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Background Dotinurad is a selective urate reabsorption inhibitor (SURI), which selectively inhibits URAT1 to lower serum uric acid levels in patients with hyperuricemia. Herein, the effects of dotinurad were compared among patient groups with different stages of renal dysfunction. Methods Patient data from four clinical trials were pooled and divided into four groups according to the stage of renal dysfunction to compare the effects of dotinurad at different stages. The grouping (stages G1–G3b) was based on the estimated glomerular filtration rate (eGFR) of the patients. In addition, patient data from a long-term study (34 or 58 weeks) were evaluated in the same manner. Results In the pooled analysis, the percentage of patients achieving a serum uric acid level of ≤ 6.0 mg/dL was 64.7–100.0% at a dose of 2 or 4 mg. In the long-term analysis, the percentage of patients achieving a serum uric acid level of ≤ 6.0 mg/dL was 60.0–100.0% at a dose of 2 or 4 mg. Although the outcomes in stage G3b were worse due to higher baseline serum uric acid levels, satisfactory outcomes were observed in all stages. Even in stages G3a and G3b, when renal function declined, the eGFR remained constant throughout the dose period. Conclusion The efficacy of dotinurad was confirmed in hyperuricemic patients with normal renal function (stage G1) and mild to moderate renal dysfunction (stage G2–G3b). Dotinurad was found to be effective in the treatment of hyperuricemia in patients with mild to moderate renal dysfunction.

Introduction Gout is an inflammatory disease triggered by deposition of urate crystals secondary to longstanding hyperuricemia, and its management implies both the treatment of flares and management of hyperuricemia. Dotinurad is a selective urate reabsorption inhibitor (SURI), potently inhibits urate transporter 1 in the apical surface of renal proximal tubular cells, and has been approved for the treatment of gout and hyperuricemia in Japan. Areas covered This overview of dotinurad covers nonclinical and clinical pharmacology studies in special populations and its efficacy and safety in Japanese hyperuricemic patients with and without gout. Expert opinion Dotinurad, as an SURI, is expected to inhibit urate reabsorption more effectively than conventional urate-lowering agents. It is noninferior to benzbromarone or febuxostat in reducing serum urate levels in hyperuricemic patients with or without gout. Its efficacy is not attenuated in patients with mild to moderate renal impairment or with hepatic impairment. At a maintenance dose of 2 or 4 mg once daily, most patients achieved the target serum urate level of ≤6 mg/dL in a long-term study. No findings that raised safety concerns, including liver injury, were identified. Dotinurad is expected to be a new therapeutic option in hyperuricemic patients with and without gout.

ObjectivesGenome-wide meta-analyses of clinically defined gout were performed to identify subtype-specific susceptibility loci. Evaluation using selection pressure analysis with these loci was also conducted to investigate genetic risks characteristic of the Japanese population over the last 2000–3000 years.MethodsTwo genome-wide association studies (GWASs) of 3053 clinically defined gout cases and 4554 controls from Japanese males were performed using the Japonica Array and Illumina Array platforms. About 7.2 million single-nucleotide polymorphisms were meta-analysed after imputation. Patients were then divided into four clinical subtypes (the renal underexcretion type, renal overload type, combined type and normal type), and meta-analyses were conducted in the same manner. Selection pressure analyses using singleton density score were also performed on each subtype.ResultsIn addition to the eight loci we reported previously, two novel loci, PIBF1 and ACSM2B, were identified at a genome-wide significance level (p–8) from a GWAS meta-analysis of all gout patients, and other two novel intergenic loci, CD2-PTGFRN and SLC28A3-NTRK2, from normal type gout patients. Subtype-dependent patterns of Manhattan plots were observed with subtype GWASs of gout patients, indicating that these subtype-specific loci suggest differences in pathophysiology along patients’ gout subtypes. Selection pressure analysis revealed significant enrichment of selection pressure on ABCG2 in addition to ALDH2 loci for all subtypes except for normal type gout.ConclusionsOur findings on subtype GWAS meta-analyses and selection pressure analysis of gout will assist elucidation of the subtype-dependent molecular targets and evolutionary involvement among genotype, phenotype and subtype-specific tailor-made medicine/prevention of gout and hyperuricaemia.

Background Dotinurad is a novel, selective urate reabsorption inhibitor (SURI), which reduces serum uric acid levels by selective inhibition of the urate transporter 1 (URAT1). The Japanese guideline for the management of hyperuricemia and gout recommends that drug selection should be based on classification of hyperuricemia as a fundamental principle. However, there may be some cases where this principle is not observed. We investigated the pharmacodynamics and safety of dotinurad in outpatients with uric acid overproduction or uric acid underexcretion type. Methods This was a multicenter, open-label, forced titration study. Patients were classified as uric acid overproduction or underexcretion type. Study treatment was initiated at 0.5 mg/day, followed by dose titration to the estimated maximum dose of 4 mg/day over 14 weeks. The primary endpoint was urinary uric acid excretion at each 24-h urine collection. Results A total of 26 hyperuricemic patients with or without gout were enrolled in the study and assigned to the uric acid overproduction group (overproduction group) or the uric acid underexcretion group (underexcretion group). Although urinary uric acid excretion, the primary endpoint, tended to be slightly greater in the overproduction group, no notable difference was noted between the two hyperuricemic types. Neither type had noteworthy safety concerns associated with dotinurad. Conclusion The results of the study demonstrated no relevant differences between the hyperuricemic types in terms of pharmacodynamic action and safety of dotinurad.

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.

Background Dotinurad is a novel, selective urate reabsorption inhibitor, which reduces serum uric acid levels by selective inhibition of the urate transporter 1. We evaluated the efficacy and safety of dotinurad versus febuxostat, a widely used drug in Japan, in hyperuricemic Japanese patients with or without gout. Methods This was a multicenter, randomized, double-blind, active-controlled, parallel-group, forced-titration study in hyperuricemic patients. Study treatment in the dotinurad and febuxostat groups was initiated at 0.5 and 10 mg/day, followed by dose titration to 2 and 40 mg/day, respectively, over 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 203 hyperuricemic patients with or without gout were enrolled in the study and randomized to receive dotinurad or febuxostat. The percent change in serum uric acid level from the baseline to the final visit was 41.82% in the dotinurad group and 44.00% in the febuxostat group. The mean difference was − 2.17% (two-sided 95% confidence interval − 5.26% to 0.92%). The lower limit of the interval was above the non-inferiority margin (− 10%), demonstrating the non-inferiority of dotinurad to febuxostat. The profiles of adverse events and adverse drug reactions raised no noteworthy safety concerns in either group. Conclusion The non-inferiority of dotinurad to febuxostat in terms of serum uric acid lowering effect was confirmed. No noteworthy safety concerns arose.

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.

Background Dotinurad, a novel selective urate reabsorption inhibitor (SURI), reduces serum uric acid levels by selectively inhibiting urate transporter 1 (URAT1) for the treatment of hyperuricemia with or without gout. We confirmed the serum uric acid lowering effect and safety of dotinurad. Methods This was a confirmatory, 12-week, randomized, multicenter, double-blind, placebo-controlled, parallel-group, dose escalation, late phase 2 study. The study arms were dotinurad 0.5, 1, 2, or 4 mg and placebo. The primary endpoint was the percent change in serum uric acid level from the baseline to the final visit. The secondary endpoint was the percentage of patients achieving a serum uric acid level ≤ 6.0 mg/dL at the final visit. Results The study drugs were administered to 200 Japanese hyperuricemic patients with or without gout. The mean percent change in serum uric acid level from the baseline to the final visit in the dotinurad 0.5, 1, 2, and 4 mg groups and the placebo group was 21.81%, 33.77%, 42.66%, 61.09%, and − 2.83%, respectively. The percentage of patients achieving a serum uric acid level ≤ 6.0 mg/dL at the final visit in each group was 23.1%, 65.9%, 74.4%, 100%, and none, respectively. Regarding safety, the incidence of adverse events did not increase with dose escalation in the dotinurad groups. No significant differences were observed in the incidence of gouty arthritis in each group. Conclusion The serum uric acid lowering effect and safety of dotinurad were confirmed in hyperuricemic patients with or without gout. ClinicalTrials.gov Identifier NCT02416167

Background Dotinurad, a novel selective urate reabsorption inhibitor (SURI) that has a future potential for the treatment of hyperuricemia, reduces serum uric acid levels by selectively inhibiting urate transporter 1 (URAT1). We evaluated the efficacy and safety of dotinurad in hyperuricemic Japanese patients with or without gout. Methods The study design was an exploratory, early phase 2 study that ran for 8 weeks. It was a randomized, multicenter, double-blind, placebo-controlled, parallel-group study, and performed in a dose escalation manner. There were four study arms consisting of dotinurad 1, 2, or 4 mg, and placebo. The primary endpoint was the percent change in serum uric acid level from the baseline to the final visit. The secondary endpoint was the percentage of patients achieving a serum uric acid level ≤ 6.0 mg/dL at the final visit. Results A total of 80 hyperuricemic patients with or without gout were enrolled and randomly assigned to the dotinurad or placebo groups. The mean percent change in serum uric acid level from the baseline to the final visit in the dotinurad 1, 2, 4 mg, and placebo groups was 37.03%, 50.91%, 64.37%, and 0.85%, respectively. The percentages of patients achieving a serum uric acid level ≤ 6.0 mg/dL at the final visit in each group were 75.0%, 89.5%, 95.2%, and none, respectively. The incidence of adverse events was comparable among all groups. Conclusion Dotinurad has a substantial serum uric acid lowering effect in patients with hyperuricemia. No serious adverse event was found. ClinicalTrials.gov Identifier NCT02344862

Attribute-based medicine is essential for patient-centered medicine. To date, the groups of patients with chronic kidney disease (CKD) requiring urate-lowering therapy are clinically unknown. Herein, we evaluated the efficacy of febuxostat using a cross-classification, attribute-based research approach. We performed post hoc analysis of multicenter, randomized, double-blind, placebo-controlled trial data for 395 patients with stage 3 CKD and asymptomatic hyperuricemia. Participants were divided into febuxostat or placebo groups and subcohorts stratified and cross-classified by proteinuria and serum creatinine concentrations. In patients stratified based on proteinuria, the mean eGFR slopes were significantly higher in the febuxostat group than in the placebo group (P = 0.007) in the subcohort without proteinuria. The interaction between febuxostat treatment and presence of proteinuria in terms of eGFR slope was significant (P for interaction = 0.019). When cross-classified by the presence of proteinuria and serum creatinine level, the mean eGFR slopes significantly differed between the febuxostat and placebo groups (P = 0.040) in cross-classified subcohorts without proteinuria and with serum creatinine level ≥ median, but not in the cross-classified subcohorts with proteinuria and serum creatinine level median. Febuxostat mitigated the decline in kidney function among stage 3 CKD patients with asymptomatic hyperuricemia without proteinuria.

Although combined therapy with peritoneal dialysis (PD) and hemodialysis (HD) is widespread in Japan, its clinical utility has been reported only in retrospective or before-and-after test lacking a control group.We conducted a prospective, multicenter, observational cohort study of 176 incident PD patients and compared patient survival and changes in clinical parameters between patients on different dialysis modalities.During a median follow-up of 41 months, 47 patients transferred to combined therapy and 35 patients transferred directly to HD. Patients transferred to combined therapy had a significantly better survival than those transferred directly to HD. However, we could not establish this difference in a multivariate analysis because only six patients died among these groups. The decreases in urea nitrogen and serum creatinine were more prominent among patients directly transferred to HD.This is the first report revealing clinical feasibility of transfer to combined therapy for PD patients.

Background: Hyperuricemia is a risk factor for the development of hypertension and is comorbid in many hypertensive patients. According to Japanese hypertension management guidelines published in 2019, a target serum uric acid level of ≤6.0 mg/dL is recommended in hypertensive patients with gout or asymptomatic hyperuricemia. Dotinurad is a novel uric acid-lowering drug classified as a selective urate reabsorption inhibitor. A pooled analysis was performed on the uric acid-lowering effect of dotinurad in 222 hypertensive patients with gout or asymptomatic hyperuricemia in four clinical trials (NCT02344862, NCT02416167, NCT03100318, NCT03372200). Moreover, we analyzed the long-term uric acid-lowering effect of dotinurad in 154 hypertensive patients with gout or asymptomatic hyperuricemia (NCT03006445).Results: In the pooled analysis, the percent change in the decrease of serum uric acid with the use of dotinurad was 42.17 ± 12.42% at a dose of 2 mg and 60.42 ± 8.03% at a dose of 4 mg; the percentage of patients who achieved a serum uric acid level of ≤6.0 mg/dL was 82.8% and 100.0%. The long-term uric acid-lowering effect of dotinurad showed almost the same results. In this study, the concomitant use of diuretics or angiotensin II receptor blockers affected the uric acid-lowering effect of dotinurad at only a dose of 2 mg in the pooled analysis.Conclusions: In the pooled analysis, dotinurad lowered serum uric acid levels. Dotinurad has an achievement rate of over 80% for serum uric acid level of ≤6.0 mg/dL in both analyses, and will be clinically useful for the management of hyperuricemic states in hypertensive patients.

Background: The levels of circulating tumor necrosis factor receptor (TNFR) 1 and 2 help predict the future decline of estimated glomerular filtration rate (eGFR) chiefly in patients with diabetes. It has been recently reported that the change ratio in TNFR1 by SGLT2 inhibitor treatment is also related with future GFR decline in patients with diabetes. The aims of this study are to investigate the association between baseline TNFR levels and early change in TNFR levels by the non-purine selective xanthine oxidase inhibitor, febuxostat, and future eGFR decline chiefly in chronic kidney disease (CKD) patients without diabetes.Methods: We conducted a post-hoc analysis of the FEATHER study on patients with asymptomatic hyperuricemia and CKD stage 3, who were randomly assigned febuxostat 40 mg/day or matched placebo. This analysis included 426 patients in whom baseline stored samples were available. Serum TNFR levels at baseline were measured using enzyme-linked immunosorbent assay. Those levels were also measured using 12-week stored samples from 197 randomly selected patients.Results: Compared with placebo, short-term febuxostat treatment significantly decreased the median percent change from baseline in serum uric acid (−45.05, 95% CI −48.90 to −41.24 mg/dL), TNFR1 (1.10, 95% CI−2.25 to 4.40), and TNFR2 (1.66, 95% CI −1.72 to 4.93), but not TNFR levels. Over a median follow-up of 105 weeks, 30 patients (7.0%) experienced 30% eGFR decline from baseline. In the Cox multivariate model, high levels of baseline TNFR predicted a 30% eGFR decline, even after adjusting for age, sex, systolic blood pressure, high sensitivity C-reactive protein, uric acid, and presence or absence of febuxostat treatment and diabetes, in addition to baseline albumin to creatinine ratio and eGFR.Conclusion: Early change in circulating TNFR levels failed to predict future eGFR decline; however, regardless of febuxostat treatment, the elevated baseline level of TNFR was a strong predictor of 30% eGFR decline even in chiefly non-diabetic CKD patients with asymptomatic hyperuricemia.

ObjectiveThe first ever genome-wide association study (GWAS) of clinically defined gout cases and asymptomatic hyperuricaemia (AHUA) controls was performed to identify novel gout loci that aggravate AHUA into gout.MethodsWe carried out a GWAS of 945 clinically defined gout cases and 1003 AHUA controls followed by 2 replication studies. In total, 2860 gout cases and 3149 AHUA controls (all Japanese men) were analysed. We also compared the ORs for each locus in the present GWAS (gout vs AHUA) with those in the previous GWAS (gout vs normouricaemia).ResultsThis new approach enabled us to identify two novel gout loci (rs7927466 of CNTN5 and rs9952962 of MIR302F) and one suggestive locus (rs12980365 of ZNF724) at the genome-wide significance level (p–8). The present study also identified the loci of ABCG2, ALDH2 and SLC2A9. One of them, rs671 of ALDH2, was identified as a gout locus by GWAS for the first time. Comparing ORs for each locus in the present versus the previous GWAS revealed three ‘gout vs AHUA GWAS’-specific loci (CNTN5, MIR302F and ZNF724) to be clearly associated with mechanisms of gout development which distinctly differ from the known gout risk loci that basically elevate serum uric acid level.ConclusionsThis meta-analysis is the first to reveal the loci associated with crystal-induced inflammation, the last step in gout development that aggravates AHUA into gout. Our findings should help to elucidate the molecular mechanisms of gout development and assist the prevention of gout attacks in high-risk AHUA individuals.

Background. Combined therapy with peritoneal dialysis (PD) and hemodialysis (HD) represents a treatment option for PD patients who cannot maintain adequacy of dialysis. Although several reports have indicated the clinical utility of combined therapy, most such studies have been small-scale, single-centered, retrospective and before-and-after test investigations lacking a control group. Methods. We conducted a prospective, multicenter, observational cohort study of 176 incident PD patients and compared patient survival and time-course changes in clinical parameters between patients switched from PD alone to combined therapy and patients switched directly to HD. Results. During a median follow-up of 41 months, 47 patients transferred to combined therapy and 35 patients transferred directly to HD. Among patients transferred to combined therapy, 66% transferred because of inadequate dialysis, and/or fluid overload, compared to only 29% among patients directly transferred to HD. Five patients died after transfer to HD alone, whereas 1 patient died after transfer to combined therapy. Although mortality was greater among patients transferred to HD directly than among patients transferred to combined therapy, this difference disappeared after matching for fluid overload and/or inadequate dialysis.Conclusion. This is the first report comparing clinical outcomes for patients on PD alone transferred to combined therapy with those for patients directly transferred to HD. Although comparison of patient survival was difficult because of the small number of deaths, PD patients suffering from inadequate dialysis and/or volume overload could clearly continue PD therapy safely by switching to combined therapy. Further study with a larger number of outcomes is needed.

Background and Objectives Topiroxostat—a novel selective xanthine oxidoreductase inhibitor—has been reported to reduce serum urate levels. The purpose of this study was to assess the efficacy and safety of long-term topiroxostat administration in Japanese hyperuricemic patients with or without gout. Methods This multicenter, open-label study evaluated the efficacy and safety of long-term twice-daily oral topiroxostat administration in patients with or without gout. The initial topiroxostat dosage was 40–80 mg/day, and the maintenance dosage was 120 mg/day, which was increased to 240 mg/day at 40 mg increments if the serum urate level exceeded 6.0 mg/dL. Results Serum urate level, which was the primary endpoint, decreased stably over time and showed significant reduction on the final visit (38.44% ± 13.34%) compared with that at the baseline. Both urinary albumin/creatinine ratio and mean blood pressure significantly improved. The overall incidence rate of adverse drug reactions to topiroxostat was 67.8%; on the final visit, the rate of adverse drug reactions was 66.7% with 120 mg/day, 72.2% with 160 mg/day, 53.8% with ≥ 200 mg/day, and 100% with the other dosages. On the final visit, the incidence of gouty arthritis, for which a causal relationship with topiroxostat could not be ruled out, was 4.1% overall, 4.8% with 120 mg/day, 0% with 160 mg/day, and 7.7% with ≥ 200 mg/day. Conclusions We verified the efficacy and safety of 58-week oral topiroxostat administration at stepwise increments to up to 240 mg/day. Study Registration JAPIC CTI-101068.

金沢大学医薬保健研究域医学系, Background: Hyperuricemia is supposed to be an independent risk factor for kidney dysfunction in diabetic patients. We attempted to examine the uric acid-lowering effect and the renoprotective effect of topiroxostat, a selective xanthine oxidoreductase inhibitor, in patients with diabetic nephropathy and hyperuricemia in this pilot study. Methods: The study design was randomized, double-blind, placebo-controlled, parallel-group study. A total of 65 patients with hyperuricemia and diabetic nephropathy with microalbuminuria were enrolled and assigned to either the topiroxostat group or the placebo group. Topiroxostat (stepwise dosing from 40 to 160 mg/day) or matching placebo was administered BID for 28 weeks. The primary endpoint was a change in the urinary albumin-to-creatinine ratio in the first-morning-void urine sample. Secondary endpoints were changes in the estimated glomerular filtration rate and the serum uric acid level. Results: At 28 weeks, there was no significant difference in the percent change from baseline in the urinary albumin-to-creatinine ratio between the two groups (topiroxostat: 0 vs. placebo: 17%, p = 0.3206), but the changes in the estimated glomerular filtration rate (− 0.2 vs. − 4.0 mL/min/1.73 m2, p = 0.0303) and the serum uric acid level (− 2.94 vs. − 0.20 mg/dL, p < 0.0001) were significantly different between the topiroxostat and placebo groups. Gouty arthritis occurred in 1 patient in the placebo group and no patients in the topiroxostat group. Conclusion: These findings support that diabetic nephropathy combined with hyperuricemia may be associated with kidney dysfunctions. Topiroxostat provides strict control of the serum uric acid level preventing decline of eGFR in these patients. © 2018 The Author(s), Embargo Period 12 months

Background Dotinurad is a novel selective urate reabsorption inhibitor (SURI) which reduces serum uric acid levels by selectively inhibiting urate transporter 1 (URAT1). This study was intended to verify the efficacy and safety of dotinurad following treatment for 34 or 58 weeks in hyperuricemic patients with or without gout. Methods This long-term study had an open-label design with dose escalation. The dose of dotinurad started at 0.5 mg/day and was increased progressively to 2 mg/day. If the serum uric acid level of patients did not reach ≤ 6 mg/dL at week 14, the dose was increased to 4 mg/day. The primary endpoint was the percent change in serum uric acid level from the baseline to each visit. Results At a dose of 2 mg, serum uric acid levels at week 34 and 58 were reduced from the baseline by 46.73% and 47.17%, respectively; at 4 mg, the respective values were 54.92% and 57.35%. At week 34 and 58, the percentages of patients achieving a serum uric acid levels ≤ 6.0 mg/dL with 2-mg dose were 89.11% and 91.30%, respectively; with 4 mg, the respective rates were 97.50% and 100.00%. In addition, the incidences of adverse events and adverse drug reactions were 65.2% and 21.8%, respectively. Conclusion Dotinurad at doses of 2–4-mg sufficiently reduced serum uric acid levels in hyperuricemic patients with or without gout, and its efficacy and safety were verified for long-term administration. ClinicalTrials.gov Identifier: NCT03006445

The present study explored the gender interaction on the risk of uric acid in the new development of hypertension.A longitudinal retrospective cohort.A total of 5,807 individuals with an average age of 38 ± 7 years old were recruited. Individuals whose blood pressure rose more than 140/90mmHg or those who newly commenced antihypertensive treatment were defined as a new onset of hypertension. Cox regression analysis was employed for the analysis.During the 10-years follow-up, 42.8% of men and 22.2% of women had developed hypertension. Factors to predict the hypertension development were male gender, older age, higher BMI, higher uric acid, and higher mean blood pressure. An association between higher uric acid levels and higher incidence of hypertension remained statistically significant in women in a multivariate model adjusted for various clinical variables (Hazard ration (HR), 1.180; 95%CI, 1.018 to 1.369), whereas such association was not found in men (HR, 1.034; 95%CI, 0.994 to 1.075). The interaction between the two genders reached statistical significance (p for interaction = 0.007).Higher uric acid is associated with the incident hypertension in the both genders. Women are more susceptible to the development of hypertension than men.

Topiroxostat, a selective xanthine oxidoreductase inhibitor, is used in Japan for the treatment of hyperuricemic patients with or without gout. In terms of the effectiveness of topiroxostat in lowering serum urate levels, the dose–response relationship has been evaluated; however, it remains to be verified. A randomized, multi-center, double-blinded study of topiroxostat was performed for Japanese hyperuricemic patients with or without gout. During the 16-week study, 157 Japanese hyperuricemic patients with or without gout were randomly assigned to receive a placebo, topiroxostat at 120 or 160 mg/day, or allopurinol at 200 mg/day. The primary endpoint of this study was to determine the lowering rate of serum uric acid levels compared to those of baseline at the end of administration. A dose–response relationship (regarding decreases in the serum urate levels) was confirmed for the placebo and topiroxostat at 120 and at 160 mg/day. Moreover, at the end of administration, the lowering rate of serum urate levels was determined to be −44.8% in the topiroxostat 160-mg/day group. No significant difference in the incidence of adverse events was observed among all groups, including the allopurinol group. The serum urate-lowering effect of topiroxostat was found to have a dose–response relationship in Japanese hyperuricemic patients with or without gout. Electronic supplementary material The online version of this article (doi:10.1007/s10067-016-3474-8) contains supplementary material, which is available to authorized users.

Summary What is known and objective In Japan, although topiroxostat, a selective xanthine oxidoreductase inhibitor, has been used for the treatment of patients with hyperuricemia including gout, no published randomized controlled studies evaluating the dose-dependent relationship with respect to the serum urate-lowering efficacy have been reported. The aim of this study was to evaluate the dose-dependent relationship with serum urate-lowering efficacy and safety of topiroxostat in Japanese hyperuricemic patients including gout. Methods We conducted an exploratory, phase 2a, multicentre, randomized, double-blind, 8-week, placebo-controlled study in Japanese hyperuricemic patients with or without gout. The study arms were placebo and topiroxostat 40, 60, 80 or 120 mg/day. The primary efficacy endpoint was the per cent change in serum urate level from baseline to the final visit. Results and discussion One hundred and eighty-seven eligible patients were randomized and 186 received at least one dose of the study drug. The study results demonstrated a dose-dependent serum urate reduction effect ranging from 40 to 120 mg/day (P < 0·001, Jonckheere–Terpstra test). The mean per cent change in serum urate level from baseline at the final visit was −30·8% in the 120-mg group and 1·6% with placebo, with a between-group difference of −32·4% ([95% confidence interval, −38·9% to −25·9%]; P < 0·001). Incidences of overall adverse events (AEs) in the topiroxostat groups were comparable to those in the placebo group; however, the incidence of AEs in the 120-mg group was statistically lower than that in the placebo group. The incidences of gouty arthritis were not statistically but numerically higher in the topiroxostat 80- and 120-mg groups. What is new and conclusions A dose-dependent serum urate-lowering efficacy of topiroxostat was observed in Japanese hyperuricemic male patients with or without gout. Further clinical studies aimed at evaluating the long-term safety and clinical efficacy are warranted.

Background: To what extent uric acid (UA) levels and/or metabolic syndrome (Mets) contribute to the onset of chronic kidney disease (CKD) is largely unknown. The present study explores how these two factors have an association with the new incidence of CKD. Methods: Study design is a cohort study. A total of 14,485 participants were eligible for the cross-sectional analysis on UA levels and the prevalence of Mets. Among those individuals, 8,223 participants without CKD and 4,839 without Mets were eligible for the longitudinal analysis of the new incidence of CKD. Parameters monitored were body mass index, systolic and diastolic blood pressure, serum creatinine concentration, estimated glolerular filtration rate, lipid profiles, plasma glucose, HbA1c. The primary predictor was the level of UA and Mets to explain the newly-developed CKD. The observation period was 4 years. Results: In a cross-sectional analysis, higher UA levels were associated with the greater prevalence of Mets. In addition, UA levels were associated with the numbers of the Mets constituents in both genders. In a longitudinal analysis, higher UA levels were associated with the greater rate of CKD and the greater incidence of Mets. In addition, the incidence of CKD at year 4 was influenced by the presence of hyperuricemia, but not by that of the Mets. The odd ratio (OR) to predict the CKD incidence was 1.42 (95% confidence intervals (CI), 0.52 to 3.78) in the presence of Mets alone, 2.10 (95% CI, 1.36 to 3.23) in the presence of hyperuricemia alone, and 3.56 (95% CI, 1.55 to 8.21) in the presence of both. Conclusion: Hyperuricemia has a greater association with the incidence of CKD than Mets does. Hyperuricemia complicated by Mets is additionally detrimental.

Rationale & Objective Epidemiologic and clinical studies have suggested that urate-lowering therapy may slow the progression of chronic kidney disease (CKD). However, definitive evidence is lacking. Study Design Randomized, double-blind, placebo-controlled trial. Setting & Participants 467 patients with stage 3 CKD and asymptomatic hyperuricemia at 55 medical institutions in Japan. Intervention Participants were randomly assigned in a 1:1 ratio to receive febuxostat or placebo for 108 weeks. Outcomes The primary end point was the slope (in mL/min/1.73 m2 per year) of estimated glomerular filtration rate (eGFR). Secondary end points included changes in eGFRs and serum uric acid levels at 24, 48, 72, and 108 weeks of follow-up and the event of doubling of serum creatinine level or initiation of dialysis therapy. Results Of 443 patients who were randomly assigned, 219 and 222 assigned to febuxostat and placebo, respectively, were included in the analysis. There was no significant difference in mean eGFR slope between the febuxostat (0.23 ± 5.26 mL/min/1.73 m2 per year) and placebo (−0.47 ± 4.48 mL/min/1.73 m2 per year) groups (difference, 0.70; 95% CI, −0.21 to 1.62; P = 0.1). Subgroup analysis demonstrated a significant benefit from febuxostat in patients without proteinuria (P = 0.005) and for whom serum creatinine concentration was lower than the median (P = 0.009). The incidence of gouty arthritis was significantly lower (P = 0.007) in the febuxostat group (0.91%) than in the placebo group (5.86%). Adverse events specific to febuxostat were not observed. Limitations GFR was estimated rather than measured, and patients with stages 4 and 5 CKD were excluded. Conclusions Compared to placebo, febuxostat did not mitigate the decline in kidney function among patients with stage 3 CKD and asymptomatic hyperuricemia. Funding Funded by Teijin Pharma Limited. Trial Registration Registered at the UMIN (University Hospital Medical Information Network) Clinical Trials Registry with study number UMIN000008343.

ObjectiveGout, caused by hyperuricaemia, is a multifactorial disease. Although genome-wide association studies (GWASs) of gout have been reported, they included self-reported gout cases in which clinical information was insufficient. Therefore, the relationship between genetic variation and clinical subtypes of gout remains unclear. Here, we first performed a GWAS of clinically defined gout cases only.MethodsA GWAS was conducted with 945 patients with clinically defined gout and 1213 controls in a Japanese male population, followed by replication study of 1048 clinically defined cases and 1334 controls.ResultsFive gout susceptibility loci were identified at the genome-wide significance level (p−8), which contained well-known urate transporter genes (ABCG2 and SLC2A9) and additional genes: rs1260326 (p=1.9×10−12; OR=1.36) of GCKR (a gene for glucose and lipid metabolism), rs2188380 (p=1.6×10−23; OR=1.75) of MYL2-CUX2 (genes associated with cholesterol and diabetes mellitus) and rs4073582 (p=6.4×10−9; OR=1.66) of CNIH-2 (a gene for regulation of glutamate signalling). The latter two are identified as novel gout loci. Furthermore, among the identified single-nucleotide polymorphisms (SNPs), we demonstrated that the SNPs of ABCG2 and SLC2A9 were differentially associated with types of gout and clinical parameters underlying specific subtypes (renal underexcretion type and renal overload type). The effect of the risk allele of each SNP on clinical parameters showed significant linear relationships with the ratio of the case–control ORs for two distinct types of gout (r=0.96 [p=4.8×10−4] for urate clearance and r=0.96 [p=5.0×10−4] for urinary urate excretion).ConclusionsOur findings provide clues to better understand the pathogenesis of gout and will be useful for development of companion diagnostics.

Familial juvenile hyperuricemic nephropathy (FJHN) is an autosomal dominant disorder caused by mutations in UMOD that encodes uromodulin. Topiroxostat, a novel non-purine analog, selectively inhibits xanthine oxidase and reduces the serum uric acid levels and the urinary albuminuria.Genomic DNA of a patient was extracted from peripheral white blood. Exons and flanking sequences of UMOD were amplified by PCR with primers. Mutation analysis was performed by direct sequencing of the PCR products. The wild-type and mutant uromodulin were expressed in HEK293 cells and analyzed by western blotting, immunoprecipitation, immunofluorescence, and flow cytometry.We identified an FJHN patient who carried a novel UMOD mutation G335A (C112Y). The levels of both cytosolic and secreted C112Y protein were significantly decreased compared with the wild-type, whereas the level of ubiquitination was higher in C112Y than that in the wild type. The half-life of C112Y was shortened and it was restored by a proteasome inhibitor MG132. Immunofluorescence revealed decreased levels of C112Y in the Golgi apparatus and on the plasma membrane. Expression of C112Y induced cellular apoptosis as revealed by flow cytometry. Apoptosis induced by C112Y was suppressed by topiroxostat.C112Y causes its protein instability resulting cellular apoptosis which could be suppressed with topiroxostat.

Hyperuricemia (HU) is common in patients with chronic kidney disease (CKD), and accumulating evidence suggests it has a pathogenic role in the progression of the disease. However, a major challenge in treating patients with HU is the adverse effects caused by urate-lowering drugs used to treat CKD. Because of these untoward effects, doses need to be reduced, which leads to suboptimal efficacy. Febuxostat has been shown to be highly efficacious in reducing serum uric acid (sUA) and is well tolerated in patients with mild kidney dysfunction. However, its safety and efficacy have not been well studied in more advanced cases of CKD. We studied the safety and efficacy of escalating doses of febuxostat over a 24-week period in 70 patients with CKD stages 3b, 4 and 5, and we also observed the changes in blood pressure, estimated glomerular filtration rate (eGFR) and proteinuria following the reduction of sUA. Drug-related adverse events (AEs) occurred in only 5 out of 70 patients. All but one of the events were mild, and all five patients fully recovered. By 24 weeks, the reduction of sUA levels was >40% in CKD stage 3b and >50% in CKD stages 4 and 5. More than 70% of patients achieved target sUA levels of 6 mg dl(-1) or less. Multivariate analysis showed that a greater reduction in sUA with febuxostat was associated with an increase in eGFR and a tendency toward decreased proteinuria. Febuxostat was safe and efficacious in the treatment of CKD stages 3b-5.

To elucidate the genotypic and phenotypic characteristics of autosomal dominant polycystic kidney disease (ADPKD) in Japanese populations, we performed a comprehensive search for mutations in PKD1 and PKD2 in 180 Japanese ADPKD patients from 161 unrelated families. We identified 112 (89 PKD1 and 23 PKD2) mutations within 135 families. Patients with PKD2 mutations account for 23.6% of all Japanese ADPKD families in this study. Seventy-five out of the 112 mutations have not been reported previously. The estimated glomerular filtration rate (eGFR) decline was significantly faster in patients with PKD1 mutations than in those with PKD2 mutations (-3.25 and -2.08 ml min(-1) year(-1) for PKD1 and PKD2, respectively, p

Monitoring of serum alkaline phosphatase (ALP) is recommended in the management of chronic kidney disease-mineral and bone disorder (CKD-MBD). However, unlike calcium, phosphate or parathyroid hormone, the relationship between serum ALP and patient outcome receiving hemodialysis (HD) in Japan is unknown.Baseline data of 185 277 HD patients with duration90 days (66 ± 12 years, males 61.9%, and median HD duration of 5.8 years) were extracted from a nationwide dialysis registry at the end of 2009 in Japan. Outcomes were then evaluated using the registry at the end of 2010 using a multivariate logistic regression analysis.During 1-year follow-up, 14 230 (7.9%) patients died of all causes, including 6396 (3.6%) cardiovascular deaths. In addition, 1586 patients (1.0%) were newly diagnosed as hip fractures. All-cause and cardiovascular mortality and the incidence of hip fracture were higher in line with the increase in baseline serum ALP. On multivariate analysis, patients with the highest ALP quartile had higher all-cause and cardiovascular mortalities and a higher incidence of hip fracture than those with the lowest quartile [odds ratio (OR) 1.46, 95% confidence interval (CI) 1.33-1.60; OR 1.25, 95% CI 1.10-1.42; and OR 1.71, 95% CI 1.33-2.18, respectively].In this large cohort study, higher serum ALP levels were independently associated not only with mortality but also with the incidence of hip fracture in Japanese HD patients. Further study is needed to test whether serum ALP measurements could improve the patient outcomes.

Background/Aims: Combining peritoneal dialysis (PD) and hemodialysis (HD) has been common treatment option in Japan. Methods: In this retrospective, multicenter, observational study, the clinical characteristics and outcomes of 104 patients (57 w 11 years, males 72%) who had switched from PD alone to combined therapy with PD and HD were studied. Clinical parameters were measured at baseline and after 3 months of combined therapy. Results: At baseline, urine volume, dialysate-to-plasma ratio of creatinine (D/P Cr), and total Kt/V were 150 ml/day (range: 0-2,000 ml/day), 0.67 w 0.11, and 1.8 w 0.4, respectively. During the first 3 months of combined therapy, body weight, urine volume, serum creatinine level, and D/P Cr decreased, whereas hemoglobin levels increased. Conclusions: In patients where PD does not result in acceptable outcomes, combined therapy with PD and HD may have potential benefits in terms of dialysis adequacy and hydration status. Video Journal Club “Cappuccino with Claudio Ronco” at http://www.karger.com/?doi=368389 i 2014 S. Karger AG, Basel

Importance Patients with chronic kidney disease have impaired vitamin D activation and elevated cardiovascular risk. Observational studies in patients treated with hemodialysis showed that the use of active vitamin D sterols was associated with lower risk of all-cause mortality, regardless of parathyroid hormone levels. Objective To determine whether vitamin D receptor activators reduce cardiovascular events and mortality in patients without secondary hyperparathyroidism undergoing hemodialysis. Design, Setting, and Participants Randomized, open-label, blinded end point multicenter study of 1289 patients in 207 dialysis centers in Japan. The study included 976 patients receiving maintenance hemodialysis with serum intact parathyroid hormone levels less than or equal to 180 pg/mL. The first and last participants were enrolled on August 18, 2008, and January 26, 2011, respectively. The final date of follow-up was April 4, 2015. Interventions Treatment with 0.5 μg of oral alfacalcidol per day (intervention group; n = 495) vs treatment without vitamin D receptor activators (control group; n = 481). Main Outcomes and Measures The primary outcome was a composite measure of fatal and nonfatal cardiovascular events, including myocardial infarctions, hospitalizations for congestive heart failure, stroke, aortic dissection/rupture, amputation of lower limb due to ischemia, and cardiac sudden death; coronary revascularization; and leg artery revascularization during 48 months of follow-up. The secondary outcome was all-cause death. Results Among 976 patients who were randomized from 108 dialysis centers, 964 patients were included in the intention-to-treat analysis (median age, 65 years; 386 women [40.0%]), and 944 (97.9%) completed the trial. During follow-up (median, 4.0 years), the primary composite outcome of cardiovascular events occurred in 103 of 488 patients (21.1%) in the intervention group and 85 of 476 patients (17.9%) in the control group (absolute difference, 3.25% [95% CI, −1.75% to 8.24%]; hazard ratio, 1.25 [95% CI, 0.94-1.67];P = .13). There was no significant difference in the secondary outcome of all-cause mortality between the groups (18.2% vs 16.8%, respectively; hazard ratio, 1.12 [95% CI, 0.83-1.52];P = .46). Of the 488 participants in the intervention group, 199 (40.8%) experienced serious adverse events that were classified as cardiovascular, 64 (13.1%) experienced adverse events classified as infection, and 22 (4.5%) experienced malignancy-related serious adverse events. Of 476 participants in the control group, 191 (40.1%) experienced cardiovascular-related serious adverse events, 63 (13.2%) experienced infection-related serious adverse events, and 21 (4.4%) experienced malignancy-related adverse events. Conclusions and Relevance Among patients without secondary hyperparathyroidism undergoing maintenance hemodialysis, oral alfacalcidol compared with usual care did not reduce the risk of a composite measure of select cardiovascular events. These findings do not support the use of vitamin D receptor activators for patients such as these. Trial Registration UMIN-CTR Identifier:UMIN000001194

Encapsulating peritoneal sclerosis (EPS) is a serious complication that occurs in patients with long-term peritoneal dialysis (PD). Investigation of risk factors that contribute to EPS in patients on long-term PD therapy is needed. In a retrospective, observational study, data were collected for 107 patients treated with PD therapy for more than 5 years. Fifty cases of EPS were compared with 57 cases of non-EPS. To evaluate the impact of PD-associated peritonitis in EPS, univariate and multivariate logistic regression models were applied. Episodes of peritonitis, number of peritonitis episodes and the duration of peritonitis were included as explanatory variables in addition to previously reported risk factors. D/P Cr and serum β2MG levels in the EPS and non-EPS groups were: 0.82 ± 0.10 and 0.67 ± 0.12 (P < 0.01), and 33.8 ± 8.54 and 29.2 ± 8.18 mg/L (P < 0.01), respectively. Episodes of peritonitis, number of peritonitis episodes and the duration of peritonitis was 68% and 42% (P < 0.01), 1.80 ± 2.19 and 0.75 ± 1.07 times (P < 0.01), and 18.1 ± 15.3 and 10.2 ± 4.90 days (P < 0.01), in the EPS and non-EPS groups, respectively. Furthermore, multivariate logistic regression models demonstrated that both D/P Cr and the duration of peritonitis were independently associated with EPS (P < 0.01 and P < 0.05, respectively). In patients on long-term PD therapy, D/P Cr and the duration of peritonitis are independently associated with EPS. Earlier treatment to promote an early recovery from PD-associated peritonitis could be critical in preventing EPS.