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Background Hereditary renal hypouricemia type-1 (RHUC1) is caused by URAT1/SLC22A12 dysfunction, resulting in urolithiasis and exercise-induced acute kidney injury (EIAKI). Because, however, there is no useful experimental RHUC1 animal model, the precise pathophysiological mechanisms underlying EIAKI have yet to be elucidated. We established a high HPRT activity Urat1-Uox double knockout (DKO) mouse as a novel RHUC1 animal model for investigating the cause of EIAKI as well as the potential therapeutic effect of xanthine oxidoreductase inhibitors (XOIs). Methods The novel Urat1-Uox DKO mice were used in a forced swimming test as loading exercise to explore the onset mechanism of EIAKI and evaluate related purine metabolism and renal injury parameters. Results Urat1-Uox DKO mice had uricosuric effects and elevated levels of plasma creatinine (Cr) and blood urea nitrogen (BUN) as renal injury markers, and decreased Cr clearance (CLCr) observed in a forced swimming test. In addition, Urat1-Uox DKO mice had increased NLRP3 inflammasome activity and downregulated levels of Na+-K+-ATPase (NKA) protein in the kidney, as Western blot analysis showed. Finally, we demonstrated that topiroxostat and allopurinol, XOIs, improved renal injury and functional parameters of EIAKI. Conclusions Urat1-Uox DKO mice are a useful experimental animal model for human RHUC1. The pathogenic mechanism of EIAKI was found to be due to increased levels of IL-1β via NLRP3 inflammasome signaling and NKA dysfunction associated with excessive urinary UA excretion. In addition, XOIs appear to be a promising therapeutic agent for the treatment of EIAKI.

Background. The treatment of some forms of arti­cular pathology with gout remains insufficiently effective, and often it’s impossible to achieve normal indicators of uricemia on the background of uric acid-normalizing medicines. The purpose of the study is to evaluate the effect of the initial parameters of purine metabolism and molecules of medium mass (MMM) of different fractions on the effectiveness of uricodepressive and uricosuric therapy of gouty arthritis. Materials and methods. One hundred five patients with primary gout were exa­mined: 92 % of men and 8 % of women aged 26 to 76 years. Before the beginning of the treatment, the content of purine metabolism factors (uric acid, oxypurinol, adenine, guanine, xanthine, hypoxanthine, xanthine oxidase, xanthine deaminase, adenosine deaminase, 5-nucleotidase, molybdenum, lead), as well as MMM of different fractions (aminopeptide (AF), peptide (PF), nucleotide (NF), chromatogra­phic (ChF)) and integral medium molecular index (MMI) were studied in the blood serum. A spectrophotometer SF46, Olympus-AU640 bioana­lyzer and an atomic absorption spectro­meter with SolAAr-Mk2-MOZe electrographitic atomi­zer were used. The efficacy of treatment was assessed after 3–5 weeks. Results. In 27 % of cases, a slight improvement was observed, in 68 % — an improvement, in 8 % — a significant improvement. Primary gout occurs with disturbances in the metabolism of uric acid, oxypurinol, purine bases, purine metabolism enzymes and purine-associated microelements. The integral changes of them depend on the type of the joint syndrome, the presence of peri­pheral and bone tophi, determine bone-destructive articular injuries, while the predictive factor for the severity of arthropathy is considered to be the high level of purine bases in the blood. In cases of gout, the concentration of AF, PF, NF, ChF increases, as well as MMI. Meanwhile, the AF content is closely related to the severity of the joint syndrome, it determines the degree of joint space narrowing and subchondral sclerosis, the development of bone erosions and meniscus changes, and the MMM of different fractions correlate with the parameters of purine metabolism. A significant improvement and improvement during the pathogenetic the­rapy is observed in 3/4 of patients that is closely related to the form of arthritis, the presence of tophi and intraarticular Hoffa’s bodies, as well as the type of hyperuricemia, depends on the use of febuxostat, statins and fibrates, the state of purine metabolism, levels of MMM, NF and ChF fractions. Conclusions. The studied metabolic factors are not only involved in the pathogenesis of gouty arthritis, but also have an impact on the efficacy of uric acid-normalizing drugs.

Fur die bestmogliche Behandlung der Gicht ist eine umfangreiche Aufklarung des Patienten uber die Erkrankung und Therapieoptionen sowie systematisches Screening auf Komorbiditaten und eine Lebensstilmodifikation elementar. Beim Management des akuten Gichtanfalls sollte moglichst fruhzeitig mit der medikamentosen Therapie begonnen werden. Hier stehen Colchicin, nichtsteroidale Antirheumatika (NSAR) und Glukokortikoide oral oder intraartikular oder eine Kombinationstherapie zur Verfugung. Canakinumab ist Mittel der Wahl bei unzureichendem Ansprechen auf die Behandlung. Fur bis zu 6 Monate nach einem Anfall ist eine medikamentose Prophylaxe indiziert. Die harnsauresenkende Therapie (ULT) sollte zeitnah nach Indikationsstellung begonnen werden. Allopurinol ist Mittel der 1. Wahl. Liegen schwere Nierenfunktionseinschrankungen, Unvertraglichkeit oder unzureichendes Therapieansprechen vor, kommen alternativ Urikosurika, Febuxostat oder die Kombination aus einem Urikosurikum mit Febuxostat in Frage. Bei unzureichendem Therapieansprechen ist auch die Kombination von Allopurinol und einem Urikosurikum moglich. Zuletzt kann auch Pegloticase off-label eingesetzt werden. Die Therapieadharenz der ULT ist unzureichend. Comprehensive education about the disease and therapeutic options as well as lifestyle modification and screening for comorbidities are essential to treating gout optimally. Early onset of therapy is important in managing acute gout flares. Colchicine, nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticoids applied either orally or intraarticularly and combination therapy are regarded first choice in gout flare therapy. In case of insufficient treatment response, Canakinumab is indicated. Gout flare prophylaxis should be implemented for up to six months after the flare. Urate-lowering therapy is recommended to be commenced as early as possible. Whilst allopurinol is the substance of first choice, patients with severe renal impairment, allopurinol intolerance or an insufficient treatment response should be treated with febuxostat, a uricosuric or a combination of both. An additional option for patients responding inadequately to allopurinol is combining allopurinol with a uricosuric. In the last resort Pegloticase can be used off-label. Treatment adherence in ULT is poor.

The incidence and prevalence of gout have increased, as have comorbid obesity, diabetes mellitus, hypertension, chronic kidney and cardiovascular disease. Gout is now the commonest type of inflammatory arthritis despite availability of safe, effective and potentially ‘curative’ urate-lowering drugs. Modern imaging studies show that gout is a chronic inflammatory crystal deposition disorder even at the first acute attack and they illuminate the need to eliminate urate crystals by continuing reduction of the serum urate below its solubility threshold. Clinical outcomes, adherence to therapy and quality of gout care in primary care and hospital practice can be greatly improved by better use of allopurinol and flare prophylaxis, greater patient engagement, education and follow-up, and by nurse-led models of care that employ a ‘treat-to-target’ principle (SUA< 360 or 300μmol/l). Advances in understanding the physiology and genetic control of urate transport in the kidney and gut have led to novel, more selective uricosuric drugs, and basic research on mediators of urate crystal-induced inflammation has pointed to alternative therapeutic targets for treating and preventing gout flares. Current guidelines for the management of gout and indications for the use of some more recently introduced drugs; febuxostat, lesinurad, pegloticase and interleukin-1 antagonists are also briefly reviewed.

Background Dotinurad is a novel selective urate reabsorption inhibitor that reduces serum urate levels in hyperuricemic patients with or without gout by selectively inhibiting urate transporter 1. This study was conducted to compare the efficacy and safety of dotinurad with those of benzbromarone. Methods In this 14-week, randomized, multicenter, double-blind, parallel-group, dose escalation, benzbromarone-controlled, phase 3 study, hyperuricemic patients with or without gout were randomized to two groups that received either dotinurad 2 mg or benzbromarone 50 mg. Dotinurad or benzbromarone was administered once a day for 14 weeks. The primary endpoint was the percent change in serum uric acid level from the baseline to the final visit. Results A total of 201 Japanese hyperuricemic patients with or without gout (dotinurad: 102, benzbromarone: 99) received at least one dose of the study drug. The mean percent change in serum uric acid level from the baseline to the final visit in the dotinurad and benzbromarone groups was 45.9% and 43.8%, respectively. Non-inferiority of dotinurad 2 mg to benzbromarone 50 mg in lowering serum uric acid was verified by the predefined non-inferiority margin (95% CI − 1.27 to 5.37%). The incidence of adverse events and adverse drug reactions was comparable between the two groups. Conclusion Dotinurad 2 mg was verified to have a non-inferior serum uric acid lowering effect compared with benzbromarone 50 mg, in Japanese hyperuricemic patients with or without gout. ClinicalTrials.gov Identifier NCT03100318.

This review aims to determine the metabolic effect of hyperuricemia in pregnant woman, especially those with gestational diabetes mellitus (GDM). In women, the serum uric acid level is lower compared to men of similar age. The value is related to higher estrogen concentration to increase uric acid clearance. Hyperuricemia already established as independent risk factors for metabolic syndrome and cardiovascular disease (CVD) as well as type 2 Diabetes Mellitus (DM). Asymptomatic hyperuricemia in non-pregnant adult women will increase insulin resistance due to oxidative stress, and production of inflammatory cytokine (tumor necrosis factor-a), which inevitably increases blood sugar level. Uric acid level and serum creatinine is lower in normal pregnancy due to increased renal clearance and the uricosuric effect of estrogen. Hyperuricemia is one of the contributing factors associated with insulin resistance among pregnancy instead direct effect of placental hormones. Earlier in the first trimester of pregnancy, the risk for GDM is increased. However, the causal effect of uric acid levels on DM still requires further study .

Background Dotinurad, a novel selective urate reabsorption inhibitor, exerts a serum uric acid-lowering effect by selectively inhibiting urate transporter 1 (URAT1) in patients with hyperuricemia. It is generally known that the progression of renal dysfunction is associated with a reduction in the serum uric acid-lowering effects of uricosuric drugs. We, therefore, investigated the pharmacokinetics (PK), pharmacodynamics (PD), and safety of dotinurad in subjects with renal dysfunction. Methods This was a parallel-group, open-label, single-dose clinical pharmacology study. Dotinurad (1 mg) was administered once, orally to subjects with mild (estimated glomerular filtration rate [eGFR], ≥ 60 to 2) or moderate (eGFR, ≥ 30 to 2) renal dysfunction or normal (eGFR, ≥ 90 mL/min/1.73 m2) renal function. Results The time-course of mean plasma concentration of dotinurad had similar profiles across the groups. Regarding PK, there was no significant difference between the renal dysfunction groups and normal renal function group. Regarding PD, the maximum reduction rate in serum uric acid levels and the fractional uric acid excretion (FE) ratio (FE0–24/FE−24–0) were significantly lower in the moderate renal dysfunction group than in the normal renal function group. However, other PD parameters were not significantly different among the groups. No notable adverse events or adverse drug reactions were observed in this study. Conclusion These results suggested that no dose adjustment might be necessary when administering dotinurad to patients with mild-to-moderate renal dysfunction. ClinicalTrials.gov Identifier: NCT02347046.

Gout is more prevalent than ever and is associated with multiple chronic comorbidities, including Chronic Kidney Disease (CKD). While goals of treatment are the same as in those without renal impairment, co-morbid CKD poses a challenge in treatment selection and requires a solid understanding of potential drug-drug interaction and drug-related toxicity. In acute gout complicated by CKD, NSAIDs should be avoided, and colchicine used with caution. Systemic corticosteroids are effective but may be replaced by anakinra, in particular in inpatients with additional comorbidities that may make corticosteroids less desirable. Allopurinol remains the first line urate lowering therapy (ULT), starting at a low dose followed by careful goal driven up-titration. Febuxostat is a reasonable alternative, though second line in light of recent cardiovascular data. Uricosuric drugs are generally less effective, while pegloticase is reserved for refractory cases of polyarticular tophaceous disease. Gout treatment must be guided by renal function but in spite of renal disease can be successfully managed.

In clinical trials, few investigations have been conducted to determine the mechanism involved in teriflunomide-associated kidney stone formation. We report the first case of recurrent teriflunomide-induced uric acid urolithiasis. A 55-year-old man with relapsing-remitting multiple sclerosis experienced three occurrences of urolithiasis several months after the initiation of teriflunomide. While serum uric acid remained stable at 280 mmol/L, 24-hour urine uric acid was increased to 2195 mmol/24h. For the third episode, computed tomography showed three bladder stones and one stone in the right calyceal group. Endovesical lithotripsy was used to extract four orange-colored stones of more than 20 mm. Stone analysis exhibited morphology subtype IIIb with 100% of anhydrous uric acid. Given the disease control, teriflunomide was continued. After urinary alkalinisation by potassium citrate, the patient remained asymptomatic at 18 months follow-up. An inhibitory effect of dihydroorotate and/or teriflunomide on urate tubular reabsorption could explain teriflunomide-associated uric acid urolithiasis. This case in a patient without risk factors suggests that multiple sclerosis patients may be at greater risk of forming uric acid urinary stones when taking teriflunomide. Alkalinization of the urine may reduce the risk of recurrence, allowing further treatment with teriflunomide.

Background This study was designed to evaluate the impact of polymorphisms in the urate transporter 1 (URAT1) gene on the uricosuric action of losartan therapy in hypertensive patients suffering from hyperuricemia. Methods A MassARRAY approach was used to detect single nucleotide polymorphism (SNP) loci in the URAT1 and CYP2C9 genes (16 and 2 loci, respectively) in 111 patients with hypertension and hyperuricemia taking losartan and in 121 healthy controls. In addition, we compared serum urate (SUA) levels and other key clinical biochemistry indices between these two patient groups. Results We detected significant differences between the two patient groups with respect to age, SUA, urea, creatine, triglycerides, high‐density lipoprotein, low‐density lipoprotein, and fasting plasma glucose (all p, 121 healthy people and 111 patients with hypertension and hyperuric acid were screened out, 16 SNP loci of URAT.1 and 2 SNP loci of CYP2C9 were detected by MASS‐ARRAY technology. Through analysis, it was found that only rs3825016 was meaningful, We observed that patients with the heterozygous genotype (CT) exhibited a more pronounced decrease in uric acid levels.

Probenecid is a uricosuric drug, which inhibits the renal excretion of procaine penicillin via inhibition of the organic anion transporter (OAT-1) system in the proximal renal tubule producing higher plasma and cerebrospinal fluid (CSF) penicillin levels.1 2 Oral probenecid is recommended to be used with intramuscular procaine penicillin for the treatment of neurosyphilis. Rates of syphilis and neurosyphilis have increased significantly over the past 20 years particularly in men who have sex with men (MSM). There …

Gout is an auto-inflammatory disease driven by urate deposits with a second co-stimulatory factor evoking an (peri)arthritic fulminant inflammation often with a debute at night; inflammatory signals are enhanced via a NLRP3 pathway. In gout patients, urate metabolism has had a positive balance for a time period of weeks to years before the arthritic syndrome or tophaecous disease becomes manifest. This may be due to katabolism or weight loss, enhanced dietary affluence, and overweight resulting in increased serum urate levels. Also, a decreased urate excretion results in proneness to hyperuricaemia and clinical gout. Pharmacotherapeutically, a negative urate balance should be the aim of clinicians and then the rational choice of treatment with uricosurics seems quite logical and promising, but has not had a thorough attention of pharma, researchers nor of clinicians, though most gout patients were and still are low excretors. Here, an overview on the 70-year-old journey mankind has made in a search for uricosurics resulting so far in only 1 registered uricosuric per continent.

Dendropanax morbifera is a well-known traditional medicine used in China and Korea to treat intestinal disorders, urosis, diuresis, and chronic glomerulonephritis. Hyperuricemia is a metabolic disorder characterized by a high uric acid level in serum due to an imbalance between uric acid production and excretion and causes gout. Recently, the prevalence of hyperuricemia worldwide has been continuously increasing. Xanthine oxidase (XOD) inhibitors (allopurinol (ALP) and febuxostat) and uricosuric agents (benzbromarone and probenecid) are used to treat hyperuricemia clinically. However, because these drugs are poorly tolerated and cause side effects, such as kidney diseases, hepatotoxicity, gastrointestinal symptoms, and hypersensitivity syndrome, only a limited number of drugs are available. We investigated the antihyperuricemic effects of Dendropanax morbifera leaf ethanol extract (DMLE) and its underlying mechanisms of action through in vitro and in vivo studies. We evaluated uric acid levels in serum and urine, and xanthine oxidase (XOD) inhibition activity in the serum and liver tissue of a hyperuricemic rat model of potassium oxonate (PO)-induced hyperuricemic rats. In vitro study, XOD-inhibitory activity was the lowest among the test substances at the IC50 of ALP. However, the IC50 of DMLE-70 was significantly low compared with that of other DMLEs ( p < 0.05 ). In PO-induced hyperuricemic rats, uric acid (UA) levels in serum and urine were significantly reduced in all DMLE-70 and allopurinol-treated (ALT) groups than in the PC group ( p < 0.05 ). UA levels in urine were lower than those in serum in all DME groups. In PO-induced hyperuricemic rats, DMEE-200 reduced UA concentration in serum and increased UA excretion in the urine. These findings suggest that DMLE exerts antihyperuricemic and uricosuric effects on promoting UA excretion by enhanced secretion and inhibition of UA reabsorption in the kidneys. Thus, DMLE may be a potential treatment for hyperuricemia and gout.

Solidago virgaurea L. is a perennial plant used in European traditional medicine as a diuretic or a remedy for inflammatory conditions of the urinary tract but also for gout, especially in the Balkans. The present study was focused on a preclinical, in vivo evaluation of antihyperuricemic, anti-inflammatory, and antihypertensive effects of a dry extract from S. virgaurea L. (ESV). Colorimetric and HPLC–MS techniques were used to identify the main chemical constituents of ESV. Antihyperuricemic effect of ESV was assessed in a rat model of hyperuricemia induced by the administration of potassium oxonate. Antihypertensive effect of ESV was evaluated in hyperuricemic rats by monitoring systolic blood pressure with a non-invasive blood-pressure recording system. The anti-inflammatory effect of ESV was tested using a rat model of paw edema. The main chemical constituents of ESV were rutin and phenolic acids represented by chlorogenic and caffeic acid. ESV demonstrated significant antihyperuricemic effects in rats due to an uricosuric mechanism. Additionally, ESV reduced the progression of arterial hypertension in hyperuricemic rats and also showed anti-inflammatory properties slightly inferior to diclofenac. The results suggest that ESV could be a natural remedy for the treatment of gout and protection against endothelial dysfunction caused by hyperuricemia.

Background: Serum urate (SU) levels in primates are extraordinarily high among mammals. Urate is a Janus-faced molecule that acts physiologically as a protective antioxidant but provokes inflammation and gout when it precipitates at high concentrations. Transporters play crucial roles in urate disposition, and drugs that interact with urate transporters either by intention or by accident may modulate SU levels. We examined whether in vitro transporter interaction studies may clarify and predict such effects. Methods: Transporter interaction profiles of clinically proven urate-lowering (uricosuric) and hyperuricemic drugs were compiled from the literature, and the predictive value of in vitro-derived cut-offs like Cmax/IC50 on the in vivo outcome (clinically relevant decrease or increase of SU) was assessed. Results: Interaction with the major reabsorptive urate transporter URAT1 appears to be dominant over interactions with secretory transporters in determining the net effect of a drug on SU levels. In vitro inhibition interpreted using the recommended cut-offs is useful at predicting the clinical outcome. Conclusions: In vitro safety assessments regarding urate transport should be done early in drug development to identify candidates at risk of causing major imbalances. Attention should be paid both to the inhibition of secretory transporters and inhibition or trans-stimulation of reabsorptive transporters, especially URAT1.

Background Patients with gout have an increased risk of urolithiasis and usually need urate-lowering therapy (ULT) for the prevention of disease progression. However, there is a paucity of clinical data regarding the risk of future urolithiasis in ULT users. Methods This nested case-control study was performed using the Taiwan National Health Insurance Research Database. The aim of this study was to examine whether ULT (xanthine oxidase inhibitors [XOIs] or uricosuric agents) is associated with risk of future urolithiasis in patients with gout. Data were collected from January 2000 to December 2012. Results This study included 2307 case patients and 2307 matched controls. Case patients had gout that developed into urolithiasis, and control patients had gout but were not diagnosed with urolithiasis during the study period. Patients had a mean age of 56.3 years at diagnosis of gout, and 83.2% were male patients. No association was detected between use of XOIs or uricosuric agents and risk of future urolithiasis. Furthermore, there was no significant difference in the risk of future urolithiasis in patients exposed to various cumulative days of XOI or uricosuric prescriptions. Conclusion The present study provides evidence that neither XOIs nor uricosuric agents are associated with risk of future urolithiasis in patients with gout. Before the availability of more clinical evidence, ensuring high fluid intake and prospective monitoring of urolithiasis development are still important for uricosuric agent users.

The aim of this review is to present current evidence about the efficacy and safety of lesinurad in combination with xanthine oxidase inhibitors (XOIs) in the treatment of hyperuricemia in patients with gout. Gout is the most common inflammatory form of arthritis. It is caused by an elevated concentration of serum uric acid (UA) that leads to the formation of monosodium urate crystals in joints and different tissues. The goal of therapy is to maintain serum UA levels at

The naturally available uricosuric agents are Tinospora cardifolia, Allium sepa, Cajanus Cajan, Piper nigrum etc., Natural medicinal plants having no side effects are more preferred when compared to synthetic medications. Uricosuric agents increase the urinary excretion of uric acid hence the natural uricosuric agent is preferred to prevent many diseases like gout, arthritis, kidney stones etc., without side effect. Uricosuric medications are the substances that increase the excretion of uric acid in urine, thus reducing the concentration of uric acid in blood plasma. Prolonged and untreated hyperuricemia results into gout, a severe inflammatory condition. Sustain hyperuricemia leads to impaired blood pressure control, renal impairment and nephropathy. The common factors for deposition of uric acid in blood are drinking alcohol and taking high purine diet. The various screening methods for the uricosuric activity are uricosuric activity in mice, Potassium oxonate induced activity, and Phenol red excretion methods are explained in this review.

This article aims to critically review the evidence on the available therapeutic strategies for the treatment of hyperuricemia. For this reason, several papers were reviewed. Xanthine oxidase inhibitors are the safest and most effective uric acid lowering drugs for the management of chronic hyperuricemia, while the efficacy of uricosuric agents is strongly modulated by pharmacogenetics. Emergent drugs (lesinurad, peglotidase) were found to be more effective for the acute management of refractory hyperuricemia, but their use is supported by a relatively small number of clinical trials so that further well-designed clinical research is needed to deepen their efficacy and safety profile.

Gout is a rare phenomenon in reproductive age women due to the uricosuric effects of estrogen. Furthermore, gout in pregnancy has been reported in only a scant number of case reports. We present the case of a 21-year-old gravida-4 para-3 female at four-weeks gestation presenting with acute polyarticular gout, complicated by Haemophilus influenzae sepsis and hyperemesis gravidarum. The gout flare was likely precipitated by primary H. influenzae bacteremia, which was successfully treated with intravenous antibiotics. The treatment of gout in pregnancy is challenging because of the limited number of guidelines. We demonstrate successful management of an acute gout flare in pregnancy with colchicine and steroid injection of the affected joint. Unfortunately, the patient suffered a miscarriage, but the link between gout flare and spontaneous abortion is tenuous.

The most recent European Alliance of Associations for Rheumatology (EULAR) recommendations for gout advise against maintaining a serum urate (SU) level of3 mg/dl for prolonged periods of time. While several Asian cohort studies have shown higher rates of mortality in individuals with extremely low SU levels, data from non-Asian cohort studies are scarce, and the relationship between hypouricemia, cardiovascular risk, and mortality remains unclear.Using data collected from the 1988-1994 and 1999-2008 National Health and Nutrition Examination Survey (NHANES), we examined the relationship between SU level and overall and cause-specific mortality in 41,807 adults in the US. We calculated multivariable hazard ratios (HRs) that were compared to a referent SU level of 5-6 mg/dl for SU categories4, 4-5, 6-7, 7-8, and8 mg/dl in men and SU categories3, 3-4, 4-5, 6-7, and7 mg/dl in women.A higher mortality risk was not observed in women who had an SU level of3 mg/dl (HR 1.09 [95% confidence interval (95% CI) 0.92-1.28]). A 28% higher mortality risk was observed in men who had an SU level of4 mg/dl (HR 1.28 [95% CI 1.13-1.45]), with a nearly three-times higher mortality risk from diabetes mellitus also noted (HR 2.89 [95% CI 1.59-5.23]), but no increase in mortality from any other specific cause.We found no long-term excess mortality risk among American women with SU levels as low as3 mg/dl, a finding which is incompatible with the notion of a causal relationship between hypouricemia and premature mortality in women. We found excess all-cause mortality and diabetes mellitus-related mortality among hypouricemic American men, which may in part be attributable to the uricosuric effect of hyperglycemia in fatal uncontrolled diabetes mellitus (analogous to reverse causality).

Background The 24-hour uric acid excretion measurement is important in assessing disease status and helping to select the appropriate uric acid-lowering agent for patients with gout, however, it is inconvenient. The authors investigated the efficacy of the random urine uric acid-to-creatinine (UA/CR) ratio to screen the patients who under-secreted 24-hour urine uric acid. Methods This was a retrospective cross-sectional study. Ninety patients with gout, without undergoing uric acid-lowering treatment were enrolled. Twenty-four-hour urine and random urine samples were obtained on the same day. Six hundred mg of uric acid in the 24-hour urine sample was used as a standard for distinguishing between over and under-excretion groups. Results The random urinary UA/CR ratio showed positive correlation with 24-hour urine uric acid excretion (γ = 0.398, P < 0.001). All the patients with the random UA/CR less than 0.2 excreted less than 600 mg uric acid in 24-hour urine collection. When the random urine UA/CR ratio < 0.2 was regarded as a positive result, the positive predictive value, negative predictive value, sensitivity, and specificity in the uric acid under-excretion were 100% (8 of 8), 64.6% (53 of 82), 21.6% (8 of 37), and 100% (53 of 53), respectively. Conclusion There is a moderate positive correlation between the random urinary UA/CR ratio and 24-hour urine uric acid excretion, so that UA/CR ratio may not be a good predictor of 24-hour urine uric acid excretion. However, the random urine UA/CR ratio 0.2 can be a useful predictor to screen the gouty patients who need to be treated with uricosuric drugs., Graphical Abstract

Recently, the US Food and Drug Administration (FDA) issued a public safety alert, responding to the results of the now-published Cardiovascular Safety of Febuxostat and Allopurinol in Patients With Gout and Cardiovascular Morbidities (CARES) trial. The CARES trial showed no significant difference between allopurinol and febuxostat in the primary composite end point of cardiovascular (CV) events in subjects with gout and established CV comorbidities at baseline. However, there was a significantly increased risk of CV and all-cause mortality with febuxostat. Urate-lowering therapy (ULT) is central to the long-term management of gout, and xanthine oxidoreductase inhibitor (XOI) therapy is the consensus first-line approach. Allopurinol is generally the first XOI used, but febuxostat is an effective XOI option, and is commonly used when allopurinol is not tolerated. These data are further relevant since CV comorbidities are common in gout. Here, we examine why the CARES trial was done, and discuss other, ongoing comparative studies of febuxostat and allopurinol whose results are awaited. We assess the strengths and limitations of the CARES trial, and appraise the robustness and biologic plausibility of the results. The CARES trial does not prove that febuxostat raises CV mortality risk, but suggests greater risk with febuxostat than allopurinol. The CARES trial results do not support first-line use of febuxostat ULT, and raise questions about febuxostat placement at various pharmacologic ULT decision tree branches. Alternatives to febuxostat that are frequently effective include allopurinol dose escalation and uricosuric therapy alone or combined with allopurinol. The FDA safety alert highlights the need for shared ULT medical decision-making with gout patients, including discussion of the CV safety of febuxostat.

Purpose of review SGLT2 inhibitors are a new class of antihyperglycemic drugs that protect kidneys and hearts of type 2 diabetic (T2DM) patients with preserved kidney function from failing. Here we discuss new insights on renal protection. Recent findings Also in T2DM patients with CKD, SGLT2 inhibition causes an immediate functional reduction in glomerular filtration rate (GFR) and reduces blood pressure and preserves kidney and heart function in the long-term, despite a lesser antihyperglycemic effect. According to modeling studies, the GFR reduction reduces the tubular transport work and metabolic demand, thereby improving renal cortical oxygenation. In humans, the latter is linked to protection from CKD. Urine metabolomics in T2DM patients suggested improved renal mitochondrial function in response to SGLT2 inhibition, and experimental studies indicated improved tubular autophagy. Modeling studies predicted that also in diabetic CKD, SGLT2 inhibition is natriuretic and potentially stimulates erythropoiesis by mimicking systemic hypoxia in the kidney. Meta-analyses indicated that SGLT2 inhibition also reduces risk and severity of acute kidney injury in T2DM patients. Studies in nondiabetic mice implied inhibition of the renal urate transporter URAT1 in the uricosuric effect of SGLT2 inhibition. Summary Renoprotection of SGLT2 inhibition involves blood glucose-dependent and independent effects and extends to CKD.

Uric acid (UA) is synthesized mainly in the liver, intestines, and vascular endothelium as the end product of an exogenous purine from food and endogenously from damaged, dying, and dead cells. The kidney plays a dominant role in UA excretion, and the kidney excretes approximately 70% of daily produced UA; the remaining 30% of UA is excreted from the intestine. When UA production exceeds UA excretion, hyperuricemia occurs. Hyperuricemia is significantly associated with the development and severity of the metabolic syndrome. The increased urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) expression, and glycolytic disturbances due to insulin resistance may be associated with the development of hyperuricemia in metabolic syndrome. Hyperuricemia was previously thought to be simply the cause of gout and gouty arthritis. Further, the hyperuricemia observed in patients with renal diseases was considered to be caused by UA underexcretion due to renal failure, and was not considered as an aggressive treatment target. The evidences obtained by basic science suggests a pathogenic role of hyperuricemia in the development of chronic kidney disease (CKD) and cardiovascular diseases (CVD), by inducing inflammation, endothelial dysfunction, proliferation of vascular smooth muscle cells, and activation of the renin-angiotensin system. Further, clinical evidences suggest that hyperuricemia is associated with the development of CVD and CKD. Further, accumulated data suggested that the UA-lowering treatments slower the progression of such diseases.

Aims Dual-urate-lowering therapy (ULT) with xanthine oxidase inhibitor and uricosuric medications is a treatment option for severe gout. Uricosuric agents can cause hyperuricosuria, a risk factor for nephrolithiasis and acute uric acid nephropathy. The aims of the present study were to simulate the relationship between suboptimal drug adherence and efficacy, and to quantify the risk of hyperuricosuria in gout patients receiving mono- and dual-ULTs. Methods The impact of poor medication adherence was studied using two-compartment pharmacokinetic (PK) models based on published evidence, and a semi-mechanistic four-compartment pharmacodynamic (PD) model. The PKPD model was used to simulate mono and dual-ULT in gout patients with either under-excretion (lowered clearance) or overproduction of uric acid, with suboptimal adherence modelled as either a single drug holiday of increasing duration or doses taken at random. Results Simulation results showed a surge in urinary uric acid occurring when dosing is restarted following missed doses. For under-excreters taking a 20-day drug holiday, the addition of 200 mg (or 400 mg) lesinurad to 80 mg febuxostat increased the percentage of patients experiencing hyperuricosuria from 0% to 1.4% (or 3.1%). In overproducers, restarting ULTs following drug holidays of more than 5 days leads to over 60% of patients experiencing hyperuricosuria. Conclusions Suboptimal medication adherence may compromise the safety and efficacy of mono- and dual-ULTs, especially in patients with gout resulting from an overproduction of uric acid. Clinicians and pharmacists should consider counselling patients with respect to the risks associated with partial adherence, and offer interventions to improve adherence or tailor treatments, where appropriate.

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

The purpose of this meta-analysis was to determine if uric acid-lowering therapy is associated with a decrease in blood pressure (BP) and serum creatinine levels.Medline, Cochrane, EMBASE, and Google Scholar databases were searched until 29 June 2016, with keywords: uric-acid-lowering therapy, allopurinol, febuxostat, uricosuric, and BP. Only randomized controlled trials were included. The primary outcomes were reduction in systolic BP (SBP) and diastolic BP (DBP), and secondary was reduction in serum creatinine level.Patients treated with allopurinol had greater reduction in SBP (standardized difference in means [SDM] = 0.321, 95% confidence interval [CI]: 0.145-0.497, p 0.001), DBP (SDM = 0.260, 95% CI: 0.102 to 0.417, p = 0.001), and creatinine level (SDM = 0.312, 95% CI: 0.008 to 0.615, p = 0.044) than control patients. Subgroup analysis showed that allopurinol significantly decreased SBP whether or not antihypertensive drugs were being administered; a decrease in DBP was only seen in patients receiving antihypertensive drugs. Low-dose allopurinol (≤300 mg/day) was more effective at reducing SBP than high-dose (300 mg/day) in patients receiving antihypertensive drugs.These results support that allopurinol decreases BP and creatinine levels in patients with hyperuricemia. KEY MESSAGES Allopurinol decreases SBP and DPB, and creatinine levels in patients with hyperuricemia. Allopurinol resulted in a significant decrease in SBP in patients with or without treatment of antihypertensive drugs. A dose of allopurinol of ≤300 mg per day might be more effective than a higher dose.

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.

Gout is characterized by precipitation of uric acid, the end product of purine metabolism, in joints, soft tissues, and the urinary system. The symptoms of acute gout are monoarthritis with severe pain, restricted joint mobility, and hyperthermia. This condition can be effectively treated with COX inhibitors, GCR agonists, as well as microtubule and IL-1 inhibitors. Symptoms of chronic gout are polyarthritis with rest pain and impaired mobility. A calorie- and purine-reduced diet is the basis of long-term gout therapy. Uricostastic drugs (XO inhibitors) alone or in combination with uricosuric drugs (inhibitors of URAT1) are used for long-term gout therapy. With rigorous diet and stringent pharmacotherapy, gout has a good prognosis.

Uric acid (UA) has been associated with hypertension, renal disease and cardiovascular disease. The aim of the present study was to compare the UA-lowering effects of a standard dose of the UA synthesis inhibitor febuxostat to a standard dose of the uricosuric agent benzbromarone, and to investigate the effects of a low-dose combination of both agents in hypertensive patients with hyperuricemia. Twenty hypertensive patients with inadequate UA control were administered febuxostat 40 mg (Feb), benzbromarone 50 mg (Ben) and febuxostat 20 mg and benzbromarone 25 mg (feb/ben) for 3 months each in a randomized modified crossover manner. UA metabolism, blood pressure (BP) and the indices of organ damage were assessed at baseline and the end of each treatment period. No significant changes were observed in BP or estimated glomerular filtration rate (eGFR) after the treatment with each UA-lowering regimen. The change in UA was significantly greater with feb/ben than with Feb. The excretion of UA and clearance of UA were higher with Ben than with Feb and feb/ben. Urinary 8-hydroxydeoxyguanosine and liver-type fatty-acid-binding protein levels were slightly lower with Ben, whereas flow-mediated dilation was slightly higher with feb/ben and Ben. The UA-lowering effects of the low-dose combination of the UA synthesis inhibitor and uricosuric agent were greater than those of the standard dose of each agent alone. The uricosuric agent may be more effective at improving vascular function than the UA synthesis inhibitor. Thus, the appropriate management of hyperuricemia with uricosuric drugs appears to be useful for hypertensive patients with hyperuricemia.

Background Benzbromarone is a potent uricosuric, but is not widely available due to concerns about hepatotoxicity. In Aotearoa New Zealand benzbromarone has been available since April 2013, subject to funding restrictions, for patients with inadequate urate-lowering response or intolerance to allopurinol and probenecid. Aim The aim of this study was to assess the safety and efficacy of benzbromarone in a real-life setting. Methods All patients who received funding for benzbromarone from 1/4/2013 to 30/9/2014 were identified. Prescribers were sent a questionnaire for each individual. Information on demographics, efficacy of previous urate-lowering drugs and reasons for discontinuation were collected. Specific information about the dose, effect on serum urate, adverse effects and liver function tests after commencing benzbromarone was recorded. Results Completed questionnaires were returned for 123/164 (75%) patients. Mean (SD) serum urate prior to benzbromarone was 0.57 (0.12) mmol/l and estimated glomerular filtration rate (eGFR) 50.3 (22.8) ml/min/1.73 m2. The median dose of benzbromarone was 100 mg/day (25-200 mg/day). Six months after commencing benzbromarone, mean (SD) serum urate was 0.35 (0.12) mmol/l. Benzbromarone related adverse events included rash (n = 4), diarrhoea (n = 9), nausea (n = 6), and urate stones (n = 3). Liver function tests abnormalities were uncommon and tended to be mild. There were 14 patient deaths; none were considered related to benzbromarone. Allopurinol had been prescribed prior to benzbromarone in 117/123 patients; median maximum allopurinol dose was 200 mg/day (range 25-600 mg/day), and 19% patients received allopurinol >300 mg/day. Conclusions Benzbromarone provides useful urate-lowering efficacy and does not appear unsafe in patients with gout. Urate-lowering therapy prescribing requires further optimisation.

This review aims to put forth an overview of natural products reducing uric acid level with hepatorenal dual effects. The prevalence of hyperuricemia increased rapidly in recent years and has closely interdependent relationship with other metabolic disorders. Current therapeutically used drugs including a few uricostatic and uricosuric chemical drugs are proved efficient to control serum uric acid level. However, their side effects as well as contraindication in some cases with liver, kidney injury, or other conditions frequently limit their clinic application. More attention thus has been paid to natural products as an alternative means in treating hyperuricemia. Many natural products have been proved efficient in downregulating uric acid level, among which some can improve hyperuricemia with hepatorenal dual effects. It means these natural products can regulate both the production and the excretion of uric acid by targeting the key metabolic enzymes mainly in liver or uric acid transporters in kidneys. Thus, these natural products could have stronger efficacy and broader application, which may be developed for the treatment of hyperuricemia in clinic.

Rationale Lesch-Nyhan syndrome (LNS) is an X-linked recessive disorder presenting with uric acid overproduction, neurocognitive disability, and behavioral disturbances. Inhalational anesthesia has been frequently used in LNS patients undergoing surgery. Characteristic compulsive self-injurious behavior and high risk of emesis may hinder inhalational induction. Propofol may be beneficial for these patients because of its easy and rapid titration for anesthetic depth during induction, early recovery from anesthesia, and antiemetic effect as well as uricosuric effect. Patient concerns A 16-year-old male adolescent was scheduled for percutaneous nephrolithotomy. He exhibited poorly controlled muscle, self-injurious behaviors and intellectual disability. Diagnosis The patient presented with neurodevelopmental delay in the first year of life, and was diagnosed with LNS, with a substitution of phenylalanine to leucine in hypoxanthine-guanine phosphoribosyltransferase (HPRT) 1 gene on the X-chromosome at 3 years of age. Interventions Total intravenous anesthesia was used for induction and maintenance of anesthesia with propofol and remifentanil using target-controlled infusion. Outcomes Time to recovery of consciousness was prolonged after uneventful surgery. Serum uric acid levels gradually increased during postoperative period. Lessons Propofol anesthesia using target-controlled infusion does not provide significant clinical advantages in rapid emergence from anesthesia and management of hyperuricemia in LNS patients undergoing urological surgery.

Objective To compare outcomes of 2 gout clinics that implemented different treatment strategies. Methods Patients newly diagnosed with gout and a follow-up of 9-15 months were included. Co-primary outcomes were the proportion of patients reaching a serum uric acid (UA) ≤0.36 mmoles/liter and free of flares. Secondary outcomes were the proportion of patients requiring treatment intensification and experiencing adverse events. One clinic adopted a strict serum UA (≤0.30 mmoles/liter target) strategy, with early addition of a uricosuric to allopurinol, and the other clinic adopted a patient-centered (PC) strategy emphasizing a shared decision based on serum UA and patient satisfaction with gout control. Independent t-tests or chi-square tests were used to test differences in outcomes, and logistic regressions were used to adjust the effect of the treatment center on outcomes for confounders. Results In total, 126 and 86 patients had a follow-up mean ± SD of 11.3 ± 1.8 versus 11.1 ± 1.9 months. In the UA strategy, 105 of 126 patients (83%) compared to 63 of 86 (74%) in the PC strategy (P = 0.10) reached the threshold of ≤0.36 mmoles/liter; and 58 of 126 (46%) versus 31 of 86 (36%) were free of flares (P = 0.15). In the UA strategy, 76 of 126 patients (60%) were on allopurinol monotherapy compared to 63 of 86 (73%) in the PC strategy (P = 0.05), yet the number of adverse events was not different (n = 25 [20%] versus n = 20 [23%]; P = 0.55). Adjusting for confounders did not substantially change these associations. Conclusion A strict UA strategy resulted in a nonsignificantly higher proportion of patients reaching a serum UA ≤0.36 mmoles/liter and being free of flares. This result was accomplished with significantly more therapy intensification. The small sample size plays a role in the significance of results.

Over the last 70 years, pharmacotherapy in gout with urate-lowering drugs has consisted of four drugs only: In 1952, a mild uricosuric probenecid became available, the xanthine oxidase inhibitor Allopurinol in 1964, and the latter became the most frequently used urate-lowering drug worldwide; in the Eurozone, the uricosuric benzbromarone was welcomed in 1977. Only in 2002, the potent non-purine xanthine oxidase inhibitor febuxostat was introduced. In many countries, uricosurics such as probenecid and benzbromarone have not been available up to now, and these days, the new uricosuric lesinurad is the first uricosuric that may be introduced in these countries, which is the reason for describing the position this novel uricosuric deserves in treating gout. Recent literature will be shortly reviewed, and the current proposed position for lesinurad will be given as an aid for clinicians.

Gout is an increasingly common chronic disorder of urate crystal deposition that manifests as flares of acute inflammatory arthritis. Hyperuricaemia is a prerequisite and a fifth of both men and woman are hyperuricaemic. The prevalence of gout is much lower than the prevalence of hyperuricaemia for reasons that are not currently clear. Gout is more common in men than women prior to menopause due to the uricosuric effects of oestrogen, but after menopause the incidence of gout rises substantially in women. Co-morbidities are an important issue in gout, with cardiovascular disease, diabetes mellitus, obesity and chronic kidney disease all common in patients with gout. Environmental factors like diet affect the incidence of gout but there is little evidence to support an emphasis on diet in treating established gout. The diagnosis of gout is often made without the use of joint aspiration and validated diagnostic rules are available for both primary and secondary care as well as classification criteria for research use. The overarching principle of the management of gout with pharmacotherapy is the need to reduce serum urate levels to below a target of 0.30 mmol/L or 0.36 mmol/L depending on whether it is tophaceous or non-tophaceous respectively. The use of allopurinol has been researched extensively and newer strategies for safer effective dosing are now recommended. Newer agents have been introduced for the treatment of gout, including febuxostat and lesinurad. A number of important questions in the field are under current investigation.

We have previously shown a strong relation between high serum uric acid and pulse wave velocity (PWV) as expression of arterial stiffness. This relation was even stronger than with blood pressure. In addition to its hypoglycemic effect, sodium-glucose transport protein 2 inhibitors (SGLT2i) may reduce serum uric acid (SUA) by a uricosuric effect. Aims: to evaluate in type 2 diabetic patients with hypertension and normal renal function the effect of canagliflozin on SUA and carotid femoral PWV. Methods: 20 patients with type 2 diabetes mellitus (DM) 10 females, 59±4y received metformin 2000mg, canagliflozin 100-300mg and amlodipine 10mg daily during 6 months. Laboratory parameters including HbA1C, fasting blood glucose level, glomerular filtration rate, SUA, 24h ambulatory blood pressure monitoring (ABPM) and PWV were determined at baseline and after a 6-month treatment course with canagliflozin 100-300mg. Results: After 6 months of treatment, PWV dropped from 12±3 to 8.5±4 m/sec, p Conclusions: Canagliflozin ameliorates arterial stiffness in patients with type 2 DM and hypertension. This effect seems to be related, among other mechanisms, such as blood pressure drop and plasma volume contraction to the reduction in serum uric acid level. Since SUA has been shown to predict the risk of cardiovascular morbidity and mortality in hypertension and DM, lowering serum uric acid by SGLT2i might be contributing to cardiovascular protection. Disclosure R.A. Sanchez: None. M.J. Sanchez: None. A.J. Ramirez: None.

Background Studies on renal solute carrier transporters have made the renal pathophysiology be in progress towards more mechanistic and the knowledge on renal drugs including drug-drug interaction be more evidentiary. Among the evidence, uricosuric phenomenon has been known that rodent experimental model is also useful for predicting human uricosuria. Objectives The aim of this study was to assess the substrate uptake at the overexpression of renal transporters, OAT1, OAT3 and URAT1 at kidney proximal tubular cell lines with or without a commercial herbal medicine, Keishibukuryogan (K-06) and to further measure serum and urinary uric acid concentrations in the setting of potassium oxonate (PO)-induced ICR mouse model with or without K-06. Methods The transporter-expressed HEK293-OAT1 and HEK293-OAT3 cells were seeded on BD poly-d-lysine microplates to uptake the [3H] estrone sulfate for 5 min in absence or presence of K-06. URAT1 was overexpressed using Xenopus oocytes being injected with in vitro-copied RNA of URAT1, and then to measure the uptake of [14C] uric acid with/without K-06. Total radioactivity was measured using a liquid scintillation counter. Serum and urinary uric acid was measured in PO ICR mice after three-day intake of K-06. They were assigned by 4 per each group; 1) control group, 2) PO-induced group, 3) PO-induced with allopurinol 50 mg/kg/day intake group and 4) PO-induced with allopurinol plus K-06 300 mg/kg/day intake group. Results To determine the kinetic parameters of concentration-dependent uptake of overexpressed OAT1 and OAT3 transporters in HEK293 cells, the K-06 inhibitory parameters on OAT1 and OAT3 were presented with the IC50 values of 49.3 and 31.5 µg/mL, respectively. The K-06 inhibited URAT1 with IC50 of 59.3 µg/mL. The K-06 (300 mg/kg) reduced serum levels of uric acid approximately 30% compared to that of PO-control group (p=0.039) and K-06 showed the slight elevation of urinary uric acid by 12% compared to that of PO-control group with no statistical significance. Conclusions The present findings demonstrated that the K-06 modulated basolateral and apical renal transporters and the K-06 showed the slight increased uric acid excretion and the uric acid lowering effect in experimental mouse setting. References [1] Becker GJ, Hewitson TD. Animal models of chronic kidney disease: useful but not perfect. Nephrol Dial Transplant2013;28:2432–8. doi: 10.1093/ndt/gft071 [2] Key difference between mouse and human kidney cells. Which isavailable at https://www.sciencedaily.com/releases/2016/03/160318181600.htm Acknowledgements This study was supported by the Traditional Korean Medicine R and D program funded by the Ministry of Health and Welfare through the Korea Health Industry Development Institute (KHIDI, Grant # HI16C0864). The commercial herbal products, Keishibukuryogan (K-06) were donated by the virtue of Kracie Pharma, Co., Ltd. Disclosure of Interest None declared

Background Gout is one of a heterogeneous group of diseases related to hyperuricemia. The measurement of 24 hour urinary uric acid excretion is frequently used to evaluate disease status and select drugs that lower uric acid level. However, 24 hour urine collection is inconvenient and frequently unreliable, due to errors in collection. Therefore, a simpler alternative to the 24 hour urine collection is needed. Objectives We investigated the utility of the random urine uric acid-to-creatinine (UA/CR) ratio in predicting 24 hour urine uric acid excretion in patients with gout. Methods Ninety patients with gout without any use of uric acid lowering agents were enrolled in this study. The mean age was 50.0±16.7 years old and the male patient was 90.0% (81/90) of all participants. For the evaluation of uric acid excretion and renal function, patients were collected 24 hour urine. Random urine uric acid and creatinine specimens were gained on the same day of 24 hour urine collection. Chronic kidney disease was defined as a creatinine clearance (CCr) level of less than 60 ml/min/1.73m2 measured in 24 hour urine collection sample. Excretion of more than 600 mg of uric acid in the 24 hour urine sample was defined as uric acid over-excretion. Results Mean serum uric acid level was 7.73±1.89 mg/dl, and the mean 24 hour uric acid excretion was 666.5±236.2 mg. The random urinary UA/CR ratio showed positive correlation with 24 hour urine uric acid excretion (γ=0.398, p Conclusions The random urine UA/CR ratio correlated with 24 hour urine uric acid excretions in patients with gout. The best cut-off random urine UA/CR ratio value to discriminate uric acid over-excretion was 0.342, with a sensitivity of 74.1% and a specificity of 66.7%. The random urine UA/CR ratio would be a useful predictor to detect patients with urinary uric acid underexcretion, who could then be treated with uricosuric drugs. Disclosure of Interest None declared

Background Gout is the most prevalent inflammatory arthritis, affecting 2.5% of adults in the UK. However, management is often inadequate in both primary and secondary care, with only 45% of patients achieving target serum urate (SUA) level Objectives To compare the management of gout in the rheumatology service against the 2007 British Society for Rheumatology (BSR) and 2006 European League Against Rheumatism (EULAR) gout guidelines, and the NICE febuxostat technology appraisal (TA164). Methods We retrospectively audited all new out-patient referrals with gout seen in our department over a 12 month period (January-December 2015). Data were collected by electronic review of case notes and completion of a structured proforma. Three mutually exclusive groups were compared: those seen once in rheumatology and discharged to GP (group1), followed-up in general rheumatology clinics (group2), or followed-up in a specialist gout clinic (group3). Follow-up SUA levels were specifically compared to EULAR ( Results 150 new consecutive gout referrals (50 per group) were included in the audit: 83% were male and mean age was 62 years. Gout was diagnosed by monosodium urate crystal identification in 16 (11%) and 25% had tophi. 43 (29%) patients were already on ULT, and 107 (71%) patients were newly commenced on ULT. Prophylactic medications were co-prescribed in 86% (130) cases. 44 patients were taking diuretics; diuretics were advised to be stopped or reduced in 12% cases. Nearly all patients starting allopurinol commenced a daily dose of ≤100 mg (99% cases). Of the patients started on a uricosuric/febuxostat, 92% had taken allopurinol previously. Of the 15 patients commenced on febuxostat, 3 (15%) had ischaemic heart disease (IHD) or cardiac failure. Chronic kidney disease (CKD) stage 3 (group1 28%, group2 22%, group3 34%), CKD stage 4/5 (2%, 2%, 10%), IHD/cardiac failure (30%, 30%, 40%), clinically evident tophi (16%, 18%, 42%) and previous allopurinol intolerance (10%, 14%, 24%) were more common in group 3 than groups 1 and 2. After 12 months, only 90 (60%) patients achieved target Conclusions Allopurinol starting dose, use of prophylaxis, and use of allopurinol first-line concorded well with national and international guidelines. We achieved target SUA levels more commonly than the UK national average in a recent national rheumatology audit. Patients discharged to the GP with a management plan prior to achieving a target SUA level achieved target less frequently suggesting that rheumatologists should follow patients in order to ensure treatment is escalated until the target SUA level is achieved. Disclosure of Interest None declared

Background Combination therapy that includes a uricosuric and xanthine oxidase inhibitor (XOI) is recommended in guidelines for patients with gout who do not meet treatment targets with XOI monotherapy alone. While the use of combination therapies has been investigated for many years, we reviewed data from the published studies to investigate the efficacy and safety of this approach. Methods Relevant published papers were identified by keyword search on PubMed and categorized according to the types of combination therapies included. Study methods and results were summarized. Outcomes of combination therapy were compared with respective monotherapies, where possible. Results Efficacy was assessed by changes in serum urate (sUA), urinary uric acid, gout flare rates, and /or tophi. Safety assessments, where reported, included adverse events and, for more recent studies, laboratory assessments. Early studies in the 1960s based on case reports or open-label designs and more recent, well-designed studies with large patient numbers provided consistent outcomes: that combination therapy with a uricosuric and a XOI provides substantially greater sUA lowering than achieved by either monotherapy. Greater sUA lowering translated to greater gout symptom control, including improved tophus resolution. Conclusions Combination therapy with a uricosuric and an XOI offers additional sUA lowering compared to monotherapy alone and can provide benefit for achieving therapeutic targets in patients with gout who do not achieve target sUA or are intolerant of XOIs at appropriate monotherapy dosing.

To provide insight into pharmacological treatment of hyperuricemia we developed a semi‐mechanistic, dynamical model of uric acid (UA) disposition in human. Our model represents the hyperuricemic state in terms of production of UA (rate, PUA), its renal filtration (glomerular filtration rate, GFR) and proximal tubular reabsorption (fractional excretion coefficient, FE). Model parameters were estimated using data from 9 Phase I studies of xanthine oxidase inhibitors (XOI) allopurinol and febuxostat and a novel uricosuric, the selective UA reabsorption inhibitor lesinurad, approved for use in combination with a XOI. The model was qualified for prediction of the effect of patients' GFR and FE on concentration of UA in serum (sUA) and UA excretion in urine and their response to drug treatment, using data from 2 Phase I and 4 Phase III studies of lesinurad. Percent reduction in sUA from baseline by a XOI is predicted to be independent of GFR,FE or PUA. Uricosurics are more effective in underexcreters of UA or patients with normal GFR. Co‐administration of a XOI and an uricosuric agent should be considered for patients with high sUA first in the treatment algorithm of gout before uptitration of XOI. The XOI dose in combination with a uricosuric can be reduced compared to XOI alone for the same target sUA to the degree dependent on patient's GFR and FE. This exposure‐response model of UA can be used to rationally select the best drug treatment option to lower elevated sUA in gout patients under differing pathophysiological situations.

Background Transient receptor potential vanilloid 2 is a calcium channel activated by probenecid. Probenecid is a Food and Drug Administration–approved uricosuric drug that has recently been shown to induce positive lusitropic and inotropic effects in animal models through cardiomyocyte transient receptor potential vanilloid 2 activation. The aim of this study was to test the hypothesis that oral probenecid can improve cardiac function and symptomatology in patients with heart failure with reduced ejection fraction and to further elucidate its calcium‐dependent effects on myocyte contractility. Methods and Results The clinical trial recruited stable outpatients with heart failure with reduced ejection fraction randomized in a single‐center, double‐blind, crossover design. Clinical data were collected including a dyspnea assessment, physical examination, ECG, echocardiogram to assess systolic and diastolic function, a 6‐minute walk test, and laboratory studies. In vitro force generation studies were performed on cardiomyocytes isolated from murine tissue exposed to probenecid or control treatments. The clinical trial recruited 20 subjects (mean age 57 years, mean baseline fractional shortening of 13.6±1.0%). Probenecid therapy increased fractional shortening by 2.1±1.0% compared with placebo −1.7±1.0% ( P =0.007). Additionally, probenecid improved diastolic function compared with placebo by decreasing the E/E′ by −2.95±1.21 versus 1.32±1.21 in comparison to placebo ( P =0.03). In vitro probenecid increased myofilament force generation (92.36 versus 80.82 mN/mm 2 , P P Conclusions Probenecid improves cardiac function with minimal effects on symptomatology and no significant adverse effects after 1 week in patients with heart failure with reduced ejection fraction and increases force development and calcium sensitivity at the cardiomyocyte level. Clinical Trial Registration URL : https://www.clinicaltrials.gov . Unique identifier: NCT 01814319.

Gout is the most common type of arthritis in developed countries that is often inadequately managed. Evidence regarding role of hyperuricaemia in poor outcomes in gout patients (e.g., disability, recurrent hospital admissions) with/without other chronic cardiometabolic comorbidities prompts the search of newer and more effective drugs. Current management of gout is limited to NSAIDS and intra-articular corticosteroids in acute gout and Allopurinol or Febuxostat with or without probenecid in chronic gout. Other drugs used as add-on therapy in refractory cases of gout who fail on monotherapy include benzbromarone and pegloticase but with limited role. Though these drugs have been available for several years, significant proportion of compliant patients fail to achieve consistent control of uric acid levels resulting in acute gout flares. Recent advances in the role of urate transporters in proximal tubules of kidney have resulted in the development of new generation uricosuric drugs including lesinurad. It is recently approved by US Food and Drug Administration (US FDA) and European Medicines Agency (EMA) in patients with uncontrolled gout along with Allopurinol or Febuxostat. Hopefully, it will contribute to fulfill the unmet goals in management of gout. This review aims at exploring the current therapeutic strategies for the management of chronic gout patients as well as their limitations and the role of Lesinurad in patients who have failed on monotherapy. The published studies and poster presentations were identified by conducting a literature search from electronic database from 1980 till January 2017, using various medical subject headings and terminologies. These studies were screened and publications considered relevant to the topic were included in the study.

Gout is common in the elderly, affecting an estimated 4.7 million people aged > 60 years in the USA alone. The incidence and prevalence of gout increases, and male predisposition to gout reduces, with increasing age. The elderly have more comorbidities, and gout manifests differently, with more frequent involvement of knees, ankles, and wrists at disease onset, systemic upset, and tophi. Comorbidities and polypharmacy make the management of gout flares challenging in this population. Intra-articular corticosteroid injection remains the treatment of choice for accessible joints, oral prednisolone is preferred over low-dose colchicine, and non-steroidal anti-inflammatory drugs (NSAIDs) are best avoided. Xanthine oxidase inhibitors (XOI) remain the first-line treatment for hyperuricemia in the elderly. Arhalofenate, an emerging uricosuric anti-inflammatory drug, prevents gout flares while reducing serum urate. It may be particularly relevant in the treatment of gout in the elderly as they are unable to tolerate long-term colchicine for flare prophylaxis and frequently have contraindications to corticosteroids and NSAIDs. However, given its modest urate-lowering effect, it can only be used in combination with an XOI, and the safety and efficacy of this drug has not been examined in the elderly or in those with chronic kidney disease. Diuretics and beta-blockers should be discontinued where feasible, whereas low-dose aspirin can be continued if otherwise indicated.

The aim of this review was to summarize the evidence for combination therapy to achieve serum urate (SUA) target levels in gout. Within this overarching aim, a second aim was to evaluate the evidence for a new uricosuric agent lesinurad, which inhibits urate transport in the kidney. In summary, this review indicates that there are a number of ways to approach patients who do not achieve a target serum urate with allopurinol (APL) monotherapy. These include higher doses of APL up to 600-800 mg/d, switching to febuxostat, or adding in a uricosuric. For the latter option, controlled supporting evidence is available for benzbromarone, probenecid, and lesinurad. All options appear similar in terms of success rates, so the choice of option comes down to physician and patient choice, cost, experience, and strength of the evidence base. Increasing the dose of APL is the cheapest option, while febuxostat is consistently superior to standard doses of APL. The strongest evidence for the uricosuric option is available for lesinurad as trials of other agents are either nonexistent or based on small single-centre trials. It is suggested that guidelines should be expanded to consider all of these evidence-based options in the not-uncommon occurrence of APL inadequate response.

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.