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Urate excretion via Abcg2 in a mouse model. (a) Concentration-dependent urate transport via Abcg2 (n=3). (b) Effect of oxonate on Abcg2-mediated urate transport (n=3). (c–e, g, h) In vivo study using Abcg2-knockout and wild-type mice. (c) Serum uric acid (SUA) levels (n=19–20). ***P=8.8×10−6. (d) Urinary excretion of urate (n=10–11). ***P=4.1×10−4 (e) Time course of intestinal urate excretion (n=4). ***P<0.001; **P=0.0066; *P=0.021. (f) Transintestinal urate transport (n=3–4). *P=0.037 and 0.034 for 20 min and 30 min, respectively. (g) Urate excretion in intestine and bile (n=3–4). ***P=3.6×10−4. All bars show means±s.e.m. P values were obtained by Student's t-test. NS, not significant. (h) Relative contribution of urinary, intestinal and biliary urate excretion pathways.
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ABCG2, also known as BCRP, is a high-capacity urate exporter, the dysfunction of which raises gout/hyperuricemia risk. Generally, hyperuricemia has been classified into urate 'overproduction type' and/or 'underexcretion type' based solely on renal urate excretion, without considering an extra-renal pathway. Here we show that decreased extra-renal u...
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... model in which urate excre- tion through the gut is easily achievable by invasive sampling. Also, Abcg2-knockout mice were treated with oxonate, a uricase inhibitor, so that the urate metabolism of this model mimicked that of humans that lacks the urate degrading enzyme, uricase 22 . First, mouse Abcg2 is revealed to mediate urate transport ( Fig. 3a) using the membrane vesicle system prepared from HEK293 cells that express mouse Abcg2. The export process by mouse Abcg2 was ATP-dependent and not saturable under the physiological concentration of urate ( Fig. 3a), indicating high-capacity urate transport activity by Abcg2. Another functional analysis demonstrated that oxonate has no ...
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... that of humans that lacks the urate degrading enzyme, uricase 22 . First, mouse Abcg2 is revealed to mediate urate transport ( Fig. 3a) using the membrane vesicle system prepared from HEK293 cells that express mouse Abcg2. The export process by mouse Abcg2 was ATP-dependent and not saturable under the physiological concentration of urate ( Fig. 3a), indicating high-capacity urate transport activity by Abcg2. Another functional analysis demonstrated that oxonate has no hazardous effect on the Abcg2-mediated urate transport (Fig. ...
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... from HEK293 cells that express mouse Abcg2. The export process by mouse Abcg2 was ATP-dependent and not saturable under the physiological concentration of urate ( Fig. 3a), indicating high-capacity urate transport activity by Abcg2. Another functional analysis demonstrated that oxonate has no hazardous effect on the Abcg2-mediated urate transport (Fig. ...
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... then tried to characterize the excretion of urate into urine, bile and intestinal lumen using the in vivo mouse model. As shown in Fig. 3c, SUA of Abcg2-knockout mice was significantly higher than that of control mice (P = 8.8×10 − 6 ), which is consistent with the increase of SUA in humans with ABCG2 dysfunction 21 . Under this condition, the urinary urate/creatinine ratio was significantly increased in Abcg2-knockout mice (P = 4.1×10 − 4 ) ( Fig. 3d), which also ...
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... vivo mouse model. As shown in Fig. 3c, SUA of Abcg2-knockout mice was significantly higher than that of control mice (P = 8.8×10 − 6 ), which is consistent with the increase of SUA in humans with ABCG2 dysfunction 21 . Under this condition, the urinary urate/creatinine ratio was significantly increased in Abcg2-knockout mice (P = 4.1×10 − 4 ) ( Fig. 3d), which also corroborates the observation in humans (Fig. 2a). On the other hand, the urate excretion from the intestine was significantly lower in Abcg2-knockout mice (Fig. 3e), which is supported by the similar results of the transintestinal urate transport experiment ( Fig. 3f; Supplementary Fig. S2). Calculated velocity of the ...
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... of SUA in humans with ABCG2 dysfunction 21 . Under this condition, the urinary urate/creatinine ratio was significantly increased in Abcg2-knockout mice (P = 4.1×10 − 4 ) ( Fig. 3d), which also corroborates the observation in humans (Fig. 2a). On the other hand, the urate excretion from the intestine was significantly lower in Abcg2-knockout mice (Fig. 3e), which is supported by the similar results of the transintestinal urate transport experiment ( Fig. 3f; Supplementary Fig. S2). Calculated velocity of the intestinal urate excretion in Abcg2-knockout mice was less than a half of that in control mice (P = 3.6×10 − 4 ) ( Fig. 3g), whereas biliary urate excre- tion showed no significant ...
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... significantly increased in Abcg2-knockout mice (P = 4.1×10 − 4 ) ( Fig. 3d), which also corroborates the observation in humans (Fig. 2a). On the other hand, the urate excretion from the intestine was significantly lower in Abcg2-knockout mice (Fig. 3e), which is supported by the similar results of the transintestinal urate transport experiment ( Fig. 3f; Supplementary Fig. S2). Calculated velocity of the intestinal urate excretion in Abcg2-knockout mice was less than a half of that in control mice (P = 3.6×10 − 4 ) ( Fig. 3g), whereas biliary urate excre- tion showed no significant difference regardless of Abcg2 genotype (Fig. 3g). From these results, we estimated the relative ...
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... from the intestine was significantly lower in Abcg2-knockout mice (Fig. 3e), which is supported by the similar results of the transintestinal urate transport experiment ( Fig. 3f; Supplementary Fig. S2). Calculated velocity of the intestinal urate excretion in Abcg2-knockout mice was less than a half of that in control mice (P = 3.6×10 − 4 ) ( Fig. 3g), whereas biliary urate excre- tion showed no significant difference regardless of Abcg2 genotype (Fig. 3g). From these results, we estimated the relative contribution of each pathway to the total urate excretion; in wild-type mice, the UUE pathway contributes approximately two-thirds, and the intes- tinal excretion pathway contributes ...
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... similar results of the transintestinal urate transport experiment ( Fig. 3f; Supplementary Fig. S2). Calculated velocity of the intestinal urate excretion in Abcg2-knockout mice was less than a half of that in control mice (P = 3.6×10 − 4 ) ( Fig. 3g), whereas biliary urate excre- tion showed no significant difference regardless of Abcg2 genotype (Fig. 3g). From these results, we estimated the relative contribution of each pathway to the total urate excretion; in wild-type mice, the UUE pathway contributes approximately two-thirds, and the intes- tinal excretion pathway contributes one-third of the total urate excretion, whereas the urate excretion into bile is 2.2% of the total urate ...
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... 3g). From these results, we estimated the relative contribution of each pathway to the total urate excretion; in wild-type mice, the UUE pathway contributes approximately two-thirds, and the intes- tinal excretion pathway contributes one-third of the total urate excretion, whereas the urate excretion into bile is 2.2% of the total urate excretion (Fig. 3h). The ratio of each urate excretion path- way is consistent with the previous literature about the estimation of urate excretion pathways in humans 4,5 . As a result of decreased intestinal excretion, the urate excretion in Abcg2-knockout mice was much more dependent on the urinary excretion pathway (Fig. 3h). Furthermore, the small ...
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... is 2.2% of the total urate excretion (Fig. 3h). The ratio of each urate excretion path- way is consistent with the previous literature about the estimation of urate excretion pathways in humans 4,5 . As a result of decreased intestinal excretion, the urate excretion in Abcg2-knockout mice was much more dependent on the urinary excretion pathway (Fig. 3h). Furthermore, the small contribution of biliary urate excretion in mice ( Fig. 3h) is also consistent with a report of human urate excre- tion, which shows that biliary urate excretion consists of less than 5 percent of the total urate excretion 23 . Taken together, ABCG2 is suggested to have an important role in extra-renal urate ...
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... path- way is consistent with the previous literature about the estimation of urate excretion pathways in humans 4,5 . As a result of decreased intestinal excretion, the urate excretion in Abcg2-knockout mice was much more dependent on the urinary excretion pathway (Fig. 3h). Furthermore, the small contribution of biliary urate excretion in mice ( Fig. 3h) is also consistent with a report of human urate excre- tion, which shows that biliary urate excretion consists of less than 5 percent of the total urate excretion 23 . Taken together, ABCG2 is suggested to have an important role in extra-renal urate excre- tion, especially in intestinal urate excretion. Accordingly, increased SUA in ...
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... and one-third of urate excretion in humans depends on the extra-renal pathway such as gut excretion 4,5,8 . Also, together with little intestinal expression of URAT1 (ref. 10), our data from an animal model indicate that the decreased expression of Urat1 in the kidney could partially account for the increased urate in urine in Abcg2-knockout mice (Fig. 3d, Supplementary Fig. S3). Therefore, it is reasonable that common dysfunction of ABCG2 can cause a decrease of urate excretion via the extra-renal pathway rather than the renal pathway. The current classification of hyperuricemia is based on the understanding of its mechanism by which hyperuricemia results from either overproduction of urate due to a ...
Similar publications
Dysfunctional variants of ATP-binding cassette transporter subfamily G member 2 (ABCG2), a urate transporter in the kidney and intestine, are the major causes of hyperuricemia and gout. A recent study found that ABCG2 is a major transporter of uremic toxins; however, few studies have investigated the relationship between ABCG2 gene polymorphisms an...
Citations
... Hyperuricemia is caused by the increased synthesis and/or decreased excretion of urate and is classified into different types based on its etiology, overproduction, and/or underexcretion. Recently, based on the discovery of ATP-binding cassette transporter G2 (ABCG2) as an intestinal urate exporter, extrarenal underexcretion type hyperuricemia was defined as described later [2][3][4]. Hyperuricemia is one of the most important risk factors of gout; therefore, urate-lowering therapy is recommended for patients with tophi and/or frequent acute gout flares (reviewed in [5]). ...
... The results showed that the serum urate levels of Abcg2 KO mice were higher than those of WT mice, similar to those observed in humans. Furthermore, Abcg2 deficiency did not decrease urate excretion into the urine but increased it, while urate excretion from the small intestine dramatically decreased [2]. This result was surprising since ABCG2 is known to be expressed in the kidney and is reported to be involved in the excretion of substrate compounds into the urine at the apical membrane. ...
... Based on these findings, the current classification of gout/hyperuricemia includes extra-renal underexcretion hyperuricemia, in which intestinal urate excretion is low because of ABCG2 dysfunction. The extra-renal underexcretion type and overproduction type are sometimes considered to be the renal overload type because distinguishing them clinically is impossible with easy examinations; this classification is considered useful when considering treatment strategies ( Figure 2) [2]. combined type (a mixture of the two). ...
Uric acid is the final purine metabolite in humans. Serum urate levels are regulated by a balance between urate production, mainly in the liver, and its excretion via the kidneys and small intestine. Given that uric acid exists as a urate anion at physiological pH 7.4, membrane transporters are required to regulate urate homeostasis. In the kidney, urate transporter 1, glucose transporter 9, and organic anion transporter 10 contribute to urate reabsorption, whereas sodium-dependent phosphate transport protein 1 would be involved in urate excretion. Other transporters have been suggested to be involved in urate handling in the kidney; however, further evidence is required in humans. ATP-binding cassette transporter G2 (ABCG2) is another urate transporter, and its physiological role as a urate exporter is highly demonstrated in the intestine. In addition to urate, ABCG2 regulates the behavior of endogenous substances and drugs; therefore, the functional inhibition of ABCG2 has physiological and pharmacological effects. Although these transporters explain a large part of the urate regulation system, they are not sufficient for understanding the whole picture of urate homeostasis. Therefore, numerous studies have been conducted to find novel urate transporters. This review provides the latest evidence of urate transporters from pathophysiological and clinical pharmacological perspectives.
... Hyperuricemia is caused by hepatic overproduction and (or) renal and (or) intestinal underexcretion of SUA, which are regulated by genetic and environmental factors and their interactions [10]. Obviously, owing to the evolutionary inactivation of Uox in humans, genetic modification of rodent Uox is an essential and most effective way to replicate human hyperuricemia and urate biology, as compared to genetically engineered mice targeting other loci (for example, SLC2A9 and ABCG2), as well as environmentally induced models [9,[11][12][13]. ...
Hyperuricemia is a common metabolic disorder with severe complications. We aimed to develop a mouse model for spontaneous hyperuricemia. Uox-/- mouse model was generated on C57BL/6J background by deleting exon 2-4 of Uox using the CRISPR/Cas9 system. The prototypic Uox-/-mice had 5.5-fold increased serum uric acid (1351.04±276.58μmol/L) as compared to the wild type mice (P<0.0001), but died by 4 weeks. After allopurinol (3ug/g) intervention, they all survived > 8 weeks. The serum uric acid was 612.55±146.98μmol/L in the 8-week-old allopurinol-rescued Uox-/-mice, which manifested multiple complications including severe renal insufficiency, hypertension, left ventricular remodeling and systolic dysfunction, aortic endothelial dysfunction, hepatic steatosis and elevated liver enzymes, as well as hyperglycemia and hypercholesteremia. The present Uox-/- mice developed spontaneous hyperuricemia complicated with urate nephropathy, cardiovascular disease and cardiometabolic disorders, and may provide a novel tool to study hyperuricemia associated early-onset cardiovascular disorders in human.
Graphical Abstract
A mouse model of hyperuricemia with multiple complications constructed by knocking out of urate oxidase (Uox) using CRISPR/Cas9 technology. Uox-/-: homozygous; Uox+/-: heterozygous; SUA: serum uric acid; ALT: alanine aminotransferase; AST: aspartate aminotransferase.
... Under normal physiological conditions, the synthesis and excretion of uric acid maintain a dynamic equilibrium, with the kidneys serving as the principal regulatory factor for uric acid excretion [12,13]. Approximately 70% of UA processing takes place through renal mechanisms, involving initial free filtration at the renal glomerulus, followed by secretion and reabsorption facilitated by renal tubules and associated transport proteins. ...
... ABCG2, also known as the human breast cancer resistance protein (BCRP), stands among the trio of human ATP-binding cassette (ABC) transporter proteins, ubiquitously distributed throughout the body. Its role extends to facilitating the cellular efflux of a diverse array of chemically and structurally varied compounds [12,71]. Revered as a "gatekeeper" in virtue of its function and localization, ABCG2 stands guard, thwarting the passage of endogenous or exogenous toxins and foreign substances across biological barricades into delicate tissues [49]. ...
... Expressed in various tissues, ABCG2 graces the luminal membranes of renal tubules and the intestines, where it orchestrates the secretion of an array of compounds, including urate. Notably, ABCG2 assumes a prominent role in urate excretion within the intestines, surpassing its involvement in other tissues, thus emerging as the primary conduit for extra-renal urate elimination [12,52]. ...
Hyperuricemia (HUA) is a metabolic disorder characterized by elevated serum uric acid levels exceeding the body’s metabolic limit. In the past two decades, the prevalence of this disease has shown an increasing trend and is becoming more common in younger individuals. As a metabolic disease, hyperuricemia has been found to correlate with cardiovascular diseases, renal diseases, and metabolic syndrome. Various complex metabolic processes are involved in the pathological process in the elevation of uric acid. Transporters are one of the most important families controlling the metabolism of uric acid. The vast majority of cases of hyperuricemia are caused by insufficient uric acid excretion and excessive reabsorption by the kidneys. Therefore, limiting the reabsorption of transport proteins is key to lowering uric acid levels. This chapter will revisit the basic situation of hyperuricemia and summarize the known mechanisms of transport proteins in HUA, as well as the therapeutic approaches developed for these transport proteins.
... Elevated intake of foods high in purines (such as seafood, beer, and red meat), long-term consumption of fructose, and unhealthy body status under excessive stress conditions can disrupt UA homeostasis, resulting in elevated plasma UA levels (3,4). High blood UA levels may induce excessive deposition of UA crystals in the body, which can cause gout (5). HUA is also a risk factor for renal damage, diabetes, hypertension, and dyslipidaemia (6,7). ...
Hyperuricaemia (HUA) is a metabolic disorder characterised by high blood uric acid (UA) levels; moreover, HUA severity is closely related to the gut microbiota. HUA is also a risk factor for renal damage, diabetes, hypertension, and dyslipidaemia; however, current treatments are associated with detrimental side effects. Alternatively, Fangyukangsuan granules are a natural product with UA-reducing properties. To examine their efficacy in HUA, the binding of small molecules in Fangyukangsuan granules to xanthine oxidase (XOD), a key factor in UA metabolism, was investigated via molecular simulation, and the effects of oral Fangyukangsuan granule administration on serum biochemical indices and intestinal microorganisms in HUA-model rats were examined. Overall, 24 small molecules in Fangyukangsuan granules could bind to XOD. Serum UA, creatinine, blood urea nitrogen, and XOD levels were decreased in rats treated with Fangyukangsuan granules compared to those in untreated HUA-model rats. Moreover, Fangyukangsuan granules restored the intestinal microbial structure in HUA-model rats. Functional analysis of the gut microbiota revealed decreased amino acid biosynthesis and increased fermentation of pyruvate into short-chain fatty acids in Fangyukangsuan granule-treated rats. Together, these findings demonstrate that Fangyukangsuan granules have anti-hyperuricaemic and regulatory effects on the gut microbiota and may be a therapeutic candidate for HUA.
... Uric acid excretion transporters include URAT1, which is present in the proximal tubule and is responsible for UA reabsorption, and ABCG2, OAT1, and OAT3, which are also involved in excretion [6,7]. Interestingly, these UA excretory transporters are involved in the renal excretion of both UA and the uremic substance, indoxyl sulfate. ...
... Especially, the expulsion of UA from the ileum is facilitated by ABCG2. Therefore, it is likely that dotinurad affects ABCG2-induced UA excretion a little and may aid the excretion of UA from the kidney and small intestine [6,7]. This could be associated with the remarkably high success rates in reaching serum UA levels below 6 mg/dL, with 91.3% achieved at a dosage of 2 mg/day and 100% at 4 mg/day, as noted in a 58-week open-label phase 3 study of dotinurad [26]. ...
... Thus, it might be possible that extremely high urinary uric acid excretion is deleterious to the kidney. The classification of hyperuricemia has recently been redefined as "overproduction type", "extra-renal (intestinal) underexcretion type", and "renal underexcretion type" with certain degrees of overlap with each other 39 . The first 2 types have been regarded as "renal overloading" of urate 18 . ...
Inhibiting tubular urate reabsorption may protect the kidney from urate-induced tubular injury. However, this approach may promote intratubular uric acid crystallization, especially in acidified urine, which could be toxic to the kidney. To assess how tubular urate handling affects kidney outcomes, we conducted a retrospective cohort study including 1042 patients with estimated glomerular filtration rates (eGFR) of 15–60 mL/min/1.73 m². The exposures were fractional excretion of uric acid (FEUA) and urinary uric acid-to-creatinine ratio (UUCR). The kidney outcome was defined as a halving of eGFR from baseline or initiating kidney replacement therapy. The median FEUA and UUCR were 7.2% and 0.33 g/gCre, respectively. During a median follow-up of 1.9 years, 314 kidney outcomes occurred. In a multivariate Cox model, the lowest FEUA quartile exhibited a 1.68-fold higher rate of kidney outcome than the highest FEUA quartile (95% confidence interval, 1.13–2.50; P = 0.01). Similarly, lower UUCR was associated with a higher rate of kidney outcome. Notably, patients in the highest quartile of FEUA and UUCR were at the lowest risk of kidney outcome even among those with aciduria. In conclusion, lower FEUA and UUCR were associated with a higher risk of kidney failure, suggesting that increased urate reabsorption is harmful to the kidney.
... Approximately 90% of hyperuricemia cases can be attributed to impaired excretion, with insufficient renal excretion as the cause in the majority of cases. In the gastrointestinal tract, involvement of the transporter ABCG2 in uric acid excretion, and in the kidneys, involvement of urate and organic anion transporters in uric acid excretion have been reported 12,13) . Mutations in the genes encoding these transporters can also be a cause of impaired uric acid excretion, and development of hyperuricemia 14,15) . ...
Gout is triggered by the accumulation of uric acid in the body, leading to hyperuricemia. Genetic, metabolic, and environmental factors can influence this condition. Excessive uric acid buildup results in the formation of monosodium urate (MSU) crystals, which precipitate in specific areas of the body, including the joints, where they can cause symptoms of gout. While the acute and chronic symptoms of gout have been well-documented, diagnosis of gout affecting the hip joint poses significant challenges. The global incidence of gout, the most prevalent form of inflammatory arthritis, is on the rise. Evaluation of the clinical signs, laboratory results, and imaging results is generally required for diagnosis of gout in cases where MSU crystals have not been detected. Hyperuricemia is considered a primary cause of arthritis symptoms, and comprehensive guidelines for treatment are available. Therefore, the choice of medication is straightforward, and moderate effectiveness of treatment has been demonstrated. Gout is a chronic disease, requiring lifelong uric acid-lowering medications, thus application of a treatment strategy based on the target blood uric acid concentration is necessary. Consequently, cases of gout will likely be observed more frequently by hip surgeons in clinical scenarios in the future. The objective of this review is to provide an overview of the pathophysiology of gout and subsequently examine recent advances in diagnostic methods and therapeutic agents based on an understanding of its underlying mechanisms. In addition, literature on gout-related issues affecting the hip joint, providing a useful reference for hip surgeons is examined.
... Основные причины повышения уровня МК в сыворотке крови. Механизмы развития ГУ можно разделить на 5 групп [16][17][18]. ...
... 9,10 Hyperuricemia classification in gout includes the most prevalent renal underexcretion type, the renal urate overload type, and a combined type of those two based on both fractional excretion of urate (FEUA) and 24-hour urinary urate excretion (UUE). 11 Patients were classified as having the renal overload type when their UUE was >600 mg/day/1.73 m 2 and their FEUA was >5.5%. ...
... m 2 were classified as having underexcretion hyperuricemia. 11 Analysis of two large Chinese gout cohorts (Qingdao, Shanghai) has shown that this particular combined-type hyperuricemia (UUE > 600 mg/day/1.73 m 2 and FEUA < 5.5%) accounts for 30% of primary gout, similar with the previous report. ...
Objective
There is an unmet need for simpler urate‐lowering therapy (ULT) regimens that achieve the serum urate target and improve the overall quality of gout care. We report a comparative effectiveness trial of febuxostat monotherapy versus benzbromarone add‐on to low‐dose febuxostat in gout specifically with combined renal urate underexcretion and overload.
Methods
A prospective randomized trial was conducted on patients with combined‐type hyperuricemia and estimated glomerular filtration rate >60 mL/min/1.73 m² 1:1 randomly assigned to febuxostat and benzbromarone combination therapy (initially febuxostat at 20 mg/day, with benzbromarone at 25 mg/day added onto 20 mg/day of febuxostat if not at target) or febuxostat monotherapy (initially 20 mg/day, escalating to 40 mg/day if not at target). The primary end point at 12 weeks was the proportion achieving a serum urate (SU) level <360 μmol/L. Other outcomes included altered liver and kidney function, new‐onset urolithiasis, and gout flares.
Results
There were 250 participants randomized; 219 completed 12‐week treatment. More patients in the febuxostat and benzbromarone combination group achieved the SU target compared to patients in the febuxostat monotherapy group (75.5% vs 47.7%; odds ratio 3.37 [95% confidence interval 1.90–5.98]). Safety profiles were comparable between the two groups.
Conclusion
Simply adding on low‐dose benzbromarone (25 mg/day) to low‐dose (20 mg/day) febuxostat showed superior urate lowering compared to febuxostat monotherapy in gout with a combined‐type hyperuricemia. For selected patients, expedited achievement of the SU target in more than 75% of patients using one titration step and low xanthine oxidase inhibitor and uricosuric doses is a potential alternative to standard ULT regimens.
... The pathogenic variants of SLC2A9 were assessed in all participants, and the frequency of rs3733591, which has been reported to be related to SUA [26][27][28], was not significantly different between the gout and asymptomatic hyperuricemia groups. This result suggests that other factors, including other urate transporters and environmental factors, contribute to the progression from asymptomatic hyperuricemia to gout, although the urate transporters ABCG2 [20,[29][30][31] and SLC2A9 [32] play an important role in regulating SUA. ...
... It has been reported that the main pathology of hyperuricemia in patients with gout is decreased urate excretion in the kidneys and intestine [29,47]. The regulation of urate excretion, especially by a cluster of urate transporters in the kidneys, is important in the homeostasis of SUA [48], which has been corroborated by the presence of type I and type II renal hypouricemia caused by SLC22A12 [49][50][51] and SLC2A9 dysfunction [32,52], respectively. ...
Gout results from monosodium urate deposition caused by hyperuricemia, but most individuals with hyperuricemia remain asymptomatic. The pathogenesis of gout remains uncertain. To identify potential biomarkers distinguishing gout from asymptomatic hyperuricemia, we conducted a genetic analysis of urate transporters and metabolomic analysis as a proof-of-concept study, including 33 patients with gout and 9 individuals with asymptomatic hyperuricemia. The variant allele frequencies of rs72552713, rs2231142, and rs3733591, which are related to serum urate levels (SUA) and gout, did not differ between the gout and asymptomatic hyperuricemia groups. In metabolomic analysis, the levels of citrate cycle intermediates, especially 2-ketoglutarate, were higher in patients with gout than in those with asymptomatic hyperuricemia (fold difference = 1.415, p = 0.039). The impact on the TCA cycle was further emphasized in high-risk gout (SUA ≥ 9.0 mg/dL). Of note, urinary nicotinate was the most prominent biomarker differentiating high-risk gout from asymptomatic hyperuricemia (fold difference = 6.515, p = 0.020). Although urate transporters play critical roles in SUA elevation and promote hyperuricemia, this study suggests that the progression from asymptomatic hyperuricemia to gout might be closely related to other genetic and/or environmental factors affecting carbohydrate metabolism and urinary urate excretion.
