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The pathophysiology of hyperuricemia in essential hypertension: a pilot study.

We have examined whether hyperuricemia in essential hypertension may be related to an increased insulin secretion thereby enhancing the tubular reabsorption of sodium and thus uric acid. Insulin hypersecretion, as elicited by the oral glucose tolerance test (OGTT), increased a mean of 5-fold in 12 essential hypertensive patients. Urinary uric acid to creatinine ratio significantly diminished by a mean of 62% after the OGTT. Simultaneously, urinary sodium to creatinine ratio decreased by a mean of 54%. These results suggest that insulin may mediate uric acid underexcretion due to its tubular sodium retaining effect in essential hypertensive patients.

Adult↗

Recent advances in the management of gout and hyperuricemia.

PURPOSE OF REVIEW: To review the recent advances in the management of gout and hyperuricemia. RECENT FINDINGS: The first quality indicators for gout management have been proposed. Selective COX II inhibitors, as well as traditional NSAIDs, are effective in acute gout. A new xanthine oxidase inhibitor, febuxostat, and pegylated uricases are in clinical trials. SUMMARY: The therapeutic aims in gout include termination of the acute attack as promptly and gently as possible, prevention of future attacks, prevention or reversal of complications of the, and prevention or reversal of associated features such as obesity, hypertriglyceridemia, hypertension, or alcoholism.

Gout↗

Marked hyperuricemia with acute renal failure: need to consider occult malignancy and spontaneous tumour lysis syndrome.

Spontaneous tumour lysis syndrome (TLS) is an extremely uncommon cause for acute renal failure (ARF). ARF presenting with hyperkalemia, hyperuricemia and hyperphosphatemia should lead to further work up for occult haematological malignancy. We describe two cases of lymphoma presenting with ARF secondary to spontaneous TLS. The ARF in the first case appeared to be due to intravenous volume depletion but eventually lead to the diagnosis of gastric lymphoma. The second patient is interesting as he is probably the first reported case of lymphoma with HIV infection presenting as spontaneous TLS. Early diagnosis and prompt renal replacement therapy does not necessarily reverse the ARF.

Acute Kidney Injury↗

Effects of acute and chronic L-arginine treatment in experimental hyperuricemia.

Experimental hyperuricemia (HU) results in preglomerular arteriolopathy, cortical vasoconstriction, and glomerular hypertension. Recently, uric acid has been shown to induce endothelial dysfunction. We therefore studied the effect of acute and chronic administration of l-arginine (a substrate for endothelial nitric oxide synthase) on the renal hemodynamic and vascular structural alterations induced by HU. To induce HU, oxonic acid (OA; 750 mg.kg(-1).day(-1)) was administered in male Sprague-Dawley rats. To study the acute effect of arginine, nine rats received l-arginine (l-Arg; 15 mg.kg(-1).min(-1)) during micropuncture. To elucidate the chronic effect of l-Arg, OA + 1% l-Arg (n = 8) and OA + 2.5% l-Arg (n = 6; drinking water) were evaluated throughout the 5-wk period. Eight normal control (N), and eight OA, rats were also studied. Kidneys were fixed by perfusion and afferent arteriole morphology was evaluated. HU rats developed the renal functional and structural alterations described and had suppressed urinary excretion of NO(2)(-)/NO(3)(-). Acute stimulation of nitric oxide (NO) synthesis markedly increased urinary NO(2)(-)/NO(3)(-), lowered systemic blood pressure, and relieved cortical vasoconstriction despite a significant increment of glomerular hypertension and afferent arteriole damage. Increasing doses of chronic l-Arg were associated with increasing excretion of urinary NO(2)(-)/NO(3)(-), reduction of systemic hypertension, and prevention of cortical vasoconstriction (2.5% l-Arg). In addition, both doses prevented glomerular hypertension and preglomerular arteriolopathy. Thus an acute relief of renal vasoconstriction in the setting of afferent arteriole damage cannot reverse glomerular hypertension, likely due to impairment in preglomerular autoregulation. On the other hand, chronic l-Arg preserved arteriolar structures probably mediated by the antiproliferative effect of NO on vascular smooth muscle cells.

Animals↗

Pharmacology of drugs for hyperuricemia. Mechanisms, kinetics and interactions.

The pharmacological profile of drugs for hyperuricemia is reviewed. These agents may reduce the amount of uric acid in blood by means of two different ways: (1) by reducing uric acid production through the inhibition of the enzyme xanthine oxidase (as allopurinol); (2) by increasing uric acid clearance through an inhibition of its renal tubular reabsorption (as probenecid), or through its metabolic conversion to a more soluble compound (as urate oxidase). Allopurinol is rapidly converted in the body to the active metabolite oxypurinol whose total body exposure may be 20-fold greater than that of the parent compound due to a much longer elimination half-life. Allopurinol undergoes several pharmacokinetic interactions with concomitant administered drugs, some of which may be potentially hazardous (especially with mercaptopurine and azathioprine). Probenecid is an uricosuric agent which undergoes extensive hepatic metabolism and whose elimination after high doses may become dose dependent. It may inhibit renal tubular secretion of several coadministered agents, including methotrexate and sulphonylureas. Rasburicase is a recombinant form of the enzyme urate oxidase which catalyzes the conversion of uric acid to the more soluble compound allantoin. Unlike allopurinol, it does not promote accumulation of hypoxanthine and xanthine in plasma, thus preventing the risk of xanthine nephropathy. Rasburicase showed no significant accumulation in children after administration of either 0.15 or 0.20 mg/kg/daily for 5 days. Rasburicase probably undergoes peptide hydrolysis and in in vitro studies was shown neither to inhibit or induce cytochrome P450 isoenzymes nor to interact with several drugs, so that no relevant interaction is expected during cotreatment in patients.

Allopurinol↗

Intensive chemotherapy in patients with lymphoma. Management of the risk of hyperuricemia.

Intensive chemotherapy with stem cell autograft is a well-established salvage treatment for relapsed/refractory lymphoma patients aged less than 65 years and it is also an effective treatment option for high-risk patients at diagnosis. Clinical applicability of autograft has been greatly amplified by the use of peripheral blood progenitor cells (PBPC), whose administration is simple and feasible, and results in lower toxicity. In addition, the development of several prophylactic measures preventing extrahemopoietic toxicities has markedly improved the feasibility and tolerability of the approach. In particular, the risk of nephrotoxicity is no more a major problem in the autograft setting since the use of proper treatments for the management of hyperuricemia, including forced hydration along with urinary alkalinization and the administration of the recombinant urate oxidase drug rasburicase. The high-dose sequential (HDS) chemotherapy program is a typical example of an intensive chemotherapy with PBPC autograft. A 15-year experience with the HDS approach in 240 lymphoma patients is reported here. The results demonstrate the clinical efficacy of HDS, with prolonged survival both in relapsed/refractory patients (54% alive) and in those treated frontline (72% alive). In addition, a very low incidence of extrahemopoietic toxicities was observed. In particular, nephrotoxicity was almost abolished, with 2 patients displaying only mild and transient renal dysfunction. In conclusion, the reported results demonstrate the therapeutic efficacy of HDS in the treatment strategy for lymphoma and emphasize the importance of delivering intensive chemotherapy with all the prophylactic measures able to minimize nephrotoxicity and other potential extrahemopoietic toxicities.

Adolescent↗

Control of hyperuricemia in subjects with refractory gout, and induction of antibody against poly(ethylene glycol) (PEG), in a phase I trial of subcutaneous PEGylated urate oxidase.

PEG-modified recombinant mammalian urate oxidase (PEG-uricase) is being developed as a treatment for patients with chronic gout who are intolerant of, or refractory to, available therapy for controlling hyperuricemia. In an open-label phase I trial, single subcutaneous injections of PEG-uricase (4 to 24 mg) were administered to 13 such subjects (11 had tophaceous gout), whose plasma uric acid concentration (pUAc) was 11.3 +/- 2.1 mg/dl (mean +/- SD). By day seven after injection of PEG-uricase, pUAc had declined by an average of 7.9 mg/dl and had normalized in 11 subjects, whose mean pUAc decreased to 2.8 +/- 2.2 mg/dl. At doses of 8, 12, and 24 mg, the mean pUAc at 21 days after injection remained no more than 6 mg/dl. In eight subjects, plasma uricase activity was still measurable at 21 days after injection (half-life 10.5 to 19.9 days). In the other five subjects, plasma uricase activity could not be detected beyond ten days after injection; this was associated with the appearance of relatively low-titer IgM and IgG antibodies against PEG-uricase. Unexpectedly, these antibodies were directed against PEG itself rather than the uricase protein. Three PEG antibody-positive subjects had injection-site reactions at 8 to 9 days after injection. Gout flares in six subjects were the only other significant adverse reactions, and PEG-uricase was otherwise well tolerated. A prolonged circulating life and the ability to normalize plasma uric acid in markedly hyperuricemic subjects suggest that PEG-uricase could be effective in depleting expanded tissue stores of uric acid in subjects with chronic or tophaceous gout. The development of anti-PEG antibodies, which may limit efficacy in some patients, is contrary to the general assumption that PEG is non-immunogenic. PEG immunogenicity deserves further investigation, because it has potential implications for other PEGylated therapeutic agents in clinical use.

Adult↗

A concise history of gout and hyperuricemia and their treatment.

First identified by the Egyptians in 2640 BC, podagra (acute gout occurring in the first metatarsophalangeal joint) was later recognized by Hippocrates in the fifth century BC, who referred to it as 'the unwalkable disease'. The term is derived from the Latin word gutta (or 'drop'), and referred to the prevailing medieval belief that an excess of one of the four 'humors'--which in equilibrium were thought to maintain health--would, under certain circumstances, 'drop' or flow into a joint, causing pain and inflammation. Throughout history, gout has been associated with rich foods and excessive alcohol consumption. Because it is clearly associated with a lifestyle that, at least in the past, could only be afforded by the affluent, gout has been referred to as the 'disease of kings'. Although there is evidence that colchicine, an alkaloid derived from the autumn crocus (Colchicum autumnale), was used as a powerful purgative in ancient Greece more than 2000 years ago, its first use as a selective and specific treatment for gout is attributed to the Byzantine Christian physician Alexander of Tralles in the sixth century AD. Uricosuric agents were first used at the end of the 19th century. In the modern era, nonsteroidal anti-inflammatory drugs are usually the drugs of choice for treating acute gout. Perhaps the most important historical advance in the treatment of hyperuricemia was the development of xanthine oxidase inhibitors, which are effective in reducing plasma and urinary urate levels and have been shown to reverse the development of tophaceous deposits.

Arthritis, Gouty↗

Hyperuricemia and adverse outcomes in cardiovascular disease: potential for therapeutic intervention.

High uric acid levels are associated with increased morbidity and mortality rates in cardiovascular disease. In this article we explore the relationship between cardiovascular disease and xanthine oxidase activity. We look at the evidence that uric acid and its production via the xanthine oxidase pathway, may directly contribute to this increased cardiovascular risk. We examine the relationship between uric acid and other established cardiovascular risk factors and look at the evidence that reducing uric acid production may have a beneficial impact on cardiovascular morbidity and mortality. We conclude that although there is currently insufficient evidence to recommend the routine use of xanthine oxidase inhibitors in those with cardiovascular disease and asymptomatic hyperuricemia, there is sufficient evidence to warrant a large scale morbidity and mortality trial.

Allopurinol↗

[Clinical observation on treatment of nonalcoholic fatty liver disease complicating hyperuricemia by Zhifang I Decoction].

OBJECTIVE: To observe the therapeutic effect of Chinese herbal recipe Zhifang I Decoction on nonalcoholic fatty liver disease (NAFLD) complicating hyperuricemia (HUA). METHODS: Forty-six patients suffering from NAFLD complicating HUA were randomly divided into treatment group (25 cases) with Zhifang I and control group (21 cases) with Xuezhikang Capsule. One course of treatment was 8 weeks. The data were processed by SPSS 11.0 statistical package after 2 courses of treatment. RESULTS: The total effective rate of the treatment group was 80.00%, which surpassed the control group (71.43%) (P<0.01); Zhifang I could improve the image of B-mode ultrasonography and was better than Xuezhikang in ameliorating the clinical symptoms (P<0.05); Zhifang I could significantly decrease the serum uric acid (UA) (P<0.01), while Xuezhikang had no obvious therapeutic effect on it (P>0.05); Zhifang I was as good as Xuezhikang in recovering alanine aminotransferase (ALT), aspartate aminotransferase (AST),gamma-glutamyltransferase (gamma-GT), total cholesterol (TC) and triglyceride (TG) (P>0.05). CONCLUSION: Zhifang I has good effect in treating NAFLD complicating HUA.

Adult↗

[A case of acute renal failure with marked hyperuricemia developing during mizoribine administration].

A 50-year-old man diagnosed as having AGA(Churg-Strauss syndrome) was administered steroid. After treatment with mizoribine, hyperuricemia and acute renal failure occurred as side effects of this drug. Accordingly we started dialysis treatment, terminated mizoribine treatment, and administered allopurinol dosage. Hemodialysis was necessary every day for 11 days and his renal function recovered after one month. In 67Ga scintigraphy, accumulation of 67Ga was seen in the kidney.

Acute Kidney Injury↗

[Avoid purine-rich foods, drink a lot, reduce weight. The most important recipes against hyperuricemia].

In 99% of the cases, the underlying cause of gout is an inborn disorder of uric acid excretion. In addition to acute arthritis, clinical consequences include tophi, chronic destruction of joints, and ulcers. The patient is endangered by the frequent renal involvement, with hypertension and renal insufficiency. Furthered by such exogenous factors as overweight, high-calorie, purine-rich foods and immoderate consumption of alcohol, hyperuricemia may develop. Basic treatment comprises dietary measures and, up to a serum uric acid concentration of 8.5 mg/dl, should be the sole measure required. The aim is to achieve a permanent lowering of uric acid concentrations in the blood to < 6.5 mg/dl. This may be achieved by reduction of overweight (including regular exercise), an energy-adapted diet with only moderate amounts of fat, restriction--or, better, banishment--of alcohol, an ovolactovegetarian diet low in purine (care must be taken with high-purine vegetablesl), moderate intake of readily assimilated carbohydrates, and adequate amounts of calorie-free liquids.

Alcohol Drinking↗

Managing malignancy-associated hyperuricemia with rasburicase.

Along with hydration and urinary alkalinization, allopurinol has been the standard agent for the management of hyperuricemia in patients with a high tumor burden who are at risk for tumor lysis syndrome. However, this agent often fails to prevent and treat this complication effectively. Rasburicase, a recombinant urate oxidase, acts at the end of the purine catabolic pathway and, therefore, does not induce accumulation of xanthine or hypoxanthine, which can precipitate in the kidneys and lead to impaired renal function. Rasburicase may represent an effective alternative to allopurinol in rapidly reducing uric acid levels, improving patients' electrolyte status, and reversing renal insufficiency. The drug initially was studied in pediatric patients with acute lymphoblastic leukemia and aggressive non-Hodgkin lymphoma; data may suggest comparable benefit in adults with similar lymphoid malignancies. Current and future trials will evaluate alternate doses and schedules of rasburicase to maintain its efficacy while reducing its cost.

Allopurinol↗

[Disfunction of thyroid gland at experimental hyperuricemia].

Thyroid gland function was investigated in rats with experimental hyperuricemia. Data obtained indicate that dyshormonal changes are secondary ones and their development depends on the state of purine metabolism. Administration of allopyrinol, an uric acid depressant drug, improved thyroid gland function.

Allopurinol↗

[Hyperuricemia and disorders in content of amino acids-purine precursors in patients with autoimmune diseases and gout].

Patients with system lupus erythematosus, rheumatic arthritis, chronic active hepatitis and gout were found to have considerable hyperuricemia and be decreased in aminoacides content, which are the predecessors of purine. Hyperactivity of xanthineoxidase and POL content were also revealed. The close correlation relation of purine indices of such patients has been observed. The obtained data allow applying methods of correction of immunity system and purine metabolism to these patients by introducing in a complex therapy inhibitors of xanthineoxidase.

Amino Acids↗

Epidemiology of hyperuricemia and gout.

Gout is an increasingly common medical problem. The traditional risk factors of male sex and high red meat or alcohol consumption have been joined by a wave of newer risk factors, such as increased longevity, the metabolic syndrome (hypertension, diabetes, dyslipidemia, truncal obesity, increased cardiovascular disease risk), use of diuretics, low-dose aspirin, or cyclosporine, and end-stage renal disease. Atypical presentations of gout in the elderly can mimic osteoarthritis and rheumatoid arthritis. There is a resurgence of interest in hyperuricemia as an independent and potentially modifiable cardiovascular risk factor. The pharmacologic management of gout in general practice suffers from a number of quality-control issues. This article reviews these and other new epidemiologic data on this ancient disease.

Adult↗

Hyperuricemia associated with high cardiac event rates in the elderly with chronic heart failure.

OBJECTIVES: Congestive heart failure (CHF) is the major cause of death and hospitalization in the elderly population. Simple markers that can be measured anywhere at low cost are necessary to identify patients at high risk. Recent studies have reported that hyperuricemia is a prognostic marker for CHF. However, it is not yet known whether serum levels of uric acid may provide prognostic information in the elderly population. Therefore, this study tried to identify the clinical characteristics of elderly CHF patients (+/-70 years) in our institution and to evaluate whether uric acid levels can effectively estimate the prognosis for elderly CHF patients. METHODS AND RESULTS: Uric acid levels were analyzed in 247 CHF patients, and patients were followed up for 451 +/- 235 days (mean +/- SD). Elderly CHF patients aged > or =70 years (123 patients) had higher rate of hypertension, lower current smoking rate and higher uric acid levels than those aged < 70 years (124 patients). There were 72 cardiac events including cardiac deaths and readmissions for worsening CHF. Multivariate analysis with the Cox proportional hazard model showed that uric acid was the only independent predictor of cardiac events (hazard ratio 1.544, 95% confidence interval 1.215-2.582, p < 0.0001) in the elderly with CHF. The highest quartile of uric acid level was associated with the highest risk of cardiac events (a 4.45-fold compared to the lowest quartile). Kaplan-Meier analysis revealed that uric acid levels effectively risk stratified elderly CHF patients for cardiac events. CONCLUSIONS: These findings suggest that measurement of uric acid levels in elderly CHF patients may add valuable prognostic information to predict cardiac events.

Aged↗

[An analysis of islet beta-cell function in hyperuricemia].

OBJECTIVE: To study the islet beta-cell function in patients with simple hyperuricemia (HUA) and to explore the relationship between the level of serum uric acid and insulin resistance. METHODS: The first and second phases of insulin secretion of beta-cell were observed after L-arginine stimulation test and oral glucose tolerance test (OGTT) in 56 hyperuricemic patients and 40 healthy controls. RESULTS: The peak value of insulin secretion in both groups was at the 2nd min and it began to decrease at the 4th min after L-arginine stimulation. However, the peak value in the HUA group was significantly higher than that in the control group (t = 3.71, P < 0.01). Fasting plasma insulin, 120-min plasma glucose and 120-min insulin during OGTT as well as modified beta-cell function index and Homa-insulin resistance (HOMA-IR) in the HUA group were obviously higher than those in the control group (t = 2.46-5.56, P < 0.05, P < 0.01). Multiple step regression analysis showed that serum uric acid was positively correlated with low density lipoprotein-cholesterol, HOMA-IR, male sex, mean arterial pressure and creatinine (t = 2.15-3.60, P < 0.05). CONCLUSION: The islet beta-cell function in hyperuricemic patients increases compensatively and the serum uric acid level is positively correlated with insulin resistance.

Adult↗