Circulating Uric Acid Levels Research Articles

Plasma uric acid levels and risk of dementia in a population-based cohort study

BackgroundGiven the opposing properties of uric acid (UA), which are intracellular prooxidant action and extracellular antioxidant action, the association of circulating UA levels with dementia remains controversial. We aimed to ascertain whether both lower and higher plasma UA levels are associated with the risk of incident dementia among middle-aged and older population. Methods1685 participants (530 men and 1155 women) aged 40–69 years at baseline (1990–1993) were randomly selected for plasma UA measurement from base cohort participants who responded to the baseline questionnaire and provided blood samples. They were followed for dementia (disabling dementia requiring care; hereinafter dementia) from 2006 to 2016 using certification records for national long-term care insurance in Japan. A Cox proportional hazards model adjusted for various lifestyle factors and past medical history (cardiometabolic disease) was applied for overall participants and sex. ResultsDementia was diagnosed in 240 participants (14.2 % overall: 16.0 % in men and 13.4 % in women). No statistically significant association with plasma UA was found in overall participants. Compared to participants with UA of 5.1–6.0 mg/dL, men with ≥6.1 mg/dL showed fully adjusted hazard ratios of 1.46 (95 % confidence interval: 0.78–2.75) for 6.1–7.0 mg/dL and 1.89 (0.97–3.66) for ≥7.1 mg/dL, while women with ≥6.1 mg/dL showed 1.13 (0.54–2.38). ConclusionsNo statistically significant association between plasma UA level and risk of dementia was found in overall participants or by sex.

Higher serum uric acid as a risk factor for frailty in older adults: A nationwide population-based study.

Uric acid (UA), the terminal breakdown product of purine metabolism, possesses contradictory roles, functioning both as an inflammatory mediator and as an antioxidant. Its clinical relevance, particularly in geriatric populations, remains a topic of ongoing debate. Aiming to elucidate whether circulating UA is detrimental or beneficial to human health, we investigate the association between serum UA concentrations and the frailty index-a comprehensive measure of biological aging in a nationally representative cohort of community-dwelling older adults. We conducted a population-based, cross-sectional study utilizing data from the Korea National Health and Nutrition Examination Survey. The sample included 4268 participants aged 65years and above. A deficit accumulation frailty index (FI) was constructed using 38 items that assess physical, cognitive, psychological, and social domains. Based on the FI, participants were categorized into non-frail (FI≤0.15), pre-frail (0.15<FI≤0.25), or frail (FI>0.25). Serum UA levels were quantified through a colorimetric enzymatic assay. After controlling for confounders such as age, sex, socioeconomic status (including income and education level), lifestyle factors (smoking status), and medical history (hypertension, diabetes, dyslipidemia, stroke, cardiovascular diseases), and body mass index, serum UA levels were observed to be significantly higher in frail participants compared with their non-frail counterparts (P<0.001). Furthermore, serum UA concentrations demonstrated a positive correlation with the FI (P<0.001), and the odds ratio for frailty per 1mg/dL increase in serum UA was 1.22 (P<0.001). Additionally, older adults in the highest quartile of UA levels exhibited a significantly higher FI and 1.66-fold increased odds of frailty compared with those in the lowest quartile (P=0.011 and P=0.005, respectively). These findings suggest that elevated circulating UA levels may act as a pro-aging factor rather than an anti-aging one in older adults, highlighting its potential role in accelerating biological aging. The data further support the utility of serum UA as a potential blood-based biomarker for frailty in this demographic, contributing to the expanding evidence on its significance in geriatric health assessments.

Obese female mice do not exhibit overt hyperuricemia despite hepatic steatosis and impaired glucose tolerance

Recent reports have clearly demonstrated a tight correlation between obesity and elevated circulating uric acid levels (hyperuricemia). However, nearly all preclinical work in this area has been completed with male mice, leaving the field with a considerable gap in knowledge regarding female responses to obesity and hyperuricemia. This deficiency in sex as a biological variable extends beyond unknowns regarding uric acid (UA) to several important comorbidities associated with obesity including nonalcoholic fatty liver disease (NAFLD). To attempt to address this issue, herein we describe both phenotypic and metabolic responses to diet-induced obesity (DIO) in female mice. Six-week-old female C57BL/6J mice were fed a high-fat diet (60% calories derived from fat) for 32 weeks. The DIO female mice had significant weight gain over the course of the study, higher fasting blood glucose, impaired glucose tolerance, and elevated plasma insulin levels compared to age-matched on normal chow. While these classic indices of DIO and NAFLD were observed such as increased circulating levels of ALT and AST, there was no difference in circulating UA levels. Obese female mice also demonstrated increased hepatic triglyceride (TG), cholesterol, and cholesteryl ester. In addition, several markers of hepatic inflammation were significantly increased. Also, alterations in the expression of redox-related enzymes were observed in obese mice compared to lean controls including increases in extracellular superoxide dismutase (Sod3), heme oxygenase (Ho)-1, and xanthine dehydrogenase (Xdh). Interestingly, hepatic UA levels were significantly elevated (∼2-fold) in obese mice compared to their lean counterparts. These data demonstrate female mice assume a similar metabolic profile to that reported in several male models of obesity in the context of alterations in glucose tolerance, hepatic steatosis, and elevated transaminases (ALT and AST) in the absence of hyperuricemia affirming the need for further study.

Sex-Specific Associations of Circulating Uric Acid with Risk of Diabetes Incidence: A Population-Based Cohort Study from Sweden.

ObjectiveTo explore the longitudinal, as well as sex-specific, associations between circulating uric acid (UA) and diabetes incidence.MethodsA cohort study of the Malmö Diet Cancer-cardiovascular Cohort (Malmö, Sweden) consisting of 3140 individuals without diabetes at baseline, was followed up until the end of 2018. Incident diabetes cases were identified by linking to local and national diabetes registers. Cox proportional hazard regression was used to assess plasma UA levels in relation to diabetes incidence with adjustment for established confounders.ResultsAt baseline, with increasing levels of UA, subjects were more likely to be older and have significantly higher body mass index, waist circumference, triglycerides, C-reactive protein, fasting glucose and 2-h plasma glucose postoral glucose tolerance test, and lower levels of high-density lipoprotein. During a mean follow-up period of 8.09±2.24 years, 315 (10.0%) participants developed diabetes, and diabetes incidence rates were 7.89, 9.48 and 18.11 per 1000 person-years for subjects in the 1st, 2nd, and 3rd tertiles of UA, respectively (log-rank test: p<0.001). With adjustment for potential confounders, elevated UA levels were significantly associated with increased risks of diabetes incidence, with the adjusted hazard ratio (HR) (95% confidence interval) for per standard deviation increment of UA of 1.22 (1.08–1.39, p=0.002). Compared with the 1st tertile of UA, the 3rd tertile showed significantly increased risk of diabetes incidence with the adjusted HR of 1.74 (1.24–2.45, p=0.002), and there was a significant trend between increasing tertiles of UA and diabetes incidence (trend test: p<0.001). Stratified analyses showed that elevated circulating UA levels were independently associated with increased risks of diabetes incidence in men but not in women, although the interaction between sex and UA was not statistically significant.ConclusionElevated circulating UA was independently associated with increased risk of diabetes incidence, especially for men.

Antioxidant properties of citric acid interfere with the uricase-based measurement of circulating uric acid

BackgroundCirculating uric acid (UA) is an important biomarker, not only in the detection and management of gout, but also in assessing the risk of related comorbidity. The impact of collection methods on clinical UA measurements has been the subject of limited study. After observing significant differences between UA concentrations of blood samples obtained by different collection tubes, we began examining the effects of exogenous tube components on measured UA concentrations. We aimed to: (1) demonstrate the variability in uricase-based UA measurements attributable to different collection methods and (2) identify factors influencing this variability. MethodsBlood samples from human subjects were collected using Serum Separator Tubes (SST tubes), Acid Citrate Dextrose (ACD) tubes, and Sodium Citrate (SC) tubes. Circulating UA concentrations were measured by chemistry analyzers utilizing the uricase method. Absorbance assays were run in order to determine the effects of citric acid, sodium citrate, and dextrose on measured absorbance in the presence of leuco crystal violet dye, hydrogen peroxide, and peroxidase. Statistical analyses—including Student’s T tests and ANOVA—were used to compare results. ResultsUA concentrations of blood samples collected in ACD tubes were significantly lower than those collected in SST tubes (P < 0.01). Samples collected in SC tubes trended towards lower UA measurements than samples collected in SST tubes, although this difference did not reach statistical significance (P = 0.06). Blood samples spiked with separate concentrations of sodium citrate (3.2 and 22.0 g/L), citric acid (8.0 g/L), and dextrose (24.5 g/L) demonstrated significantly lower UA measurements compared to controls (P < 0.01). Absorbance assays demonstrated that increasing concentrations of citric acid and sodium citrate—in the presence of leuco crystal violet, hydrogen peroxide, and peroxidase—decreased the amount of oxidized dye in the uricase method of UA measurement in a dose-dependent manner (P < 0.01). In contrast, dextrose did not significantly alter the amount of oxidized dye available. DiscussionOur results indicate that citric acid obstructs accurate uricase-based UA measurement, providing falsely low values. Citric acid, a known antioxidant, scavenges hydrogen peroxide, a key intermediate using the uricase method. By scavenging hydrogen peroxide, citric acid decreases the amount of oxidized leuco dye leading to falsely low UA measurements. Therefore, collection tubes, like ACD and SC tubes, which contain concentrations of citric acid or its conjugate base sodium citrate should not be used to measure circulating UA levels when utilizing uricase-based measurement methods.

Preterm Adolescents Exhibit Higher Blood Pressure and Sodium Retention with Higher Uric Acid and Differential Circulating Renin‐Angiotensin System Expression

Preterm birth increases the risk of developing early cardiovascular disease in the future, but the underlying mechanisms are poorly understood. We previously showed that adolescents born preterm have higher blood pressure (BP), blunted pressure natriuresis, higher angiotensin II (Ang II) but lower Ang‐(1–7), and higher uric acid. The influence of preterm birth on uric acid metabolism may foster an increased risk of cardiovascular disease in part through chronic alterations in the renin‐angiotensin system (RAS) and increased sodium retention. Thus, we hypothesize that the preterm birth‐induced increase in uric acid correlates with higher BP, attenuated sodium excretion, and differential RAS expression with higher Ang II and lower Ang‐(1–7) in adolescence.A cohort of 175 adolescents born preterm was compared to 51 term controls. We recorded systolic and diastolic BP z‐scores. Circulating levels of Ang II and Ang‐(1–7) were quantified, their ratio calculated, and evaluated in relation to serum uric acid, spot urine sodium‐to‐creatinine ratios, and BP using Spearman correlation coefficients and generalized linear models by preterm birth status.Compared to those born term, adolescents born preterm had higher mean systolic and diastolic BP z‐scores (−0.4 vs −0.86, p&lt;0.001, and −0.26 vs −0.53, p=0.03, respectively) and a higher rate of hypertension (12% vs 2%, p=0.03). Higher SBP z‐score correlated with a higher Ang II:Ang‐(1–7) ratio (coefficient 0.18, p=0.02) and higher uric acid (β: 0.11 mg/dL, 95% CI 0.002 to 0.22 mg/dL). Higher serum uric acid correlated with lower Ang‐(1–7) (β: −0.02 pmol/L, 95% CI −0.04 to −0.001 pmol/L) and a higher Ang II:Ang‐(1–7) ratio (β: 0.04, 95% CI 0.008 to 0.08). Plasma Ang II correlated with a lower urine sodium:creatinine ratio (β: −0.01 pmol/L, 95% CI −0.02 to −0.004 pmol/L), a relationship that was stronger in adolescents born preterm compared to term (β: −0.01 pmol/L, 95% CI −0.02 to −0.001 pmol/L vs β: 0.001 pmol/L, 95% CI −0.009 to 0.01 pmol/L, interaction term p=0.04).In summary, the present study finds that in adolescents born preterm who have higher uric acid, BP, plasma Ang II, and lower Ang‐(1–7), higher plasma Ang II relative to Ang‐(1–7) correlated with higher serum uric acid, lower urinary sodium excretion, and higher BP. We propose that prematurity may increase the risk of early cardiovascular disease in part through increased circulating levels of uric acid that may differentially influence the expression of Ang II and Ang‐(1–7), leading to increased sodium retention and elevated BP.Support or Funding InformationEunice Kennedy Shriver National Institute of Child Health and Human Development (P01 HD047584; HD084227), the American Heart Association (AHA 14GRNT20480131), the Clinical Research Unit of Wake Forest Baptist Medical Center (MCRR/NIH M01‐RR07122), the Wake Forest Clinical and Translational Science Award (NIH UL1 TR001420), and Forsyth Medical Center and Wake Forest School of Medicine Department of Pediatrics.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Uric acid may be protective against cognitive impairment in older adults, but only in those without cardiovascular risk factors

Uric acid (UA) may not only prevent development of cognitive dysfunction owing to its antioxidant efficacy, but also may worsen cognitive functions by gaining pro-oxidant character. The present study attempts to uncover this paradoxical association between UA and cognitive impairment in elderly. 1374 elderly patients were retrospectively evaluated and included in the study. Participants underwent determination of circulating UA levels and comprehensive geriatric assessment. A serum UA concentration≥7.0mg/dL in males and ≥5.7mg/dL in females were considered hyperuricemia. The mean age of patients was 76.72±8.76years. The prevalence of hyperuricemia was 36.6%. Significant differences was determined between the patients with and without hyperuricemia in terms of age, gender, body mass index, score of Charlson Comorbidity Index (CCI), triglyceride level, and the prevalence of dementia, diabetes, hypertension and Congestive Heart Failure (CHF) (p<0.05). When the effect of diabetes, hypertension and CHF between the groups has been statistically adjusted, the prevalence of dementia was significantly higher in those with lower UA in the absence of effect of DM, HT and CHF (p<0.05). Higher UA is associated with better cognitive performance in the absence of cardiovascular risk factors, and these risk factors may potentially suppress this protective effect of higher UA in the older adults.

Administration of Uric Acid in the Emergency Treatment of Acute Ischemic Stroke.

Oxidative stress is one of the main mechanisms implicated in the pathophysiology of inflammatory and neurodegenerative diseases of the central nervous system (CNS). Uric acid (UA) is the end product of purine catabolism in humans, and it is the main endogenous antioxidant in blood. Low circulating UA levels have been associated with an increased prevalence and worse clinical course of several neurodegenerative and inflammatory diseases of the CNS, including Parkinson's disease and multiple sclerosis. Moreover, the exogenous administration of UA exerts robust neuroprotective properties in experimental models of CNS disease, including brain ischemia, spinal cord injury, meningitis, and experimental allergic encephalitis. In experimental brain ischemia, exogenous UA and the thrombolytic agent alteplase exert additive neuroprotective effects when administered in combination. UA is rapidly consumed following acute ischemic stroke, and higher UA levels at stroke admission are associated with a better outcome and reduced infarct growth at follow-up. A recent phase II trial demonstrated that the combined intravenous administration of UA and alteplase is safe and prevents an early decrease of circulating UA levels in acute ischemic stroke patients. Moreover, UA prevents the increase in the circulating levels of the lipid peroxidation marker malondialdehyde and of active matrix metalloproteinase (MMP) 9, a marker of blood-brain barrier disruption. The moderately sized URICOICTUS phase 2b trial showed that the addition of UA to thrombolytic therapy resulted in a 6% absolute increase in the rate of excellent outcome at 90 days compared to placebo. The trial also showed that UA administration resulted in a significant increment of excellent outcome in patients with pretreatment hyperglycemia, in females and in patients with moderate strokes. Overall, the encouraging neuroprotective effects of UA therapy in acute ischemic stroke warrants further investigation in adequately powered clinical trials.

Consumption of sucrose-sweetened soft drinks increases plasma levels of uric acid in overweight and obese subjects: a 6-month randomised controlled trial.

Sucrose-sweetened soft drinks (SSSDs) are associated with the development of metabolic disorders. Fructose is a major component of SSSDs and is demonstrated to induce uric acid (UA) production and stimulate fat accumulation independent of excess caloric intake. UA induce insulin resistance and low-grade inflammation, suggesting that UA may have a causal role in the development of metabolic complications. The objective of this study is to investigate the long-term effects of consuming SSSDs on circulating levels of UA in overweight and obese subjects. Using a previously published study, circulating UA levels were assessed at baseline and after 6 months using chromogenic enzymatic absorptiometry. The study included 47 overweight and obese subjects without diabetes, randomised to consume 1 l daily of either SSSD (regular cola), isocaloric semi-skimmed milk, diet cola or water for 6 months. Circulating UA levels increased ~15% (P = 0.02) after the 6-month intervention in the SSSD group with no change in the other groups. In the SSSD group, circulating UA levels increased significantly after the intervention in both absolute (P = 0.005) and relative values (P = 0.004). The change in UA after the intervention correlated with changes in liver fat (P = 0.005), triglycerides (P = 0.02) and insulin (P = 0.002). In this secondary analysis daily intake of 1 l SSSD for 6 months was found to increase circulating UA levels compared with isocaloric milk, diet cola and water. Thus, a high daily intake of SSSDs in overweight and obese subjects without overt diabetes may increase the risk of developing metabolic complications through the elevation of UA. This trial is registered at ClinicalTrials.gov as NCT00777647.

Prognositc Value of Urc acid Levels in Elderly Chronic Heart Failure Patients

Several circulating neurohormones and inflammatory markers have been shown to have a prognostic significance in chronic heart failure (CHF). Elevated levels of uric acid (UA) have been reported to predict adverse cardiovascular prognosis in CHF patients. However, there were few reports describing clinical value of circulating UA levels in elderly CHF patients.

Uric Acid and Dementia in Community-Dwelling Older Persons

Background: The biological action of uric acid (UA) in humans is controversial. UA is considered an antioxidant compound, but preclinical evidence suggests a proinflammatory action. Epidemiological studies found that hyperuricemia is associated with conditions leading to dementia. Our aim is to investigate the relationship between UA levels and dementia in older persons. Methods: Cross-sectional study performed in 1,016 community-dwelling older persons participating in the InCHIANTI study. Participants underwent determination of circulating UA levels and neuropsychological evaluation. A multivariate logistic regression model was used to estimate the probability of participants belonging to the highest and middle UA tertile to be affected by dementia compared to those in the lowest tertile. Results: Demented persons had higher UA levels (p = 0.001) and the prevalence of persons affected by dementia increased across UA tertiles (p < 0.0001). Independent of several confounders, persons belonging to the highest UA tertile had a threefold (OR = 3.32; 95% CI: 1.06–10.42) higher probability to suffer from a dementia syndrome while those in the middle UA tertile tended to have a higher probability of being demented compared to those in the lowest tertile. Conclusion: In a population-based sample, high circulating UA levels are associated with an increased likelihood to be affected by a dementia syndrome.