Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018099 (gout)
 5,192 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Urate is the major inert end product of purine degradation in higher primates in contrast to most other mammals because of the genetic silencing of hepatic oxidative enzyme uricase. The kidney plays a dominant role in urate elimination. The kidney excretes 70% of the daily urate production. Therefore, it is important to understand renal urate handling mechanism because the under excretion of urate has been implicated in the development of hyperuricemia that leads to gout. The urate transport systems exist in the proximal tubule but they are complicated because of their bidirectional transport and the species differences. Recently, we have identified the urate-anion exchanger URAT1 (SLC22A12) in the human kidney and found that defects in SLC22A12 lead to idiopathic renal hypouricemia. URAT1 is targeted by uricosuric and antiuricosuric agents that affect urate excretion. Molecular identification of urate transporting proteins will lead to the new drug development for hyperuricemia.
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PMID:Renal urate handling: clinical relevance of recent advances. 1591

Uric acid might often be regarded as a simple marker of renal disease. Although it is well known that hyperuricemia causes gout which is associated with renal insufficiency and cardiovascular disease, one might think that it could attribute to the intrarenal urate crystal, but not to uric acid per se. In order to clarify the role of uric acid in the kidney, we hypothesized that uric acid causes renal disease. To generate mild hyperuricemia without intrarenal crystal in rats, we used low doses of an uricase inhibitor (2% oxonic acid). Hyperuricemia induced systemic hypertension, glomerular hypertrophy/hypertension, afferent arteriolar sclerosis, and macrophage infiltration in normal rat kidney. In progressive renal disease, such as cyclosporine nephropathy and remnant kidney in rat, uric acid accelerated the progression of renal disease. Thus, we concluded that uric acid is not a simple marker, but a cause of renal disease.
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PMID:Uric acid--a uremic toxin? 1636 44

The connection of gout and hyperuricaemia with gluttony, overindulgence in food and alcohol and obesity dates from ancient times. Studies from different parts of the world suggest that the incidence and severity of hyperuricaemia and gout may be increasing. Uric acid (urate) is the end product of purine degradation. Although most uric acid is derived from the metabolism of endogenous purine, eating foods rich in purines contributes to the total pool of uric acid. Sustained hyperuricaemia is a risk factor for acute gouty arthritis, chronic tophaceous gout, renal stones and possibly cardiovascular events and mortality. Before starting lifelong urate-lowering drug therapy, it is important to identify and treat underlying disorders that may be contributing to hyperuricaemia. It is relevant to recognize the strong association of the insulin resistance syndrome (IRS) (abdominal obesity, dyslipidaemia, hypertension, raised serum insulin levels and glucose intolerance) with hyperuricaemia. Consumption of meat, seafood and alcoholic beverages in moderation and attention to food portion size is important. Moderation in the consumption of not only beer but also other forms of alcohol is essential. In the obese, controlled weight management has the potential to lower serum urate in a quantitatively similar way to relatively unpalatable "low purine" diets. Non-fat milk and low-fat yogurt have a variety of health benefits and dairy products may have clinically meaningful antihyperuricaemic effects. In addition, fruits, such as cherries and high intakes of vegetable protein diet may reduce serum urate levels.
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PMID:Dietary factors and hyperuricaemia. 1637 34

Uric acid, the naturally occurring degradation product of purine metabolism, is a danger signal, driving maturation of dendritic cells. It is well known that uric acid crystals display potent proinflammatory properties--the cause of gout--whereas the biological properties of soluble uric acid are less well documented. We have demonstrated previously that nucleic acids of endogenous and exogenous origin display proinflammatory properties. The aim of the present study was to assess the impact of soluble uric acid on in vivo inflammatory responses. Mice were administered with uric acid suspension in saline or saline alone prior to induction of neutrophil-mediated inflammation, delayed-type hypersensitivity, histamin-induced edema (measure of vasodilation capacity), as well as double-stranded (ds)RNA-triggered arthritis. Frequency and severity of arthritis were decreased significantly in mice exposed to dsRNA and simultaneously treated with uric acid as compared with saline-treated controls. Also, granulocyte-mediated inflammatory response and vasodilation capacity were reduced significantly in mice treated with uric acid as compared with their control group. The data suggest that down-regulation of inflammation was mediated by skewing the inflammatory response from the peripheral sites to the peritoneal cavity and down-regulating vasodilatatory capacity and thereby affecting leukocyte migration. In contrast, the T cell-mediated delayed-type hypersensitivity reaction was not affected significantly in mice exposed to uric acid. These findings demonstrate that uric acid displays a potent, distant anti-inflammatory effect in vivo. This property seems to be mediated by down-regulation of neutrophil influx to the site of inflammatory insult.
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PMID:Uric acid, a nucleic acid degradation product, down-regulates dsRNA-triggered arthritis. 1638 38

Mammals that degrade uric acid are not affected by gout or urate kidney stones. It is not fully understood how they convert uric acid into the much more soluble allantoin. Until recently, it had long been thought that urate oxidase was the only enzyme responsible for this conversion. However, detailed studies of the mechanism and regiochemistry of urate oxidation have called this assumption into question, suggesting the existence of other distinct enzymatic activities. Through phylogenetic genome comparison, we identify here two genes that share with urate oxidase a common history of loss or gain events. We show that the two proteins encoded by mouse genes catalyze two consecutive steps following urate oxidation to 5-hydroxyisourate (HIU): hydrolysis of HIU to give 2-oxo-4-hydroxy-4-carboxy-5-ureidoimidazoline (OHCU) and decarboxylation of OHCU to give S-(+)-allantoin. Urate oxidation produces racemic allantoin on a time scale of hours, whereas the full enzymatic complement produces dextrorotatory allantoin on a time scale of seconds. The use of these enzymes in association with urate oxidase could improve the therapy of hyperuricemia.
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PMID:Completing the uric acid degradation pathway through phylogenetic comparison of whole genomes. 1648

Hyperuricemia is common after renal and cardiac transplantations, but it is rarely reported after liver transplantations. The aim of this study is to determine the frequency of hyperuricemia in children following orthotopic liver transplantation and the effects of calcineurin inhibitors tacrolimus and cyclosporine) on blood uric acid levels. Between September 1997 to January 2004, 76 liver transplantations were performed in 70 children (male/female; 39/31) at Ege University, Organ Transplantation Center (37 deceased donation and 39 live donors). Patients who had been transplanted within the last three months and patients who died within six months after liver transplantation were excluded from the study. Finally 59 patients were included in this study. Uric acid levels were measured before transplantation and after transplantation within six months intervals for two yr. In these series 17 cases had increased uric acid levels after liver transplantation (28.8%). Serum uric acid levels in both groups (tacrolimus or cyclosporine) were detected to be significantly higher than initial values at 12th months (p < 0.05). Hyperuricemia developed in eight patients receiving cyclosporine (eight of 11; 72%) whereas nine patients receiving tacrolimus developed hyperuricemia (nine of 48; 18%). However, the rate of having high uric acid levels was significantly higher in cyclosporine group compared tacrolimus group (p = 0.001, OR: 11.5, CI 95% 2.5-52.4). Uric acid levels were also significantly higher in cyclosporine group in 12th and 18th months (respectively, p = 0.003 and p = 0.003). Serum creatinine levels at 12th, 18th and 24th months were significantly higher in cyclosporine group than tacrolimus group (respectively, p = 0.009, p = 0.04 and p = 0.02). Hyperuricemia is a common complication after liver transplantation in children. Cyclosporine may cause hyperuricemia more often in respect to tacrolimus and this may be related to the impairment of renal functions. Complications developing because of hyperuricemia such as gout disease or renal calculi are quite rare in children.
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PMID:Frequency of hyperuricemia and effect of calcineurin inhibitors on serum uric acid levels in liver transplanted children. 1691 88

Gout is a chronic metabolic disease caused by a disorder of the purine metabolism leading to hyperuricaemia. It is determined by the deposition of monosodium urate crystals in joints and other tissues which causes an acute inflammatory response and can induce a permanent tissue damage which defines the urate chronic joint disease which is characterised by the appearance of ulceration of the joint cartilage, marginal osteophytosis, geodic and erosive lesions and chronic inflammation of synovial membrane. Gout and hyperuricaemia usually occur after the age of 30 years and more frequently in men. Hyperuricaemia is the result of an increased production of uric acid or its hypoexcretion by the kidneys, or both. In the pathogenesis of gout and hyperuricaemia are involved genetic and environmental factors; further, different pathologic condition such as glycogenosis, renal insufficiency, use of some drugs, are associated with gout. Treatment of acute gout includes colchicine, nonsteroidal anti-inflammatory drugs and glucocorticoids, whereas in the intercritical periods colchicine is effective for preventive purposes. Urate-lowering therapy with xanthine-oxidase inhibitors or uricosuric agents is indicate only in patients with more than two gout crisis per year, tophaceous deposits, uric acid nephrolithiasis, and interstitial renal disease, as asymptomatic hyperuricaemia does not requires any treatment but can be controlled with preventive dietetic measures and changes in lifestyle.
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PMID:Pathogenesis, clinical findings and management of acute and chronic gout. 1721 86

Gout, a common inflammatory arthritis, can be diagnosed with absolute certainty. Gout results from the body's reaction to urate crystals deposited in tissues, and this pathophysiology is well understood. If used appropriately, available therapies can be entirely effective in not only treating the symptoms of gout, but also in eliminating the excess urate from the body, thereby eradicating the disease. Because of these facts, management of patients with gout should be successful. However, management of gout is particularly challenging in the elderly, even though the principles of management are the same for all age groups. The purpose of this article is to review these principles and discuss them as they pertain to the elderly. The classic gout attack is acute in onset, extremely painful and associated with marked swelling, warmth, erythema and tenderness of a single joint. However, the diagnosis of gout may be challenging in the elderly because atypical presentations are more common in this group. Treatment of acute gout involves the use of NSAIDs, colchicine, corticosteroids or corticotropin (adrenocorticotropic hormone). Unfortunately, co-morbid conditions such as chronic kidney disease, peptic ulcer disease and congestive heart failure may make the use of these agents dangerous or contraindicated. Thus, it is important to try to treat an acute flare of gout at the earliest sign, because the sooner treatment is initiated, the faster the inflammation will resolve. Urate-lowering agents include allopurinol and uricosuric agents. These also must be used judiciously in the elderly. However, if used at the lowest dose that maintains the serum urate level below 5.0-6.0 mg/dL, the excess urate in the body will be eliminated, acute flares will no longer occur and tophi will resolve. Gout is often seen in association with hypertension, excessive alcohol consumption, obesity and hypertriglyceridaemia. These conditions and the medications used to treat them may contribute to the hyperuricaemia. Treating these conditions and using medications that do not promote hyperuricaemia will aid in the management of gout. Despite the challenges that often complicate the management of gout in the elderly, an understanding of the pathophysiology of the disease and both the indications and limitations of the medications used should allow successful treatment.
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PMID:Management of gout in older adults: barriers to optimal control. 1723 45

Uric acid is the end-product of purine catabolism. Hyperuricaemia is implicated in disorders such as gout and urolithiasis and recent epidemiological evidence suggests an association between increasing uric acid levels and increased cardiovascular morbidity and mortality. A direct causal role remains to be established but recent studies of losartan, atorvastatin and fenofibrate suggest that uric acid reduction contributes to attenuation of cardiovascular risk. Furthermore, several small studies of xanthine oxidase inhibition (the most common method of uric acid reduction) have shown improvements in measures of cardiovascular and endothelial function of a similar magnitude to those of other proven preventative strategies. This review introduces the epidemiological data, discusses strategies to lower uric acid and outlines the available clinical trial data supporting uric acid reduction as a potential and novel method of reducing the burden of cardiovascular disease.
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PMID:Uric acid reduction: a new paradigm in the management of cardiovascular risk? 1762 23

Uric acid is an important diagnostic marker of catabolism of the purine nucleosides, and accurate measurements of serum uric acid are necessary for proper diagnosis of gout or renal disease appearance. A candidate reference method involving isotope dilution coupled with liquid chromatography/mass spectrometry (LC/MS) has been described. An isotopically labeled internal standard, [1,3-(15)N(2)] uric acid, was added to serum, followed by equilibration and protein removal clean up to prepare samples for liquid chromatography/mass spectrometry electrospray ionization (LC/MS-ESI) analyses. (M-H)(-) ions at m/z 167 and 169 for uric acid and its labeled internal standard were monitored for LC/MS. The accuracy of the measurement was evaluated by a comparison of results of this candidate reference method on lyophilized human serum reference materials for uric acid (Standard Reference Materials SRM909b) with the certified values determined by gas chromatography/mass spectrometry reference methods and by a recovery study for the added uric acid. The method performed well against the established reference method of ion-exchange followed by derivatization isotope dilution (ID) gas chromatography mass spectrometry (ID-GC/MS). The results of this method for uric acid agreed well with the certified values and were within 0.10%. The amounts of uric acid recovered and added were in good agreement for the three concentrations. This method was applied to determine uric acid in samples of frozen serum pools. Excellent precision was obtained with within-set CVs of 0.08-0.18% and between-set CVs of 0.02-0.07% for LC/MS analyses. Liquid chromatography/tandem mass spectrometry electrospray ionization (LC/MS/MS-ESI) analysis was also performed. The LC/MS and LC/MS/MS results were in very good agreement (within 0.14%). This LC/MS method, which demonstrates good accuracy and precision, and is in the speed of analysis without the need for a derivatization stage, qualifies as a candidate reference method. This method can be used as an alternative reference method to provide an accuracy base to which the routine methods can be compared.
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PMID:Determination of serum uric acid using high-performance liquid chromatography (HPLC)/isotope dilution mass spectrometry (ID-MS) as a candidate reference method. 1770 12


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