Lesinurad, a novel, oral compound for gout, acts to decrease serum uric acid through inhibition of urate transporters in the kidney.

BackgroundExcess body burden of uric acid promotes gout. Diminished renal clearance of uric acid causes hyperuricemia in most patients with gout, and the renal urate transporter (URAT)1 is important for regulation of serum uric acid (sUA) levels. The URAT1 inhibitors probenecid and benzbromarone are used as gout therapies; however, their use is limited by drug-drug interactions and off-target toxicity, respectively. Here, we define the mechanism of action of lesinurad (Zurampic®; RDEA594), a novel URAT1 inhibitor, recently approved in the USA and Europe for treatment of chronic gout.MethodssUA levels, fractional excretion of uric acid (FEUA), lesinurad plasma levels, and urinary excretion of lesinurad were measured in healthy volunteers treated with lesinurad. In addition, lesinurad, probenecid, and benzbromarone were compared in vitro for effects on urate transporters and the organic anion transporters (OAT)1 and OAT3, changes in mitochondrial membrane potential, and human peroxisome proliferator-activated receptor gamma (PPARγ) activity.ResultsAfter 6 hours, a single 200-mg dose of lesinurad elevated FEUA 3.6-fold (p < 0.001) and reduced sUA levels by 33 % (p < 0.001). At concentrations achieved in the clinic, lesinurad inhibited activity of URAT1 and OAT4 in vitro, did not inhibit GLUT9, and had no effect on ABCG2. Lesinurad also showed a low risk for mitochondrial toxicity and PPARγ induction compared to benzbromarone. Unlike probenecid, lesinurad did not inhibit OAT1 or OAT3 in the clinical setting.ConclusionThe pharmacodynamic effects and in vitro activity of lesinurad are consistent with inhibition of URAT1 and OAT4, major apical transporters for uric acid. Lesinurad also has a favorable selectivity and safety profile, consistent with an important role in sUA-lowering therapy for patients with gout

A novel homozygous SLC2A9 mutation associated with renal-induced hypouricemia

Hereditary renal hypouricemia (RHUC) is a genetically heterogenous disorder characterized by defective uric acid (UA) reabsorption resulting in hypouricemia and increased fractional excretion of UA; acute kidney injury (AKI) and nephrolithiasis are recognized complications. Type 1 (RHUC1) is caused by mutations in the SLC22A12 gene, whereas RHUC2 is caused by mutations in the SLC2A9 gene. Patient ethnicity is diverse but only few Caucasian families with an SLC2A9 mutation have been reported. The current report describes the clinical history, biochemical and molecular genetics findings of a native Austrian family with RHUC2. The propositus presented with 2 episodes of exercise-induced AKI and exhibited profound hypouricemia. Mutational screening of the SLC22A12 and SLC2A9 genes was performed. The molecular analyses revealed the homozygous c.512G>A transition that leads to the p.Arg171His missense substitution in SLC2A9, confirming the diagnosis of RHUC2. Segregation study of the causal mutation revealed that the mother and elder sister were heterozygous carriers, whereas the younger sister was found to be homozygous. We report the identification of a novel mutation in SLC2A9 as the cause of RHUC2 in a native Austrian family. We show that glucose transporter 9 mutations cause severe hypouricemia in homozygous individuals and confirm the high risk of AKI in male individuals harbouring these mutations. In our literature review, we provide an overview of the putative underlying pathophysiology, potential renal complications, findings on kidney biopsy as well as potential long-time renal sequela

Risk Factors in the Incidence of Gouty Arthritis in Masohi Town, Central Maluku Regency in 2010

The gouty arthritis incidence rate in Masohi Townof Central Maluku Regency is 54 people based on the data from the general  hospital in Masohi. The aim of study was to find out the risk factor in the incidence of gouty arthritis in Masohi Town of Central Maluku Regency. The study was analytic observation using a control case study. The number of respondents was 196 people consisting of 98 cases and 98 controls. The data were analyzed by using odds ratio (OR) and multiple logistic regression. The results of the study indicate that the risk factors in the incidence of gouty arthritis are hypertension (OR = 2.20 CI 95%; 1.24-3.90), central obesity (OR = 3.04 CI 95%; 1.66-5.55), alcoholic comsumption (OR = 2.28 CI 95%; 1.29-4.05), purine food consumption (OR = 5.14 CI 95% 2.80-9.44), gout history in family (OR = 3.10 CI 95%; 1.73-5.55), and soft drink consumption (OR = 1.33 CI 95%; 0.72-2.45). The multivariate analysis indicates that the most dominant factor affecting the incidence of gouty arthritis is purine food consumption (p = 0.000).  Since the consumption of purine food is the most dominant factor affecting the incidence of gouty arthritis, diet pattern is necessary for the patients

Early-onset metabolic syndrome in mice lacking the intestinal uric acid transporter SLC2A9

Excess circulating uric acid, a product of hepatic glycolysis and purine metabolism, often accompanies metabolic syndrome. However, whether hyperuricemia contributes to development of metabolic syndrome or is merely a by-product of other processes that cause this disorder has not been resolved. Additionally, how uric acid is cleared from the circulation is incompletely understood. Here, we present a genetic model of spontaneous, early-onset metabolic syndrome in mice lacking the enterocyte urate transporter Glut9 (encoded by the SLC2A9 gene). Glut9-deficient mice develop impaired enterocyte uric acid transport kinetics, hyperuricemia, hyperuricosuria, spontaneous hypertension, dyslipidemia, and elevated body fat. Allopurinol, a xanthine oxidase inhibitor, can reverse the hypertension and hypercholesterolemia. These data provide evidence that hyperuricemia per se could have deleterious metabolic sequelae. Moreover, these findings suggest that enterocytes may regulate whole-body metabolism, and that enterocyte urate metabolism could potentially be targeted to modulate or prevent metabolic syndrome

Роль полиморфизмов SLC2A9 и ABCG2 генов в возникновении гиперурикемии и подагры

У статті наведені сучасні дані про вплив найбільш поширених поліморфізмів SLC2A9 і ABCG2 генів, що кодують протеїни, які залучені в систему ниркового транспорту уратів і, таким чином, асоційованих з рівнем сечової кислоти або подагрою. Проведена характеристика поліморфізмів SLC2A9 і ABCG2 генів: V253I, Q126X, Q141K. Визначено, що GCA і GTC гаплотипи Q126X і Q141K поліморфізмів можуть бути предикторами подагри. Проаналізовано взаємозв'язок поліморфізмів SLC2A9 і ABCG2 генів з наявністю гіперурикемії в залежності від статі, компонентами метаболічного синдрому, з відповіддю на алопуринол. Встановлено, що Q141K варіант (rs2231142) може прямо модулювати BCRP-опосередкований транспорт алопуринолу і оксипуринолу, К аллель пов'язаний з меншим зниженням рівня сечової кислоти при лікуванні цим препаратом.В статье приведены современные данные о влиянии наиболее распространенных полиморфизмов SLC2A9 и ABCG2 генов, кодирующих протеины, которые вовлечены в систему почечного транспорта уратов и, таким образом, ассоциированных с уровнем мочевой кислоты или подагрой. Проведена характеристика полиморфизмов SLC2A9 и ABCG2 генов: V253I, Q126X, Q141K. Определено, что GCA и GTC гаплотипы Q126X и Q141K полиморфизмов могут быть предикторами подагры. Проанализирована взаимосвязь полиморфизмов SLC2A9 и ABCG2 генов с наличием гиперурикемии в зависимости от пола, компонентами метаболического синдрома, с ответом на аллопуринол. Установлено, что Q141K вариант (rs2231142) может прямо модулировать BCRP–опосредованный транспорт аллопуринола и оксипуринола, К аллель связан с меньшим снижением уровня мочевой кислоты при лечении данным препаратом.The article provides modern information about influence of the most common SLC2A9 and ABCG2 gene polymorphisms. These genes encode urate transporters (BCRP and GLUT9) that`s why associated with uric acid level and gout. The polymorphisms V253I, Q126X, Q141K of SLC2A9 and ABCG2 genes were characterized. GCA и GTC haplotypes of Q126X and Q141K variants can be predictors of gout. The relationship of these polymorphisms with hyperuricaemia according to gender, metabolic syndrome components, with the response to allopurinol was analyzed. It has been established that Q141K polymorphism can directly modulate BCRP-mediated allopurinol and oxypurinol efflux, the K allele is associated with a lower reduction in serum uric acid in response to allopurinol treatment

Recurrent exercise-induced acute kidney injury by idiopathic renal hypouricemia with a novel mutation in the SLC2A9 gene and literature review

OBJETIVO: Comparar a sensibilidade do método de difusão em ágar e do método de extração utilizando as linhagens celulares RC-IAL (células fibroblásticas de rim de coelho) e HeLa (células epiteliais de carcinoma do colo do útero humano), na avaliação da citotoxicidade "in vitro" de materiais de uso médico-hospitalar. MATERIAL E MÉTODO: Foram testadas 50 amostras escolhidas por sorteio, entre as já conhecidamente positivas e negativas e identificadas como: algodão, espuma, borracha, látex, celulose e acrílico. Além, das amostras citadas foram testadas experimentalmente várias concentrações de SDS (duodecil sulfato de sódio) nas culturas celulares RC-IAL e HeLa. RESULTADOS: Das 50 amostras testadas , 44 (88%) foram positivas para os dois métodos. Mas quando comparado o SDS nos dois métodos foram observados resultados positivos nas concentrações de 0,5 a 0,05 µg/ml no método de difusão em ágar e no método de extração somente foi observado efeito citotóxico até a concentração de 0,25 µg/ml. CONCLUSÃO: Os resultados encontrados são similares aos observados por outros autores que testaram materiais como, por exemplo, ligas metálicas. Quando foi usado o SDS observou-se, nas duas linhagens celulares, diferenças favoráveis ao método de difusão em ágar em duas concentrações, isto é, a sensibilidade deste método foi significantemente maior, por inspecção, em relação ao método de extração, além de se constituir em método mais simples de ser realizado

Recurrent exercise-induced acute renal failure in a young Pakistani man with severe renal hypouricemia and SLC2A9 compound heterozygosity.

BACKGROUND: Familial renal hypouricemia (RHUC) is a hereditary disease characterized by hypouricemia, high renal fractional excretion of uric acid (FE-UA) and can be complicated by acute kidney failure and nephrolithiasis. Loss-of-function mutations in the SLC22A12 gene cause renal hypouricemia type 1 (RHUC1), whereas renal hypouricemia type 2 (RHUC2) is caused by mutations in the SLC2A9 gene. CASE PRESENTATION: We describe a 24-year-old Pakistani man who was admitted twice to our hospital for severe exercise-induced acute renal failure (EIARF), abdominal pain and fever; he had very low serum UA levels (0.2 mg/dl the first time and 0.09 mg/dl the second time) and high FE-UA (200% and 732% respectively), suggestive of RHUC. Mutational analyses of both urate transporters revealed a new compound heterozygosity for two distinct missense mutations in the SLC2A9 gene: p.Arg380Trp, already identified in heterozygosity, and p.Gly216Arg, previously found in homozygosity or compound heterozygosity in some RHUC2 patients. Compared with previously reported patients harbouring these mutations, our proband showed the highest FE-UA levels, suggesting that the combination of p.Arg380Trp and p.Gly216Arg mutations most severely affects the renal handling of UA. CONCLUSIONS: The clinical and molecular findings from this patient and a review of the literature provide new insights into the genotype-phenotype correlation of this disorder, supporting the evidence of an autosomal recessive inheritance pattern for RHUC2. Further investigations into the functional properties of GLUT9, URAT1 and other urate transporters are required to assess their potential research and clinical implications

Urate Handling in the Human Body

Elevated serum urate concentration is the primary cause of gout. Understanding the processes that affect serum urate concentration is important for understanding the etiology of gout and thereby understanding treatment. Urate handing in the human body is a complex system including three major processes: production, renal elimination, and intestinal elimination. A change in any one of these can affect both the steady-state serum urate concentration as well as other urate processes. The remarkable complexity underlying urate regulation and its maintenance at high levels in humans suggests that this molecule could potentially play an interesting role other than as a mere waste product to be eliminated as rapidly as possible

Alteração do Transporte de Ácido Úrico na Glicosúria Renal Familiar e Expressão de SGLT2 no Rim Normal e Patológico

Familial renal glucosuria (FRG) is a rare co -dominantly inherited benign phenotype characterized by the presence of glucose in the urine. It is caused by mutations in the SLC5A2 gene that encodes SGLT2, a Na+ -glucose co -transporter. The purpose of our current work was twofold: to characterize the molecular and phenotype findings of an FRG cohort and, in addition, to detail the SGLT2 expression in the adult human kidney. The phenotype of FRG pedigrees was evaluated using direct sequencing for the identification of sequence variations in the SLC5A2 gene. The expression of SGLT2 in the adult human kidney was studied by immunofluorescence on kidney biopsy specimens. In the absence of renal biopsies from FRG individuals, and in order to evaluate the potential disruption of SGLT2 expression in a glucosuric nephropathy, we have selected cases of nucleoside analogues induced proximal tubular toxicity. We identified six novel SLC5A2 mutations in six FRG pedigrees and described the occurrence of hyperuricosuria associated with hypouricaemia in the two probands with the most severe phenotypes. Histopathological studies proved that SGLT2 is localized to the brush -border of the proximal tubular epithelia cell and that this normal pattern was found to be disrupted in cases of nucleoside analogues induced tubulopathy. We present six novel SLC5A2 mutations, further contributing to the allelic heterogeneity in FRG, and identified hyperuricosuria and hypouricaemia as part of the FRG phenotype. SGLT2 is localized to the brush -border of the proximal tubule in the adult human normal kidney, and aberrant expression of the co -transporter may underlie the glucosuria seen with the use of nucleoside analogues

High-glucose feeding of gilthead seabream (Sparus aurata) larvae: effects on molecular and metabolic pathways

Nutritional programming has begun to arouse interest as a novel tool to alter specific metabolic pathways or functions in farmed animals. The aim of the present study was to explore the potential of early glucose stimuli to induce changes in nutrient metabolism of gilthead seabream. Nutritional conditioning was performed by delivering glucose-rich feed at three distinct recurrent periods of larval feeding regime: during first-feeding with rotifers (3 days after hatching, DAH) and mid-feeding with Artemia metanauplii (20DAH) and the beginning of inert diet feeding (30DAH), called the Recurrent treatment (REC). As opposed, the control treatment (CTRL) did not experience any glucose stimuli. At post-larval stage (from 50 to 60DAH), both treatments were challenged with a high-carbohydrate diet (50%). The immediate response to the early stimuli was assessed through gene expression of metabolic markers and by nutrient metabolism using [C-14] tracers. Each dietary stimulus induced metabolic changes on REC larvae, shown by altered expression of some genes, including those involved in glycolysis, and by a different pattern of glucose utilization. However, none of the molecular adaptations (except G6PDH gene) were persistent in the viscera and muscle of challenged post-larvae from REC group. In contrast, the glucose metabolism of challenged REC post-larvae revealed a shift towards a higher catabolism and lower glucose retention in tissues, compared to the CTRL group, suggesting an improvement of glucose oxidation pathways. In addition, the REC group showed a higher bio-conversion of glucose into lipids, indicating enhanced hepatic lipogenesis. The early stimuli did not affect the relative retention or use of amino acids or the growth and survival of challenged fish, up to 60DAH. In summary, although not substantiated at a molecular level, our data reveal that a recurrent high-glucose stimulus during larval stages affects the short-term modulation of pathways for glucose utilization in gilthead seabream. (C) 2015 Elsevier B.V. All rights reserved