Asymptomatic hyperuricaemia: a silent activator of the innate immune system.
Nature reviews. Rheumatology
Asymptomatic hyperuricaemia affects ~20% of the general population in the USA, with variable rates in other countries. Historically, asymptomatic hyperuricaemia was considered a benign laboratory finding with little clinical importance in the absence of gout or kidney stones. Yet, increasing evidence suggests that asymptomatic hyperuricaemia can predict the development of hypertension, obesity, diabetes mellitus and chronic kidney disease and might contribute to disease by stimulating inflammation. Although urate has been classically viewed as an antioxidant with beneficial effects, new data suggest that both crystalline and soluble urate activate various pro-inflammatory pathways. This Review summarizes what is known about the role of urate in the inflammatory response. Further research is needed to define the role of asymptomatic hyperuricaemia in these pro-inflammatory pathways.
10.1038/s41584-019-0334-3
Plasma urate concentration and risk of coronary heart disease: a Mendelian randomisation analysis.
The lancet. Diabetes & endocrinology
BACKGROUND:Increased circulating plasma urate concentration is associated with an increased risk of coronary heart disease, but the extent of any causative effect of urate on risk of coronary heart disease is still unclear. In this study, we aimed to clarify any causal role of urate on coronary heart disease risk using Mendelian randomisation analysis. METHODS:We first did a fixed-effects meta-analysis of the observational association of plasma urate and risk of coronary heart disease. We then used a conventional Mendelian randomisation approach to investigate the causal relevance using a genetic instrument based on 31 urate-associated single nucleotide polymorphisms (SNPs). To account for potential pleiotropic associations of certain SNPs with risk factors other than urate, we additionally did both a multivariable Mendelian randomisation analysis, in which the genetic associations of SNPs with systolic and diastolic blood pressure, HDL cholesterol, and triglycerides were included as covariates, and an Egger Mendelian randomisation (MR-Egger) analysis to estimate a causal effect accounting for unmeasured pleiotropy. FINDINGS:In the meta-analysis of 17 prospective observational studies (166 486 individuals; 9784 coronary heart disease events) a 1 SD higher urate concentration was associated with an odds ratio (OR) for coronary heart disease of 1·07 (95% CI 1·04-1·10). The corresponding OR estimates from the conventional, multivariable adjusted, and Egger Mendelian randomisation analysis (58 studies; 198 598 individuals; 65 877 events) were 1·18 (95% CI 1·08-1·29), 1·10 (1·00-1·22), and 1·05 (0·92-1·20), respectively, per 1 SD increment in plasma urate. INTERPRETATION:Conventional and multivariate Mendelian randomisation analysis implicates a causal role for urate in the development of coronary heart disease, but these estimates might be inflated by hidden pleiotropy. Egger Mendelian randomisation analysis, which accounts for pleiotropy but has less statistical power, suggests there might be no causal effect. These results might help investigators to determine the priority of trials of urate lowering for the prevention of coronary heart disease compared with other potential interventions. FUNDING:UK National Institute for Health Research, British Heart Foundation, and UK Medical Research Council.
10.1016/S2213-8587(15)00386-1
Association between serum uric acid level and chronic liver disease in the United States.
Afzali Anita,Weiss Noel S,Boyko Edward J,Ioannou George N
Hepatology (Baltimore, Md.)
UNLABELLED:Elevated serum uric acid (UA) levels strongly reflect and may even cause oxidative stress, insulin resistance, and metabolic syndrome, which are risk factors for the progression of liver disease. We sought to determine whether serum UA levels are associated with the development of cirrhosis or the presence of elevated serum liver enzymes. We used cohort data from the first National Health and Nutrition Examination Survey (NHANES I) to determine whether the baseline serum UA level was associated with the incidence of hospitalization or death due to cirrhosis among 5518 participants during a mean follow-up of 12.9 years (range = 4-21 years) after the exclusion of the first 4 years of follow-up. We also used cross-sectional data from NHANES 1988-1994 (n = 10,993) and NHANES 1999-2006 (n = 6186) to determine whether the serum UA level was associated with elevated serum alanine aminotransferase (ALT) or gamma-glutamyl transferase (GGT), two markers of hepatic necroinflammation. Compared to persons in the lower third of the distribution of serum UA (<4.8 mg/dL), those in the top third (>6 mg/dL) had a higher risk of cirrhosis-related hospitalization or death [adjusted hazard ratio (AHR) = 2.8, 95% confidence interval (CI) =1.3-5.7], whereas the risk was not substantially increased in persons within the middle third (serum UA level = 2.6-4.8 mg/dL, AHR = 1.3, 95% CI = 0.6-2.7). A higher serum UA level was associated with greater mean serum ALT and GGT levels and a greater probability of elevated serum ALT and GGT. CONCLUSION:The serum UA level is associated with the development of cirrhosis and the presence of elevated serum liver enzymes after adjustments for important causes and risk factors of chronic liver disease.
10.1002/hep.23717
Serum concentrations of uric acid and the metabolic syndrome among US children and adolescents.
Ford Earl S,Li Chaoyang,Cook Stephen,Choi Hyon K
Circulation
BACKGROUND:The association between concentrations of uric acid and the metabolic syndrome in children and adolescents remains incompletely understood. The objective of this study was to examine how these 2 were associated in a nationally representative sample of US children and adolescents. METHODS AND RESULTS:We performed a cross-sectional analysis of 1370 males and females aged 12 to 17 years using data from the National Health and Nutrition Examination Survey 1999-2002. The prevalence of the metabolic syndrome was < 1% among participants in the lowest quartile of serum concentration of uric acid, 3.7% in the second quartile, 10.3% in the third quartile, and 21.1% in the highest quartile. Compared with the lowest 2 quartiles of uric acid together (< or = 291.5 micromol/L), the odds ratios were 5.80 (95% confidence interval, 3.22 to 10.46) for those in the third quartile (> 291.5 to < or = 339 micromol/L or > 4.9 to < or = 5.7 mg/dL) and 14.79 (95% confidence interval, 7.78 to 28.11) for those in the top quartile (> 339 micromol/L) after adjustment for age, sex, race or ethnicity, and concentrations of C-reactive protein. Starting with the lowest quartile of concentration of uric acid, mean concentrations of serum insulin were 66.2, 66.7, 79.9, and 90.9 pmol/L for ascending quartiles, respectively (P for trend <0.001). CONCLUSIONS:Among US children and adolescents, serum concentrations of uric acid are strongly associated with the prevalence of the metabolic syndrome and several of its components.
10.1161/CIRCULATIONAHA.106.657627
An unexpected role for uric acid as an inducer of T helper 2 cell immunity to inhaled antigens and inflammatory mediator of allergic asthma.
Kool Mirjam,Willart Monique A M,van Nimwegen Menno,Bergen Ingrid,Pouliot Philippe,Virchow J Christian,Rogers Neil,Osorio Fabiola,Reis e Sousa Caetano,Reis E Sousa Caetano,Hammad Hamida,Lambrecht Bart N
Immunity
Although deposition of uric acid (UA) crystals is known as the cause of gout, it is unclear whether UA plays a role in other inflammatory diseases. We here have shown that UA is released in the airways of allergen-challenged asthmatic patients and mice, where it was necessary for mounting T helper 2 (Th2) cell immunity, airway eosinophilia, and bronchial hyperreactivity to inhaled harmless proteins and clinically relevant house dust mite allergen. Conversely, administration of UA crystals together with protein antigen was sufficient to promote Th2 cell immunity and features of asthma. The adjuvant effects of UA did not require the inflammasome (Nlrp3, Pycard) or the interleukin-1 (Myd88, IL-1r) axis. UA crystals promoted Th2 cell immunity by activating dendritic cells through spleen tyrosine kinase and PI3-kinase δ signaling. These findings provide further molecular insight into Th2 cell development and identify UA as an essential initiator and amplifier of allergic inflammation.
10.1016/j.immuni.2011.03.015
The endogenous danger signal, crystalline uric acid, signals for enhanced antibody immunity.
Behrens Marshall D,Wagner Wolfgang M,Krco Christopher J,Erskine Courtney L,Kalli Kimberly R,Krempski James,Gad Ekram A,Disis Mary L,Knutson Keith L
Blood
Studies have shown that the immune system can recognize self-antigens under conditions (eg, cell injury) in which the self-tissue might elaborate immune-activating endogenous danger signals. Uric acid (UA) is an endogenous danger signal recently identified to be released from dying cells. Prior work has shown that UA activates immune effectors of both the innate and adaptive immune system, including neutrophils and cytotoxic T-cell immunity. However, it was unclear whether UA could enhance antibody immunity, which was examined in this study. When added to dying tumor cells or with whole protein antigen, UA increased IgG1-based humoral immunity. Further, UA blocked growth of tumor in subsequent tumor challenge experiments, which depended on CD4, but not CD8, T cells. Sera derived from UA-treated animals enhanced tumor growth, suggesting it had little role in the antitumor response. UA did not signal for T-cell expansion or altered tumor-infiltrating leukocyte populations. Consistent with the lack of T-cell expansion, when applied to dendritic cells, UA suppressed T-cell growth factors but up-regulated B cell-activating cytokines. Understanding the nature of endogenous danger signals released from dying cells may aid in a better understanding of mechanisms of immune recognition of self.
10.1182/blood-2007-10-117184
The role of serum uric acid as an antioxidant protecting against cancer: prospective study in more than 28 000 older Austrian women.
Strasak A M,Rapp K,Hilbe W,Oberaigner W,Ruttmann E,Concin H,Diem G,Pfeiffer K P,Ulmer H,
Annals of oncology : official journal of the European Society for Medical Oncology
BACKGROUND:It has been hypothesized that serum uric acid (SUA), via its antioxidant properties may protect against carcinogenesis. However, few epidemiological investigations have addressed this association and previous findings are inconsistent. PATIENTS AND METHODS:We prospectively investigated the relation of SUA levels to subsequent cancer mortality in a large cohort of 28613 elderly Austrian women with a median follow-up of 15.2 years. Adjusted Cox proportional hazards models were calculated to evaluate SUA as an independently related factor to fatal cancer events. RESULTS:High SUA (>5.41 mg/dL) was independently associated with increased risk of total cancer mortality (p<0.0001); the adjusted hazard ratio for the highest versus lowest quartile of SUA was 1.27 (1.08-1.48). SUA levels were further positively related to deaths from malignant neoplasms of breast and female genital organs (P = 0.02) and nervous system and unspecified sites (P = 0.02). We found no evidence for an inverse relationship between SUA levels and risk of total or site-specific cancer mortality. CONCLUSION:Our results are contrary to the proposed antioxidant and protective effect of SUA against cancer and rather suggest high SUA concentrations to be associated with outcome possibly reflecting more serious prognostic indication.
10.1093/annonc/mdm338
High serum uric acid as a novel risk factor for type 2 diabetes.
Dehghan Abbas,van Hoek Mandy,Sijbrands Eric J G,Hofman Albert,Witteman Jacqueline C M
Diabetes care
OBJECTIVE:To investigate the association between serum uric acid level and risk of type 2 diabetes. RESEARCH DESIGN AND METHODS:The population for analysis consisted of 4,536 subjects free from diabetes at baseline. During a mean of 10.1 years of follow-up, 462 subjects developed diabetes. RESULTS:The age- and sex-adjusted hazard ratios (HRs) (95% CIs) for diabetes were 1.30 (0.96-1.76) for the second, 1.63 (1.21-2.19) for the third, and 2.83 (2.13-3.76) for the fourth quartile of serum uric acid, in comparison with the first quartile. After adjustment for BMI, waist circumference, systolic and diastolic blood pressure, and HDL cholesterol, the HRs decreased to 1.08 (0.78-1.49), 1.12 (0.81-1.53), and 1.68 (1.22-2.30), respectively. CONCLUSIONS:The results of this population-based study suggest that serum uric acid is a strong and independent risk factor for diabetes.
10.2337/dc07-1276
Serum uric acid levels predict new-onset type 2 diabetes in hospitalized patients with primary hypertension: the MAGIC study.
Viazzi Francesca,Leoncini Giovanna,Vercelli Marina,Deferrari Giacomo,Pontremoli Roberto
Diabetes care
OBJECTIVE:Recent studies suggest that uric acid may predict the development of diabetes in the general population. Whether this association holds true in primary hypertension and is independent of renal function and metabolic syndrome is not clear at present. RESEARCH DESIGN AND METHODS:In a prospective, observational study, 758 untreated hypertensive patients were evaluated at baseline and followed-up for 11 years. RESULTS:A total of 8,332 person-years of follow-up revealed that slightly elevated uric acid levels (i.e., ≥318 μmol/l for women and ≥420 μmol/l for men) at baseline were associated with a significantly higher risk of developing diabetes (hazard ratio 3.65 [95% CI 1.99-6.69], P < 0.0001), even after adjustment for several confounding factors such as metabolic syndrome (2.78 [1.35-5.70], P = 0.0054). CONCLUSIONS:Uric acid is an independent predictor of diabetes in primary hypertension.
10.2337/dc10-0918
Serum uric acid correlates with extracellular superoxide dismutase activity in patients with chronic heart failure.
Alcaino Hernan,Greig Douglas,Chiong Mario,Verdejo Hugo,Miranda Rodrigo,Concepcion Roberto,Vukasovic José Luis,Diaz-Araya Guillermo,Mellado Rosemarie,Garcia Lorena,Salas Daniela,Gonzalez Leticia,Godoy Ivan,Castro Pablo,Lavandero Sergio
European journal of heart failure
Increased serum uric acid has been identified as an independent risk factor for cardiovascular disease. However, because of its antioxidant capacity, uric acid may play a beneficial role in endothelial function. This paradoxical relationship between uric acid and endothelial function in chronic heart failure patients remains poorly understood. Thirty-eight chronic heart failure patients (New York Heart Association functional class II-III, mean age 58+/-10 years and mean left ventricular ejection fraction 25+/-8%) and twelve age-and-sex-matched healthy controls were studied. Chronic heart failure patients showed higher uric acid levels (7.3+/-2.3 mg/dL vs. 6.1+/-0.2 mg/dL, p<0.05) and lower extracellular superoxide dismutase activity (136+/-36 U ml(-1) min(-1) vs. 203+/-61 U ml(-1) min(-1), p<0.01) and endothelium-dependent vasodilatation (4.0+/-1.6% v. 9.1+/-3.0%, p<0.01) when compared with control subjects. In chronic heart failure patients, correlations between both uric acid levels and extracellular superoxide dismutase activity (r=0.45; p<0.01), and uric acid and endothelium-dependent vasodilatation (r=0.35; p=0.03) were detected. These correlations were not observed in healthy individuals, suggesting a positive effect of uric acid on endothelial function partially mediated by modulation of extracellular superoxide dismutase activity in chronic heart failure.
10.1016/j.ejheart.2008.05.008
Serum uric acid and cognitive function and dementia.
Euser S M,Hofman A,Westendorp R G J,Breteler Monique M B
Brain : a journal of neurology
Uric acid is a risk factor of cardiovascular disease, as well as a major natural antioxidant, prohibiting the occurrence of cellular damage. The relation between uric acid and cognitive decline, in which both vascular mechanisms and oxidative stress are thought to play a role, is unknown. Therefore we assessed the relation between serum uric acid levels and the risk of subsequent dementia in a prospective population-based cohort study among 4618 participants aged 55 years and over. Additionally, we investigated the relation between serum uric acid and cognitive function later in life (on average 11.1 years later) in a subsample of 1724 participants who remained free of dementia during follow-up. All analyses were adjusted for age, sex and cardiovascular risk factors. Our data showed that only after correcting for several cardiovascular risk factors, higher serum uric acid levels were associated with a decreased risk of dementia (HR, adjusted for age, sex and cardiovascular risk factors, 0.89 [95% confidence interval (CI) 0.80-0.99] per standard deviation (SD) increase in uric acid). In participants who remained free of dementia, higher serum uric acid levels at baseline were associated with better cognitive function later in life, for all cognitive domains that were assessed [adjusted difference in Z-score (95% CI) per SD increase in uric acid 0.04 (0.00-0.07) for global cognitive function; 0.02 (-0.02 to 0.06) for executive function; and 0.06 (0.02-0.11) for memory function], but again only after correcting for cardiovascular risk factors. We conclude that notwithstanding the associated increased risk of cardiovascular disease, higher levels of uric acid are associated with a decreased risk of dementia and better cognitive function later in life.
10.1093/brain/awn316
Uric acid is a danger signal activating NALP3 inflammasome in lung injury inflammation and fibrosis.
Gasse Pamela,Riteau Nicolas,Charron Sabine,Girre Sandra,Fick Lizette,Pétrilli Virginie,Tschopp Jürg,Lagente Vincent,Quesniaux Valérie F J,Ryffel Bernhard,Couillin Isabelle
American journal of respiratory and critical care medicine
RATIONALE:Lung injury leads to pulmonary inflammation and fibrosis through myeloid differentiation primary response gene 88 (MyD88) and the IL-1 receptor 1 (IL-1R1) signaling pathway. The molecular mechanisms by which lung injury triggers IL-1beta production, inflammation, and fibrosis remain poorly understood. OBJECTIVES:To determine if lung injury depends on the NALP3 inflammasome and if bleomycin (BLM)-induced lung injury triggers local production of uric acid, thereby activating the NALP3 inflammasome in the lung. METHODS:Inflammation upon BLM administration was evaluated in vivo in inflammasome-deficient mice. Pulmonary uric acid accumulation, inflammation, and fibrosis were analyzed in mice treated with the inhibitor of uric acid synthesis or with uricase, which degrades uric acid. MEASUREMENTS AND MAIN RESULTS:Lung injury depends on the NALP3 inflammasome, which is triggered by uric acid locally produced in the lung upon BLM-induced DNA damage and degradation. Reduction of uric acid levels using the inhibitor of uric acid synthesis allopurinol or uricase leads to a decrease in BLM-induced IL-1beta production, lung inflammation, repair, and fibrosis. Local administration of exogenous uric acid crystals recapitulates lung inflammation and repair, which depend on the NALP3 inflammasome, MyD88, and IL-1R1 pathways and Toll-like receptor (TLR)2 and TLR4 for optimal inflammation but are independent of the IL-18 receptor. CONCLUSIONS:Uric acid released from injured cells constitutes a major endogenous danger signal that activates the NALP3 inflammasome, leading to IL-1beta production. Reducing uric acid tissue levels represents a novel therapeutic approach to control IL-1beta production and chronic inflammatory lung pathology.
10.1164/rccm.200808-1274OC
Caught red-handed: uric acid is an agent of inflammation.
Shi Yan
The Journal of clinical investigation
Inflammation occurs in response to both pathogenic insult and tissue damage under sterile conditions, with the latter contributing to the pathogenesis of many diseases. Although several endogenous substances, including uric acid, have been suggested to alert the body to danger and to stimulate inflammation, little is known about their contribution to such responses in vivo. In this issue of the JCI, Kono et al. use newly generated mice with reduced levels of uric acid to investigate its role as an endogenous signal of tissue damage in inflammatory responses to hepatic injury. They find that uric acid is released from dying tissues and induces inflammation to cell death but is not involved in the response to microbial molecules or sterile irritant particles. I believe this to be the first report of an endogenous danger signal acting as a physiological regulator of inflammation.
10.1172/JCI43132
Elevated serum uric acid concentrations independently predict cardiovascular mortality in type 2 diabetic patients.
Zoppini Giacomo,Targher Giovanni,Negri Carlo,Stoico Vincenzo,Perrone Fabrizia,Muggeo Michele,Bonora Enzo
Diabetes care
OBJECTIVE:There is limited information on whether increased serum uric acid levels are independently associated with cardiovascular mortality in type 2 diabetes. We assessed the predictive role of serum uric acid levels on all-cause and cardiovascular mortality in a large cohort of type 2 diabetic individuals. RESEARCH DESIGN AND METHODS:The cohort included 2,726 type 2 diabetic outpatients, who were followed for a mean period of 4.7 years. The independent association of serum uric acid levels with all-cause and cardiovascular mortality was assessed by Cox proportional hazards models and adjusted for conventional risk factors and several potential confounders. RESULTS:During follow-up, 329 (12.1%) patients died, 44.1% (n = 145) of whom from cardiovascular causes. In univariate analysis, higher serum uric acid levels were significantly associated with increased risk of all-cause (hazard ratio 19 [95% CI 1.12-1.27], P < 0.001) and cardiovascular (1.25 [1.16-1.34], P < 0.001) mortality. After adjustment for age, sex, BMI, smoking, hypertension, dyslipidemia, diabetes duration, A1C, medication use (allopurinol or hypoglycemic, antihypertensive, lipid-lowering, and antiplatelet drugs), estimated glomerular filtration rate, and albuminuria, the association of serum uric acid with cardiovascular mortality remained statistically significant (1.27 [1.01-1.61], P = 0.046), whereas the association of serum uric acid with all-cause mortality did not. CONCLUSIONS:Higher serum uric acid levels are associated with increased risk of cardiovascular mortality in type 2 diabetic patients, independent of several potential confounders, including renal function measures.
10.2337/dc09-0625
Uric acid promotes an acute inflammatory response to sterile cell death in mice.
Kono Hajime,Chen Chun-Jen,Ontiveros Fernando,Rock Kenneth L
The Journal of clinical investigation
Necrosis stimulates inflammation, and this response is medically relevant because it contributes to the pathogenesis of a number of diseases. It is thought that necrosis stimulates inflammation because dying cells release proinflammatory molecules that are recognized by the immune system. However, relatively little is known about the molecular identity of these molecules and their contribution to responses in vivo. Here, we investigated the role of uric acid in the inflammatory response to necrotic cells in mice. We found that dead cells not only released intracellular stores of uric acid but also produced it in large amounts postmortem as nucleic acids were degraded. Using newly developed Tg mice that have reduced levels of uric acid either intracellularly and/or extracellularly, we found that uric acid depletion substantially reduces the cell death-induced inflammatory response. Similar results were obtained with pharmacological treatments that reduced uric acid levels either by blocking its synthesis or hydrolyzing it in the extracellular fluids. Importantly, uric acid depletion selectively inhibited the inflammatory response to dying cells but not to microbial molecules or sterile irritant particles. Collectively, our data identify uric acid as a proinflammatory molecule released from dying cells that contributes significantly to the cell death-induced inflammatory responses in vivo.
10.1172/JCI40124
Uric acid as a danger signal in gout and its comorbidities.
Rock Kenneth L,Kataoka Hiroshi,Lai Jiann-Jyh
Nature reviews. Rheumatology
Uric acid is a waste product of purine catabolism. This molecule comes to clinical attention when it nucleates to form crystals of monosodium urate (MSU) in joints or other tissues, and thereby causes the inflammatory disease of gout. Patients with gout frequently suffer from a number of comorbid conditions including hypertension, diabetes mellitus and cardiovascular disease. Why MSU crystals trigger inflammation and are associated with comorbidities of gout has been unclear, but recent studies provide new insights into these issues. Rather than simply being a waste product, uric acid could serve a pathophysiological role as a local alarm signal that alerts the immune system to cell injury and helps to trigger both innate and adaptive immune responses. The inflammatory component of these immune responses is caused when urate crystals trigger both inflammasome-dependent and independent pathways to generate the proinflammatory cytokine IL-1. The resulting bioactive IL-1 stimulates the inflammation of gout and might contribute to the development of other comorbidities. Surprisingly, the same mechanisms underlie the inflammatory response to a number of irritant particles, many of which also cause disease. These new insights help to explain the pathogenesis of gout and point to potential new therapeutic targets for this and other sterile inflammatory diseases.
10.1038/nrrheum.2012.143
High-normal serum uric acid increases risk of early progressive renal function loss in type 1 diabetes: results of a 6-year follow-up.
Diabetes care
OBJECTIVE:We previously described a cross-sectional association between serum uric acid and reduced glomerular filtration rate (GFR) in nonproteinuric patients with type 1 diabetes. Here, we prospectively investigated whether baseline uric acid impacts the risk of early progressive renal function loss (early GFR loss) in these patients. RESEARCH DESIGN AND METHODS:Patients with elevated urinary albumin excretion (n = 355) were followed for 4-6 years for changes in urinary albumin excretion and GFR. The changes were estimated by multiple determinations of albumin-to-creatinine ratios (ACRs) and serum cystatin C (GFRcystatin). RESULTS:At baseline, the medians (25th-75th percentiles) for uric acid, ACR, and GFRcystatin values were 4.6 mg/dl (3.8-5.4), 26.2 mg/g (15.1-56.0), and 129 ml/min per 1.73 m(2) (111-145), respectively. During the 6-year follow-up, significant association (P < 0.0002) was observed between serum uric acid and development of early GFR loss, defined as GFRcystatin decline exceeding 3.3% per year. In baseline uric acid concentration categories (in mg/dl: <3.0, 3.0-3.9, 4.0-4.9, 5.0-5.9, and >or=6), the risk of early GFR loss increased linearly (9, 13, 20, 29, and 36%, respectively). This linear increase corresponds to odds ratio 1.4 (95% CI 1.1-1.8) per 1 mg/dl increase of uric acid. The progression and regression of urinary albumin excretion were not associated with uric acid. CONCLUSIONS:We found a clear dose-response relation between serum uric acid and risk of early GFR loss in patients with type 1 diabetes. Clinical trials are warranted to determine whether uric acid-lowering drugs can halt renal function decline before it becomes clinically significant.
10.2337/dc10-0227
Could uric acid have a pathogenic role in pre-eclampsia?
Martin Annabel C,Brown Mark A
Nature reviews. Nephrology
Interest has been renewed over the role of uric acid in the pathogenesis of hypertension, endothelial dysfunction and renal dysfunction, which are all features of pre-eclampsia. Uric acid is not a consistent predictive factor for the development of pre-eclampsia but its levels generally increase once the disease manifests, and plasma levels of uric acid approximately correlate with disease severity. Hyperuricemia in pre-eclampsia was once thought to result solely from reduced renal clearance, but levels of uric acid are now also thought to increase through increased uric acid production caused by trophoblast breakdown, cytokine release and ischemia. Uric acid can promote endothelial dysfunction, damage and inflammation, which leads to oxidation. Pre-eclampsia, which is characterized by widespread endothelial dysfunction and inflammation, might be propagated by uric acid through these known in vitro activities. Of note, however, uric acid can also act as a scavenger of oxygen free radicals. Plasma urate measurements are currently used to support the diagnosis of pre-eclampsia during pregnancy. As further studies define the role of uric acid in the development of pre-eclampsia, monitoring levels of this factor may again become essential to the future treatment of pre-eclampsia.
10.1038/nrneph.2010.125
Association of plasma uric acid with ischaemic heart disease and blood pressure: mendelian randomisation analysis of two large cohorts.
BMJ (Clinical research ed.)
OBJECTIVES:To assess the associations between both uric acid levels and hyperuricaemia, with ischaemic heart disease and blood pressure, and to explore the potentially confounding role of body mass index. DESIGN:Mendelian randomisation analysis, using variation at specific genes (SLC2A9 (rs7442295) as an instrument for uric acid; and FTO (rs9939609), MC4R (rs17782313), and TMEM18 (rs6548238) for body mass index). SETTING:Two large, prospective cohort studies in Denmark. PARTICIPANTS:We measured levels of uric acid and related covariables in 58,072 participants from the Copenhagen General Population Study and 10,602 from the Copenhagen City Heart Study, comprising 4890 and 2282 cases of ischaemic heart disease, respectively. MAIN OUTCOME:Blood pressure and prospectively assessed ischaemic heart disease. RESULTS:Estimates confirmed known observational associations between plasma uric acid and hyperuricaemia with risk of ischaemic heart disease and diastolic and systolic blood pressure. However, when using genotypic instruments for uric acid and hyperuricaemia, we saw no evidence for causal associations between uric acid, ischaemic heart disease, and blood pressure. We used genetic instruments to investigate body mass index as a potentially confounding factor in observational associations, and saw a causal effect on uric acid levels. Every four unit increase of body mass index saw a rise in uric acid of 0.03 mmol/L (95% confidence interval 0.02 to 0.04), and an increase in risk of hyperuricaemia of 7.5% (3.9% to 11.1%). CONCLUSION:By contrast with observational findings, there is no strong evidence for causal associations between uric acid and ischaemic heart disease or blood pressure. However, evidence supports a causal effect between body mass index and uric acid level and hyperuricaemia. This finding strongly suggests body mass index as a confounder in observational associations, and suggests a role for elevated body mass index or obesity in the development of uric acid related conditions.
10.1136/bmj.f4262
Serum uric acid is associated with mortality and heart failure hospitalizations in patients with complicated myocardial infarction: findings from the High-Risk Myocardial Infarction Database Initiative.
von Lueder Thomas G,Girerd Nicolas,Atar Dan,Agewall Stefan,Lamiral Zohra,Kanbay Mehmet,Pitt Bertram,Dickstein Kenneth,Zannad Faiez,Rossignol Patrick,
European journal of heart failure
AIMS:Serum uric acid (SUA) levels are associated with poorer outcomes in healthy cohorts and patients with stable and unstable coronary heart disease. We investigated the relationship between SUA and clinical outcomes in subjects with acute myocardial infarction (MI) complicated by reduced left ventricular (LV) function, heart failure (HF), or both. METHODS AND RESULTS:Univariable and multivariable Cox proportional hazards modelling was performed to study the association of baseline SUA and all-cause mortality, cardiovascular (CV) mortality, and HF hospitalization in an individual patient meta-analysis of four merged large randomized trials (CAPRICORN, EPHESUS, OPTIMAAL, and VALIANT). Three trials (excluding VALIANT) reported SUA, which was available in a total of 12 677 subjects. The ranges of SUA for quartiles I-IV were 45-280, 281-344, 345-420, and 420-1640 mmol/L, respectively. While almost 90% of patients in the lowest SUA quartile were alive after a mean follow-up of 23 ± 11 months, <70% were alive in the highest SUA quartile. Compared with the lowest SUA quartile as reference, hazard ratios (HRs) and 95% confidence intervals (CIs) of SUA quartiles III and IV showed an increase in all-cause mortality [HR 1.18, 95% CI 0.95-1.46, and HR 1.36, 95% CI 1.11-1.67) and CV mortality (HR 1.27, 95% 1.01-1.61, and HR 1.47, 95% CI 1.17-1.83). SUA quartiles III and IV also exhibited increased HF hospitalization (HR 1.22, 95% CI 1.09-1.36, and HR 1.28, 95% CI 1.14-1.43; P < 0.001 for all comparisons) in multivariable analyses. The addition of SUA was associated with a significant improvement in reclassification to predict CV mortality (net reclassification improvement 17.6%, 95% CI 14.9-20.5%, P < 0.001). CONCLUSIONS:Elevated SUA is associated with poor outcomes in patients after MI complicated by reduced LV function, HF, or both. The quantification of SUA, a low-cost routinely available biomarker, could improve risk stratification of patients with complicated MI.
10.1002/ejhf.419
Elevated Serum Uric Acid Is Associated With Greater Risk for Hypertension and Diabetic Kidney Diseases in Obese Adolescents With Type 2 Diabetes: An Observational Analysis From the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) Study.
Bjornstad Petter,Laffel Lori,Lynch Jane,El Ghormli Laure,Weinstock Ruth S,Tollefsen Sherida E,Nadeau Kristen J,
Diabetes care
OBJECTIVE:Elevated serum uric acid (SUA) is increasingly recognized as a risk factor for kidney disease in adults with diabetes, but data in youth are limited. We hypothesized that elevated SUA predicts development of elevated urinary albumin excretion (UAE) and hypertension over time in teens with type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS:Serum creatinine, cystatin C, SUA, and the urine albumin-to-creatinine ratio (UACR) were assessed in 539 obese youth, ages 12-17 years, with T2D duration <2 years at baseline in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study. Estimated glomerular filtration rate (eGFR) was calculated using creatinine and cystatin C. Hypertension was defined as systolic or diastolic blood pressure ≥130/80 mmHg and elevated UAE as UACR ≥30 mg/g. Cox proportional hazards models evaluated the relationship between SUA and outcome variables longitudinally over an average follow-up of 5.7 years, adjusting for age, sex, race/ethnicity, BMI, HbA, eGFR, ACE inhibitor/angiotensin receptor blocker use, and TODAY treatment group assignment. RESULTS:At baseline, hyperuricemia (≥6.8 mg/dL) was present in 25.6% of participants, hypertension in 18.7%, and elevated UAE in 6.1%. During follow-up of up to 7 years, hypertension developed in 37.4% and UAE in 18.0%. Higher baseline SUA increased the risk of incident hypertension (hazard ratio [HR] 1.19, 95% CI 1.03-1.38, per 1 mg/dL increase in SUA) and elevated UAE (HR 1.24, 95% CI 1.03-1.48) in adjusted models. CONCLUSIONS:Hyperuricemia was common in youth with T2D. Higher baseline SUA independently increased the risk for onset of hypertension and elevated UAE. Research is needed to determine whether SUA-lowering therapies can impede development of diabetic kidney disease and hypertension in T2D youth.
10.2337/dc18-2147
Uric acid and incident dementia over 12 years of follow-up: a population-based cohort study.
Latourte Augustin,Soumaré Aicha,Bardin Thomas,Perez-Ruiz Fernando,Debette Stéphanie,Richette Pascal
Annals of the rheumatic diseases
OBJECTIVES:In patients with gout, maintaining too low serum uric acid (SUA) level with urate-lowering therapy is a concern because uric acid is thought to be neuroprotective. However, the relation between SUA and dementia remains debated. This study aimed to investigate the impact of SUA level on the incidence of dementia. METHODS:We assessed the longitudinal association between SUA level and incident dementia (Diagnostic and Statistical Manual of Mental Disorders Version IV (DSM-IV) criteria) in a large cohort of healthy older people from the community (Three-City Dijon cohort). Additionally, we investigated the relation between SUA level and MRI markers of brain ageing (white matter hyperintensity volume (WMHV), lacunes and hippocampal volume). RESULTS:The study sample comprised 1598 people (mean (SD) age 72.4(4.1) years, 38.3% male). During the 13,357 person-years of follow-up (median duration: 10.1 years), dementia developed in 110 participants (crude incidence rate: 8.2/1000 person-years). After multiple adjustments, the multivariate HR with the highest (≥75th percentile) versus lowest SUA level was 1.79 (95% CI 1.17 to 2.73; p=0.007). The association was stronger with vascular or mixed dementia (HR=3.66 (95% CI 1.29 to 10.41), p=0.015) than Alzheimer's disease (HR=1.55 (95% CI 0.92 to 2.61), p=0.10). There was a non-significant trend towards an association between high SUA level and extensive WMHV (p=0.10), a biomarker of small vessel disease, but not hippocampal volume (p=0.94) or lacunes (p=0.86). The association between SUA level and vascular or mixed dementia might be affected by interim strokes. CONCLUSIONS:Risk of dementia, especially vascular or mixed dementia, may be increased with high SUA levels in elderly people.
10.1136/annrheumdis-2016-210767
Serum uric acid as a predictor of mortality and future exacerbations of COPD.
Bartziokas Konstantinos,Papaioannou Andriana I,Loukides Stelios,Papadopoulos Alexandros,Haniotou Aikaterini,Papiris Spyridon,Kostikas Konstantinos
The European respiratory journal
Serum uric acid is increased in respiratory disease, especially in the presence of hypoxia and systemic inflammation. We evaluated serum uric acid as a biomarker for prediction of mortality and future acute exacerbation of chronic obstructive pulmonary disease (AECOPD). Serum uric acid was measured in 314 eligible consecutive patients on admission for AECOPD. Patients were evaluated monthly for 1 year. Uric acid levels were higher in patients with more severe airflow limitation and in those experiencing frequent exacerbations. High uric acid levels (≥6.9 mg·dL(-1)) were an independent predictor of 30-day mortality in multivariate Cox regression analysis (HR 1.317, 95% CI 1.011-1.736; p=0.044), but not of 1-year mortality. Patients with high serum uric acid required more prolonged hospitalisation, and more often needed noninvasive ventilation and admission to the intensive care unit within 30 days. In addition, high uric acid levels were associated with increased risk and hospitalisation for AECOPD in 1 year in multivariate Poisson regression analysis (incidence rate ratio 1.184 (95% CI 1.125-1.246) and 1.190 (95% CI 1.105-1.282), respectively; both p<0.001). Serum uric acid is associated with increased 30-day mortality and risk for AECOPD and hospitalisations in 1-year follow-up. This low-cost biomarker may be useful in the identification of high-risk chronic obstructive pulmonary disease patients that could benefit from intensive management.
10.1183/09031936.00209212
Safety and efficacy of uric acid in patients with acute stroke (URICO-ICTUS): a randomised, double-blind phase 2b/3 trial.
Chamorro Angel,Amaro Sergio,Castellanos Mar,Segura Tomás,Arenillas Juan,Martí-Fábregas Joan,Gállego Jaime,Krupinski Jurek,Gomis Meritxell,Cánovas David,Carné Xavier,Deulofeu Ramón,Román Luis San,Oleaga Laura,Torres Ferran,Planas Anna M,
The Lancet. Neurology
INTRODUCTION:Uric acid is an antioxidant with neuroprotective effects in experimental models of stroke. We assessed whether uric acid therapy would improve functional outcomes at 90 days in patients with acute ischaemic stroke. METHODS:URICO-ICTUS was a randomised, double-blind, placebo-controlled, phase 2b/3 trial that recruited patients with acute ischaemic stroke admitted to ten Spanish stroke centres. Patients were included if they were aged 18 years or older, had received alteplase within 4·5 h of symptom onset, and had an eligible National Institutes of Health Stroke Scale (NIHSS) score (>6 and ≤25) and premorbid (assessed by anamnesis) modified Rankin Scale (mRS) score (≤2). Patients were randomly allocated (1:1) to receive uric acid 1000 mg or placebo (both infused intravenously in 90 min during the infusion of alteplase), stratified by centre and baseline stroke severity. The primary outcome was the proportion of patients with excellent outcome (ie, an mRS score of 0-1, or 2 if premorbid score was 2) at 90 days, analysed in the target population (all randomly assigned patients who had been correctly diagnosed with ischaemic stroke and had begun study medication). The study is registered with ClinicalTrials.gov, number NCT00860366. FINDINGS:Between July 1, 2011, and April 30, 2013, we randomly assigned 421 patients, of whom 411 (98%) were included in the target population (211 received uric acid and 200 received placebo). 83 (39%) patients who received uric acid and 66 (33%) patients who received placebo had an excellent outcome (adjusted risk ratio 1·23 [95% CI 0·96-1·56]; p=0·099). No clinically relevant or statistically significant differences were reported between groups with respect to death (28 [13%] patients who received uric acid vs 31 [16%] who received placebo), symptomatic intracerebral haemorrhage (nine [4%] vs six [3%]), and gouty arthritis (one [<1%] vs four [2%]). 516 adverse events occurred in the uric acid group and 532 in the placebo group, of which 61 (12%) and 67 (13%), respectively, were serious adverse events (p=0·703). INTERPRETATION:The addition of uric acid to thrombolytic therapy did not increase the proportion of patients who achieved excellent outcome after stroke compared with placebo, but it did not lead to any safety concerns. FUNDING:Institute of Health Carlos III of the Spanish Ministry of Health and Fundación Doctor Melchor Colet.
10.1016/S1474-4422(14)70054-7
Uric Acid Is an Independent Risk Factor for Decline in Kidney Function, Cardiovascular Events, and Mortality in Patients With Type 1 Diabetes.
Pilemann-Lyberg Sascha,Hansen Tine Willum,Tofte Nete,Winther Signe Abitz,Theilade Simone,Ahluwalia Tarunveer Singh,Rossing Peter
Diabetes care
OBJECTIVE:Previous studies have provided inconclusive results on the role of uric acid (UA) in risk prediction. Here we aimed to improve the power and precision of the predictive value of UA for the risk of decline in kidney function, cardiovascular events (CVEs), and mortality in patients with type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS:Plasma UA was measured in 670 patients with T1D and various degrees of albuminuria, ranging from normoalbuminuria to macroalbuminuria. Associations of UA with an estimated glomerular filtration rate (eGFR) decline of ≥30%, CVEs, and mortality were analyzed. The median follow-up time was 5.3 years [interquartile range (IQR) 2.7-6.2 years] for a decline in eGFR of ≥30%, 5.8 years (2.5-6.4 years) for progression in albuminuria status, 5.1 years (4.7-5.6 years) for CVE, and 6.2 years (5.8-6.7 years) for mortality. Both univariable and multivariable associations of UA with relevant outcomes and variables were reported. Hazard ratios (HRs) were calculated per doubling of the UA level. RESULTS:A doubling in UA level was associated with a higher risk of decline in eGFR of ≥30% ( = 89) (HR 3.18 [IQR 1.71-5.93]; < 0.001), CVE ( = 94) (HR 2.25 [IQR 1.20-4.21]; = 0.011), and mortality ( = 58) (HR 2.58 [IQR 1.12-5.90]; = 0.025) in adjusted analyses. Adding UA to the adjusted model including conventional risk factors improved the relative integrated discrimination index by 12.6% for a decline in eGFR of ≥30% ( < 0.001), 6.5% for CVE ( = 0.010), and 11.8% ( = 0.003) for mortality. A doubling in UA level was also associated with a steeper decline in eGFR ( < 0.0026) and a steeper increase in urine albumin-to-creatinine ratio ( < 0.0027) in adjusted analysis. CONCLUSIONS:In individuals with T1D, a higher UA level is associated with a higher risk of decline in kidney function, CVE, and mortality, independently of other risk factors. Our results suggest that UA has a promising role in risk stratification among individuals with T1D.
10.2337/dc18-2173
Uric acid and risk of heart failure: a systematic review and meta-analysis.
Huang He,Huang Baotao,Li Yulin,Huang Yan,Li Jing,Yao Hongmei,Jing Xianchao,Chen Jianrong,Wang Ji
European journal of heart failure
AIMS:We aimed to perform a systematic review and meta-analysis to assess the association between serum uric acid and incident heart failure (HF)/prognosis of HF patients. METHODS AND RESULTS:A systematic electronic literature search was conducted in Embase (Ovid SP, from 1974 to May 2013), Medline (Ovid SP, from 1946 to May 2013), and the Chinese Biomedical Literature Database (CBM, from 1978 to May 2013) to identify studies reporting on the association between serum uric acid and HF. Either a random effects model or a fixed effects model was used for pooling data. Five studies reporting on incident HF and 28 studies reporting on the adverse outcomes of HF patients were included. The results showed that hyperuricaemia was associated with an increased risk of incident HF [hazard ratio (HR) 1.65, 95% confidence interval (CI) 1.41-1.94], and the risk of all-cause mortality (HR 2.15, 95% CI 1.64-2.83), cardiovascular mortality (HR 1.45, 95% CI 1.18-1.78), and the composite of death or cardiac events (HR 1.39, 95% CI 1.18-1.63) in HF patients. For every 1 mg/dL increase in serum uric acid, the odds of development of HF increased by 19% (HR 1.19, 95% CI 1.17-1.21), and the risk of all-cause mortality and the composite endpoint in HF patients increased by 4% (HR 1.04, 95% CI 1.02-1.06) and 28% (HR 1.28, 95% CI 0.97-1.70), respectively. Subgroup analyses supported the positive association between serum uric acid and HF. CONCLUSIONS:Elevated serum uric acid is associated with an increased risk of incident HF and adverse outcomes in HF patients.
10.1093/eurjhf/hft132
The case for uric acid-lowering treatment in patients with hyperuricaemia and CKD.
Nature reviews. Nephrology
Hyperuricaemia is common among patients with chronic kidney disease (CKD), and increases in severity with the deterioration of kidney function. Although existing guidelines for CKD management do not recommend testing for or treatment of hyperuricaemia in the absence of a diagnosis of gout or urate nephrolithiasis, an emerging body of evidence supports a direct causal relationship between serum urate levels and the development of CKD. Here, we review randomized clinical trials that have evaluated the effect of urate-lowering therapy (ULT) on the rate of CKD progression. Among trials in which individuals in the control arm experienced progressive deterioration of kidney function (which we define as ≥4 ml/min/1.73 m² over the course of the study - typically 6 months to 2 years), treatment with ULT conferred consistent clinical benefits. In contrast, among trials where clinical progression was not observed in the control arm, treatment with ULT was ineffective, but this finding should not be used as an argument against the use of uric acid-lowering therapy. Although additional studies are needed to identify threshold values of serum urate for treatment initiation and to confirm optimal target levels, we believe that sufficient evidence exists to recommend routine measurement of serum urate levels in patients with CKD and consider initiation of ULT among those who are hyperuricaemic with evidence of deteriorating renal function, unless specific contraindications exist.
10.1038/s41581-019-0174-z