality was defined as mortality for any cause, CVM as death due to fatal myocardial infarction, stroke, sudden cardiac death, or heart failure. A total of 22 714 subjects were included in the analysis. Multivariate Cox regression analyses identified an independent association between SUA and total mortality (hazard ratio, 1.53 [95% CI, 1.21-1.93]) or CVM (hazard ratio, 2.08 [95% CI, 1.146-2.97]; <0.001). Cutoff values of SUA able to discriminate total mortality (4.7 mg/dL [95% CI, 4.3-5.1 mg/dL]) and CVM status (5.6 mg/dL [95% CI, 4.99-6.21 mg/dL]) were identified. The information on SUA levels provided a significant net reclassification improvement of 0.26 and of 0.27 over the Heart Score risk chart for total mortality and CVM, respectively (<0.001). Sex-specific cutoff values for total mortality and CVM were also identified and validated. In conclusion, SUA levels increasing the risk of total mortality and CVM are significantly lower than those used for the definition of hyperuricemia in clinical practice. Our data provide evidence of a cardiovascular SUA threshold that might contribute in clinical practice to improve identification of patients at higher risk of CVM.
10.1161/HYPERTENSIONAHA.119.13643
Impact of Uric Acid on Hypertension Occurrence and Target Organ Damage: Insights From the STANISLAS Cohort With a 20-Year Follow-up.
Kanbay Mehmet,Girerd Nicolas,Machu Jean-Loup,Bozec Erwan,Duarte Kevin,Boivin Jean-Marc,Wagner Sandra,Ferreira João Pedro,Zannad Faiez,Rossignol Patrick
American journal of hypertension
BACKGROUND:Recent studies have shown that hyperuricemia may be associated with incident hypertension (HTN). We examined whether serum uric acid (SUA) is a predictor of HTN and target organ damage (TOD) 20 years later in initially healthy middle-aged individuals. METHODS:Participants from the Suivi Temporaire Annuel Non-Invasif de la Santé des Lorrains Assurés Sociaux (STANISLAS) a single-center familial longitudinal cohort study (961 initially healthy adults and 570 children) underwent clinical and laboratory measurements at baseline and after approximately 20 years. Blood pressure (BP: using ambulatory BP measurements), urine albumin-to-creatinine ratio, estimated glomerular filtration rate (eGFR), left ventricular hypertrophy (LVH), diastolic dysfunction, and carotid-femoral pulse wave velocity (PWV) were measured at the end of follow-up. RESULTS:In the parent population, higher baseline or last SUA levels and higher change in SUA (ΔUA) were significantly associated with an increased risk of HTN development, even after adjusting for known HTN risk factors (all P < 0.01). Higher baseline SUA was marginally associated with an increased risk of having high carotid-femoral PWV (P = 0.05). The association of SUA with BP increase was body mass index dependent (the increase in BP being greater in leaner subjects; interactionp < 0.05), and the association of SUA with eGFR decline was age dependent (the decline in eGFR being greater in older subjects; interactionp < 0.05). There was no significant association between SUA and diastolic dysfunction or LVH. In the whole population (i.e. including children), a significant association between SUA at baseline and the risk of HTN and higher carotid-femoral PWV was also found (both P < 0.02). CONCLUSIONS:Increased SUA is associated with the development of HTN and vascular/renal TOD in initially healthy midlife subjects.
10.1093/ajh/hpaa030
Pharmacological inhibition of fatty acid-binding protein 4 alleviated kidney inflammation and fibrosis in hyperuricemic nephropathy.
Shi Min,Guo Fan,Liao Dan,Huang Rongshuang,Feng Yuying,Zeng Xiaoxi,Ma Liang,Fu Ping
European journal of pharmacology
Hyperuricemia is an independent risk factor for chronic kidney disease (CKD). Excessive uric acid (UA) level in the blood leads to hyperuricemic nephropathy (HN), which is characterized by glomerular hypertension, arteriolosclerosis and tubulointerstitial fibrosis. Fatty acid binding protein 4 (FABP4) is a potential mediator of inflammatory responses which contributes to renal interstitial fibrosis. However, the roles of FABP4 in HN remains unknown. In the study, a mouse model of HN induced by feeding a mixture of adenine and potassium oxonate, severe kidney injury and interstitial fibrosis, as well as the increased kidney-expressed FABP4 protein level were evident, accompanied by the activation of inflammatory responses. Oral administration of BMS309403, a highly selective FABP4 inhibitor, improved renal dysfunction, inhibited the mRNA level of KIM-1 and NGAL, as well as reduced the expression of proinflammatory cytokines and fibrotic proteins in the injured kidneys. BMS309403 treatment also inhibited the FABP4 activity and further suppressed the activation of JAK2-STAT3 and NF-kB P65 signaling pathways in the hyperuricemia-injured kidneys and UA-stimulated human tubular epithelial (HK-2) cells, respectively. In summary, our study for the first time demonstrated that FABP4 played a crucial role in kidney inflammation and fibrosis via the regulation of JAK2-STAT3 and NF-kB P65 pathways in HN mice. The results suggested that FABP4 inhibition might be a promising therapeutic strategy for HN.
10.1016/j.ejphar.2020.173570
Sex-specific differences in the prevalence of and risk factors for hyperuricemia among a low-income population in China: a cross-sectional study.
Qi Dongwang,Liu Jie,Wang Conglin,Wang Lixia,Zhang Xinxin,Lin Qiuxing,Tu Jun,Wang Jinghua,Ning Xianjia,Cui Jingqiu
Postgraduate medicine
: China has already entered the aging society, and its aging population is the largest worldwide. Accordingly, several aging-related conditions including hyperuricemia are becoming a public health concern owing to their increasing prevalence in rural areas. However, the sex-specific differences in the risk factors for hyperuricemia among the middle-aged and elderly in rural North China are unclear. Thus, this study aimed to evaluate sex-specific differences in the prevalence of and risk factors for hyperuricemia in low-income adults in rural North China. : This population-based cross-sectional study recruited participants aged ≥50 years from the Tianjin Brain Study between April and August 2019. After excluding those who had cancer, severe psychiatric disturbances, hepatic failure, and serious renal disease (i.e., an estimated glomerular filtration rate (eGFR) of <30 mL/min/1.73 m), 3119 (1392 men and 1727 women) eligible participants were included. Basic information and blood samples were collected, and data were analyzed using logistic regression models. : Hyperuricemia was prevalent in 14.4% (men, 14.2%; women, 14.5%)of the participants, and the prevalence significantly increased with increasing age in both sexes (male, = 0.034; female, < 0.001). In multivariate analysis, obesity, metabolic syndrome, and high levels of total cholesterol, 2 h plasma glucose, and blood urea nitrogen were risk factors for hyperuricemia in both men and women. Physical activity was a risk factor in men, while a high white blood cell count was a risk factor in women. A high eGFR was a protective factor in both sexes. : Hyperuricemia was highly prevalent in low-income adults in Tianjin, with men and women showing differences in risk profiles and comorbidities. Early management of hyperuricemia according to sex-specific risk factors should be considered in primary care to reduce the prevalence and burden of hyperuricemia in rural China.
10.1080/00325481.2020.1761133
The causal role of elevated uric acid and waist circumference on the risk of metabolic syndrome components.
Biradar Mahantesh I,Chiang Kuang-Mao,Yang Hsin-Chou,Huang Yen-Tsung,Pan Wen-Harn
International journal of obesity (2005)
BACKGROUND/OBJECTIVES:Hyperuricemia has been found to cluster with multiple components of metabolic syndrome (MetS). It is unclear whether hyperuricemia is a downstream result of MetS or may play an upstream role in MetS development. Using the Mendelian randomization (MR) method, we examined the causal relationship between elevated uric acid and the various components of MetS with waist circumference as a positive control. SUBJECTS/METHODS:Data from 10k participants of Taiwan Biobank was used to carry out MR analysis with uric acid risk score (wGRS) and waist circumference wGRS as instrumental variables and components of MetS as the outcomes. RESULTS:We found that genetically increased serum uric acid corresponds to a significant increment of triglyceride (β = 0.065, p < 0.0001), systolic blood pressure (β = 1.047, p = 0.0005), diastolic blood pressure (β = 0.857, p < 0.0001), and mean arterial pressure (β = 0.920, p < 0.0001), but a significant reduction of high-density lipoprotein cholesterol (β = -0.020, p = 0.0014). Uric acid wGRS was not associated with fasting serum glucose, HbA1C, waist circumference, or BMI. On the other hand, waist circumference was causally associated with all the components of MetS including uric acid. CONCLUSIONS:Our MR investigation shows that uric acid increment may augment the risk of MetS through increasing blood pressure and triglyceride levels and lowering HDL-C value but not through accumulating fat or hyperglycemia. High waist circumference may be a causal agent for all the components of MetS including hyperuricemia.
10.1038/s41366-019-0487-9
Role of asymptomatic hyperuricemia in the progression of chronic kidney disease and cardiovascular disease.
Waheed Yousuf,Yang Fan,Sun Dong
The Korean journal of internal medicine
Previous research has investigated whether hyperuricemia serves as an independent risk factor for cardiovascular and renal diseases. Hyperuricemia is defined as an abnormally high level of uric acid (UA; i.e., serum urate level > 6.8 mg/dL). Hyperuricemia has been considered a complication of chronic kidney disease (CKD). However, it seems to play a pathogenic role in the progression of renal diseases. There has been increasing focus on the link between hyperuricemia and CKD. The results of randomized controlled trials have implied independent associations between hyperuricemia and the progression of cardiovascular and renal morbidities. These associations may be mediated by renin-angiotensin system activation, nitric oxide synthase inhibition, and macrovascular/microvascular disease development. There remains controversy regarding the use of serum UA level as an indirect index of renal vascular disease. This literature review focuses on the role of asymptomatic hyperuricemia in the progression of CKD, as well as the association between hyperuricemia and cardiovascular disease. It also provides a general overview of the physiological metabolism of UA.
10.3904/kjim.2020.340
Differences in the association between glycemia and uric acid levels in diabetic and non-diabetic populations.
Kuo Kuan-Ting,Chang Yin-Fan,Wu I-Hsuan,Lu Feng-Hwa,Yang Yi-Ching,Wu Jin-Shang,Chang Chih-Jen
Journal of diabetes and its complications
AIMS:Our study aimed to investigate the influence of different glycemic statuses and their fasting plasma glucose/2-hour post-load glucose on uric acid level. METHODS:A total of 14,787 subjects were recruited after excluding subjects with medication for hyperuricemia or diabetes. Fasting plasma glucose (FPG), 2-hour post-load glucose (2hPG), and uric acid (UA) were measured. Then, subjects were divided into normal glucose tolerance (NGT), impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and diabetes. RESULTS:After adjustment for clinical variables, in NGT group, there was no significant relationship found between UA level and FPG. However, there was a positive association between UA level and 2hPG (β = 0.003, 95% CI: 0.002~0.004). A similar trend was also observed between UA level and 2hPG in IFG group (β = 0.004, 95% CI: 0.000~0.009) and IGT group (β = 0.005, 95% CI: 0.002~0.008), but relationship between UA level and FPG remained insignificant. In diabetes group, UA level was negatively associated with both FPG (β = -0.008, 95% CI: -0.010 ~ -0.007) and 2hPG (β = -0.005, 95% CI: -0.006 ~-0.003). CONCLUSIONS:In non-diabetic individuals, UA level increased with 2hPG, but not with FPG, and UA level was inversely associated with both FPG and 2hPG in diabetic population.
10.1016/j.jdiacomp.2019.05.004
Association Between Vitamin D and Uric Acid in Adults: A Systematic Review and Meta-Analysis.
Isnuwardana Ronny,Bijukchhe Sanjeev,Thadanipon Kunlawat,Ingsathit Atiporn,Thakkinstian Ammarin
Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme
Association between vitamin D and uric acid is complex and might be bidirectional. Our study aimed to determine the bidirectional association between vitamin D and uric acid in adults. Using MEDLINE via PubMed and Scopus, we systematically searched for observational or interventional studies in adults, which assessed the association between serum vitamin D and serum uric acid, extracted the data, and conducted analysis by direct and network meta-analysis. The present review included 32 studies, of which 21 had vitamin D as outcome and 11 had uric acid as outcome. Meta-analysis showed a significant pooled beta coefficient of serum uric acid level on serum 25(OH)D level from 3 studies of 0.512 (95% confidence interval: 0.199, 0.825) and a significant pooled odds ratio between vitamin D deficiency and hyperuricemia of 1.496 (1.141, 1.963). The pooled mean difference of serum 25(OH)D between groups with hyperuricemia and normouricemia was non-significant at 0.138 (-0.430, 0.707) ng/ml, and the pooled mean difference of serum uric acid between categories of 25(OH)D were also non-significant at 0.072 (-0.153, 0.298) mg/dl between deficiency and normal, 0.038 (-0.216, 0.292) mg/dl between insufficiency and normal, and 0.034 (-0.216, 0.283) mg/dl between deficiency and insufficiency. In conclusion, increasing serum uric acid might be associated with increasing 25(OH)D level, while vitamin D deficiency is associated with hyperuricemia. These reverse relationships should be further evaluated in a longitudinal study.
10.1055/a-1240-5850
A pilot study to identify the longitudinal serum metabolite profiles to predict the development of hyperuricemia in essential hypertension.
Zhao Heru,Zhang Yin,Liu Bin,Zhang Lulu,Bao Mei,Li Li,Zhao Ning,Hussain Muhummad,Wang Yuexi,Yi Jianfeng,Chen Peng,Lu Cheng
Clinica chimica acta; international journal of clinical chemistry
BACKGROUND:Essential hypertension (EHT) is the most prevalent chronic medical condition and a major risk factor for cardiovascular morbidity and mortality. EHT often progresses and combines with hyperuricemia (HU) in clinical cases, which increases organ damage in patients with EHT. We compared serum metabolites in EHT patients with EHT + HU patients and to find metabolic markers and related pathways in the progression of EHT to EHT + HU. METHODS:A longitudinal study was carried out in 35 patients (initially EHT and EHT + HU one year later). With 10 metabolites in EHT + HU identified as potential biomarkers, linoleic acid metabolism, sphingolipid metabolism, steroid hormone biosynthesis, starch and sucrose metabolism and purine metabolism interacted with EHT + HU. RESULTS:Distinct changes in the metabolomics profile of sera were observed among healthy controls (HC), EHT and EHT + HU groups. Uric acid (UA), L-lactic acid, and quinolinic acid may play important roles in the progression from EHT to EHT + HU. They were mainly involved in pyruvate metabolism, purine metabolism and nicotinate and nicotinamide metabolism pathways. CONCLUSIONS:The continuous elevation of L-lactic acid and quinolinic acid might be useful for understanding the mechanisms of pathogenesis in EHT + HU and provide prospects for preventing the development of EHT and HU.
10.1016/j.cca.2020.08.002
Cardio-renal protective effect of the xanthine oxidase inhibitor febuxostat in the 5/6 nephrectomy model with hyperuricemia.
Omizo Hiroki,Tamura Yoshifuru,Morimoto Chikayuki,Ueno Masaki,Hayama Yuto,Kuribayashi-Okuma Emiko,Uchida Shunya,Shibata Shigeru
Scientific reports
Although hyperuricemia has been shown to be associated with the progression of cardiovascular disorder and chronic kidney disease (CKD), there is conflicting evidence as to whether xanthine oxidase (XO) inhibitors confer organ protection besides lowering serum urate levels. In this study, we addressed the cardio-renal effects of XO inhibition in rodent CKD model with hyperuricemia. Sprague-Dawley rats underwent 5/6 nephrectomy and received a uricase inhibitor oxonic acid for 8 weeks (RK + HUA rats). In some rats, a XO inhibitor febuxostat was administered orally. Compared with control group, RK + HUA group showed a significant increase in albuminuria and renal injury. Febuxostat reduced serum uric acid as well as urinary albumin levels. Histological and immunohistochemical analysis of the kidney revealed that febuxostat alleviated glomerular, tubulointerstitial, and arteriolar injury in RK + HUA rats. Moreover, in the heart, RK + HUA showed individual myofiber hypertrophy and cardiac fibrosis, which was significantly attenuated by febuxostat. We found that renal injury and the indices of cardiac changes were well correlated, confirming the cardio-renal interaction in this model. Finally, NF-E2-related factor 2 (Nrf2) and the downstream target heme oxygenase-1 (HO-1) protein levels were increased both in the heart and in the kidney in RK + HUA rats, and these changes were alleviated by febuxostat, suggesting that tissue oxidative stress burden was attenuated by the treatment. These data demonstrate that febuxostat protects against cardiac and renal injury in RK + HUA rats, and underscore the pathological importance of XO in the cardio-renal interaction.
10.1038/s41598-020-65706-6
Molecular and Histopathological Study on the Ameliorative Impacts of Petroselinum Crispum and Apium Graveolens against Experimental Hyperuricemia.
Soliman Mohamed Mohamed,Nassan Mohamed Abdo,Aldhahrani Adil,Althobaiti Fayez,Mohamed Wafaa Abdou
Scientific reports
Hyperuricemia is an abnormal metabolic condition characterized by an increase in uric acid levels in the blood. It is the cause of gout, manifested by inflammatory arthritis, pain and disability. This study examined the possible ameliorative impacts of parsley (PAR) and celery (CEL) as hypouricemic agents at biochemical, molecular and cellular levels. PAR and CEL alone or in combination were orally administered to hyperuricemic (HU) mice and control mice for 10 consecutive days. Serum levels of uric acid and blood urea nitrogen (BUN), xanthine oxidase activity, antioxidants, inflammatory (IL-1β and TNF-α) and anti-inflammatory cytokines (IL-10) were measured. mRNA expression of urate transporters and uric acid excretion genes in renal tissues were examined using qRT-PCR (quantitative real time PCR). Normal histology and immunoreactivity of transforming growth factor-beta 1 (TGF-β1) in kidneys was examined. Administration of PAR and CEL significantly reduced serum BUN and uric acids in HU mice, ameliorated changes in malondialdehyde, catalase, and reduced glutathione, glutathione peroxidase (GPX), IL-1β, TNF-α and IL-10 in hyperuricemic mice. Both effectively normalized the alterations in mURAT-1, mGLUT-9, mOAT-1 and mOAT-3 expression, as well as changes in TGF-β1 immunoreactivity. Interestingly, combined administration of PAR and CEL mitigated all examined measurements synergistically, and improved renal dysfunction in the hyperuricemic mice. The study concluded that PAR and CEL can potentially reduce damaging cellular, molecular and biochemical effects of hyperuricemia both individually and in combination.
10.1038/s41598-020-66205-4
Elevated triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio increased risk of hyperuricemia: a 4-year cohort study in China.
Liu Xin-Yao,Wu Qiao-Yu,Chen Zhi-Heng,Yan Guang-Yu,Lu Yao,Dai Hai-Jiang,Li Ying,Yang Ping-Ting,Yuan Hong
Endocrine
PURPOSE:Previous studies revealed that high serum uric acid (SUA) levels correlated with increased triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio. However, evidence is lacking regarding whether TG/HDL-C is an independent risk factor or just a simple marker of hyperuricemia. We aimed to investigate the relationship between TG/HDL-C and the risk of hyperuricemia in Chinese population. METHODS:This retrospective cohort study involved 15,198 subjects (43.14 ± 13.13 years, 54.9% men) who were free of hyperuricemia at baseline. The association between TG/HDL-C and the risk of hyperuricemia, in the total sample and stratified by subgroups, was examined by multiple logistic regression analyses. RESULTS:During 4 years follow-up, hyperuricemia occurred in 2365 (15.6%) participants. The cumulative incidence of hyperuricemia was significantly elevated with increasing TG/HDL-C quartiles (5.9, 10.8, 18.4, and 27.5%, respectively). After multivariate adjustment, the odds ratio for hyperuricemia in the highest compared with the lowest quartile of TG/HDL-C was 1.80 (95% confidence interval [CI] 1.49, 2.18), and each SD increment of TG/HDL-C ratio caused a 10% additional risk for hyperuricemia. Moreover, subgroup analyses showed that the association between TG/HDL-C and the risk of hyperuricemia was more pronounced in women and normal-weight adults. The results were consistent when analyses were restricted to participants without metabolic syndrome. CONCLUSIONS:TG/HDL-C ratio was positively related to the risk of hyperuricemia in Chinese population, particularly in women and normal-weight individuals. These findings suggested the potential of TG/HDL-C ratio to serve as an independent risk indicator in the prevention of hyperuricemia.
10.1007/s12020-019-02176-5
Hyperuricemia, the heart, and the kidneys - to treat or not to treat?
Renal failure
BACKGROUND:Hyperuricemia is a state in which the serum levels of uric acid are elevated. As such it has a pronounced effect on vascular and renal function with their consequences, while also showing some antioxidant effects that show to be beneficial. SUMMARY:Hyperuricemia has shown to have a J-shaped relationship with mortality, is frequently associated with development and progression of heart and kidney disease, and is correlated with malnutrition-inflammation-atherosclerosis syndrome, although several Mendelian studies have failed to show an association with morbidity and mortality. Hyperuricemia is usually associated with gout flares and tophi development but can also present as asymptomatic hyperuricemia. It is still uncertain whether asymptomatic hyperuricemia is an independent risk factor for cardiovascular or renal disease and as such its treatment is questionable. KEY MESSAGES:Some possible tools for future decision making are the use of noninvasive techniques such as pulse wave analysis, urinary sediment analysis, and joint ultrasound, which could help identify individuals with asymptomatic hyperuricemia that could benefit from urate lowering therapy most.
10.1080/0886022X.2020.1822185
The Role of Noncoding RNAs in Gout.
Li Xue,Pan Yunyan,Li Wei,Guan Peiwen,You Chongge
Endocrinology
Over the past decade, noncoding ribonucleic acids (ncRNAs) have been shown to have crucial functional importance in health and disease. ncRNAs have been well studied and may be involved in the development of inflammatory arthritis, including gouty arthritis. Gout is also associated with metabolic pathway disorders, such as hyperuricemia, due to disturbed purine nucleotide metabolism or excretion of uric acid through the kidney. Moreover, their presence in the circulation has led to the idea that ncRNAs might serve as biomarkers for specific disease states to guide clinical decision-making. Therefore, we summarize the emerging evidence and review the current literature on the regulatory role of miRNAs and lncRNAs in gout pathophysiology. We further discuss the opportunities and challenges of ncRNAs as new blood-based biomarkers for future studies aimed at translation into clinical applications in the diagnosis and therapy of gout.
10.1210/endocr/bqaa165
Rationale, design, and baseline characteristics of a study to evaluate the effect of febuxostat in preventing cerebral, cardiovascular, and renal events in patients with hyperuricemia.
Kojima Sunao,Matsui Kunihiko,Ogawa Hisao,Jinnouchi Hideaki,Hiramitsu Shinya,Hayashi Takahiro,Yokota Naoto,Kawai Naoki,Tokutake Eiichi,Uchiyama Kazuaki,Sugawara Masahiro,Kakuda Hirokazu,Wakasa Yutaka,Mori Hisao,Hisatome Ichiro,Waki Masako,Ohya Yusuke,Kimura Kazuo,Saito Yoshihiko,
Journal of cardiology
BACKGROUND:Since uric acid is associated with cardiovascular and renal disease, a treatment to maintain blood uric acid level may be required in patients with hyperuricemia. This study aims to evaluate preventive effects of febuxostat, a selective xanthine oxidase inhibitor, on cerebral, cardiovascular, and renal events in patients with hyperuricemia compared to conventional treatment. METHODS AND RESULTS:This study is a prospective randomized open-label blinded endpoint study. Patient enrolment was started in November 2013 and was completed in October 2014. The patients will be followed for at least 3 years. The primary endpoint is a composite of cerebral, cardiovascular, and renal events, and all deaths including death due to cerebral, cardiovascular, and renal disease, new or recurring cerebrovascular disease, new or recurring non-fatal coronary artery disease, cardiac failure requiring hospitalization, arteriosclerotic disease requiring treatment, renal impairment, new atrial fibrillation, and all deaths other than cerebral or cardiovascular or renal disease. These events will be independently evaluated by the Event Assessment Committee under blinded information regarding the treatment group. The study was registered at ClinicalTrials.gov with the identifier NCT01984749.
10.1016/j.jjcc.2016.02.015
Ideal Cardiovascular Health Metrics and Incident Hyperuricemia.
Li Zheng,Meng Lingmin,Huang Zhe,Cui Liufu,Li Weijuan,Gao Jingsheng,Wang Zhanqi,Zhang Rui,Zhou Jing,Zhang Ge,Chen Shuohua,Zheng Xiaoming,Cong Hongliang,Gao Xiang,Wu Shouling
Arthritis care & research
OBJECTIVE:Hyperuricemia has been shown to be associated with increased risks of gout and cardiovascular diseases. We prospectively investigated the association between the American Heart Association (AHA) ideal cardiovascular health metrics, including smoking, body mass index, dietary intake, physical activity, blood pressure, total cholesterol, and fasting blood glucose, and the risk of developing hyperuricemia. METHODS:We included 77,787 Chinese adults, ages ≥18 years (60,951 men and 16,836 women), without hyperuricemia at the baseline (2006) in this study. Information on the cardiovascular health metrics at baseline was collected. Incident hyperuricemia cases were identified by elevated serum uric acid concentrations, which were repeatedly assessed in 2006, 2008, 2010, and 2012, respectively. Cox regression was used to calculate the hazard ratios (HRs) and 95% confidence intervals (95% CIs) for incident hyperuricemia according to the baseline ideal cardiovascular health metrics. RESULTS:We observed an inverse relation between the greater numbers of ideal cardiovascular health metrics at baseline and lower risks of developing hyperuricemia during 6 years of followup. After adjusting for age, sex, alcohol consumption, and other potential confounders, the HRs for incident hyperuricemia were 0.95, 0.84, 0.72, and 0.64 (95% CIs 0.58-0.70, P for trend < 0.0001) for participants who met 2, 3, 4, and 5-7 metrics, respectively, compared with those who met 0-1 cardiovascular health metrics. CONCLUSION:Greater cardiovascular health metrics were associated with lower risk of hyperuricemia in this Chinese population, suggesting that the modifiable construct defined by the AHA could be of significance in reducing the risk of developing hyperuricemia-related diseases, such as gout.
10.1002/acr.22830
Urate-lowering therapy for asymptomatic hyperuricaemia: A need for caution.
Stamp Lisa,Dalbeth Nicola
Seminars in arthritis and rheumatism
OBJECTIVE:The observed associations of hyperuricaemia with hypertension, cardiovascular disease and kidney disease are receiving increasing interest. The potential role of urate-lowering therapy in the management of these "non-gout diseases" has been raised, and in some countries it is already recommended. However, there is no consistent definition of hyperuricaemia or asymptomatic hyperuricaemia, much remains unknown about the causal role of urate in these "non-gout diseases" and there is currently a lack of evidence about the effects of urate lowering on disease progression. In addition, there is potential for serious adverse effects associated with urate-lowering therapies with recent evidence suggesting that asymptomatic hyperuricaemia may be an independent risk factor for the potentially fatal allopurinol hypersensitivity syndrome. METHODS:Pubmed was searched in January 2016 using the search term "asymptomatic hyperuricaemia". RESULTS AND CONCLUSIONS:Herein, we discuss the issues related to treating asymptomatic hyperuricaemia, which at present seems premature.
10.1016/j.semarthrit.2016.07.015
Association of hyperuricemia with renal outcomes, cardiovascular disease, and mortality.
Liu Wan-Chun,Hung Chi-Chih,Chen Szu-Chia,Yeh Shih-Meng,Lin Ming-Yen,Chiu Yi-Wen,Kuo Mei-Chuan,Chang Jer-Ming,Hwang Shang-Jyh,Chen Hung-Chun
Clinical journal of the American Society of Nephrology : CJASN
BACKGROUND AND OBJECTIVES:Hyperuricemia is an independent risk factor for mortality, cardiovascular disease, and renal disease in general population. However, the relationship between hyperuricemia with clinical outcomes in CKD remains controversial. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:The study investigated the association between uric acid with all-cause mortality, cardiovascular events, renal replacement therapy, and rapid renal progression (the slope of estimated GFR was less than -6 ml/min per 1.73 m(2)/y) in 3303 stages 3-5 CKD patients that were in the integrated CKD care system in one medical center and one regional hospital in southern Taiwan. RESULTS:In all subjects, the mean uric acid level was 7.9 ± 2.0 mg/dl. During a median 2.8-year follow-up, there were 471 (14.3%) deaths, 545 (16.5%) cardiovascular events, 1080 (32.3%) participants commencing renal replacement therapy, and 841 (25.5%) participants with rapid renal progression. Hyperuricemia increased risks for all-cause mortality and cardiovascular events (the adjusted hazard ratios for quartile four versus quartile one of uric acid [95% confidence interval] were 1.85 [1.40-2.44] and 1.42 [1.08-1.86], respectively) but not risks for renal replacement therapy (0.96 [0.79-1.16]) and rapid renal progression (1.30 [0.98-1.73]). CONCLUSIONS:In stages 3-5 CKD, hyperuricemia is a risk factor for all-cause mortality and cardiovascular events but not renal replacement therapy and rapid renal progression.
10.2215/CJN.09420911
Mouse models for human hyperuricaemia: a critical review.
Lu Jie,Dalbeth Nicola,Yin Huiyong,Li Changgui,Merriman Tony R,Wei Wen-Hua
Nature reviews. Rheumatology
Hyperuricaemia (increased serum urate concentration) occurs mainly in higher primates, including in humans, because of inactivation of the gene encoding uricase during primate evolution. Individuals with hyperuricaemia might develop gout - a painful inflammatory arthritis caused by monosodium urate crystal deposition in articular structures. Hyperuricaemia is also associated with common chronic diseases, including hypertension, chronic kidney disease, type 2 diabetes and cardiovascular disease. Many mouse models have been developed to investigate the causal mechanisms for hyperuricaemia. These models are highly diverse and can be divided into two broad categories: mice with genetic modifications (genetically induced models) and mice exposed to certain environmental factors (environmentally induced models; for example, pharmaceutical or dietary induction). This Review provides an overview of the mouse models of hyperuricaemia and the relevance of these models to human hyperuricaemia, with an emphasis on those models generated through genetic modifications. The challenges in developing and comparing mouse models of hyperuricaemia and future research directions are also outlined.
10.1038/s41584-019-0222-x
Asymptomatic hyperuricemia and cardiovascular mortality in patients with chronic kidney disease who progress to hemodialysis.
Petreski Tadej,Ekart Robert,Hojs Radovan,Bevc Sebastjan
International urology and nephrology
PURPOSE:Hyperuricemia has been associated with higher mortality in the general population, but less is known about CKD patients. The aim of our study was to determine the impact of elevated serum uric acid on cardiovascular mortality of CKD patients who later progress to hemodialysis. METHODS:In this retrospective study, 120 CKD patients (entire population of patients with ESKD on January 1st, 2012) were observed from their first visit at the Nephrology outpatient clinic, while transitioning to hemodialysis, and until their death or January 1, 2016. After non-cardiovascular death exclusion, 83 CKD patients (33 female, 50 male) were left for further analysis. The average time of observation was 8.8 ± 4.2 years. Serum uric acid was measured regularly (every 3 months). No patients were treated for hyperuricemia. Mean uric acid of 420 µmol/L was set as a cut-off between normouricemic and hyperuricemic patients as per the laboratory's reference values. Survival rates were analyzed using Kaplan-Meier survival curves. Three Cox regression models were used to assess the influence of uric acid on survival. RESULTS:Mean uric acid was 379.8 ± 71.6 µmol/L (range 220-574). Sixty-three (75.9%) patients were normouricemic and 20 (24.1%) were hyperuricemic. Cholesterol was the only variable to show statistically significant difference (p = 0.004) between the groups. Bivariate analysis revealed an association between death and age, hyperuricemia, arterial hypertension, and history of cardiovascular disease. Kaplan-Meier survival analysis showed higher risk of cardiovascular death for hyperuricemic patients (log rank test; p < 0.0005). In Cox regression models, hyperuricemia remained a predictor of cardiovascular mortality (SE = 0.500, Exp(B) = 14.120, 95% CI 5.297-37.640) in our patients next to age and arterial hypertension. CONCLUSION:The results indicate an association between hyperuricemia and cardiovascular mortality in CKD patients who transition to hemodialysis.
10.1007/s11255-019-02154-w
Cardiovascular and renal effects of hyperuricaemia and gout.
Viazzi F,Leoncini G,Pontremoli R
Reumatismo
A number of epidemiological studies have reported an association between serum uric acid levels and a wide variety of high-risk conditions including hypertension, insulin resistance, and kidney and cerebro-cardiovascular disease. All things considered, serum uric acid may induce cardiovascular and kidney events both directly and indirectly by promoting other well-known mechanisms of damage. While asymptomatic hyperuricemia is currently not considered to be an indication for urate lowering therapy, there is growing evidence indicating a linear relationship between pharmacological reduction in serum uric acid and incidence of cardiovascular and renal events.
10.4081/reumatismo.2011.253
Hyperuricaemia and development of type 2 diabetes mellitus in Asian population.
Choi Byoung Geol,Kim Dae Jin,Baek Man Jong,Ryu Yang Gi,Kim Suhng Wook,Lee Min Woo,Park Ji Young,Noh Yung-Kyun,Choi Se Yeon,Byun Jae Kyeong,Shim Min Suk,Mashaly Ahmed,Li Hu,Park Yoonjee,Jang Won Young,Kim Woohyeun,Kang Jun Hyuk,Choi Jah Yeon,Park Eun Jin,Park Sung-Hun,Lee Sunki,Na Jin Oh,Choi Cheol Ung,Kim Eung Ju,Park Chang Gyu,Seo Hong Seog,Oh Dong Joo,Rha Seung-Woon
Clinical and experimental pharmacology & physiology
Recently, meta-analysis studies reported that hyperuricaemia is associated with higher incidence of type 2 diabetes mellitus (T2DM), however, there are limited data on the Asian population. The aim of this observational study is to estimate the long-term impact of hyperuricaemia on the new-onset T2DM and cardiovascular events. This study is based on a single-centre, all-comers, and large retrospective cohort. Subjects that visited from January 2004 to February 2014 were enrolled using the electronic database of Korea University Guro Hospital. A total of 10 505 patients without a history of T2DM were analyzed for uric acid, fasting glucose and haemoglobin (Hb) A1c level. Inclusion criteria included both Hb A1c <5.7% and fasting glucose level <100 mg/dL without T2DM. Hyperuricaemia was defined as a uric acid level ≥7.0 mg/dL in men, and ≥6.5 mg/dL in women. To adjust baseline confounders, a propensity score matching (PSM) analysis was performed. The impact of hyperuricaemia on the new-onset T2DM and cardiovascular events were compared with the non-hyperuricaemia during the 5-year clinical follow-up. After PSM, baseline characteristics of both groups were balanced. In a 5-year follow-up, the hyperuricaemia itself was a strong independent predictor of the incidence of new-onset T2DM (HR, 1.78; 95% CI, 1.12 to 2.8). Hyperuricaemia was a strong independent predictor of new-onset T2DM, which suggests a substantial implication for a correlation between uric acid concentration and insulin resistance (or insulin sensitivity). Also, hyperuricaemia is substantially implicated in cardiovascular risks and the further long-term cardiovascular events in the crude population, but it is not an independent predictor of long-term cardiovascular mortality in the matched population.
10.1111/1440-1681.12911
Hyperuricemia and Cardiovascular Disease.
Zhang Shuangshuang,Wang Yong,Cheng Jinsong,Huangfu Ning,Zhao Ruochi,Xu Zhenyu,Zhang Fuxing,Zheng Wenyuan,Zhang Dandan
Current pharmaceutical design
Purine metabolism in the circulatory system yields uric acid as its final oxidation product, which is believed to be linked to the development of gout and kidney stones. Hyperuricemia is closely correlated with cardiovascular disease, metabolic syndrome, and chronic kidney disease, as attested by the epidemiological and empirical research. In this review, we summarize the recent knowledge about hyperuricemia, with a special focus on its physiology, epidemiology, and correlation with cardiovascular disease. This review also discusses the possible positive effects of treatment to reduce urate levels in patients with cardiovascular disease and hyperuricemia, which may lead to an improved clinical treatment plan.
10.2174/1381612825666190408122557
Hyperuricemia and Risk of Cardiovascular Outcomes: The Experience of the URRAH (Uric Acid Right for Heart Health) Project.
Maloberti Alessandro,Giannattasio C,Bombelli M,Desideri G,Cicero A F G,Muiesan M L,Rosei E A,Salvetti M,Ungar A,Rivasi G,Pontremoli R,Viazzi F,Facchetti R,Ferri C,Bernardino B,Galletti F,D'Elia L,Palatini P,Casiglia E,Tikhonoff V,Barbagallo C M,Verdecchia P,Masi S,Mallamaci F,Cirillo M,Rattazzi M,Pauletto P,Cirillo P,Gesualdo L,Mazza A,Volpe M,Tocci G,Iaccarino G,Nazzaro P,Lippa L,Parati G,Dell'Oro R,Quarti-Trevano F,Grassi G,Virdis A,Borghi C,
High blood pressure & cardiovascular prevention : the official journal of the Italian Society of Hypertension
The latest European Guidelines of Arterial Hypertension have officially introduced uric acid evaluation among the cardiovascular risk factors that should be evaluated in order to stratify patient's risk. In fact, it has been extensively evaluated and demonstrated to be an independent predictor not only of all-cause and cardiovascular mortality, but also of myocardial infraction, stroke and heart failure. Despite the large number of studies on this topic, an important open question that still need to be answered is the identification of a cardiovascular uric acid cut-off value. The actual hyperuricemia cut-off (> 6 mg/dL in women and 7 mg/dL in men) is principally based on the saturation point of uric acid but previous evidence suggests that the negative impact of cardiovascular system could occur also at lower levels. In this context, the Working Group on uric acid and CV risk of the Italian Society of Hypertension has designed the Uric acid Right for heArt Health project. The primary objective of this project is to define the level of uricemia above which the independent risk of CV disease may increase in a significantly manner. In this review we will summarize the first results obtained and describe the further planned analysis.
10.1007/s40292-020-00368-z
Gout and hyperuricaemia in the USA: prevalence and trends.
Singh Gurkirpal,Lingala Bharathi,Mithal Alka
Rheumatology (Oxford, England)
OBJECTIVES:Several recent observations have suggested that the prevalence of gout may be increasing worldwide, but there are no recent data from the USA. We analysed the prevalence of hyperuricaemia and gout in the US population from 2007-08 to 2015-16. METHODS:We studied adults ⩾20 years of age from the National Health and Nutrition Examination Survey from 2007-08 to 2015-16. Persons with gout were identified from the home interview question 'Has a doctor or other health professional ever told you that you had gout?' Hyperuricaemia was defined as a serum urate level >0.40 mmol/l (6.8 mg/dl) (supersaturation levels at physiological temperatures and pH). RESULTS:In 2015-16, the overall prevalence of gout among US adults was 3.9%, corresponding to a total affected population of 9.2 million. Hyperuricaemia (>0.40 mmol/l or 6.8 mg/dl) was seen in 14.6% of the US population (estimated 32.5 million individuals). No significant trends were identified in the age-adjusted prevalence of gout and hyperuricaemia. Statistical comparisons between 2007-08 and 2015-16 age-adjusted rates were not significant. CONCLUSION:While the age-adjusted prevalence of gout and hyperuricaemia has remained unchanged in the most recent decade from 2007-08 to 2015-16, the estimated total number of persons with self-reported gout has increased from 8.3 million to 9.2 million. The age-adjusted prevalence of hyperuricaemia has declined slightly, but the total number of affected individuals is virtually identical (32.5 million in 2015-16 compared with 32.1 million in 2007-08).
10.1093/rheumatology/kez196
Role of Hyperhomocysteinemia and Hyperuricemia in Pathogenesis of Atherosclerosis.
Zhao Junjie,Chen Hailin,Liu Ning,Chen Jun,Gu Youquan,Chen Jiangjun,Yang Kui
Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association
BACKGROUND:The mechanisms of hyperhomocysteinemia (HHcy) and hyperuricemia (HUA) that promote atherosclerosis were seldom explored and always indefinite. Therefore, we will discuss some new reviews about the role of HHcy and HUA in the pathogenesis of atherosclerosis. METHODS:This study was conducted by reading a lot of literature, including basic research and clinical application research. RESULTS:HHcy is known as an independent risk factor for atherosclerosis. Possible mechanisms for the association between homocysteine and atherosclerosis include stimulating smooth muscle cell growth, reducing endothelial cell growth and endothelial cell relaxation, and decreasing synthesis of high-density lipoprotein. HUA causes endothelial dysfunction and thereby increases oxidative stress, inducing vascular smooth muscle cell proliferation and reducing endothelial nitric oxide bioavailability. HUA plays a role in the development and pathogenesis of metabolic syndrome, hypertension, stroke, and atherosclerosis. CONCLUSIONS:Accelerated atherosclerosis may be a consequence of the combined effect of HHcy and HUA.
10.1016/j.jstrokecerebrovasdis.2016.10.012