High Serum Uric Levels Research Articles

Serum urate levels and the risk of hip fractures: data from the Cardiovascular Health Study

PurposeUric acid inhibits vitamin D activation experimentally and higher serum urate levels are associated with higher parathyroid hormone levels in humans suggesting a link between uric acid and bone health. We hypothesized that hyperuricemia may increase the risk of fractures in older adults. Methods1963 men and 2729 women ≥65years of age who participated in the Cardiovascular Health Study and had baseline serum urate levels were included in the study. The primary outcome was incident hip fracture, assessed prospectively through June, 2008 by inpatient and outpatient records. The analysis was stratified by sex a priori. ResultsThere was a U-shaped relationship between serum urate levels and hip fractures in men. Men in the lowest and the highest urate quartiles (<4.88 and ≥6.88mg/dL respectively) had a significantly higher rate of fractures in unadjusted analysis. However, upon multivariate adjustment, only the HR for hip fracture in highest quartile versus the reference remained significant (HR 1.9; 95% C.I. 1.1, 3.1; p value 0.02). High serum urate levels were not associated with hip fractures in women. ConclusionIn this large prospective cohort of community-dwelling older adults, increased serum urate levels were associated with an increased risk of hip fractures in men. Further studies are needed to confirm these findings and to understand the mechanisms that underlie them.

Serum Urate and the Risk of Parkinson's Disease: Results From a Meta-Analysis

Serum urate may exert protective effects against Parkinson's disease (PD) through its antioxidant capacities. In this article, we examine the hypothesis that high serum urate levels are associated with lower risk of PD. We searched NCBI (PubMed), ISI Web of Science and EMBASE for studies that reported the risk of PD associated with serum urate. Fixed or random effects meta-analysis was used to pool results across studies, and further analysis was used to assess the effects by gender. Six studies met the inclusion criteria involving a total of 33 185 participants. Overall, we found a 33% reduction in PD incidence among persons with high serum urate level (relative risk [RR]=0.67; 95% confidence interval [CI], 0.50-0.91). Subgroup analysis was performed with 20 641 men and 12 544 women included, indicating statistically significant protective effects of serum urate in men (RR=0.60; 95% CI, 0.40-0.90) but not in women. A dose-response trend of serum urate to reduce PD risk was also observed involving 11 795 participants (RR=0.77; 95% CI, 0.68-0.88). Additionally, high serum urate levels seemed to slow the clinical decline of PD patients (RR=0.56; 95% CI, 0.43-0.72). In light of these findings, our study confirms previous findings of a robust association between high serum urate level and PD risk, especially in men. It also suggests that long-term exposure to high serum urate may be linked to the delay of PD progression, however more well-designed investigations are needed.

An exploratory study of serum urate levels in patients with amyotrophic lateral sclerosis

Urate is a natural antioxidant, and high serum urate levels could be protective against the development of amyotrophic lateral sclerosis (ALS). To determine if serum urate concentrations were lower in ALS patients than in healthy controls, we compared serum urate levels in 132 ALS patients and 337 age/sex-matched controls. Median urate levels were lower in ALS patients compared to controls (4.2mgl/dL [range:1.4-8.2], vs. 4.7 [1.7-13.1]; p=0.04). In univariate analysis, high urate levels were less likely to be associated with ALS (odds ratio [OR]: 0.53; 95% CI: 0.29-0.97; p=0.04), but after adjusting for age, sex and kidney function, the association was not statistically significant (OR: 0.63; 95% CI: 0.32-1.24; p=0.18). Urate levels were lower in bulbar-onset ALS (3.9mg/dL), compared to limb-onset ALS (4.3; p=0.001), and in cases with longer disease duration compared to controls (4.1mg/dL, vs. 4.7; p=0.01). In this cross-sectional study, lower levels of serum urate were evident in ALS cases with bulbar-onset and longer disease duration, but were likely to be related to the malnutrition induced by ALS.

Serum uric acid predicts changes in reports of non-gouty chronic pain: a prospective study among women with inflammatory and non-inflammatory pain

Widespread pain has earlier been associated with an increase in serum urate (SU). The aim of this study was to longitudinally study the relation between changes in pain reporting and the level of SU among women with chronic pain. Consecutive female patients (n = 124; aged 20-70 years), at rheumatology and rehabilitation practices, with chronic musculoskeletal pain of different origins were followed for 1 year with repeated blood samples and questionnaires. Complete data were obtained from 107 individuals. Factors that predicted an increase in pain extension during 12 months were studied in a logistic regression model. Changes in SU showed a significant correlation (r = 0.36) with changes in the number of reported pain locations. An initially high SU level (OR = 4.46), frequent use of alcohol (OR = 1.32) and a high number of pain locations (OR = 1.24) independently predicted an increase in pain extension during 12 months, whereas the use of steroids (OR = 0.21) in patients with inflammatory disorders resulted in a decreased number of reported pain locations. A relative increase in SU in combination with report of a high number of pain locations turned out to be a risk factor of increased pain extension in a cohort of women with chronic non-gouty pain followed during 1 year. The importance of SU in relation to chronic pain and its prognosis needs to be validated in larger studies.

Febuxostat: the evidence for its use in the treatment of hyperuricemia and gout

Gout is a common and disabling cause of arthritis in middle-aged and elderly populations, with its main predisposing factor being hyperuricemia (serum urate > 6.8 mg/dL). Options for treatment of chronic gout until 2008 were allopurinol, a xanthine oxidase inhibitor, and the group of drugs known as uricosurics that stimulate the renal excretion of uric acid. A proportion of patients, including some with chronic kidney disease and solid organ transplantations, could not be treated with the those therapies because of intolerance, drug interactions, or adverse events. Febuxostat is a nonpurine xanthine oxidase inhibitor, recently approved in Europe and the United States for the treatment of chronic gout. To review the clinical evidence (phase II and III studies) of the effectiveness and safety of febuxostat for treatment of hyperuricemia and gout. Febuxostat, at doses ranging from 40 to 240 mg/day, is efficacious in reducing serum urate in patients with hyperuricemia and gout, comparing favorably with fixed doses of allopurinol in that respect. Early safety signals with respect to liver test abnormalities and cardiovascular outcomes have not been confirmed in recent large prospective trials but need to be further monitored. Given its low cost and extensive clinical experience, allopurinol will likely remain the first-line drug for management of hyperuricemia and gout. Febuxostat may provide an important option in patients unable to use allopurinol, those with very high serum urate levels, or in the presence of refractory tophi.

Uric acid in Parkinson's disease

Recent studies have provided evidence that uric acid may play a role in the development and progression of Parkinson's disease (PD). Uric acid is a natural antioxidant that may reduce oxidative stress, a mechanism thought to play a role in the pathogenesis of PD. Higher levels of serum urate (SU) may have a neuroprotective effect. High SU levels reduced the risk of developing PD and correlated with slower PD progression. Among PD patients SU levels were lower as compared with controls. The manipulation of SU levels holds promise in the treatment of PD. It is possible that a high purine diet in patients with PD may slow progression of the disease. Milk and meat consumption as well as exercise modify the risk of developing PD possibly through their influence on SU levels. In this article, we review the association between PD and SU levels and its implication on the management of PD.

Serum urate is associated with baseline renal dysfunction but not survival or deterioration in renal function in malignant phase hypertension.

There has been speculation whether serum uric acid levels are an independent prognostic factor in patients with hypertension. To investigate the clinical associations and prognostic value of serum urate in patients with malignant phase hypertension (MHT), by comparing clinical features in patients with serum urate levels above and below the median levels for this population, and secondly, by performing a survival analysis in these patients. Review of the data on 153 patients (98 males; mean age 50.3 years, SD 13.5) with MHT on the west Birmingham MHT register. Median uric acid levels in this population was 0.41 mmol/l (6.9 mg/dl), with an interquartile range of 0.34-0.50 mmol/l (5.7-8.4 mg/dl). Clinical characteristics of patients with a serum urate <0.41mmol/1 (group 1) were compared to those with levels above the median (0.41 mmol/l, group 2). Mean duration of follow-up was similar in both groups. The mean diastolic blood pressure at presentation and both mean systolic and diastolic blood pressures at follow-up were significantly higher in group 2 (that is, those with high serum urate levels) (unpaired t test, P= 0.039). There was also more renal dysfunction in group 2 patients with MHT, with higher mean serum urea and creatinine levels, both at presentation and at follow-up (unpaired t test, P< 0.01). The commonest causes of death were myocardial infarction (n = 7), heart failure (n = 4), stroke (n = 10) and renal failure (n = 5). There was no difference in mean survival duration between groups 1 and 2 (Kaplan-Meier, 64.6 versus 66.8 months; log-rank test, P= 0.519). Serum urate levels also did not predict the rise in serum creatinine levels (log-rank test, P= 0.84) or urea (P= 0.4033) amongst these patients. Using a multivariate Cox proportional hazards analysis, the only independent predictors of outcomes (death or the need for dialysis) were age (P = 0.007) and serum creatinine levels at presentation (P = 0.0046). Our analysis of a large series of patients with MHT shows that those with high urate levels had higher diastolic blood pressures and greater renal impairment at baseline. At follow-up, patients with median serum urate >0.41 mmol/l showed a greater deterioration in renal function and higher blood pressures, but no significant difference in survival. Serum urate levels also do not appear to be predictive of the deterioration in renal function or overall survival in patients with MHT.

Serum uric acid levels and microalbuminuria in mild hypertensive patients.

A low proportion of mild hypertensive patients, recently diagnosed in a primary care setting are microalbuminuric. These patients show a higher serum urate than normoalbuminuric hypertensive patients. The higher serum urate levels in microalbuminuric hypertensive patients may be due to insulin resistance and hyperinsulinemia, which may enhance renal urate reabsorption.

Serum uric acid and related factors in 500 hospitalized subjects

The study purpose was to determine the following in a large sample of hospitalized patients: (1) the prevalence of hyperuricemia, (2) the association of hyperuricemia with other metabolic disorders, and (3) the factors independently predicting hyperuricemia. Five hundred adult patients (250 men and 250 women) were randomly selected from those admitted as inpatients over a period of 5 months. In all patients, body mass index (BMI), blood pressure, and serum glucose, lipid, creatinine, urea nitrogen, and urate concentrations were measured. The presence of diseases or use of medications known to affect serum urate levels were recorded. The mean level of serum urate was 5.6 mg/dL in the whole sample, 6.0 mg/dL in men and 5.3 mg/dL in women ( P = .003, men v women). The prevalence of hyperuricemia was 27.6% (28.8% and 26.4% in men v women, P = nonsignificant). A definite or probable secondary hyperuricemia was found in 87.7% of the subjects. Hyperuricemia was rarely isolated (21%), whereas it was frequently associated with hypertension (60.1%), hyperlipidemia (31.2%), diabetes (28.3%), and obesity (21.7%). In 26.8% of the subjects, hyperuricemia was associated with two metabolic disorders, in 13.8% with three, and in 2.9% with four. Multiple metabolic disorders (three to four) were found in 16.7% of subjects with hyperuricemia. Serum urate levels progressively increased across a range of subjects from those without diabetes, hyperlipidemia, hypertension, or obesity to those with one, two, or a greater number of associated metabolic abnormalities. Multiple stepwise regression analysis showed that 43% of serum urate variability was explained by urea nitrogen levels, triglyceride levels, diuretic therapy, the inverse of creatinine (as an index linearly related to creatinine clearance), and BMI. These results indicate that in hospitalized subjects, hyperuricemia is (1) frequent, (2) a secondary phenomenon in most cases, and (3) frequently associated with other metabolic disorders. The major predictors of high serum urate levels are BMI, triglycerides, parameters of renal function, and use of diuretics. These variables explain a large proportion of serum urate variability.

Short-term effect of magnesium sulfate infusion on renal function in preeclamptic women.

Magnesium (Mg) plays an important role in cardiovascular homeostasis. A deficiency may be of importance for the etiology of disorders that have vasospasm in common. Mg administration can reduce the peripheral vascular resistance and thus enhance organ perfusion. We observed that Mg sulfate infusion could have a beneficial effect upon the serum urate concentration in preeclamptic women, presumably by affecting the renal function. A study comprising 10 preeclamptic women with a high serum urate level (413-788 umol/l) was carried out. Glomerular filtration rate (GFR) was measured by determination of iohexol clearance. 30 mmol Addex-Magnesium was then given i.v. during 12 h and a second GFR determination performed the next day. We had expected the GFR to increase, but to our surprise, it decreased (in mean, from 74.2 ml/[min x 1.73 m2] to 71.3; p < 0.05; Wilcoxon signed-ranks test). There were no significant changes of blood pressure, proteinuria, blood thrombocytes, transaminases, serum creatinine or serum urate. We conclude that in preeclamptic women with renal dysfunction, Mg infusion therapy had no favourable effect upon either blood pressure nor GFR in the short-term perspective.

Renal handling of uric acid in gout: Impaired tubular transport of urate not dependent on serum urate levels

Metabolic studies were conducted in 56 patients with primary gout and in ten normal subjects to assess differences in the tubular transport mechanisms of urate. Renal handling of uric acid was examined by means of pyrazinamide and probenecid tests at increased and pharmacologically reduced serum urate concentrations in both groups. Patients with gout showed similar serum urate levels and glomerular filtration rates than controls at both serum urate levles. Pyrazinamide decreased urinary uric acid excretion to less than 1.0% of the urate filtered load in both groups at increased and diminished serum urate concentrations. The maximum uricosuric response promoted by probenecid at high serum urate levels was (mean ± SD) 3,707 ± 443 μg/min/1.73 m 2 in controls and 2,215 ± 738 μg/min/1.73 m 2 in patients with gout ( P < 0.01). Forty-four patients had a daily uric acid excretion rate below 700 mg/1.73 m 2, and all of them showed a diminished uricosuric response to probenecid. When serum urate was reduced in normal subjects and 30 patients to a mean of 2.1 and 2.3 mg/dL, respectively, probenecid elicited a significantly lower urate excretion rate in gout (532 ± 202 μg/min/1.73 m 2) than in controls (922 ± 136 μg/min/1.73 m 2; P < 0.01). Among these 30 patients examined in their basal state and at decreased serum urate levels, uric acid excretion following probenecid was normal in six and diminished in 24 in both situations. The difference between maximum uricosuria and basal urate excretion was not increased in gouty patients. [2- 14C]uric acid kinetics showed a metabolic clearance rate of 6.3 ± 1.5 L/24 h/m 2 in five gouty normoexcretors and 3.5 ± 0.8 L/24 h/m 2 in three underexcretors ( P < 0.01), classified according to both 24-hour uric acid excretion and the uricosuric response elicited by probenecid. These data suggest an impaired tubular secretion of urate in most patients with gout that is not normalized by decreasing serum urate levels. The impaired tubular transport of urate may contribute to increased serum urate in primary gout.

Serum urate as a predictor of fetal outcome in severe pre-eclampsia.

Maternal serum urate levels were studied in 50 normal pregnancies and 72 cases of severe pre-eclampsia. Markedly elevated levels of serum urate were found in severe pre-eclampsia, compared with normal pregnancy. In severe pre-eclampsia significantly higher levels were found prior to parturition in cases of growth retardation and perinatal distress, compared with patients whose newborns were of normal size and condition. Particularly high serum urate levels were found early in the third trimester in cases of perinatal death. A slight but significant correlation was found between the weight centile of the newborn and the last maternal urate level before parturition. A rapidly rising urate level reliably predicted perinatal distress. The last maternal serum urate before parturition was correlated with the hemoglobin and erythrocyte volume fraction values in the same blood sample.

Uricemia and Urinary Acidification in Renal Calcium Stone Disease

Serum urate concentrations were determined in 487 consecutive patients with stone disease and in 89 controls. Male controls had higher concentrations than female controls but men and women with stones had lower concentrations than controls. Renal acidification defects, incomplete and complete forms, were found in 25 per cent of the patients with stones, with the highest frequency in patients with hyperuricemia. Patients with proximal renal acidification defects had a higher serum urate concentration than patients with normal acidification of the urine. The urinary excretion of urate was higher in hyperuricemic than in normouricemic patients but lower in patients with hyperuricemia and renal acidification defects than in those with hyperuricemia and normal acidification of the urine. This finding indicates that underexcretion rather than overproduction contributes to the higher serum urate concentration in patients with renal acidification defects. Stone patients with high serum urate levels, especially in combination with renal acidification defects, had more severe stone disease and underwent more operations than other patients with stones. Thus, hyperuricemia does not appear to be a common feature in patients with calcium stone disease, although it is associated with formation of large stones for unknown reasons.

Urate excretion in old age.

Serum urate levels were marginally higher in 11 nonbacteriuric elderly men (5.1 +/- 1.8 mg%) than in 24 nonbacteriuric women (3.9 +/- 1.6 mg%) of the same age. Bacteriuric elderly subjects (6 men, 7 women) had lower levels, these being closely similar in the two sexes (3.4 and 3.6 mg%, respectively). Significant reductions of CIn, Ccreat, and TMPAH were observed for bacteriuric men, but not for bacteriuric women. Further, the CUrate:CIn ratio was higher in bacteriuric men and in women, bacteriuric or not, and was not depressed during the TMPAH periods. Increased daily intake of protein from 60 to 75 g was associated with higher serum urate levels in a larger group of subjects. We conclude that: (1) women, even at the age of 80 have a lower serum urate, related to a higher CUrate; (2) bacteriuria increases the ratio CUrate:CIn, particularly in men; (3) secretory mechanisms for urate differ from those of p-aminohippurate in the human, and (4) dietary protein overrides the effect of bacteriuria on serum urate without affecting the male:female ratio.

Genetics of Hyperuricemia And Achievement

To the Editor:— Recent investigations correlating hyperuricemia with achievement have been prompted by the relatively frequent occurrence of gout among the eminent in history. 1-3 A genetic family evaluation is a logical extension of the clinical studies. Particularly suitable for consideration are the Harrisons of Virginia who for ten consecutive generations in this country have occupied high elective public office. Among these and the equally eminent cognate line of Lee, several cases of acute gouty arthritis have been documented. Already published but uncorrelated historical data permit genetic association and analysis. 4,5 A high serum urate level is characteristic of noninvolved members of families where gout is manifest. Also, such arthritis is known to occur in relatively few individuals with familial hyperuricemia. Achievement, leadership, range of activity, and drive correlate with elevated serum urate levels, this being established in university professors, military personnel of high intelligence, medical students, and executives. 1,2

Uric Acid Metabolism in Normal Man and in Primary Gout

Rate of Uric Acid Production in Primary GoutSome 25 or 30 per cent of patients with primary gout are habitual overexcretors of uric acid113 —they eliminate it in gross excess via the kidneys and gut, on a diet low in purines and restricted in proteins, while maintaining high serum urate levels — and hence perforce must synthesize abnormally large amounts. Such patients invariably give unequivocally confirmatory evidence of severalfold overproduction of uric acid when tested by the isotope-dilution method101,102 or by the rate of incorporation of isotope-labeled precursors into uric acid. When tagged glycine is given to gouty overexcretors . . .