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The relationship of sex steroids to uric acid levels in plasma and urine.

The effect of endogenous and exogenously administered oestrogens, androgens and progesterone on plasma and urinary uric acid and uric acid clearance was studied in a total of 65 healthy volunteers, including normal menstruating and post-menopausal women, girls with primary amenorrhoea and adult male subjects. A serial study throughout a full cycle in 3 women showed an inverse relationship between plasma uric and synthetic oestrogens produced a fall in plasma uric acid concentration through a uricosuric effect in most subjects of both sexes. Testosterone propionate caused a definite increase in plasma uric acid levels in post-menopausal women while endogenous testosterone changes due to Leydig cell stimulation produced no definite effect in male subjects. Administration of a progesterone preparation produced an effect similar to that of oestrogens in post-menopausal women. The evidence presented here supports ithe view that sex steroids play a significant part in uric acid regulation in biological fluids of both sexes.

Adolescent↗

Trypanosoma musculi: influence of uric acid on in vitro formation of metacyclic trypomastigotes.

Uric acid is the most important constituent in the urine of insects. Infective metacyclic forms of the stercorarian trypanosomes are produced in the rectum of their insect vector and are thus in contact with uric acid. Using a culture system which permitted the growth of the insect stages of Trypanosoma musculi, we studied the influence of uric acid on the metacyclogenesis of this parasite. When added to the culture, uric acid enhanced the production of metacyclic forms. Furthermore, it rendered these trypanosomes highly infective by the oral route. It is suggested that uric acid may play an important role on the metacyclogenesis of T. musculi.

Animals↗

The defect of uric acid metabolism in Eck-fistula rats.

Because of the discovery of uric acid urolithiasis in rats after end-to-side portacaval anastomosis (PCA), uric acid metabolism was studied in these animals and in appropriate controls. Hyperuricemia and hyperuricosuria were observed in all experimental rats. The fraction of purine catabolites excreted in the urine as uric acid increased from an average of 4.8% to 15.3%. If 14C-uric specifically labeled at position 6 (6-14C-ua) was infused intravenously and the exhalation of 14CO2 was used to calculate a hepatic uric acid clearance, it decreased from 2.14 to 0.97 ml/min/100 gm despite a normal content of hepatic uricase activity as measured in liver homogenates. The fraction of the filtered amount of uric acid excreted in the urine increased from an average of 11% to 30%. Increased supersaturation of the urine with uric acid after PCA may be expected to contribute to the formation of uric acid urolithiasis. This investigation defines a hepatic and renal functional defect in uric acid metabolism which occurs as a result of the PCA.

Allantoin↗

Determination of 15N isotopic enrichment and concentrations of allantoin and uric acid in urine by gas chromatography/mass spectrometry.

A method for the determination of 15N enrichment and concentration of allantoin and uric acid simultaneously in urine using gas chromatography/mass spectrometry (GC/MS) is described. The urine samples contained [1,3-15N2] uric acid and its oxidation product allantoin. The uric acid and allantoin were isolated using an AG1-X8 (Cl-form) anion-exchange column and heated with a mixture containing 1:1 dimethylformamide and N-(tert-butyldimethylsilyl)-N-methyltrifluoroacetamide (MTBSTFA). The tert-butyldimethylsilyl (TBDMS) derivatives of allantoin and uric acid formed were injected into a gas chromatograph interfaced with a mass spectrometer operated under electron impact ionization conditions. Isotope ratio measurements were made from the abundance of the M-57 ions at m/z 398, 399 and 400 for allantoin and at m/z 567 and 569 for uric acid. 15N2 allantoin (99 at.%) was produced from [1,3-15N2] uric acid by treatment with uricase and used as a standard. Quantitation of allantoin and uric acid was based on isotopic dilution by spiking the urine sample with known quantities of 99 at.% [15N] uric acid and allantoin internal standards. The observed isotope ratio measurements from the prepared standards matched the theoretical values. Coefficients of variation in measurements of isotope ratio and concentration were 0.2 and 0.5%, respectively. The method was applied in a study to measure the urinary recovery of [1,3-15N2] uric acid continuously infused for 8-10 h into the blood of four sheep each on two occasions. Within 24 h, 65.9 +/- 9.1% of the tracer was excreted in the urine unchanged. Little was converted into allantoin (approximately 7% of the dose). The total recovery (5 days) of the infused tracer averaged 69.5 +/- 7.6% as uric acid and 76.8 +/- 9.3% as the sum of uric acid and allantoin. Uricase activities in plasma, liver and kidney of sheep were also measured using [1,3-15N2] uric acid as a substrate. Uricase activity was estimated to be 0.6 mU g-1 wet tissue in the liver and there appeared to be none in plasma and kidney. The low uricase activities in sheep tissues appeared to explain the limited conversion of the intravenously administered [15N] uric acid to allantoin but did not explain the large quantities of allantoin excreted in urine (8.96 +/- 0.86 and 1.36 +/- 0.25 mmol d-1 for allantoin and uric acid, respectively). The GC/MS method for the determination of 15N enrichment and concentration of allantoin and uric acid in urine is accurate and precise and provides a useful tool for studies on uric acid and allantoin metabolism.

Allantoin↗

Four methods for determining uric acid compared with a candidate reference method.

Uric acid as measured in serum by three different uricase (EC 1.7.3.3) methods (aca, Ektachem, and SMAC) and by the SMAC method with phosphotungstic acid was compared with a candidate Reference Method for uric acid. Serum specimens from 83 patients (uric acid concentrations, 19 to 141 mg/L) were analyzed by all five methods. Results were compared by using linear regression analysis, and the mean difference between results by the candidate Reference Method and the four other methods was calculated. Compared with the candidate Reference Method, the aca method gave the smallest deviation from zero for the intercept and the smallest mean difference, and the SMAC phosphotungstic acid method showed a slope closest to unity. The SMAC uricase method had the largest intercept and greatest deviation of the slope from unity.

Autoanalysis↗

Excretion of tamm-horsfall protein in patients with uric acid stones.

The cause of reduced Tamm-Horsfall protein excretion in patients suffering from uric acid diathesis is still unknown. Our investigation was conducted based on the hypothesis that the solubility of uric acid is increased by Tamm-Horsfall protein and that an increased uric acid content in the urine might cause a decrease in Tamm-Horsfall protein. In 20 patients with uric calculi the excretion of Tamm-Horsfall protein, uric acid, calcium, and citrate was measured. 65% of the patients had pure uric acid stones (group I) and 35% showed mixed stones with at least 30% of uric acid (group II). Reduced Tamm-Horsfall protein excretion was found in 63% of the patients of group I and in 43% of the patients of group II. The excretion of Tamm-Horsfall protein was significantly reduced in pure uric acid stone formers compared to normal subjects (p < 0. 0001). The excretion of uric acid was elevated in 61% of the patients of group I and in 86% of the patients of group II. There was no significant correlation between Tamm-Horsfall protein excretion and uric acid excretion (r = 0.2139). Calcium excretion was elevated in 57% of the patients with mixed stones. The excretion of citrate was reduced in almost all of the patients of groups I and II. Our results do not support the hypothesis that an increased content of uric acid in the urine causes a decrease in Tamm-Horsfall protein. In our opinion the lower excretion of Tamm-Horsfall protein in some of the stone patients might be caused by damage in the distal tubular epithelium. Moreover, it has to be supposed that there are defects both in the distal and the proximal tubule in patients prone to develop uric acid calculi.

Albuminuria↗

Development and analytical application of an uric acid biosensor using an uricase-immobilized eggshell membrane.

An uric acid biosensor fabricated from a uricase-immobilized eggshell membrane and an oxygen electrode was presented. The detection schemes involve the enzymatic reactions of the uricase leading to the depletion of dissolved oxygen level upon exposure to uric acid solution. The decrease in oxygen level was monitored and related to the uric acid concentration. The scanning electron micrographs show the microstructure of the eggshell membrane within which the uricase is successfully immobilized. The effects of enzyme loading, pH, temperature, and phosphate buffer concentration on the response of the biosensor were investigated in detail. The uric acid biosensor has a linear response range of 4.0-640 microM with a detection limit of 2.0 microM (S/N=3). The response time was less than 100 s. The biosensor exhibited good repeatable response to a 0.10mM uric acid solution with a relative standard deviation of 3.1% (n=7). The reproducibility of fabrication of the biosensors using four different membranes was good with a R.S.D. of 3.2%. The biosensor showed extremely good stability with a shelf-life of at least 3 months. Some common potential interferents in samples such as glucose, urea, ascorbic acid, lactic acid, glycine, DL-alpha-alanine, DL-cysteine, KCl, NaCl, CaCl2, MgSO4, and NH4Cl showed no interferences on the response of the uric acid biosensor. The biosensor was successfully applied to determine the uric acid level in some human serum and urine samples, and the results agreed well with those obtained by a commercial colorimetric assay kit.

Animals↗

Effect of Tofu (bean curd) ingestion and on uric acid metabolism in healthy and gouty subjects.

The effect of Tofu (bean curd) ingestion on uric acid metabolism was examined in 8 healthy and 10 gout subjects. Ingestion of Tofu increased plasma concentration of uric acid, together with increases in uric acid clearance and urinary excretion of uric acid. However, the increase in plasma concentration of uric acid was fairy small. Interestingly, no significant rise in the plasma, urinary and clearance of uric acid was observed in gout patients with uric acid clearance > 6.0 mL/min (lower normal limit). The results suggest that tofu is a preferable source of protein, especially in gout patients with uric acid clearance > 6.0 mL/min.

Adult↗

Relationship between hypertriglyceridemia and uric acid production in primary gout.

The relationship between uric acid metabolism and lipid levels was analyzed in 148 male subjects with primary gout. The subjects were divided into three groups according to their alcohol consumption: heavy drinkers, moderate drinkers, and nondrinkers or mild drinkers. There was no correlation between urinary uric acid excretion and serum triglyceride (TG) levels in the heavy group, but a marginally significant correlation was shown in the moderate group (P less than .05), and a significant correlation was observed in the nondrinker or mild group (P less than .001). This relationship in the nondrinker or mild group was also found to be significant after adjustment for BMI and age by multiple regression analysis. Serum lipoproteins were analyzed by sequential preparative ultracentrifugation in 21 patients with primary gout who neither drank alcohol nor were obese; VLDL-TG level, but not the VLDL cholesterol level, was found to be significantly correlated with 24-hour urinary uric acid excretion. These results indicate that there is a close correlation between the degree of uric acid production, as judged by 24-hour urinary uric acid excretion, and lipoprotein TG metabolism when the influence of alcohol intake is excluded.

Alcohol Drinking↗

Close correlation between visceral fat accumulation and uric acid metabolism in healthy men.

We evaluated the effect of accumulation of intraabdominal visceral fat on the metabolism of uric acid in 50 healthy male subjects to elucidate any relationship between such obesity and hyperuricemia. The area of abdominal fat (visceral fat and subcutaneous fat) was measured at the level of the umbilicus by abdominal computed tomographic scanning. Serum and urinary concentrations of uric acid and creatinine were determined with an autoanalyzer. Uric acid clearance and the ratio of urinary uric acid to creatinine excreted in urine were calculated. Univariate and multivariate analyses were used to evaluate the relationship between uric acid metabolism and body fat. The size of the area of visceral fat was significantly correlated with the serum concentration of uric acid (r = .37, P < .01), uric acid clearance (r = -.34, P < .05), and the urinary uric acid to creatinine ratio (r = .65, P < .0001). The size of the area of subcutaneous fat was significantly correlated only with the urinary uric acid to creatinine ratio (r = .38, P < .01). Multivariate analyses, including body mass index (BMI), showed that the size of the visceral fat area was the strongest contributor to an elevated serum concentration of uric acid, a decrease in uric acid clearance, and an increase in the urinary uric acid to creatinine ratio. These results suggest that accumulation of visceral fat may have a greater adverse effect on the metabolism of uric acid than BMI or accumulation of subcutaneous fat. Clearly, patients with hyperuricemia should lose weight to reduce excessive visceral fat stores, to help avoid attacks of gout.

Abdomen↗

Measurement of uric acid levels in chicken cecal contents.

Uric acid levels in the cecal contents of White Leghorn males aged 6, 10, and 24 weeks of age were constant at approximately 2 mg/100 ml. Fecal samples obtained from these birds contained, respectively, 99, 107, and 156 mg/100 ml uric acid. The addition of growth promoting level of antibiotics or other feed additive to the ration of 10-week-old White Leghorn males had no effect upon cecal uric acid levels.

Animals↗

Effect of natural oestrogen/gestagen therapy on uric acid metabolism in post-menopausal women.

Uric acid metabolism was studied in groups of early post-menopausal women before and during long-term administration of natural oestrogen/gestagen (n = 21), bendroflumethiazide (n = 19) or placebo (n = 34). Serum uric acid rose definitely, by 13.0% during thiazide, and decreased slightly, by 4.9%, during hormone treatment. The latter deviation did not differ significantly from that of -2.9% seen in the placebo group. The urinary excretion rates of uric acid observed during thiazide and hormone treatment did not differ significantly from that of the placebo group. It is concluded, that within the present design of study, which readily permits detection of the well-known hyperuricaemic action of thiazide, oestrogen/gestagen hardly affects uric acid metabolism.

Adult↗

UV absorption by uric acid in diurnal bird aqueous humor.

PURPOSE: To analyze the components responsible for the UV absorbance in diurnal bird aqueous humor. METHODS: The absorbance studies were carried out using a Hitachi spectrophotometer (U 2000). Uric acid was determined by high-performance liquid chromatography (LC-10 system; Shimadzu, Kyoto, Japan). Chicken and turkey eyes were examined. RESULTS: The UV absorbance in chicken aqueous was largely accounted for by the presence of protein, tryptophan, tyrosine, ascorbic acid, and uric acid. Ascorbic acid was low (23 micromol/l). Uric acid was, on the other hand, remarkably high (151 micromol/l) compared with that in mammals (cattle, 16 micromol/l). Principally the same results were obtained in chicken and turkey. CONCLUSIONS: Uric acid is a significant UV-absorbing substance in the aqueous humor of diurnal birds with its peak absorbance at 292 nm. The hypothesis that the aqueous humor acts as a UV filter seems to be valid also for the avian eye. However, in these eyes uric acid fulfills the role that ascorbic acid does in mammals.

Absorption↗

Experimental meningitis in the rat: protection by uric acid at human physiological blood concentrations.

The natural peroxynitrite scavenger uric acid was previously shown to be protective in a rat model of pneumococcal meningitis; however, rats have much lower blood uric acid levels than humans. Therefore, we evaluated its therapeutic effect at human physiological blood concentrations. Intraperitoneal pretreatment with uric acid increased its blood concentrations from 44.9+/-10.0 microM in untreated rats to 169.8+/-122.6 microM and reduced the cerebrospinal fluid (CSF) pleocytosis from 12767+/-2520 to 8376+/-2450 cells/microl (P<0.05) and the intracranial pressure from 11.6+/-3.0 to 4.3+/-1.2 mm Hg (P<0.05). Coadministration of oxonic acid, an inhibitor of urate oxidase, increased the blood uric acid levels to 355.0+/-79.6 microM and further reduced the CSF pleocytosis (4190+/-1749 cells/microl, P<0.05) and the intracranial pressure (1.4+/-2.4 mm Hg). Uric acid+oxonic acid also had a beneficial effect when administered 2 or 4 h after the induction of meningitis. We demonstrate a dose-dependent anti-inflammatory effect of uric acid at blood levels in the human physiological range.

Animals↗

The effects of vitamin C supplementation on serum concentrations of uric acid: results of a randomized controlled trial.

OBJECTIVE: Reductions in serum uric acid levels are clinically relevant. Previous studies have suggested a uricosuric effect of vitamin C. Whether vitamin C reduces serum uric acid is unknown. We undertook this study to determine the effects of vitamin C supplementation on serum uric acid concentrations. METHODS: The study was a double-blinded placebo-controlled randomized trial conducted in research units affiliated with an academic institution. Study participants were 184 nonsmokers, randomized to take either placebo or vitamin C supplements (500 mg/day) for 2 months. RESULTS: At the end of the study period, serum uric acid levels were significantly reduced in the vitamin C group (mean change -0.5 mg/dl [95% confidence interval -0.6, -0.3]), but not in the placebo group (mean change 0.09 mg/dl [95% confidence interval -0.05, 0.2]) (P < 0.0001). The same pattern of results was evident in subgroups defined by age, sex, race, body mass index, chronic illness, diuretic use, and quartiles of baseline serum ascorbic acid levels. In the subgroups, from the lowest to the highest quartile of baseline serum uric acid, net mean changes (95% confidence intervals) in serum uric acid with vitamin C supplementation were -0.4 (-0.8, 0.01), -0.5 (-0.9, -0.2), -0.5 (-0.8, -0.2), and -1.0 (-1.6, -0.4) mg/dl (P = 0.06, 0.005, 0.003, and 0.002, respectively). Compared with placebo, vitamin C increased the estimated glomerular filtration rate. CONCLUSION: Supplementation with 500 mg/day of vitamin C for 2 months reduces serum uric acid, suggesting that vitamin C might be beneficial in the prevention and management of gout and other urate-related diseases.

Adult↗

Uric acid elimination in the urine. Pathophysiological implications.

Uric acid, a weak organic acid, has very low pH-dependent solubility in aqueous solutions. About 70% of urate elimination occurs in urine, the kidney standing as a major determinant of plasma levels. The complex renal handling results in a fractional clearance of less than 10%. Recently identified urate-specific transporter/channels are involved in tubular handling and extracellular transport. Extracellular fluid, rather than urine output, is the main regulator of urate excretion. A number of interfering agents, including widely used drugs such as aspirin, losartan, diuretics, may decrease or increase urate elimination. Hyperuricemia induced by hypouricosuria often accompanies the metabolic syndrome, and insulin resistance has been hypothesized as the common underlying defect. Hyperuricosuria, associated with dehydration or exercise, results in acute uric acid nephropathy, and causes an obstructive acute renal failure (ARF). This reversible ARF can be prevented by forced hydration with bicarbonate or saline solutions. Renal hypouricemia, due to mutations of urate transporter, is a rare cause of exercise-induced ARF. The existence of chronic urate nephropathy, gouty nephropathy, is still under discussion. Uric acid nephrolithiasis results from supersaturation, strongly influenced by low urine pH, rather than altered urate turnover. Alkali and fluid intake prove successful in managing uric acid stones.

Acute Kidney Injury↗

High uric acid and urea clearance in cirrhosis secondary to increased "effective vascular volume".

Since urea and uric acid clearance are affected by the effective intravascular volume, we measured the fractional urea and uric acid excretion in cirrhosis. High urea and uric acid clearances were observed in 30 and 55 percent, respectively, of 20 consecutive cirrhotic patients with normal renal function. In seven patients with a high fractional uric acid excretion, 5 mg of isosorbide dinitrate every four hours for 24 hours induced a significant increase in the serum uric acid level (from 3.7 +/- 0.8 mg/dl to 4.4 +/- 0.8 mg/dl; less than 0.001) with a concomitant decrease in the fractional uric acid excretion (from 14.0 +/- 3.2 percent to 8.8 +/- 3.1 percent; less than 0.02). During the same test, the blood urea level increased from 3.3 +/- 1.1 mmol/liter to 4.1 +/- 1.2 mmol/liter (p less than 0.005) with a decrease in fractional excretion from 51 +/- 4.5 percent to 39 +/- 5 percent (p less than 0.001). The oral intake of sulfinpyrazone in six of these patients induced a normal uricosuric response. In two cirrhotic patients with ascites, 40 mg of furosemide associated with a 24-hour severe water restriction was also shown to normalize the high fractional excretion of both urea and uric acid. In nine patients with ascites, we observed a significant increase in blood urea and uric acid concentration despite the absence of change in creatinine clearance once ascites was removed by diuretics. On the basis of these findings, we believe that the high fractional excretion of both urea and uric acid frequently observed in cirrhosis is related to an increase in the effective vascular volume.

Blood Volume↗

Idiopathic uric acid lithiasis: epidemiologic and metabolic aspects.

Of 264 patients with urolithiasis those with pure uric acid or urate stones were compared to those with other types of calculi for differences in epidemiologic factors and uric acid, calcium and phosphate metabolism. Patients with uric acid stones were predominantly older men. These patients had comparatively lower incomes and spent less money on food but consumed more alcohol. The urinary pH was lower than in the other groups. The absence of abnormally elevated serum uric acid levels and elevated 24-hour urinary uric acid excretion suggests this variety of uric acid lithiasis to be idiopathic in nature. This finding is supported by the results of standardized oral purine loading, which showed no post-loading differences in serum levels and revealed urinary concentrations in 12 patients with pure uric acid stones and 10 normal subjects. However, there is evidence to suggest that this condition may be a precursor of primary gout. Hereditary mechanisms are absent and the relapse rate is the same as in patients with other stones. Therefore, our results suggest the existence of an idiopathic variety of uric acid lithiasis that, at least in central Europe, occurs more frequently than previously assumed. The condition is not inherited, alcohol consumption is a major etiologic factor and there is no evidence of a causative role of abnormalities in purine metabolism.

Age Factors↗