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Serum uric acid concentrations were determined in horses known to be carriers of combined immunodeficiency gene(s) and in presumed noncarrier horses. Uric acid concentrations were significantly higher (P less than 0.005) in carrier horses than in presumed noncarrier horses. However, there was some overlap in serum uric acid concentrations between carrier and presumed noncarrier horses.
Fifteen normal pregnant women were studied. Serial measurements of serum total, free and bound uric acid and their clearances were done in early (10-20 weeks), mid- (20-30 weeks) and advanced (30-40 weeks) pregnancy, and after delivery (4-5 weeks). The following was observed. 1. A decrease in early and mid-pregnancy of total and free uric acid (p less than 0.001). 2. A gradual increase from the early to advanced pregnancy of bound uric acid (p less than 0.001). 3. An increase in early and mid-pregnancy of total uric acid clearance and a similar but more pronounced increase of free uric acid clearance (p less than 0.001). These findings explain many differences in previous conflicting reports concerning the metabolic behavior of uric acid, and place future investigation thereof on a more promising basis in normal and abnormal pregnancy.
Peroxynitrite is implicated in numerous human diseases. Hence, there is considerable interest in potential therapeutic peroxynitrite scavengers. It has been claimed that uric acid is a powerful peroxynitrite scavenger. We previously observed that uric acid is a powerful inhibitor of tyrosine nitration induced by peroxynitrite, but fails to prevent alpha(1)-antiproteinase (alpha(1)-AP) inactivation induced by peroxynitrite. However, the reactivity of peroxynitrite is significantly modified by bicarbonate and this has not been considered in evaluating the scavenging activity of uric acid and other endogenous antioxidant compounds. In the presence of bicarbonate (25 mM), the ability of uric acid, ascorbate, Trolox, and GSH to inhibit peroxynitrite-mediated tyrosine and guanine nitration is decreased. Protection against peroxynitrite-mediated alpha(1)-AP inactivation is also decreased by ascorbate, Trolox, and GSH, but it is enhanced by uric acid. Bicarbonate also inhibits the ability of these compounds to prevent peroxynitrite-mediated ABTS radical cation formation. However, the abilities of these antioxidants to prevent peroxynitrite-mediated bleaching of pyrogallol red are enhanced by bicarbonate. These results show that physiologic concentrations of bicarbonate substantially modify the ability of uric acid to prevent peroxynitrite-mediated reactions. This study highlights the need to use several different assays in the presence of physiologically relevant concentrations of bicarbonate when assessing compounds for peroxynitrite scavenging, in order to avoid misleading results.
1. Four chickens were used in nine successive experiments using a single injection radioisotope dilution technique to study the kinetics of endogenous uric acid and urea metabolism. 2. Starvation lowered uric acid and urea entry rates, but elevated the extent of degradation of these compounds. 3. Urea turnover time and the extent of urea pool degradation were higher, and urea excretion rate was lower than that of uric acid. 4. In colostomised chickens, the extent of uric acid and urea degradation were lower than in non-colostomised birds. 5. The average uric acid and urea entry rates in chickens fed on a diet containing 200 g protein/kg were 7.32 and 2.6 mumol/h g liver, respectively. 6. It is concluded that the contribution of uric acid and urea to the nitrogen economy of the birds is negligible.
A critical survey of the literature suggests that elevated serum uric acid is definitely associated with hypertension and may function as an independent risk factor in the development of this disease. The possible role of an elevated serum uric acid as an independent risk factor for the development of ischemic heart disease remains controversial and the association of these two factors may depend on the relationship between uric acid and hypertension. There is no evidence available to define the metabolic turnover of uric acid in hypertensives. The exact mechanisms underlying elevated serum uric acid values during diuretic treatment are unclear, but depend initially upon diuretic-induced extracellular volume depletion.
In 50 type-1 and 50 type-2 diabetic patients serum uric acid levels were measured. Type-1 diabetics showed significantly lower serum uric acid levels in comparison to type-2 diabetics (p < 0.02). This significant difference has been observed in both women (p < 0.001) and men (p < 0.01). Serum uric acid level was lower in type-1 diabetics than in healthy controls but only in diabetic men the difference was statistically significant (p < 0.001). Male type-2 diabetic patients showed serum uric acid levels similar to the controls, but levels were higher in women with type-2 diabetes (p < 0.001). The results of this study show that in type-1 diabetic patients the serum uric acid levels are lower in normal (creatinine clearance > or = 80 ml/min) as well as in slightly decreased (creatinine clearance < 80 ml/min) glomerular filtration rate. But in type-2 diabetic patients the serum uric acid levels were significantly higher when glomerular filtration rate was below 80 ml/min in contrast to normal renal function (p < 0.05).
Although hyperuricemia is a well-known adverse effect of cyclosporine (CsA) treatment, there are contradictory data regarding the effect of tacrolimus on uric acid levels. The aim of this study was to examine the influences of CsA and tacrolimus-based treatment regimens on serum uric acid levels in 155 renal transplant recipients with normal allograft function who underwent renal transplantation between 1999 and 2002. Serum uric acid levels were recorded at 1, 6, 12, 18, and 24 months follow-up. The patients were treated with CsA-based (n = 73), tacrolimus-based (n = 47), or conversion from CsA-based to tacrolimus-based (n = 35) immunosuppressive regimens. Serum uric acid levels for patients in the CsA and tacrolimus groups were 6.3 +/- 1.6 versus 7.9 +/- 1.9 mg/dL and 6.5 +/- 1.8 versus 8.0 +/- 1.8 mg/dL at the study outset and 24 months, respectively. Both of the treatment regimens showed progressively increasing serum uric acid levels (P < .001). Serum uric acid levels of patients with treatment conversion from CsA to tacrolimus were 8.6 +/- 2.8 mg/dL before conversion and 8.1 +/- 1.9 mg/dL after conversion. There was no alteration in serum uric acid levels after the change of treatment (P > .05). These findings indicate that, compared with CsA, tacrolimus offers no advantage for serum uric acid levels in renal transplant recipients.
Experimental evidence supports a causative role for uric acid in the pathogenesis of hypertension. Prospective studies have variably adjusted for relevant confounders and have been of relatively limited duration. We prospectively examined the relationship between uric acid level and the development of hypertension in the Normative Aging Study, a longitudinal cohort of healthy adult men. Of the 2280 initial men in the Normative Aging Study, 2062 had available information for inclusion in the analysis. Cox proportional hazards model was used to examine the relationship between baseline serum uric acid level and the development of hypertension adjusting for age, body mass index, abdominal circumference, smoking, alcohol, plasma triglycerides, total cholesterol, and plasma glucose. A total of 892 men developed hypertension over a mean of 21.5 years of follow-up. Serum uric acid level independently predicted the development of hypertension in age-adjusted (relative risk [RR]: 1.10; 95% CI: 1.06 to 1.15: P<0.001) and multivariable (RR: 1.05; 95% CI: 1.01 to 1.10; P=0.02) models. Among 1277 men at risk for the development of hypertension at the time of their first serum creatinine measurement, 508 (39.8%) developed hypertension over a mean of 10.3+/-5.5 years of follow-up. Additionally adjusting for calculated glomerular filtration rate in this subset, serum uric acid remained associated with the development of hypertension (RR: 1.06; 95% CI: 1.01 to 1.12; P=0.03). The baseline serum uric acid level is a durable marker of risk for the development of hypertension. The association is independent of elements of the metabolic syndrome, alcohol intake, and renal function.
Independent from sex, the concentration of uric acid in serum decreases slowly in normal individuals from 55--58 years on. The older is an individual, the lower is the concentration of uric acid. This phenomenon is the consequence of a restriction of the synthesis of nucleic acids, parallel to ageing. Results suggests that the concentration of uric acids can be considered to be parameters of ageing.
OBJECTIVE: Homocysteine increases the damage to the cardiovascular system in different ways, one of them is the formation of reactive oxygen species resulting from the auto-oxidation of homocysteine. At the same time, uric acid is one of the major antioxidants in the plasma and protects the cells towards increased ROS activity. In humans, allantoin is only formed from non-enzymatic oxidation of uric acid by free radicals. We aimed to determine the levels of homocysteine, uric acid and allontoin in patients with coronary artery diseases, and to evaluate the possible correlation between homocysteine and allantoin. METHODS AND RESULTS: Plasma total homocysteine, uric acid and allantoin levels of 50 patients with coronary artery diseases and 23 healthy controls were determined by HPLC methods. Commercial diagnostic kits were used for the determination of other biochemical parameters. We obtained higher homocysteine, uric acid and allantoin levels in patients than in controls (p < 0.0001). Homocysteine levels were positively correlated with uric acid (r = 0.435, p < 0.0001) and allantoin (r = 0.583, p < 0.0001) levels in the whole study population. This correlation was persistent between allantoin and homocysteine after adjustment of these parameters for age, sex and creatinine. We accepted 15.0 micromol/l as a cut-off value between normal and mildly elevated homocysteine levels for patients and controls. Twenty-five patients showed moderate hyperhomocysteinaemia. The mean allantoin and uric acid values of the moderate hyperhomocysteinaemic group were significantly higher than that of the group having lower homocysteine levels than this cut-off value (p < 0.0001 for allantoin, p < 0.02 for uric acid). CONCLUSION: Results imply that there is increased allantoin production resulting from uric acid oxidation by free radicals in hyperhomocysteinaemic patients with coronary artery disease. The possible significance of the relationship between homocysteine and allantoin warrants further study.
Although hyperuricemia has long been associated with renal disease, uric acid has not been considered as a true mediator of progression of renal disease. The observation that hyperuricemia commonly is associated with other risk factors of cardiovascular and renal disease, especially hypertension, has made it difficult to dissect the effect of uric acid itself. However, recent epidemiologic evidence suggests a significant and independent association between the level of serum uric acid and renal disease progression with beneficial effect of decreasing uric acid levels. Furthermore, our experimental data using hyperuricemic animals and cultured cells have provided robust evidence regarding the role of uric acid on progression of renal disease. Hyperuricemia increased systemic blood pressure, proteinuria, renal dysfunction, vascular disease, and progressive renal scarring in rats. Recent data also suggest hyperuricemia may be one of the key and previously unknown mechanisms for the activation of the renin-angiotensin and cyclooxygenase-2 (COX-2) systems in progressive renal disease. Although we must be cautious in the interpretation of animal models to human disease, these studies provide a mechanism to explain epidemiologic data that show uric acid is an independent risk factor for renal progression. Although there is no concrete evidence yet that uric acid bears a causal or reversible relationship to progressive renal disease in humans, it is time to reevaluate the implication of hyperuricemia as an important player for progression of renal disease and to try to find safe and reasonable therapeutic modalities in individual patients based on their clinical data, medication history, and the presence of cardiovascular complications.
Birds resemble man in that both lack uricase and therefore uric acid (urate) is the end product of purine metabolism in both animals. Although urate is largely excreted by the kidneys in both species, it has generally been accepted that the renal handling of urate in the chicken differs from that in man in that drugs which are known to be uricosuric in man do not produce a uricosuric response in birds. This suggests that tubular reabsorption of urate is either minimal or lacking in birds. The present study used the in vivo Sperber chicken technique to investigate the acute effects of diuretics which are known to alter urate clearance in man. Our results show that both ethacrynic acid and furosemide can selectively increase the apparent tubular excretion of [14C]urate, suggesting that the chicken kidney is capable of reabsorbing urate. Chlorothiazide is known to decrease urate clearance in both man and the chicken and was found in this study also to decrease the renal tubular excretion of [14C]urate formed within the chicken kidney during infusion of [14C]hypoxanthine or [14C]guanine.
A method for the flow injection analysis of glucose and uric acid in serum using immobilized enzymes in column form and chemiluminescence detection is described. The method is based on the determination of chemiluminescence formed by the reaction of a luminol-ferricyanide mixture with hydrogen peroxide which is produced by the action of the respective oxidases on glucose and uric acid. Glucose or uric acid in serum were determined with 1 microliter of the sample at a speed of 120 samples/h without carryover and at an assay time of approximately 10 s. The immobilized glucose oxidase column measured only 1.0 X 5 mm, and the immobilized uricase column 1.0 X 20 mm. The present method gave perfect linearity of the data up to 4.0 g glucose per liter or 0.10 g uric acid per liter with satisfactory precision, reproducibility, and accurate reaction recoveries. Furthermore, the present method was hardly affected by ascorbic acid, while the peroxidase-linked colorimetric method is usually influenced significantly by ascorbic acid. Both column reactors showed good operational stability for a 2-month period, during which time they were repeatedly used for analyses over 2000 times. The results on glucose and uric acid correlated satisfactorily with those obtained by other well-established methods.
The inhibition of xanthine oxidase by its reaction product, uric acid, was studied by steady state kinetic analysis. Uric acid behaved as an uncompetitive inhibitor of xanthine oxidase with respect to the reducing substrate, xanthine. Under 50 microM xanthine and 210 microM oxygen, the apparent K(i) for uric acid was 70 microM. Uric acid-mediated xanthine oxidase inhibition also caused an increase in the percentage of univalent reoxidation of the enzyme (superoxide radical production). Steady-state rate equations derived by the King-Altman method support the formation of an abortive-inhibitory enzyme-uric acid complex (dead-end product inhibition). Alternatively, inhibition could also depend on the reversibility of the classical ping-pong mechanism present in xanthine oxidase-catalyzed reactions.
OBJECTIVE: To investigate the incidence of gout and the interaction between uric acid level and other risk factors in the development of gout. METHODS: Two hundred twenty-three asymptomatic hyperuricemic men initially studied in 1991-92 were reassessed in 1996-97. Gout was clinically diagnosed by a senior rheumatologist based on history and physical according to the clinical criteria of Wallace. Basic demographic and lifestyle variables as well as biochemical data were collected in both baseline and followup periods. Both the stability analysis and the analysis of repeated relationships were applied. RESULTS: The 5-year cumulative incidence of gout was 18.83% (42/223). The risk factors for gout based on the analysis of repeated relationships were uric acid level, alcohol consumption, use of diuretics, and obesity. The only predictor of gout at baseline was uric acid level. After adjusting for baseline uric acid level, followup uric acid increase, persistent alcohol consumption, use of diuretics in the followup period, and body mass index increase were independent predictors for gout among asymptomatic hyperuricemic men. Excessive alcohol consumption, particularly if occasional, was the most important factor in the development of gout, even when the concentration of uric acid level was below 8 mg/dl. CONCLUSION: Uric acid level is the key factor for prevention of gout and needs constant monitoring. Other contributing or possible etiologic factors such as alcohol consumption, diuretics use, and excess weight gain carry an increased risk of gout attack among patients with hyperuricemia.
We have isolated and identified nine cultures of aerobic bacteria capable of growing on an elective medium containing uric acid as the only source of carbon, nitrogen, and energy. Four of these cultures were identified as Aerobacter aerogenes, two as Klebsiella pneumoniae, and the remainder as Serratia killiensis, Pseudomonas aeruginosa, and Bacillus species. Another culture identified as P. fluorescens required both glucose and uric acid for growth. When 23 laboratory stock cultures were inoculated into the uric acid medium, A. aerogenes, B. subtilis, Mycobacterium phlei, P. aeruginosa, and S. marcescens were able to grow. These five cultures also grew when the uric acid was replaced with adenine, guanine, hypoxanthine, xanthine, or allantoin, but growth was poor. In all of these media, including the uric acid medium, addition of glucose along with the nitrogenous compounds yielded good growth. Induction experiments demonstrated that the ability of A. aerogenes, K. pneumoniae, P. aeruginosa, P. fluorescens, S. kiliensis, S. marcescens, B. subtilis, and Bacillus sp. to degrade uric acid is an induced property. Of these organisms, only Bacillus sp. accumulated a small amount of intracellular uric acid.
Hyperuricemia is associated with renal disease, but it is usually considered a marker of renal dysfunction rather than a risk factor for progression. Recent studies have reported that mild hyperuricemia in normal rats induced by the uricase inhibitor, oxonic acid (OA), results in hypertension, intrarenal vascular disease, and renal injury. This led to the hypothesis that uric acid may contribute to progressive renal disease. To examine the effect of hyperuricemia on renal disease progression, rats were fed 2% OA for 6 wk after 5/6 remnant kidney (RK) surgery with or without the xanthine oxidase inhibitor, allopurinol, or the uricosuric agent, benziodarone. Renal function and histologic studies were performed at 6 wk. Given observations that uric acid induces vascular disease, the effect of uric acid on vascular smooth muscle cells in culture was also examined. RK rats developed transient hyperuricemia (2.7 mg/dl at week 2), but then levels returned to baseline by week 6 (1.4 mg/dl). In contrast, RK+OA rats developed higher and more persistent hyperuricemia (6 wk, 3.2 mg/dl). Hyperuricemic rats demonstrated higher BP, greater proteinuria, and higher serum creatinine than RK rats. Hyperuricemic RK rats had more renal hypertrophy and greater glomerulosclerosis (24.2 +/- 2.5 versus 17.5 +/- 3.4%; P < 0.05) and interstitial fibrosis (1.89 +/- 0.45 versus 1.52 +/- 0.47; P < 0.05). Hyperuricemic rats developed vascular disease consisting of thickening of the preglomerular arteries with smooth muscle cell proliferation; these changes were significantly more severe than a historical RK group with similar BP. Allopurinol significantly reduced uric acid levels and blocked the renal functional and histologic changes. Benziodarone reduced uric acid levels less effectively and only partially improved BP and renal function, with minimal effect on the vascular changes. To better understand the mechanism for the vascular disease, the expression of COX-2 and renin were examined. Hyperuricemic rats showed increased renal renin and COX-2 expression, the latter especially in preglomerular arterial vessels. In in vitro studies, cultured vascular smooth muscle cells incubated with uric acid also generated COX-2 with time-dependent proliferation, which was prevented by either a COX-2 or TXA-2 receptor inhibitor. Hyperuricemia accelerates renal progression in the RK model via a mechanism linked to high systemic BP and COX-2-mediated, thromboxane-induced vascular disease. These studies provide direct evidence that uric acid may be a true mediator of renal disease and progression.
The present study was undertaken to investigate the effect of theophylline on serum uric acid and then to elucidate the mechanisms of action of theophylline as a cause of hyperuricemia. There was a significant increase of serum uric acid levels in male asthmatic patients who received theophylline compared to male control subjects without theophylline (6.3 +/- 0.4 mg/ml, mean +/- SEM, versus 4.3 +/- 0.2 mg/ml, p less than 0.01). A significant correlation of serum levels of uric acid and theophylline was demonstrated in asthmatic patients who received 200 to 400 mg sustained-release theophylline (male group, r = 0.480, p less than 0.001; female group, r = 0.398, p less than 0.01). Intravenous administration of aminophylline in three healthy adult male patients did not inhibit uric acid clearance, suggesting that inhibition of excretion of uric acid by theophylline is unlikely. Theophylline slightly inhibited hypoxanthine guanine phosphoribosyltransferase activity in human erythrocyte lysates at concentrations over 5 mM that is considerably more than therapeutic concentrations of theophylline as determined by the conversion of [14C]hypoxanthine to [14C]inosinic acid. Theophylline caused a moderate inhibition of [14C]hypoxanthine uptake by K-562 cells (approximately 50%) at 10mM that is over 100 times as high as those achieved clinically. Further studies remain to be performed to elucidate the exact mechanisms of theophylline-induced hyperuricemia.