Nephrolithiasis in gout: prevalence and characteristics of Brazilian patients

Abstract Background: The aims of this article were to assess the prevalence of nephrolithiasis and the factors associated with nephrolithiasis in Brazilian patients with primary gout. Methods: One hundred twenty-three patients with primary gout were recruited from a tertiary referral hospital in São Paulo, Brazil. All patients underwent ultrasonography and had their clinical and laboratory characteristics assessed. Results: One hundred fifteen (93.5%) patients were male, with a mean age of 62.9 ± 9.4 years. Twenty-three (18.7%) patients had asymptomatic nephrolithiasis (detected only by ultrasonography), 7 (6.0%) had symptomatic nephrolithiasis (detected by ultrasonography and a positive clinical history), and 13 (10.0%) had a history of kidney stones, but ultrasonography at evaluation did not show nephrolithiasis. Therefore, 35.0% of the patients had nephrolithiasis (detected either by ultrasonography and/or a positive clinical history). Nephrolithiasis was associated with male gender (43 [100%] vs 72 [90%], p = 0.049), the use of potassium citrate (13 [30.2%] vs 0, p < 0.001) and the use of medications for diabetes (10 [23.3%] vs 8 [10%], p = 0.047) and dyslipidemia (15 [34.9%] vs 10 [12.5%], p = 0.003); benzbromarone had an inverse association with nephrolithiasis (21 [48.8%] vs 55 [68.8%], p = 0.030). In patients with and without nephrolithiasis, no differences were found in the laboratory and ultrasonography characteristics, including serum uric acid levels, urinary uric acid excretion and urine pH. Conclusions: The prevalence of nephrolithiasis in primary gout was 35.0%, and 18.7% of the patients were asymptomatic. Nephrolithiasis was associated with male gender, diabetes and dyslipidemia. A positive history of nephrolithiasis probably biased the prescription of potassium citrate and benzbromarone.(AU)

Benzbromarone in the treatment of gout

Abstract Background Benzbromarone is a uricosuric drug that has been used in the treatment of gout over the last 30 years. Due to its potent inhibition of the dominant apical (luminal) urate exchanger in the human proximal tubule URAT1, it reduces the urate reabsorption, diminishing serum urate levels and therefore preventing gout flares. Main body of the abstract Through several clinical trials, Benzbromarone has been proved effective and safe, inclusive in patients with chronic kidney disease and as combination therapy with allopurinol. Due to hepatotoxicity reports, it was withdrawn from the European market by the manufacturer, however many authors have questioned the product's withdrawal due to a lack of clinical evidence in order to support its hepatotoxicity. Benzbromarone is still available in several European countries, New Zealand, Brazil and several other countries. Despite the product's marketing over more than 20 years after the first hepatotoxicity reports, we have found only five reports in our literature search, and no prospective or retrospective study correlating hepatotoxicity with benzbromarone use. Short conclusion Benzbromarone is a safe and effective molecule for the treatment of gout. However, due to in vitro and in vivo data related to hepatotoxicity, it is prudent to prescribe it with some caution, especially for patients with an already known liver condition.

Multifocal Osteonecrosis in a Patient with Gout: Case Report and Review of the Literature

Osteonecrosis (ON) is a common comorbidity in gout; however, avascular ON of multiple sites is unusual. Multifocal ON is defined as osteonecrotic lesions affecting three or more separate anatomic sites. We report a case of a 31-year-old woman diagnosed with gout, who had multifocal ON. Initially, she was treated with benzbromarone, colchicine, and meloxicam. Two years later, she developed severe tophi and was diagnosed with chronic renal failure. Magnetic resonance imaging (MRI) of both legs revealed bilateral ON of the femoral head. She underwent bilateral hip replacement surgeries. After two years, she had pain and limited movements in the left shoulder, with tophi identified via dual-energy computed tomography. Despite management with non-steroidal anti-inflammatory drugs, colchicine, and prednisolone, she had persistent shoulder pain. MRI of the left shoulder revealed ON. She therefore underwent left shoulder replacement surgery. Following the case report, we review the literature on multifocal ON with gout.

Prevention of Comorbidity and Acute Attack of Gout by Uric Acid Lowering Therapy

The object of this study was to evaluate the effect of uric acid lowering therapy in reducing the new development of comorbidities and the frequency of acute attacks in gout patients. We retrospectively reviewed patients who were diagnosed to have gout with at least 3 yr of follow up. They were divided into 2 groups; 53 patients with mean serum uric acid level (sUA) or =6 mg/dL. Comorbidities of gout such as hypertension (HTN), type II diabetes mellitus (DM), chronic kidney disease, cardiovascular disease (CVD) and urolithiasis were compared in each group at baseline and at last follow-up visit. Frequency of acute gout attacks were also compared between the groups. During the mean follow up period of 7.6 yr, the yearly rate of acute attack and the new development of HTN, DM, CVD and urolithiasis was lower in the adequately treated group compared to the inadequately treated group. Tight control of uric acid decreases the incidence of acute gout attacks and comorbidities of gout such as HTN, DM, CVD and urolithiasis.

Effect of total saponin of Dioscorea on chronic hyperuricemia and expression of URAT1 in rats / 中国中药杂志

<p><b>OBJECTIVE</b>To study the preventive and therapeutic effects of total saponin of Dioscorea (TSD) on chronic hyperuricemia, and its effect on urate transporter 1 (URAT1) in rats.</p><p><b>METHOD</b>Ninety male rats were randomly divided into 6 groups: the normal group, the model group, TSD high-, medium- and low-dose (300, 100, 30 mg x kg(-1)) groups and the benzbromarone (10 mg x kg(-1)) group. Potassium oxonate and ethambutol were adopted to establish the chronic hyperuricemia model Since the third week, all the rats were intragastrically administered with drugs for 4 weeks, once a day, in order to determine their uric acid in serum and urine, uric acid excretion and xanthine oxidase (XOD). URAT1 mRNA and URAT1 protein expression in rat renal tubular cells were determined by RT-PCR and immunohistochemistry method respectively.</p><p><b>RESULT</b>Serum uric acid level of the model group increased significantly, while uric acid excretion decreased, with high expressions of renal URAT1 mRNA and URAT1 protein. TSD could dose-dependently reduce the serum uric acid level of chronic hyperuricemia rats, increase the concentration of uric acid and uric acid excretion in urine, and reduce renal URAT1 mRNA and URAT1 protein expression. Its effects were similar with that of benzbromarone, but with no significant effect on XOD and urinary volume of chronic hyperuricemia rats.</p><p><b>CONCLUSION</b>TSD has an obvious effect of anti-hyperuricemia It may reduce the reabsorption of uric acid by inhibiting the high expression of rat renal URAT1.</p>

Stage-based treatment of integrative medicine on the quality of life in patients with gout / 中国中西医结合杂志

<p><b>OBJECTIVE</b>To investigate the quality of life in patients with gout and their influencing factors, and to observe the effects of the intervention program of stage-based treatment of integrative medicine (IM).</p><p><b>METHODS</b>Totally 120 patients with acute attack of gout within 72 h were randomly assigned to the treatment group and the control group, 60 in each group. Patients in the treatment group were treated with Huzhang Tongfeng Granule (HTG), diclofenac sodium extended-release capsule and Jinhuang Ointment (JO) in the acute stage, and Yinlian Tongfeng Granule (YTG) and Benzbromarone Tablet (BT) in the intermission stage. Patients in the control group were treated with diclofenac sodium extended-release capsule in the acute stage, and BT in the intermission stage. All patients were treated for 12 weeks. The quality of life (QOL) before and after treatment was investigated by questionnaire.</p><p><b>RESULTS</b>Before treatment there were no statistical difference in the physiological function, psychological function, social function, health self-awareness and total score between the two groups (P > 0.05). After treatment the scores of the four aspects and the total score were significantly improved in the two groups (P < 0.01). And the improvement of the treatment group was better than that of the control group (P < 0.01). There was no statistical difference in the gender, age, marital status, educational level, QOL with or without associated disease between the two groups (P > 0.05). The QOL of patients with joint stiffness or deformity was less than that of those without joint stiffness or deformity (P < 0.01). The total QOL scores of the gout patients were obviously correlated with the course of diseases (r = -0.324, P < 0.01).</p><p><b>CONCLUSIONS</b>The QOL of patients with gout was correlated with the course of disease and joint stiffness or deformity. Stage-based treatment of IM could significantly improve the QOL of f out patients.</p>

Assessment on the clinical efficacy and safety of xiezhuo chubi recipe in treating hyperuricemia / 中国中西医结合杂志

<p><b>OBJECTIVE</b>To observe the clinical efficacy and safety of Xiezhuo Chubi Recipe (XCR) on hyperuricemic patients.</p><p><b>METHODS</b>99 patients with hyperuricemia were randomly assigned to the XCR group, the Benzbromarone group, and the blank control group. Patients in the XCR group took XCR, one dosage daily, twice per day. Patients in the Benzbromarone group took Benzbromarone Tablet (50 mg each tablet, once per day). Patients in the blank control group were not treated with any drug, but only with clinical observation. Twenty days consisted of one course of treatment. The laboratory data including uric acid, blood routines, urine routines, the liver function, and the renal function were statistically analyzed before and after treatment.</p><p><b>RESULTS</b>The blood uric acid decreased in the three groups after treatment (P<0.05). The total effective rate was 85.71% in the XCR group, 92.86% in the Benzbromarone group, and 23.33% in the blank control group. There was no statistical difference between the XCR group and the Benzbromarone group (P>0.0167). There was no significant difference in the safety indices such as blood routines, urine routines, liver functions, and renal functions of the XCR group between before and after treatment (P>0.05).</p><p><b>CONCLUSION</b>XCR could effectively reduce the uric acid level with higher safety.</p>

Management of Complicated Gout / 대한내과학회지

Chronic tophaceous gout results from long-term uncontrolled hyperuricemia with accumulation of urate crystals in joints, soft tissues, tendon sheaths and bony prominence. Urate-lowering agents should be administered to reduce serum uric acid level to less than 5 mg/dL for tophi reabsorption. Surgical indications include restoration of joint and tendon dysfunction, nerve decompression, debridement of septic joints, pain relief and cosmesis. Gout patients are at greater risk of forming uric acid stones. The renal tubular abnormality related to gout and metabolic syndrome leads to excretion of acidic urine, which favors formation of the relatively insoluble uric acid than more soluble urate. The corner stone of treatment of uric acid stone is urine alkalinization. Lowering serum uric acid with allopurinol and increasing urine volume are also important. Allopurinol is poorly tolerated and ineffective or contraindicated in some patients. Benzbromarone, a uricosuric agent is a useful alternative but possible hepatotoxicity should be monitored. Desensitization of allopurinol can be attempted to patients with mild cutaneous hypersensitivity. For gout patients with chronic renal failure, allopurinol dose need to be adjusted and nonsteroidal anti-inflammatory drugs and colchicine may be contraindicated.

The Effect of Hypouricemic Treatment on the Renal Function in Patients with Gout

OBJECTIVE: Hyperuricemia is known as a risk factor that causes and worsens kidney diseases through a variety of mechanisms. Recent animal studies reported that the correction of hyperuricemia improved the renal function, but there have been few human studies. This study examined whether a hypouricemic treatment affects the renal function in Korean patients with gout. METHODS: Two hundred sixty-seven gout patients who were prescribed uric acid lowering agents for more than 1 year were enrolled at the Division of Rheumatology in the National Health Insurance Corporation Ilsan Hospital and Yonsei University Severance Hospital from January 2005 to January 2010. The following were examined: the levels of serum uric acid and serum creatinine, the amount of 24-hour urine uric acid, glomerular filtration rate (GFR), and abdominal ultrasound findings at baseline and follow-up. RESULTS: Mean age of the study subjects was 54.4+/-13.9 years. Two hundred forty-seven patients were male and 20 patients were female. The mean treatment duration was 35.0+/-19.5 months. Among the 267 patients, 219 and 19 patients received monotherapy with allopurinol and benzbromarone respectively, and 29 patients received combination therapy with allopurinol and benzbromarone. After the treatment with uric acid lowering agents, the serum uric acid and creatinine levels decreased significantly (8.05+/-1.96 mg/dL vs 6.16+/-1.46 mg/dL, p<0.001, 1.25+/-0.46 mg/dL vs 1.18+/-0.42 mg/dL, p=0.001, respectively) and the GFR increased significantly (74.4+/-27.0 mL/min/1.73 m3 vs 80.2+/-31.6 mL/min/1.73 m3, p<0.001). CONCLUSION: Treatment with hypouricemic agents reduced the levels of serum uric acid and improved the renal function. These results suggest that a hypouricemic treatment might improve the kidney function in gout patients.

Rising Gout, Life Threatening Public Enemy

Gout is an inflammatory arthritis characterized by recurrent attacks of inflammation caused by precipitation of monosodium urate crystals (MSU) in the joint and is associated with impaired quality of life. The incidence and prevalence of gout is increasing world wide due to the increasing size of the elderly population, kidney disease, diuretic use, dietary changes, and obesity. Furthermore, emerging evidence suggests that gout is strongly associated with metabolic syndrome and may lead to myocardial infarction, type 2 diabetes mellitus, and premature death. Urate nephropathy is also increasing. Thus, the overall disease and the economic burden of gout is substantial and increasing sharply. Although traditional urate lowering agents including allopurinol, probenecid, and benzbromarone have been available for many years, questions still remain about the optimal dosing regimen. Many patients remain undertreated for this potentially curable disorder. Fortunately, more scientific data and evidence for proper management of gout are available. Renewed interest in gout has led to advances in dietary advice and development of new therapeutic options. The importance of risk factors for gout should be emphasized and patients with gout and hyperuricemia should be educated so that they can achieve a good quality of life and longevity. In this review, the comorbidity, mortality, and economic burdens of gout will be presented. In addition, the importance of proper management and patient education will be stressed.

An update on the management of hyperuricemia and gout / 대한내과학회지

Gout is a common chronic inflammatory arthritis that can lead to significant disability. Gout is one of the few rheumatologic diseases that can be diagnosed with certainty and can be cured with appropriate therapy. Alcohol and dietary consumption are related to hyperuricemia and gout attacks. A moderate intake of purine-rich vegetables or protein is not related to an increased risk of gout. A weight-reducing, calorie-restricted diet with moderate carbohydrate restriction was beneficial for gout patients and reduced the serum uric acid and frequency of gout attacks, although these findings need to be confirmed. Clinicians should consider therapeutic options that do not increase the serum uric acid when treating associated conditions in gout patients. The acute gout attack can be treated appropriately with non-steroidal anti-inflammatory drugs, colchicine, or glucocorticoids. Hypouricemic treatment reduces the uric acid concentration by inhibiting its production (allopurinol) or enhancing its excretion (benzbromarone). Allopurinol is the agent used most commonly, but the recommended dose often fails to control the serum uric acid. Benzbromarone effectively reduces the serum uric acid, but possible hepatotoxicity should be monitored. Febuxostat, a new xanthine oxidase inhibitor, was recently approved by the Federal Drug Administration (FDA). PEGylated uricase, a potent parenteral hypouricemic agent, is under investigation for the treatment of gout.

Acute Tubular Necrosis in a Kidney Transplant Patient Using Benzbromarone: A Case Report / 대한이식학회지

Benzbromarone is a uricosuric agent for hyperuricemia and gout. Some of its well-known side effects include hypersensitivity, renal calculi, and gastrointestinal problems. Although the drug was withdrawn from U.S. market due to severe hepatotoxicity, it is still available in some countries including Korea. We describe a 19-year-old male who was admitted with general weakness and azotemia after use of benzbromarone. A kidney biopsy revealed acute tubular necrosis without an evidence of urate nephropathy. After discontinuation of benzbromarone, the renal function returned to baseline. This is the first case of acute tubular necrosis associated with benzbromarone use.

The inhibition of CYP2C9 isoenzyme in Cunninghamella blakesleeana AS 3. 910 / 药学学报

<p><b>AIM</b>To investigate the variation of CYP2C9 isoenzyme activity in the microbial model in response to inhibitors of CYP2C9.</p><p><b>METHODS</b>Using C. blakesleeana AS 3. 910 as a model strain, the impact of CYP2C9 inhibitors on the metabolites yields of CYP2C9 substrates was determined and the drug-drug interactions among CYP2C9 substrates were evaluated. Liquid chromatography-mass spectrometry was used to analyze biotransformation products.</p><p><b>RESULTS</b>Benzbromarone decreased the yield of 4'-hydroxytolbutamide from 100% to 14.5%; sulfaphenazole decreased the yield of O-demethylindomethacin from 75.2% to 9.9%; valproic acid decreased the yield of 4'-hydroxydiclofenac from 98.6% to 2.7%, separately. Tolbutamide, indomethacin and diclofenac interacted with each other, resulting in the decreased formation of metabolites catalyzed by CYP2C9.</p><p><b>CONCLUSION</b>Three CYP2C9 inhibitors inhibit the activity of CYP2C9 isoenzyme in C. blakesleeana AS 3. 910 differently, and there are drug-drug interactions among CYP2C9 substrates.</p>

The Effect of Low Dose Aspirin on Serum and Urinary Uric Acid Level in Gouty Arthritis Patients / 대한류마티스학회지

OBJECTIVE: To investigate the effect of low dose aspirin on serum and urinary uric acid level in gouty arthritis patients. METHODS: 22 male gouty arthritis patients (12 treated with allopurinol and 10 with benzbromarone) were enrolled in a prospective study. Mean age (+/-SD) was 57.3+/-10.4 years. Patients had been treated with hypouricemic agent for at least 3 months. Low dose of aspirin (100 mg/ day) were administered for 4 weeks. During the study period, hypouricemic agents were remained on the same dosage. Demographic data were collected at baseline. Laboratory tests including serum uric acid, blood urea nitrogen, creatinine, 24 hours urine uric acid, creatinine clearance (Ccr), and 24 hours urine urea nitrogen were measured at baseline and then every 4 weeks for 12 weeks. RESULTS: At baseline, there was no difference in age, serum uric acid, 24 hours urine uric acid, Ccr and 24 hours urine urea nitrogen between allopurinol and benzbromarone groups. After aspirin treatment, levels of serum uric acid (p=0.901 by paired t-test in allopurinol group, p=0.617 in benzbromarone group), 24 hours urine uric acid (p=0.789, p=0.410), Ccr (p=0.480, p=0.219), 24 hours urine urea nitrogen (p=0.284, p=0.250) did not change significantly at 0 and 4 weeks. Acute gouty attack did not occur during the study period. CONCLUSION: Low dose aspirin does not influence serum uric acid level or urinary uric acid excretion in gouty arthritis patients treated with allopurinol or benzbromarone.

The efficacy of combined low dose of Allopurinol and benzbromarone compared to standard dose of Allopurinol in hyperuricemia.

OBJECTIVE: To compare the efficacy of combined low dose of hypouricemic drugs (Allopurinol 100 mg and benzbromarone 20 mg; Allomaron) and standard dose 300 mg of allopurinol in hyperuricemia. MATERIAL AND METHOD: A prospective, open study of 94 hyperuricemic patients was done at King Chulalongkorn Memorial Hospital. Each group of 47 patients was given a combined low dose of hypouricemic drugs (Allopurinol 100 mg and benzbromarone 20 mg; Allomaron) and a standard dose 300 mg of allopurinol. Serum uric acid was measured before and 4 weeks after receiving the drugs. The efficacy was measured from the difference of the level of serum uric acid before and after receiving the drugs. RESULTS: The patients receiving the combined low dose of hypouricemic drugs and standard dose of allopurinol showed a mean reduction of serum uric acid of 2.5+/-3.4 mg/dl and 4.1+/-2.7 mg/dl consecutively. There was a statistically significant difference between the 2 groups (P = 0.010). CONCLUSION: This study demonstrates that the efficacy of standard dose 300 mg of allopurinol is superior to a combined low dose of allopurinol and benzbromarone in lowering the level of serum uric acid level.

Efficacy of benzbromarone compared to allopurinol in lowering serum uric acid level in hyperuricemic patients.

This study was aimed to evaluate the efficacy of benzbromarone compared to allopurinol in lowering serum uric acid level in hyperuricemic patients with normal renal function (serum creatinine < or = 1.5). The authors conducted a crossover study consisting of two four-week treatment periods of allopurinol 300 mg/day and benzbromarone 100 mg/day separated by a four-week washout period. Fourteen patients with mean age and duration of hyperuricemia of 60.78 +/- 8.62 and 6.93 +/- 3.69 years, respectively, were recruited and all completed our study protocol. This study was a crossover design consisting of two four-week treatments of allopurinol and benzbromarone separated by a four-week washout period. The serum uric acid level was reduced from 9.89 +/- 1.43 mg/dl to 5.52 +/- 0.83 mg/dl and from 9.53 +/- 1.48 to 4.05 +/- 0.87 mg/dl by allopurinol and benzbromarone, respectively. The efficacy of benzbromarone in lowering serum uric acid level was significantly superior to allopurinol (p=0.005). No patient reported clinical side effects during treatment with either drug. In conclusion, the authors have shown that benzbromarone is more effective than allopurinol in the reduction of serum uric acid levels in hyperuricemic patients with normal renal function.

Exercise-induced Acute Renal Failure in a Patient with Renal Hypouricemia / 대한신장학회잡지

We report a case of exercise-induced acute renal failure associated with renal hypouricemia in a 35- year-old man who complained of oliguria and back pain after swimming. Laboratory tests revealed that serum blood urea nitrogen and creatinine level were elevated, the serum uric acid concentration was subnormal(2.1 mg/dL). After conservative treatment, renal function was recovered. But, uric acid level decreased to 0.4 mg/dL. In addition, there was no supression of urate clearance to creatinine clearnace ratio(CUA/CCr) following the administration of pyrazinamide, and no increase of CUA/CCr after benzbromarone. Therefore, we think the cause of renal hypouricemia in this patient may be the subtotal defect in the urate transport.

Study on Effect of Benzbromarone in the Patients with Gout / 대한류마티스학회지

OBJECTIVE: Benzbromarone is a most potent uricosuric agent which has been marketed in Europe. The purpose of this study was to evaluate the safety and efficacy of benzbromarone as a uric acid lowering agent in gouty patients in Korea. METHOD: Twenty-one patients with gout, who were lower excreter of uric acid and had no other complication of gout, were treated with benzbromarone for 6 months. In these patients we checked complete blood count, liver function test, BUN, creatinine, serum uric acid, 24 hour urine uric acid excretion and uric acid clearance before and after treatment with benzbromarone. RESULTS: Significant improvements(p<0.01) were found in the serum uric acid level, 24h uric acid excretion and uric acid clearance. The mean serum uric acid decreased from 8.2mg/dl to 5.1mg/dl at the end of 6 months; mean urinary uric acid excretion increased from 425.9mg/day to 760.3mg/day; and the uric acid clearance increased from 3.5mL/min to 10.9mL/min. There are no clinical or laboratory side effects, except skin rash in the one patient. CONCLUSION: Benzbromarone was effective to control plasma uric acid concentration at doses ranging from 25 to 50mg/day.

Avaliaçäo da funçäo renal de pacientes portadores de gota em uso da benzobromarona / Evaluation of renal function in patients with gout using with benzbromarone

A funçäo renal de 20 pacientes portadores de gota primária foi avaliada em estudo aberto, näo comparativo e unicêntrico, na vigência de tratamento com benzobromarona*. Foram incluídos no presente estudo somente pacientes normo ou hipoexcretores de ácido úrico. O fármaco foi administrado por via oral, na posologia de 100 mg diários, em uma única tomada, durante três semanas. Constatou-se um flagrante aumento da uricosúria em todos os casos avaliados, bem como uma acentuada reduçäo da uricemia. Os valores de calcemia, calciúria, fosfatemia, uréia, creatinina, sódio, potássio e a clearance de creatinina urinária näo mostraram alteraçöes importantes. Quanto à tolerabilidade ao medicamento, esta foi considerada boa, apesar de efeitos colaterais, facilmente controláveis, estarem presentes em 10 (50%) pacientes. Em nenhum dos casos foi necessário interromper-se a terapia