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Determinants of plasma uric acid.

Obesity, alcohol consumption, and hematocrit provide an index of plasma uric acid, which in path analysis has a cultural heritability of 0.11 in children and 0.23 in parents, a small maternal effect, and a genetic heritability of 0.25 in both generations. Preliminary evidence for a major locus is destroyed by the omission of one exceptional child. There is no evidence against the polygenic hypothesis for hyperuricemia in the Japanese-American population studied.

Adult↗

The application of a sensitive uricase-peroxidase couple reaction to a centrifugal fast analyser for the determination of uric acid.

A uricase-peroxidase coupled system, for the determination of uric acid, applied to a CentrifiChem-500 centrifugal fast analyser is described. Relatively large amounts of ascorbic acid, due to the inclusion of an ascorbate oxidase urine diluent, and hemoglobin appear not to interfere with the procedure while the incorporation of potassium ferrocyanide into the reagents has led to the near-total elimination of bilirubin interference. The incubation period is relatively short compared with other similar procedures and the one reagent system has made the procedure simple to perform. The use of sodium 2-hydroxy-3,5-dichlorobenzenesulfonate and 4-aminoantipyrene in the oxidative coupling reaction has incorporated the advantages of increased sensitivity, over phenol-4-aminoantipyrene systems, as well as the amenability of the reagent towards lyophilization or "dry-fill".

Ampyrone↗

Relation between serum uric acid and angiographically defined coronary artery disease in postmenopausal women.

Serum uric acid (UA) levels were studied in 40 postmenopausal women and 57 men, almost matched for age and body mass index (BMI) and undergoing coronary angiography. For women, the mean value of UA increased as the number of coronary arteries with > or = 50% stenosis increased. Its value was significantly higher (p < 0.05) in a three-vessel disease group than that of a group without stenosis. No significant changes were seen in men. However, the increase in UA for postmenopausal women was statistically (p < 0.05) correlated with serum triglyceride levels. Possibly, UA is not an independent coronary risk factor. However, elevated UA levels may suggest the prevalence of severe coronary artery stenosis for postmenopausal women.

Aged↗

Uric acid levels and vascular disease.

There is evidence showing that serum uric acid (SUA) levels predict the risk for vascular events. For example, up to 29% of the reduction in the primary composite endpoint seen in the LIFE trial (favouring losartan versus atenolol) can be attributed to a fall in SUA levels. We also discuss the findings of the GREACE study (treating to target with atorvastatin versus 'usual' care) in relation to SUA levels. In this brief comment we extend this argument to consider the SUA-lowering effect of other drugs commonly prescribed in patients with vascular disease (e.g. statins, fibrates and antihypertensive agents). A judicious use of drugs (alone or in combination) will result in small reductions in SUA levels. These changes may translate into a substantial reduction in the risk of vascular events. Results retrieved from completed trials together with new prospective findings will support or refute the proposed association between lowering SUA levels and reducing vascular morbidity and mortality.

Diuretics↗

Uric acid homeostasis in lean and obese girls during pubertal development.

Serum uric acid concentration and fractional excretion were evaluated in lean (n = 67) and obese (n = 56) girls before and during pubertal development. In both lean and obese girls, uricemia gradually increased as puberty advanced. Obese girls were hyperuricemic compared with lean controls (prepubertal: 184 +/- 83 v 130 +/- 29 mumol/L, P = .007; Tanner stage II-III: 190 +/- 53 v 178 +/- 47 mumol/L, NS; Tanner stage IV-V: 232 +/- 53 v 191 +/- 53 mumol/L, P = .02). Fractional excretion of urate decreased with puberty in lean girls (6.46% +/- 2.29%, 4.61% +/- 2.48%, and 3.54% +/- 1.84%), but not in obese subjects (3.74% +/- 2.27%, 4.01% +/- 1.90%, and 4.26% +/- 2.26%). Urate homeostasis was similar in prepubertal obese girls and in adolescent lean controls. We conclude that an increased serum urate concentration occurring at puberty may be due to decreased renal clearance of urate in lean girls, and at least in part to urate overproduction in obese subjects. Obesity may prematurely evoke changes in urate metabolism usually observed at puberty.

Adolescent↗

[A new role of uric acid as an antioxidant in human plasma].

Free radical attack upon uric acid (UA) nonenzymatically generates allantoin (ALT), and the presence of ALT in human plasma suggests free radical intervention within the body. To assess this possibility, we determined plasma ALT in patients with chronic renal failure (CRF) and some other diseases by high-performance liquid-chromatography (HPLC). Heparinized blood samples were obtained from 15 healthy controls, CRF patients under conservative management (n = 13) or hemodialysis (HD) treatment (n = 8) and patients with gout (n = 11) or rheumatoid arthritis (RA, n = 13). Although not seen in normal plasma samples, ALT was detected in 63% and 31% of patients receiving HD and conservative treatment, respectively. The plasma ALT level decreased after each HD session. ALT was also detected in 18% and 23% of the patients with gout and RA, respectively. ALT was found to be generated by ultraviolet radiation or by the addition of H2O2 to a normal pool-plasma. Addition of Fe(2+) and H2O2 increased the ALT level to about twice that of only H2O2. Addition of either catalase, desferal, EDTA, DMTU, DMSO or mannitol to the plasma decreased ALT generation. These findings suggest that ALT is generated from UA attacked by free radicals, especially by the hydroxyl radical, and that UA plays a role as an antioxidant in the plasma of patients with CRF and some other diseases.

Allantoin↗

Effect of acute administration of salmon and human calcitonin on blood urate and renal excretion of uric acid in patients with Paget's disease of bone.

The sc injection of salmon calcitonin (CT) (100 MRC U) or human CT (50 MRC U) to Pagetic patients reduces the plasma urate concentration and increases the renal excretion of uric acid. This effect is independent of the natriuretic, phosphaturic, or glycosuric actions of CT and is not due to the transient increment of the glomerular filtration rate noted after CT administration. Our results suggest that the hypouricemia observed during CT treatment is related, at least in part to a direct action on the renal handling of uric acid.

Aged↗

Investigation of serum calcium, phosphorus, albumine uric acid and lipid parameters in sportsmen and sedanters.

In this study, it was aimed to investigate the differences in blood lipid fractions which are important risk factors for atherosclerosis and to show how the levels of serum albumin, uric acid, ionized calcium, inorganic phosphorus change with exercises between sportsmen and sedanters. 25 sportsmen and 25 sedanters (13 male, 12 female in each group) aged 18-23 were chosen for the study. From the venous blood samples taken from the two groups, levels of serum total lipid, total cholesterol, HDL-cholesterol, LDL-cholesterol, VLDL-cholesterol, triglyceride, albumin, uric acid, ionized calcium, inorganic phosphorus were analyzed. Student's t-test was used for the statistical analyses. There were some important changes in the levels of serum triglyceride, VLDL-cholesterol and ionized calcium of sportsmen compared to those of controls.

Adolescent↗

Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer: a hypothesis.

During primate evolution, a major factor in lengthening life-span and decreasing age-specific cancer rates may have been improved protective mechanisms against oxygen radicals. We propose that one of these protective systems is plasma uric acid, the level of which increased markedly during primate evolution as a consequence of a series of mutations. Uric acid is a powerful antioxidant and is a scavenger of singlet oxygen and radicals. We show that, at physiological concentrations, urate reduces the oxo-heme oxidant formed by peroxide reaction with hemoglobin, protects erythrocyte ghosts against lipid peroxidation, and protects erythrocytes from peroxidative damage leading to lysis. Urate is about as effective an antioxidant as ascorbate in these experiments. Urate is much more easily oxidized than deoxynucleosides by singlet oxygen and is destroyed by hydroxyl radicals at a comparable rate. The plasma urate levels in humans (about 300 microM) is considerably higher than the ascorbate level, making it one of the major antioxidants in humans. Previous work on urate reported in the literature supports our experiments and interpretations, although the findings were not discussed in a physiological context.

Adult↗

Uric Acid Levels and Cardiovascular and Cerebrovascular Diseases: A Mendelian Randomization Study.

INTRODUCTION: The relationship between uric acid (UA) levels and cardiovascular and cerebrovascular diseases (CCVD) is controversial. A two-sample Mendelian randomization (MR) study was conducted to explore the causal effects of UA levels on CCVD. METHODS: Genetic variants strongly associated with UA levels were selected as instrumental variables from the Genome-Wide Association Study (GWAS) dataset. The GWAS data, sourced from the Global Urate Genetics Consortium (GUGC), comprised a sample size of 110,347 individuals. The selected CCVD outcomes included stroke, coronary artery disease (CAD), as well as atrial fibrillation and flutter. The primary analytical approach employed the inverse-variance weighted (IVW) method, supplemented by MR-Egger and weighted median as complementary methods. Sensitivity analysis was performed to test heterogeneity and pleiotropy. RESULTS: The MR analysis results indicated a causal association between UA levels and stroke (odds ratio [OR]: 1.002; 95% confidence interval [CI]: 1.000-1.003; p = 0.036), CAD (OR: 1.118; 95% CI: 1.044-1.197; p = 0.001), as well as atrial fibrillation and flutter (OR: 1.141; 95% CI: 1.037-1.256; p = 0.007). The results of MR-Egger and weighted median methods confirmed the direction of the IVW results, enhancing the robustness of the findings. No significant anomalies were detected in the sensitivity analysis. CONCLUSION: The MR study suggests that UA levels exert causal effects on stroke, CAD, as well as atrial fibrillation and flutter.

Humans↗

A reagent less fluorescent sol-gel biosensor for uric acid detection in biological fluids.

The simultaneous encapsulation of a coupled uricase-peroxidase system and amplex red in a sol-gel matrix allows one to obtain a reagent-less and ready-to-use fluorescent biosensor for the accurate detection of uric acid in highly diluted biological fluids. The detection limit of the prepared biosensor was found to be 20 nM and was linear up to 1 microM. The high sensitivity found for the biosensor permitted a reliable determination of uric acid concentrations in the presence of interfering species (e.g., ascorbic acid) just by sample dilution (up to 50000 for urine and 10000 for serum and blood). The sol-gel encapsulation preserved the hierarchy of the enzyme activity as demonstrated by the performance of the fluorescent biosensor.

Ascorbic Acid↗

Influence of allopurinol and two diets on 24-hour urinary excretions of uric acid, xanthine, and ammonia by healthy dogs.

Hyperxanthinuria and xanthine uroliths have been recognized with increased frequency in dogs with ammonium urate uroliths that had been given allopurinol. We hypothesized that dietary modification might reduce the magnitude of uric acid and xanthine excretion in urine of dogs given allopurinol. To test this hypothesis, excretion of metabolites, volume, and pH were determined in 24-hour urine samples produced by 6 healthy Beagles during periods of allopurinol administration (15 mg/kg of body weight, PO, q 12 h) and consumption of 2 special purpose diets: a 10.4% protein (dry matter), casein-based diet and a 31.4% protein (dry matter), meat-based diet. Significantly lower values of uric acid (P = 0.004), xanthine (P = 0.003), ammonia (P = 0.0002), net acid (P = 0.0001), titratable acid (P = 0.0002), and creatinine (P = 0.01) excreted during a 24-hour period were detected when dogs consumed the casein-based diet and were given allopurinol, compared with the 24-hour period when the same dogs consumed the meat-based diet and were given allopurinol. For the same 24-hour period, urine pH values, urine volumes, and urine bicarbonate values were significantly (P = 0.0004, P = 0.04, and P = 0.002, respectively) higher during the period when the dogs were fed the casein-based diet and given allopurinol than when they were fed the meat-based diet and given allopurinol. Endogenous creatinine clearance was significantly (P = 0.006) lower when dogs were fed the casein-based diet and given allopurinol than when they were fed the meat-based diet and given allopurinol.(ABSTRACT TRUNCATED AT 250 WORDS)

Allopurinol↗

Low molecular weight immunosuppressive factors found in elevated amounts in cancer ascitic fluids of mice. 1. Isolation, identification and immunosuppressive effects of uric acid and uracil.

A definite increase in two low molecular weight factors, G10-2 and G10-3 was found in Ehrlich ascitic fluids, parallel to tumor growth. The isolation and identification of the two factors were attempted through gel filtration and reversed phase column chromatography, using ascitic fluids obtained 13 days after intraperitoneal implantation of Ehrlich tumor cells. As a result, two highly purified factors were observed upon examination by high performance liquid chromatography. Additional analytical data, collected by UV spectrum, NMR spectrum and mass analysis, allowed us to identify G10-2 as uric acid and G10-3 as uracil. Detailed immunological analysis of uric acid and uracil revealed that the augmenting activities of mouse and human NK cells by mouse IFN alpha/beta or human rIFN alpha A/D were impaired in the presence of either compound at concentrations of 0.07 mM, the concentration detectable in the ascitic fluid of tumor bearing mice.

Animals↗

Uric acid and anti-TNF antibody improve mitochondrial dysfunction in ob/ob mice.

The mechanisms responsible for low mitochondrial respiratory chain (MRC) activity in the liver of patients with nonalcoholic steatohepatitis are unknown. In this study, we examined the cause of this dysfunction in ob/ob mice. Forty-six mice were distributed in six groups: group I: C57BL/6J mice; group II: C57BL/6J Lep(-/-) mice (ob/ob); group III, ob/ob mice treated with manganese [III] tetrakis (5,10,15,20 benzoic acid) porphyrin (MnTBAP); group IV, ob/ob mice treated with IgG1 immunoglobulin; group V, ob/ob mice treated with anti-TNF antibody; group VI: ob/ob mice treated with uric acid. In liver tissue, we measured MRC activity, fatty acid beta-oxidation, tumor necrosis factor (TNF), inducible nitric oxide synthase (iNOS), 3-tyrosine-nitrated proteins, 3-tyrosine-nitrated mitochondrial proteins, including cytochrome c and ND4 subunit of complex I. MRC activity was decreased in ob/ob mice. TNF levels, iNOS protein expression, and tyrosine nitrated proteins were markedly increased in the liver of ob/ob mice. In these animals, mitochondrial proteins were markedly tyrosine nitrated, particularly the ND4 subunit of complex I and cytochrome c. Treatment of these animals with uric acid, a peroxynitrite scavenger, anti-TNF antibody, or MnTBAP decreased tyrosine nitrated proteins, improved the activity of MRC complexes, and led to a marked regression of hepatic steatosis and inflammation. In conclusion, MRC dysfunction and liver lesions found in ob/ob mice are likely to reflect the tyrosine nitration of mitochondrial proteins by peroxynitrite or a peroxynitrite-derivate radical. Increased hepatic TNF and iNOS expression might enhance peroxynitrite formation and inhibition of MRC complexes.

Animals↗

Pregnancy in xanthinuria: demonstration of fetal uric acid production?

This paper reports biochemical studies in a pregnant xanthinuric female (McKusick 27830) and compares the results with findings in three other xanthinurics studied by us, including a previously unreported female who had a nephrectomy for xanthine stones. The findings of raised levels of uric acid in plasma and urine at presentation in the third trimester of pregnancy, and the subsequent fall to almost undetectable levels 6 weeks post-partum, is regarded as evidence of the extent of fetal uric acid production and clearance by the maternal circulation.

Adult↗

Role of urinary inhibitors of crystallization in uric acid nephrolithiasis: Dalmatian dog model.

OBJECTIVES: To study the role of urinary inhibitors on crystallization-nephrocalcin, Tamm-Horsfall protein (THP), and glycosaminoglycans (GAGs)-in hyperuricosuric nephrolithiasis using Dalmatian dogs, a breed well-known for high levels of uric acid excretion, in an in vivo model. METHODS: Urine samples were collected from 10 stone-forming Dalmatian dogs and from 5 age-matched Dalmatians without kidney stones. Purine derivatives present in urine were studied by high-performance liquid chromatography. THP, GAGs, and nephrocalcin were isolated and measured. RESULTS: As expected, the Dalmatians excreted a large amount of uric acid in urine, but without differences between the two groups (0.42 +/- 0.08 mg/mg creatinine versus 0.48 +/- 0.11 mg/mg creatinine for stone-forming and healthy Dalmatians, respectively, P = 0.64). No other metabolites were derived from purine in their urine. Stone-forming Dalmatians showed significantly lower urinary excretion of THP than did normal Dalmatians (0.09 +/- 0.03 mg/mg creatinine versus 0.21 +/- 0.03 mg/mg creatinine, P <0.03). The urinary excretion of GAGs was lower in the stone-forming Dalmatians, although the difference was not statistically significant. Inhibition of calcium oxalate monohydrate crystal growth caused by nephrocalcin isoforms from healthy and stone-forming dogs were in the same order of approximately 10(-7) M, as calculated from a Langmuir isotherm type plot. CONCLUSIONS: The urinary excretion of THP and GAGs was decreased in stone-forming Dalmatians compared with healthy ones. Our results support the suitability of Dalmatian dogs as an in vivo model to investigate the interrelationship of urine inhibitors of crystallization and hyperuricosuria.

Animals↗

Prevention of uric acid stone formation by sodium bicarbonate in an ileostomy patient--a case report.

A 38 year old female underwent a proctocolectomy and ileostomy for ulcerative colitis in February, 1974. For 8 year post-operatively, she excreted innumerable renal stones, mainly composed of uric acid. Her urine was highly acidic and hyperuricosuric with a low concentration of sodium. Sodium bicarbonate 4 gm/day, t.i.d., was started in October 1985, after which her renal stone excretion completely ceased (up until March, 1987), except for one incidence of stone excretion when she discontinued therapy for a week. During the sodium bicarbonate therapy, her urinary pH and Na concentration were elevated. Furthermore, sodium bicarbonate significantly elevated the urinary pH and Na concentration of other ileostomy patients. Thus, sodium bicarbonate could be used for the possible prophylaxis of uric acid formation in selected ileostomy patients.

Adult↗

Uptake of uric acid, xanthine and hypoxanthine by brush-border membrane vesicles from mouse small intestine.

Using mouse small intestine brush-border membrane vesicles virtually free of xanthine oxidase (EC 1.2.3.2) and free of uricase (EC 1.7.3.3) the uptake of the purines uric acid, xanthine and hypoxanthine have been studied. The sodium-dependent overshoot phenomenon shown to exist for the uptake into the vesicles for D-glucose and L-phenylalanine was not observed with the purines. However, the uptake of the three purines in the presence of NaCl or KCl was greater than the uptake in the presence of either NaSCN or mannitol. Although 12.9% of the xanthine uptake and 17.6% of the hypoxanthine uptake was attributed to binding to the membranes, almost all the uric acid uptake was due to transport into an osmotically active space. The apparent intravesicular volume, calculated after 60 min incubation, for the three purines was consistently greater than the values obtained with D-glucose, L-glucose and L-phenylalanine equilibration, suggesting slow continuing penetration of purines associated with swelling or an apparent accumulation of purines within the vesicles associated with normal vesicle volume.

Animals↗