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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

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 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

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 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

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.

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

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.

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.

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

We recently showed dihydropyridine- and voltage-sensitive Ca(2+) entry in cultured parathyroid cells from patients with secondary hyperparathyroidism. To determine whether normal parathyroid cells have a similar extracellular Ca(2+) entry system, cells were isolated from normal (non-hyperplastic) human parathyroid glands. Fluorescence signals related to the cytoplasmic Ca(2+) concentration ([Ca(2+)]I) were examined in these cells. Cells loaded with fluo-3/AM showed a transient increase in fluorescence (Ca(2+) transient) following a 10-s exposure to a 150 mM K(+) solution in the presence of millimolar concentrations of external Ca(2+). The Ca(2+) transient was reduced by dihydropyridine antagonists or 0.5 mM Cd(2+), but enhanced by FPL-64176, an L-type Ca(2+)-channel agonist. Ca(2+) transients induced by the 10-s exposure to 3.0 mM extracellular Ca(2+) ([Ca(2+)]o) were also inhibited by dihydropyridine antagonists or 0.5 mM Cd(2+). These results provide the first evidence that normal human parathyroid cells express a dihydropyridine-sensitive Ca(2+) entry system that may be involved in the [Ca(2+)]o-induced change in [Ca(2+)]I. This system might provide a compensatory pathway for negative feedback regulation of parathyroid hormone secretion under physiological conditions.

A recent genome-wide association study for diabetic nephropathy in European type 1 diabetes identified 3 candidate loci for diabetic nephropathy. In this study, we examined the association of the 3 single nucleotide polymorphism (SNP) loci with susceptibility to diabetic nephropathy in Japanese subjects with type 2 diabetes. We genotyped 3 SNPs, rs7583877 in AFF3, rs12437854 in the RGMA-MCTP2 locus and rs7588550 in ERBB4, for 2,300 Japanese patients with type 2 diabetes [initial study, 1,055 nephropathy cases with overt proteinuria or with end-stage renal disease (ESRD) and 1,245 control patients with normoalbuminuria]. The association of these SNPs with diabetic nephropathy was examined by using a logistic regression analysis. We observed a significant association of rs7588550 in ERBB4 with diabetic nephropathy in the Japanese patients with type 2 diabetes, although the effect direction was not consistent with that in the European study [p = 0.0126, odds ratio (OR) = 0.79, 95 % confidence interval (CI): 0.65–0.95]. We further examined the association of rs7588550 with diabetic nephropathy in an independent Japanese cohort (596 nephropathy cases and 311 controls) and observed the same trend of the association with the initial study. We did not observe any association of the remaining 2 SNP loci with diabetic nephropathy in the present Japanese sample. The association of SNP loci derived from GWAS in European type 1 diabetes with diabetic nephropathy was not replicated in the Japanese patients with type 2 diabetes, although the ERBB4 locus may have some effect also in Japanese type 2 diabetes.

SummaryWhat is known and Objective Febuxostat is a new non-purine selective inhibitor of xanthine oxidase for the treatment of hyperuricaemia in patients with gout. Febuxostat is recommended as the first-line pharmacologic urate-lowering therapy for gout in the American College of Rheumatology guidelines. Febuxostat has not been reported to cause severe complications, especially haematological abnormalities. Our objective is to report two cases of neutropenia associated with initiation of febuxostat therapy for hyperuricaemia in patients with chronic kidney disease (CKD). Case summary A 74-year-old woman with liver cirrhosis and CKD was treated with febuxostat for hyperuricaemia during hospitalization. Eleven days after febuxostat administration, she developed neutropenia. A 68-year-old man with type 2 diabetes mellitus on intermittent haemodialysis was treated with febuxostat for hyperuricaemia during hospitalization. Three days after febuxostat administration, he developed neutropenia. In the two cases, febuxostat treatment was discontinued and granulocyte colony-stimulating factor was administered, with concomitant recovery of the neutrophil count. What is new and Conclusion We believe this to be the first published case of neutropenia associated with initiation of febuxostat therapy for hyperuricaemia. According to the Naranjo probability scale, febuxostat was the probable cause of neutropenia. In view of the wide clinical usage of this drug, physicians and pharmacists should be alerted to this possible complication.

♦ Background The angiogenic response is partly involved in the progression of encapsulating peritoneal sclerosis (EPS). However, the details of the angiogenic response, especially for lymphatic vessels in patients with EPS, remain unclear. In addition, because of technical limitations, morphology studies reported to date have examined only the parietal peritoneum. The morphologies of parietal and visceral lymphatic vessels in patients with EPS both need to be analyzed. ♦ Methods We examined peritoneal samples from 18 patients with EPS who underwent enterolysis of the visceral peritoneum and compared them with samples from 17 autopsy cases (controls). To examine the angiogenic response, we performed immunohistochemistry for the endothelial markers CD34 (blood vessels) and podoplanin (lymphatic vessels) and for the cell proliferation marker Ki-67. Immunogold electron microscopy analysis for podoplanin was also performed. In 7 of 18 cases, we compared differences in the angiogenic response of the parietal and visceral peritoneal membranes. ♦ Results Angiogenic responses were more frequent in the compact zone than in regenerated layers. The number of capillaries positive for anti-CD34 and anti-podoplanin monoclonal antibodies per unit area of visceral peritoneal tissue was, respectively, 41.1 ± 29.3/mm2 in EPS patients and 2.7 ± 4.4/mm2 in controls ( p ≤ 0.01) and 48.1 ± 43.9/mm2 in EPS patients and 4.1 ± 5.4/mm2 in controls ( p ≤ 0.01). The percentage of capillaries positive for anti–Ki-67, CD34, and podoplanin was 4.6% in EPS patients ( p ≤ 0.01) and 0.8% in controls ( p = 0.09). The immunogold electron microscopy analysis revealed that podoplanin was localized to endothelial cells with anchoring filaments, a specific feature of lymphatic vessels. Furthermore, compared with parietal peritoneal membrane, visceral peritoneal membrane had a more prominent podoplanin-positive capillary profile, but not a prominent CD34-positive capillary profile. In addition, fibroblast-like cells double-positive for podoplanin and smooth muscle actin were markedly increased in the degenerated layer, as previously reported. ♦ Conclusions Our study demonstrated that lymphatic vessels are increased in the visceral peritoneum of patients with EPS.

AIMS Iron metabolism is an important factor of anemia in chronic kidney disease (CKD). Hepcidin is a regulator of iron homeostasis and has a major role in the anemia of chronic disease (ACD). Oxidative stress (OS) is also associated with iron metabolism. However, the clinical utility of hepcidin, especially its association with OS, in CKD patients not receiving dialysis is still unclear. METHODS We recruited 117 patients (62 ± 15 years, 85 males, and median estimated glomerular filtration rate (eGFR) 22 ml/min/1.73 m2) with CKD not receiving dialysis. Serum 8-hydroxy-2'-deoxyguanosine (8-OHdG), a marker of DNA oxidative injury, and serum hepcidin-25 were measured by ELISA and by liquid chromatography tandem mass spectrometry, respectively. RESULTS Hepcidin-25 was associated positively with ferritin, high-sensitive C-reactive protein (hsCRP) and 8-OHdG, and negatively with eGFR and hemoglobin. Sex, oral iron, hemoglobin, transferrin saturation (TSAT), ferritin, and hsCRP were independently associated with hepcidin-25 in a multiple regression model. In contrast, neither eGFR nor 8-OHdG independently affected hepcidin- 25. CONCLUSIONS The close association between hepcidin and serum ferritin, oral iron and hsCRP indicates that it plays a key role in the pathogenesis of anemia in patients with CKD not receiving dialysis. In contrast, effects of eGFR and OS were not apparent.

BACKGROUND We investigated the influence of cinacalcet on serum Ca and P in hemodialyzed patients with or without a high PTH level, according to K/DOQI guideline, to control serum Ca and P levels. METHODS We recruited 130 patients in this prospective cohort study and classified them into Group A (iPTH > 300 pg/ml), Group B (iPTH = 181 - 300 pg/ml), and Group C (iPTH ≤ 180 pg/ml). After 24 weeks on cinacalcet, serum Ca, P and iPTH were measured. RESULTS The achievement rate of the target iPTH level in JSDT guideline was significantly higher in Group B compared with Group A. The achievement rate of serum Ca and P target levels in the Japanese Society for Dialysis Therapy (JSDT) guideline was higher in Group C. In Group A and Group C, the simultaneous achievement rates (Ca, P, and iPTH) in KDOQI guideline increased after treatment with cinacalcet (p < 0.01). There was no difference in the reduction of Ca and P among the groups, while the iPTH reduction was significantly lower in groups B and C compared with that in A. CONCLUSION Administration of cinacalcet to patients with or without high PTH levels, according to the K/DOQI guideline, facilitates the control of Ca and P levels.

The BK virus is a double-stranded DNA virus to which 90% of adults have been exposed. BK virus infections typically result in an oral or respiratory infection; however, BK virus reactivation is an infectious disease of concern in kidney transplant recipients. The prevalence of BK virus nephropathy (BKN) in kidney transplant recipients is approximately 5%, and most cases occur within one yr after kidney transplantation. Graft survival of BKN is reported to be 30-60%, and the standard treatment strategy for BKN is reducing immunosuppressive therapy and close monitoring for rejection. Viral infection is most common in the early post-transplantation phase, and BKN or acute rejection is one of the major factors involved in graft loss. However, in this report, we describe the successful management of BKN and cytomegalovirus infection concurrent with plasma cell-rich acute rejection.

Recent findings have demonstrated that stem cells can differentiate into mature tissue when supplied with a niche containing factors identical to those in the normal developmental program. A niche for the development of an organ can be provided by xenotransplantation of a similar developing organ. However, this process has many technical, safety, and ethical concerns. Here, we established xenotransplantation models that control endogenous mesenchymal stem cell (MSC) differentiation into mature erythropoietin (EPO)-producing tissue in a niche provided by a developing xenometanephros. Transplantation of rat metanephroi into mouse omentum, and similarly pig metanephroi into cat omentum, led to the recruitment of host cells and EPO production. EPO-expressing cells were not differentiated from integrating vessels because they did not coexpress endothelial markers (Tie-2 and VE-cadherin). Instead, EPO-expressing cells were shown to be derived from circulating host cells, as shown by enhanced green fluorescent protein (EGFP) expression in the grown transplants of chimeric mice bearing bone marrow from a transgenic mouse expressing EGFP under the control of the EPO promoter. These results suggest that donor cell recruitment and differentiation in a xenotransplanted developing organ may be consistent between species. The cells responsible for EPO expression were identified as MSCs by injecting human bone marrow-derived MSCs and endothelial progenitor cells into NOD/SCID mice. Furthermore, using metanephroi from transgenic ER-E2F1 suicide-inducible mice, the xenotissue component could be eliminated, leaving autologous EPO-producing tissue. Our findings may alleviate adverse effects due to long-lasting immunosuppression and help mitigate ethical concerns. Disclosure of potential conflicts of interest is found at the end of this article.

Tubulointerstitial nephritis (TIN) is histopathologically characterized by the infiltration of leukocytes, edema, and fibrosis of the renal interstitium with or without tubulitis and vasculitis. TIN is not usually accompanied by specific glomerular lesions. We herein report the case of a 65-year-old male with a diagnosis of non-small cell lung carcinoma that showed acute renal failure, together with proteinuria and microscopic hematuria. The renal biopsy findings showed severe and diffuse TIN, despite the fact that glomerulonephritis (GN) with cellular crescents was only focally identified. In this case, the GN was of the pauci-immune type, but the serum tests for anti-neutrophil cytoplasmic antibodies were negative. No disorders known to be associated with TIN were detected. The pathogenesis involved in this unusual presentation of a concomitant occurrence of TIN and pauci-immune GN is currently unclear.

OBJECTIVE The Jikei Optimal Antihypertensive Treatment (JOINT) study originally evaluated the effect of a fixed-dose formulation of losartan (LOS) (50 mg) plus 12.5 hydrochrolthiazide (HCTZ) for achieving better blood pressure (BP) control in patients with uncontrolled hypertension. This study is a sub-analysis of the JOINT study, focusing on the effect of LOS/HCTZ on the uric acid (UA) metabolism. METHODS Among 228 participants in the JOINT study, a total of 164 patients whose blood and urinary UA specimens were available were included in the present analyses. RESULTS Six months after switching from the prior antihypertensive agent(s) to a single tablet formulation of LOS/HCTZ, the overall serum UA concentration (sUA) increased from 6.0 ± 1.6 mg/dL to 6.2 ± 1.6 mg/dL (p=0.029). The urinary UA/creatinine (Cr) ratio increased from 0.45 +/- 0.21 to 0.50 +/- 0.25 (p=0.014), and the fractional excretion of UA (FEUA) also increased, from 7.1 +/- 3.6 to 7.0 +/- 4.3, p=0.04). Multivariate regression analyses of the basal parameters showed the change in sUA (ΔUA) to correlate with the basal sUA (β=-0.483, p

AIM The transcription factor c-Jun is a major component of the activator protein-1 complex involved in renal physiological events, such as inflammation and fibrosis. We recently demonstrated c-Jun activation in peritubular capillary (PC) endothelial cells and infiltrating cells in acute antibody-mediated rejection after kidney transplantation. However, the clinicopathological role of PC endothelial c-Jun activation has remained undetermined. MATERIAL AND METHOD We investigated endothelial c-Jun activation in PC using phosphorylated c-Jun (p-c-Jun) immunohistochemical staining in 21 cases of chronic active antibody-mediated rejection (CAMR), 14 cases of interstitial fibrosis and tubular atrophy (IF/TA) lacking specific etiology, and 8 normal control subjects (NC). RESULTS In CAMR cases, swollen PC endothelial cells showed strong p-c-Jun staining. More p-c-Jun-positive endothelial cells in PC were observed in CAMR than in IF/TA and NC subjects (p < 0.01). These findings were significantly correlated with reduced PC (rs = -0.78, p = 0.0005), the "ci + ct" score of the Banff classification (rs = 0.81, p = 0.0003) and serum creatinine level (rs = 0.48, p = 0.03). CONCLUSION Endothelial c-Jun activation in PC may contribute to PC loss, interstitial fibrosis and late allograft deterioration in CAMR. These data suggest that c-Jun is an appropriate therapeutic target of CAMR.

Summary What is known and objective There are no clinical reports that have compared topiroxostat, a selective xanthine oxidase inhibitor, with allopurinol in serum urate-lowering efficacy. The aim of this study was to compare the efficacy and safety of topiroxostat and allopurinol in Japanese hyperuricemic patients with or without gout. Methods A phase 3, multicentre, randomized, double-blind, double-dummy, active-controlled, parallel-group study conducted in Japan. Patients who had inadequate serum urate levels (a gout patient: serum urate level ≥416·4 μmol/L; an asymptomatic hyperuricemic patient with specific complications (urinary lithiasis, hypertension, hyperlipidemia and/or diabetes): serum urate level ≥475·8 μmol/L; and an asymptomatic hyperuricemic patient with no specific complications: serum urate level ≥535·3 μmol/L) were randomized to topiroxostat 120 mg/day or allopurinol 200 mg/day, with an equal allocation ratio, for 16 weeks. To prevent the onset of gouty arthritis by rapid serum urate reduction, these doses were increased in a stepwise manner. The primary efficacy endpoint was the per cent change in serum urate level from baseline to the final visit. Results and discussion Overall, 206 patients were randomly assigned to topiroxostat and allopurinol. Two hundred and three patients (allopurinol: n = 105, topiroxostat: n = 98) received at least one dose of the study drug and had their serum urate level assessed at least once. The baseline characteristics were comparable between groups. The mean age of patients was 53·0 ± 11·4 years and 99% of patients were male. The primary efficacy endpoint was −34·3 ± 11·1% in the allopurinol group (n = 105) and −36·3 ± 12·7% in the topiroxostat group (n = 98). Non-inferiority of the serum urate-lowering efficacy of topiroxostat to allopurinol was proved by the predefined non-inferiority margin (95% confidence interval, −5·3 to 1·3%). The overall incidences of adverse events and adverse drug reactions were similar between both groups. What is new and conclusion Topiroxostat 120 mg/day provides non-inferior serum urate reduction compared with allopurinol 200 mg/day and is well tolerated in Japanese hyperuricemic patients with or without gout.

Background Hypertension is a leading cause of cardiovascular (CV) disease in the general population. Although hypertension is very common in maintenance hemodialysis (HD) patients, adequate blood pressure (BP) values and measurement timing have not been defined. Methods A total of 49 hypertensive HD patients were recruited. Average age was 63 ± 11 years, and duration of dialysis therapy was 6.2 ± 4.2 years. Dialysis unit BPs and various types of home BPs were separately measured, and which BPs were the most critical markers in evaluating the effect of hypertension on left ventricular hypertrophy and CV events was investigated. Results Predialysis systolic BPs were not correlated with any home BPs. Left ventricular mass index (LVMI) had a significant positive correlation with home BPs, especially morning systolic BPs on HD days (P

The differential diagnosis of acute poststreptococcal glomerulonephritis (APSGN) and idiopathic membranoproliferative glomerulonephritis (MPGN) is sometimes difficult, as they share several key features in their laboratory and histological findings, especially during the acute phase of the diseases. We herein report an idiopathic case of MPGN in which the glomerular deposition of nephritis-associated plasmin receptor (NAPlr), a recently identified nephritic antigen for APSGN, was demonstrated. A 24-year-old postpartum woman developed nephrotic syndrome and hypocomplementemia. Although she showed no apparent findings of a prior infection, her serum titer of antistreptolysin O antibody was elevated. Renal biopsies were performed twice at intervals of 6 months, both of which showed findings fully consistent with those of MPGN. Of note, fluorescent immunostaining for NAPlr was positive in the glomeruli of the first biopsy but not in the second. Despite the use of a corticosteroid, hypocomplementemia persisted for more than 1 year. It was therefore suggested that a streptococcal infection may have influenced the development of glomerular injury in this idiopathic case of MPGN.

Recent genome-wide association studies showed that serum uric acid (SUA) levels relate to ABCG2/BCRP gene, which locates in a gout-susceptibility locus revealed by a genome-wide linkage study. Together with the ABCG2 characteristics, we hypothesized that ABCG2 transports urate and its dysfunction causes hyperuricemia and gout. Transport assays showed ATP-dependent transport of urate via ABCG2. Kinetic analysis revealed that ABCG2 mediates high-capacity transport of urate (Km: 8.24 ± 1.44 mM) even under high-urate conditions. Mutation analysis of ABCG2 in 90 Japanese hyperuricemia patients detected six nonsynonymous mutations, including five dysfunctional variants. Two relatively frequent dysfunctional variants, Q126X and Q141K, were then examined. Quantitative trait locus analysis of 739 Japanese individuals showed that Q141K increased SUA as the number of minor alleles of Q141K increased (p = 6.60 × 10(-5)). Haplotype frequency analysis revealed that there is no simultaneous presence of Q126X and Q141K in one haplotype. Becuase Q126X and Q141K are assigned to nonfunctional and half-functional haplotypes, respectively, their genotype combinations are divided into four functional groups. The association study with 161 male gout patients and 865 male controls showed that all of those with dysfunctional ABCG2 increased the gout risk, especially those with ≤1/4 function (OR, 25.8; 95% CI, 10.3-64.6; p = 3.39 × 10(-21)). These genotypes were found in 10.1% of gout patients, but in only 0.9% of control. Our function-based clinicogenetic (FBCG) analysis showed that combinations of the two dysfunctional variants are major causes of gout, thereby providing a new approach for prevention and treatment of the gout high-risk population.

The ATP-binding cassette, subfamily G, member 2 (ABCG2/BCRP) gene encodes a well-known transporter, which exports various substrates including nucleotide analogs such as 3'-azido-3'-deoxythymidine (AZT). ABCG2 is also located in a gout-susceptibility locus (MIM 138900) on chromosome 4q, and has recently been identified by genome-wide association studies to relate to serum uric acid (SUA) and gout. Becuase urate is structurally similar to nucleotide analogs, we hypothesized that ABCG2 might be a urate exporter. To demonstrate our hypothesis, transport assays were performed with membrane vesicles prepared from ABCG2-overexpressing cells. Transport of estrone-3-sulfate (ES), a typical substrate of ABCG2, is inhibited by urate as well as AZT and ES. ATP-dependent transport of urate was then detected in ABCG2-expressing vesicles but not in control vesicles. Kinetic analysis revealed that ABCG2 is a high-capacity urate transporter that maintained its function even under high-urate concentration. The calculated parameters of ABCG2-mediated transport of urate were a Km of 8.24 ± 1.44 mM and a Vmax of 6.96 ± 0.89 nmol/min per mg of protein. Moreover, the quantitative trait locus (QTL) analysis performed in 739 Japanese individuals revealed that a dysfunctional variant of ABCG2 increased SUA as the number of minor alleles of the variant increased (p = 6.60 × 10(-5)). Because ABCG2 is expressed on the apical membrane in several tissues, including kidney, intestine, and liver, these findings indicate that ABCG2, a high-capacity urate exporter, has a physiological role of urate homeostasis in the human body through both renal and extrarenal urate excretion.

BACKGROUND The adverse histological features predicting a progressive loss of renal function in idiopathic membranous nephropathy (IMN), before the establishment of impaired renal function with advanced glomerulosclerosis and/or interstitial fibrosis, are still poorly understood. The present study examined the relationship between the glomerular density (GD; non-sclerotic glomerular number/renal cortical area of biopsy) and the renal prognosis in IMN patients, especially in those without any apparent renal dysfunction at the time of diagnosis. METHODS The predictive value of the factors at biopsy, including the GD, on the renal outcome was retrospectively analyzed in the 65 IMN patients with an estimated glomerular filtration rate (eGFR) of ≥ 60 mL/min/1.73 m(2) (mean, 80 mL/min/1.73 m(2)) at biopsy. RESULTS The individual values for GD ranged from 1.6 to 6.5/mm(2) with 4-fold variation. A lower GD was associated with progression based on a ≥ 50% reduction in eGFR or reaching to end-stage renal disease. An association between a lower GD and progression was observed, especially in patients with persistent proteinuria of ≥ 1 g/day at follow-up. In contrast, any patients who achieved proteinuria of

Renal hypouricemia is a clinical disorder attributed to an increased renal urate excretion rate and is well known to involve a high risk of urolithiasis and exercise-induced acute kidney injury (AKI). This report concerns two interesting cases of nephrotic syndrome (NS)-induced AKI associated with renal hypouricemia. A 64-year-old female (Case 1) and a 37-year-old male (Case 2) were hospitalized because of AKI (serum creatinine: 2.07 mg/dl and 3.3 mg/dl, respectively), oliguria and NS. They were treated with prednisolone and temporary hemodialysis. Renal function improved, but hypouricemia persisted during hospitalization. Histological findings in both cases led to a diagnosis of minimal change nephrotic syndrome and identification of the diuretic phase of tubulointerstitial damage because of findings such as acute tubular necrosis. Furthermore, distal tubules of Case 2 showed an amorphous mass, possibly a uric acid crystal. Analysis of the two cases with the URAT1 gene, encoded by SLC22A12, found a homozygous mutation in exon 4 (W258stop) of each one. Our cases show that patients with renal hypouricemia may be susceptible to AKI without involvement of exercise if they possess some facilitators. Renal hypouricemic patients should therefore be carefully examined for all complications from renal hypouricemia because of high risk of AKI.

Background Allopurinol has been widely used for treatment of hyperuricemia, however, it may be associated with various adverse effects. Febuxostat has been identified as a potentially safe and efficacious alternative. Objectives A multicenter, open-label, parallel, between-group comparative study was conducted to investigate the effects of renal function on the pharmacokinetics, pharmacodynamics, and safety of febuxostat, a novel inhibitor of uric acid synthesis. Methods Based on creatinine clearance (Ccr), 29 subjects were assigned to 3 groups: normal renal function (Ccr ≥ 80 mL/min), mild renal dysfunction (80 mL/min > Ccr ≥ 50 mL/min), or moderate renal dysfunction (50 mL/min > Ccr ≥ 30 mL/min). Febuxostat was repeatedly orally administered at a dose of 20 mg/d for 7 days. Results Impaired renal function caused a slight increase in systemic exposure to unchanged febuxostat and its oxidative metabolites, but the exposure did not increase through repeated administration. Moreover, renal impairment did not markedly reduce the effects of febuxostat on plasma uric acid levels. There were no clinically significant adverse events even in patients with impaired renal function. Conclusions Febuxostat is considered an inhibitor of uric acid synthesis that could be used in patients with mild to moderate renal impairment without dose adjustment.

Background: There is no clinical classification of immunoglobulin A nephropathy (IgAN) in clinical practice. In this study, we used receiver-operating characteristic (ROC) analysis to create accurate clinical grades based on clinical parameters associated with the development of end-stage renal disease (ESRD) in IgAN patients. Methods: We performed a retrospective analysis of 116 patients with IgAN. The association between clinical variables and progression to ESRD was examined. Results: Logistic regression analysis indicated that 24-hour urinary protein excretion (UPE) and the estimated glomerular filtration rate (eGFR) at the time of renal biopsy (RBx) were independently associated with the development of ESRD. When combining UPE and eGFR, the areas under the curve were superior to those for UPE or eGFR alone. Moreover, two-graph ROC analysis indicated that the threshold values for UPE and eGFR in predicting future ESRD were 1.0 g/day and 64.0 ml/min/1.73 m2, respectively. Of note, the patients were classified into 4 grades by levels of UPE and/or eGFR, and the OR for risk of ESRD rose significantly from grade I to grade IV. Conclusion: The combination of UPE and eGFR at the time of RBx can improve the predictive accuracy of risk for subsequent ESRD in IgAN patients.

Background: Differences in nephron number and/or glomerular size between individuals, in relation to intrauterine growth retardation or low birth weight, have been suggested to affect the clinical course of minimal change nephrotic syndrome (MCNS) in children. However, no previous study has investigated the potential influences of these histological variables on the clinical course of adult patients with MCNS. Methods: The glomerular density (GD; the number of non-sclerotic glomeruli per renal cortical area) and the glomerular volume (GV) were evaluated using renal biopsy specimens from adult patients with a histological diagnosis of MCNS (n = 50). Relationships between these variables and clinicopathological features, including the initial response to corticosteroid therapy, were analyzed. Results: Both the GD (1.5–6.5/mm2) and the GV (1.2–4.4 × 106 µm3) showed about 4-fold variations, and a close inverse correlation was observed between these two variables. Notably, the MCNS patients with a low GD showed a trend towards having similar clinicopathological characteristics as patients with a histological diagnosis of focal segmental glomerular sclerosis, as compared to the MCNS patients with a high GD. In addition, during the initial treatment with corticosteroids, the number of patients achieving complete remission was significantly lower in the MCNS patients with a low GD than that in the MCNS patients with a high GD. Conclusion: These results suggest that the GD in renal biopsies may be an important determinant of the glomerular size variability, and can therefore influence the clinical phenotype, such as the response to corticosteroid therapy, in adult patients with MCNS.

c-Jun is a transcription factor that belongs to the activator protein-1 family of proteins. In human kidney disease, c-Jun is activated in glomerular and tubular cells and plays a major role in renal pathophysiology. However, the contribution of this pathway to renal allograft rejection has not been determined. We investigated whether c-Jun is activated in acute allograft rejection. c-Jun activation was assessed with immunohistochemistry using phospho-specific c-Jun antibodies in control human renal tissue and renal tissue from patients with acute cellular rejection, acute antibody-mediated rejection, and no rejection in the month after transplantation. In patients with acute cellular rejection, c-Jun activation was observed primarily in infiltrated T cells associated with tubulitis, interstitial cell infiltration, and endarteritis. The number of infiltrated phosphorylated c-Jun-positive cells in the tubules and interstitium was correlated with the Banff classification "t" and "i" scores. In patients with acute antibody-mediated rejection, c-Jun activation was observed in injured endothelial cells as well as in infiltrated cells, including macrophages, in the glomerular and peritubular capillaries. Furthermore, the serum creatinine levels and changes in serum creatinine from the previous year were significantly correlated with the total tubulointerstitial phosphorylated c-Jun-positive score (representing the number of positive nuclei in the tubules, interstitium, and peritubular capillaries). In conclusion, c-Jun was activated in acute antibody-mediated rejection and acute cellular rejection and was associated with reduced graft function. These findings suggest that c-Jun plays a key role in pathological events and may represent a novel therapeutic target in acute renal allograft rejection.