Target Uric Acid Research Articles

Lesinurad: what the nephrologist should know.

Lesinurad is an oral inhibitor of the monocarboxylic/urate transporter URAT1 encoded by the SLC22A12 gene. Market authorization was granted in February 2016 in Europe and December 2015 in the USA. As a potentially nephrotoxic uricosuric drug acting on the kidney, nephrologists should become familiar with its indications and safety profile. The approved indication is treatment of gout in combination with a xanthine oxidase (XO) inhibitor in adult patients who have not achieved target serum uric acid levels with an XO inhibitor alone. It is not indicated for asymptomatic hyperuricaemia or for patients with estimated creatinine clearance <45 mL/min. The only authorized daily dose is 200 mg and cannot be exceeded because of the nephrotoxicity risk. Nephrotoxicity is thought to be related to uricosuria. At the 200 mg/day dose, serum creatinine more than doubled in 1.8% of lesinurad patients (versus 0% in placebo) and in 11% of these it was not reversible. In addition, it is subject to a risk management plan given the potential association with cardiovascular events. In randomized clinical trials, the association of lesinurad with either allopurinol or febuxostat achieved a greater reduction in serum uric acid (∼1 mg/dL lower) than the XO inhibitors alone, and this allowed the serum uric acid target to be met in a higher proportion of patients, which was the primary endpoint. However, no clinical differences were observed in gout flares or tophi, although these were not the primary endpoints.

Treatment Options for Gout.

1-2% of adults in Germany suffer from gout. Gout is one of the few rheumatological diseases that can be cured. It arises through the deposition of uric acid crystals in joints as a result of hyperuricemia. Painful redness and swelling of the affected joints are typical findings. Multiple pertinent guidelines and treatment recommendations have been published, but there is reason to believe that patients with gout are not always treated accordingly. This review is based on relevant publications from the years 2000-2016 that were retrieved by a selective search in the Cochrane and PubMed databases. In a person with normal renal function, asymptomatic hyperuricemia is not an indication for treatment to lower the serum uric acid level. The drugs of first choice for acute gouty arthritis are nonsteroidal antiinflammatory drugs (NSAID), corticosteroids, and colchicine. Treatment with xanthine oxidase inhibitors (XOI) or uricosuric drugs is indicated for patients with a recurrent or severe course; the target uric acid value is <6 mg/dL. Long-term treatment should be initiated only after resolution of the acute attack. For patients with refractory gout, lesinurad (approved in February 2016) in combination with XOI is a new treatment option that can be considered. Comprehensive patient education and counseling is an important component of the treatment of patients with gout. Regular laboratory follow-up is necessary as well. The prevalence of gout is rising around the world. Patients with gout could benefit greatly from consistent implementation of the existing treatment guidelines and recommendations. In the future, controlled trials should be conducted to determine the best time to start treatment and the optimal target level for the serum uric acid concentration in terms of a risk/benefit analysis.

Time to target uric acid to retard CKD progression.

Uric acid (UA) remains a possible risk factor of chronic kidney disease (CKD) but its potential role should be elucidated given a fact that multidisciplinary treatments assure a sole strategy to inhibit the progression to end-stage renal disease (ESRD). In clinical setting, most observational studies showed that elevation of serum uric acid (SUA) independently predicts the incidence and the development of CKD. The meta-analysis showed that SUA-lowering therapy with allopurinol may retard the progression of CKD but did not reach conclusive results due to small-sized studies. Larger scale, randomized placebo-controlled trials to assess SUA-lowering therapy are needed. Our recent analysis by propensity score methods has shown that the threshold of SUA should be less than 6.5mg/dL to abrogate ESRD. In animal models an increase in SUA by the administration of oxonic acid, uricase inhibitor, or nephrectomy can induce glomerular hypertension, arteriolosclerosis including afferent arteriolopathy and tubulointerstitial fibrosis. The ever-growing discoveries of urate transporters prompt us to learnUA metabolism in the kidney and intestine. One example is that the intestinal ABCG2 may play a compensatory role at face of decreased renal clearance of UA in nephrectomized rats, the trigger of which is not a uremic toxin but SUA itself. This review will summarize the recent knowledge on the relationship between SUA and the kidney and try to draw a conclusion when and how to treat asymptomatic hyperuricemia accompanied by CKD. Finally we will address a future perspective onUA study including a Mendelian randomization approach.

Novel medication approved for gout

Novel medication approved for gout

Gout and the heart: beyond comorbidities

Gout patients are well known to suffer from cardiovascular (CV) diseases, such as myocardial infarction or stroke, but it had been linked to the frequent comorbidities they present (i.e., metabolic syndrome). However, recent reports have revealed that gout independently associates with an increased incidence of CV events, leading to higher mortality. This likely relates to the persistent, subclinical inflammation due to monosodium urate crystals. Optimal management of gout, which aims at crystal dissolution, should reduce this increased CV risk, though this has not been proven yet. However, a rapid clearance of crystals through a lower serum uric acid target, well below its saturation point is worth considering, at least in patients with a high CV risk. This review will focus on analyzing the association between gout and CV disease and its proper management, addressing whether gout-specific treatment may differ in this subgroup of patients.

Compliance in intercriticalgout patients and its related factors

To study the compliance and its related factors of gout patients during the intercritical period. A total of 218 gout patients were recruited. Compliance and cognition of gout were evaluated via telephone interview. Case control study was performed between compliance patients and non-compliance ones to explore the factors affecting patients' compliance. The association between compliance scores and cognition scores was evaluated by linear regression and correlation analysis. Of 218 patients, 136 valid questionnaires were collected. The investigation showed that 52.9% (72/136) had more than 20 gout attacks so far. Only 15.4% (21/136) patients had no gout attack during the latest one year. The average compliance score was 3.93 ± 1.78 (total score was 8), and the percentage of non-compliance was 69.9% (95/136). Cognition score was 65.63 ± 18.63 (total score was 100). Among the 136 gout patients, 37 patients (27.2%) were non-cognition, 54 (39.7%) were partial-cognition and 45 (33.1%) were fully-cognition. Only 50.7% (69/136) accepted the concept of long term treatment with urate lowering drugs (ULD), 19.9% (27/136) patients knew the uric acid target and 29.4% (40/136) patients had no confidence to control this disease. Case control study revealed that the percentage of non-cognition in non-compliance group was higher than compliance group, and that of partial-cognition and fully-cognition were lower, although differences had no statistical significance (P > 0.05). Besides, health insurance was better for compliance group (P > 0.05). There was linear correlation between compliance and cognition scores (t = 6.83, P < 0.01) among gout patients. This study indicates that efforts should be made to improve recognition and medical coverage for gout, which could be a very rewarding strategy for patients' compliance and gout control.

Rational pharmacotherapy (RPT) in goutology: Define the serum uric acid target & treat-to-target patient cohort and review on urate lowering therapy (ULT) applying synthetic drugs

A gout revolution is at hand as can be seen from the number of publications and our recent increase in a better understanding of gout regarding imaging, regarding pathogenetic involvement of crystals, cells and cytokines, as well as regarding new pharmacotherapeutic options. We should now focus on rational pharmacotherapy to significantly improve gout care. With modern combinations of xanthine oxidase inhibition PLUS uricosuric all serum urate concentrations can be targeted. The pharmacotherapeutic literature of synthetic urate lowering treatment is reviewed and a plea is given for rational pharmacotherapy combining different modes of action aiming at the rheumatologically predefined optimal serum urate concentrations instead of a more reluctant approach to just lower a serum urate to any lower level with a fixed dose allopurinol.

Treatment of gout patients with impairment of renal function: a systematic literature review.

To assess the efficacy and safety of gout-specific medications in gout patients with a comorbidity and/or comedication. A systematic literature search for gout, its medication, and the most common comorbidities and comedications, using serum uric acid (SUA) levels as the primary, and adverse events as the secondary outcomes. Eight trials met inclusion criteria. Trials covered treatment with allopurinol, benzbromarone, rasburicase, or febuxostat in a gout population with mild or moderate renal insufficiency. High risk of bias (5/8 trials) and heterogeneity precluded formal metaanalysis. The trials showed the following hierarchy in efficacy (lowering the SUA below 6.0 mg/dl): febuxostat 80 mg (44%-71%) > febuxostat 40 mg (43%-52%) > allopurinol 100 mg or 200 mg (0-46%) after 6 months of therapy; rasburicase (46%) > allopurinol 300 mg (16%) after 7 days of therapy; benzbromarone 100-200 mg (93%) > allopurinol 100-200 mg (63%) after 9-24 months of therapy. The combination of allopurinol and benzbromarone seemed to be effective, with a significant reduction in the SUA from 7.8 to 5.7 mg/dl (p < 0.05) after 1 month. One study showed that 89% achieved the target SUA using higher doses of allopurinol than usually recommended for patients with renal impairment without an apparent increase in adverse events. In addition, allopurinol and benzbromarone significantly improved renal function. In gout patients with renal insufficiency febuxostat, rasburicase, benzbromarone, and allopurinol + benzbromarone seemed to be effective and safe; allopurinol may be cautiously titrated until the target uric acid level has been reached, and may improve renal function.

Efficacy and safety of febuxostat in the treatment of hyperuricemia in stable kidney transplant recipients

BackgroundPost-transplant hyperuricemia (PTHU), defined as serum uric acid concentration ≥7.0 mg/dL or need for treatment with allopurinol or benzbromarone, reduces long-term allograft survival in kidney transplant recipients. Febuxostat, a new nonpurine selective xanthine oxidase inhibitor, is well tolerated in patients with moderate renal impairment. However, its efficacy and safety in kidney recipients with PTHU is unclear. We therefore assessed the efficacy and safety of febuxostat in stable kidney transplant recipients with PTHU.MethodsOf 93 stable adult kidney transplant recipients, 51 were diagnosed with PTHU (PTHU group) and 42 were not (NPTHU group). Of the 51 patients with PTHU, 26 were treated with febuxostat (FX group) and 25 were not (NFX group), at the discretion of each attending physician. One-year changes in serum uric acid concentrations, rates of achievement of target uric acid (<6.0 mg/dL), estimated glomerular filtration rates in allografts, and adverse events were retrospectively analyzed in the FX, NFX, and NPTHU groups.ResultsThe FX group showed significantly greater decreases in serum uric acid (−2.0±1.1 mg/dL versus 0.0±0.8 mg/dL per year, P<0.01) and tended to show a higher rate of achieving target uric acid levels (50% versus 24%; odds ratio 3.17 [95% confidence interval 0.96–10.5], P=0.08) than the NFX group. Although baseline allograft estimated glomerular filtration rates tended to be lower in the FX group than in the NFX group (40±14 mL/min/1.73 m2 versus 47±19 mL/min/1.73 m2), changes in allograft estimated glomerular filtration rate were similar (+1.0±4.9 mL/min/1.73 m2 versus −0.2±6.9 mL/min/1.73 m2 per year, P=0.50). None of the patients in the FX group experienced any severe adverse effects, such as pancytopenia or attacks of gout, throughout the entire study period. Nephrologists were more likely than urologists to start febuxostat in kidney transplant recipients with PTHU (69% versus 8%).ConclusionTreatment with febuxostat sufficiently lowered uric acid levels without severe adverse effects in stable kidney transplant recipients with PTHU.

Urate lowering therapy with febuxostat in daily practice-a multicentre, open-label, prospective observational study.

Introduction. Febuxostat, a novel xanthine oxidase inhibitor for the treatment of symptomatic hyperuricemia, showed superiority over allopurinol in the reduction of serum uric acid levels in pivotal studies. Whether this holds true the FORTE (febuxostat in the oral urate lowering treatment: effectiveness and safety) study was conducted to evaluate treatment with febuxostat under daily practice conditions. Materials/Methods. The multicentre, open-label, and prospective observational study was conducted in 1,690 German medical practices from 9/2010 to 5/2011. Safety and efficacy data were assessed at baseline and week 4. Results. Data from 5,592 gout patients (72.6% male, mean age 63.7 years) were collected. Under urate lowering treatment with febuxostat mean serum uric acid levels decreased significantly from 8.9 ± 1.9 mg/dL (534.0 ± 114.6 μmol/L) at baseline to 6.2 ± 2.5 mg/dL (372.0 ± 150.0 μmol/L) at week 4. 67% which reached the mean uric acid target (6.1 ± 1.0 mg/dL [366.0 ± 59.4 μmol/L]). Only 43.1% of patients received concomitant flare prophylaxis. A total of 178 adverse events (mostly gout flares) were reported in 152 patients (2.6%). Conclusion. Febuxostat lowers serum uric acid levels effectively in routine clinical practice. Overall, treatment with febuxostat in both available dosages (80 mg/120 mg) was safe and well tolerated.

Safety and Efficacy of Allopurinol in Chronic Kidney Disease

To review the evidence surrounding the use of allopurinol in chronic kidney disease (CKD) and discuss safety and efficacy considerations of such use. A literature search was conducted through MEDLINE (1950-July 2013), PubMed (1965-July 2013), and International Pharmaceutical Abstracts (1970-July 2013) using the search terms allopurinol and kidney or renal. In addition, reference citations from publications identified were reviewed. All articles in English identified from the data sources were evaluated for inclusion. Gout management with allopurinol in patients with CKD can be challenging because of the risk of adverse events and uncertain efficacy. Not all gout treatment guidelines provide recommendations for allopurinol use specifically in patients with CKD. Literature regarding the safety and efficacy of dosing allopurinol in CKD has shown inconsistent results and is based primarily on retrospective, case cohort or observational data. Some trials have demonstrated an increased risk of allopurinol-induced adverse reactions in patients with CKD, whereas others have not confirmed renal insufficiency as a risk factor. More CKD patients achieved a target uric acid level in studies where the allopurinol dose was titrated to effect as compared with those studies in which patients were given renally adjusted or untitrated allopurinol doses. Studies evaluating allopurinol use in patients with CKD have reported inconsistent findings relative to safety and efficacy. Providers should be aware of the potential risk of allopurinol hypersensitivity syndrome as well as the need for reducing the initiation dose and gradual titration of allopurinol to safely achieve a target serum urate level in this population.

SAT0363 Evaluation of the Use of Colchicine in the Management of Chronic Gout

BackgroundThe rising cost of colchicine in the United States for the treatment of gout resulted in our evaluation of the use of colchicine in the management of gout.ObjectivesThe purpose of...

AB1083 Audit of best practice in gout management, dept of rheuamtology, new cross hospital wolverhampton

BackgroundGout is a condition characterised by the deposition of urate crystals in joint spaces. Prevalence is rising and affecting more than 1% of the western population.A study has shown an...

Allopurinol Still Called First Therapy for Gout

Allopurinol Still Called First Therapy for Gout

Opportunities for improving medication use and monitoring in gout

Purpose:To study patterns and predictors of medication use and laboratory monitoring in gout.Methods:In a cohort of veterans with a diagnosis of gout prescribed allopurinol, colchicine or probenecid, quality of care...

Status of Uric Acid Management in Hypertensive Subjects

Hyperuricemia in hypertensive subjects has been considered one of risk factors of cardiovascular diseases. We investigated the status of uric acid management in 799 hypertensive subjects (432 females and 367 males; mean age 70.9 years) managed by 43 doctors (19 cardiologists and 24 noncardiologists; 25 private practice doctors and 18 hospital doctors). The serum uric acid level was available in 85.7% of the patients. This availability was equivalent regardless of facility size, and more cardiologists than noncardiologists monitored this information. The prevalence of hyperuricemia was 17.5% and was higher in men and in patients with high triglyceridemia, left ventricular hypertrophy, renal dysfunction, proteinuria, and smokers, but was not higher in subjects with chronic heart failure, diabetes mellitus, and those with prescriptions for diuretics and beta-blockers. The average serum uric acid level was higher in men and patients with chronic heart failure, renal dysfunction, high triglyceridemia, low high-density cholesterolemia, smokers, and subjects prescribed beta-blockers. Fifty percent of hyperuricemic patients were medicated, and 48.6% of them cleared the uric acid target level (6 mg/dL). No differences were observed in the treatment rate or the achievement rate of the target between genders, concurrent diseases, and physician specialties. Although doctors, especially cardiologists, have a high concern for the serum uric acid level, they do not intervene intensively, and specific treatment for individual patterns is not routinely given. Thus, more attention to uric acid management is necessary in hypertensive subjects to prevent cardiovascular diseases.