Xanthine oxidoreductase (XOR) is the sole urate-producing enzyme in humans and represents a significant target for the treatment of gout. It has long been known that mammalian XOR undergoes conversion from the dehydrogenase to oxidase form. This paper describes the molecular mechanism of this activity conversion based on findings from chemical modification and structure-function analyses of site-directed mutant enzymes. A number of reports have indicated that reactive oxygen species (ROS) produced by xanthine oxidase are linked to various pathological symptoms. This presentation will discuss the significance of enzyme activity conversion in the immune system and the latest findings on the long-term effects of ROS in genetically modified ROS-hyperproducing mice.

An ex-post assessment of the dissemination and application of the world-first “Clinical practice guideline for renal hypouricemia (1^st edition)” published in 2017 (hereinafter “GL”) was conducted with medical doctors, its intended users. A total of 193 responses were obtained that showed an even balance between three groups: members of the Japanese Society of Gout and Uric & Nucleic Acids, the Japanese Society for Pediatric Nephrology, and others. There were significant differences among the three groups as to their views on the dissemination of the GL and on some of the implementation assessments. Responses on the use of education and multi-disciplinary cooperation showed no differences, although the proportion of positive answers was fairly low, at approximately 40%: a lower figure than for other questions on implementation. To be able to utilize GL more widely among patients and healthcare providers, it would be effective to make decision aids and establish an agenda for quantitative evaluation of GL usage.

The effectiveness of long-term administration of urate-lowering drugs in patients with decreased renal function has been reported for allopurinol and febuxostat, but little has been done for topiroxostat. We selected 53 patients with gout/hyperuricemia whose estimated glomerular filtration rate (eGFR) before starting topiroxostat was less than 60 mL/min/1.73 m² and who had been receiving topiroxostat for more than 5 years, during the 9 years from September 2014, when long-term administration of topiroxostat became available, to September 2023. We investigated the effects of topiroxostat on the renal function in these 53 patients. The number of cases gradually decreased after the 6th year of topiroxostat treatment, and was 13 cases during the longest period of 8 years. Topiroxostat was started at 40 mg/day (20 mg x 2), with mean daily doses ranging from 96.4 to 105.3 mg. The serum uric acid level significantly decreased from 8.9 ± 1.6 to 5.6 ± 0.8 mg/dL one year later, and remained at an average of 5.0 mg/dL each year, and the rate of patients with serum uric acid levels below 6.0 mg/dL was 73.6 to 95.5%. eGFR increased from 53.2 ± 5.0 mL/min/1.73 m² at the start of treatment to 56.0 ± 6.2 mL/min/1.73 m² after 1 year, 56.2 ± 6.5 mL/min/1.73 m² after 2 years, and it gradually decreased, thereafter but the value remained higher than that at the start of treatment until 5 years later. There were only 18 patients in whom the serum uric acid level was below 6.0 mg/dL in all years, but in such cases, the serum uric acid level was maintained at an average of 4.0 mg/dL after 2 years, and eGFR was 53.8±3.9 mL/min/1.73 m², improved to 56.6±4.4 min/mL/1.73 m² after 1 year, 57.8±5.0 mL/min/1.73 m² after 2 years, and contined to improve after 5 years, but not after 3 years. The significant increase was maintained until 7 years, and the value remained higher than that when starting topiroxostat. These results suggest that topiroxostat may have the effect of improving long-term moderate renal function decline. Furthermore, it is considered that long-term renal function improvement effects of topiroxostat might be better achieved by maintaining serum uric acid levels below 6.0 mg/dL.

Japanese guidelines for the treatment of hyperuricemia and gout recommend a 60-minute clearance test to determine the type classification of hyperuricemia; however, the current judgment method may determine the type classification as the uric acid underexcretion type even if uric acid clearance (uric acid excretion ability) has not decreased. When examining the results of clearance tests conducted on 2,272 patients with gout, 22 were classified as the uric acid underexcretion type even though uric acid clearance had not decreased. Such cases should not be classified as the uric acid underexcretion type, and diagnosis of the uric acid underexcretion type should be determined when urinary uric acid excretion is 0.51 mg/kg/hr or less than and uric acid clearance is below 7.3 mL/min/1.73 m². When classifying such cases as the normal type, there were 1,684 cases (74.1%) of the uric acid underexcretion type, 309 cases (13.6%) of the renal overload type, 224 cases (9.9%) of the mixed type, and 55 cases (2.4%) of the normal type. Compared with the frequency of the type classification of hyperuricemia described in the guidelines established about 40 years ago, these results showed a 14.1% higher rate for the uric acid underexcretion type and a 15.1% lower rate for the mixed type. According to a survey by the Ministry of Health, Labour and Welfare, Japanese men's weight had increased by about 10 kg in 2019 compared with 1975. It is considered that due to the increased body weight, the amount of urinary uric acid excreted per unit weight, which is an indicator of uric acid production, was calculated to be low, and the factors contributing to uric acid production decreased, resulting in an increase in the frequency of the uric acid underexcretion type. In the future, it will be necessary to revise the type classification criteria for hyperuricemia to take into account the current physique of Japanese people.

Purpose: This study examined the use of gout medication by prefecture using the sex and age-adjusted standardized claim-data ratio (SCR) score calculated based on the National Data Base (NDB).
Methods: We compared the use of total and each type of medication for gout by prefecture using SCR score based on the 2020 NDB.
Results: The SCR scores for the total use of gout medication were, in the highest group, Kochi (SCR score 126.9), Oita (115.4), and Saga (114.5), and in the lowest group, Toyama (82.4), Saitama (86.8), and Chiba (87.3), in decreasing order. The SCR scores for the use of colchicine were, in the highest group, Kochi (SCR score 175.8), Kagoshima (150.9) and Miyazaki (142.0), and in the lowest group, Akita (60.0), Shiga (66.9) and Tottori (67.3). The SCR score ratios of the total use of gout medication/colchicine, which may reflect the degree of treatment for asymptomatic hyperuricemia, were, in the highest group, Akita (1.69), Tottori (1.55), Shizuoka (1.47), and in the lowest group, Okinawa (0.70), Kagoshima (0.72) and Kochi (0.72). The drug combinations with significant SCR score correlations between drugs were colchicine and febuxostat/allopurinol, febuxostat and dotinurad, and potassium citrate/sodium citrate hydrate and benzbromarone.
Conclusion: This study showed a large difference in the use of gout medications by region and a possible existence of a combination pattern of commonly used drugs in Japan. This result suggested the need to promote the equalization of gout and hyperuricemia treatment according to regional conditions.

Soybeans are considered a high-purine vegetable, and excessive intake of natto, a processed product of soybeans, can lead to gout flares. Purines contained in commercially available natto were measured using two HPLC methods (total purine-based analysis and molecular type purine simultaneous analysis methods). The total amount of purines contained in natto was 56.6 mg/100 g, bring about 50% of the previously reported content. It has been revealed that natto has a low content of polymeric nucleic acids and a high content of nucleosides and purine bases, which are easily absorbed in the intestinal tract. A registered dietitian interviewed 63 patients with gout and hyperuricemia who were able to achieve a serum uric acid level of 6 mg/dL or less on treatment with dotinurad, regarding their habits of cating purine-containing foods and natto. On comparing serum uric acid levels and urinary uric acid excretion among subjects divided into four groups based on their dietary habits of natto intake, there were no significant differences between patients who had a dietary habit of eating 1 pack (40 g) of natto 5 or more days a week (11 cases) and those who did not eat natto (26 cases). The amount of purines derived from natto as a percentage of the daily purine intake was only 6.9±2.8% in patients who had the habit of eating natto five or more days a week. The dietary habit of consuming up to 1 pack (40 g) of natto per day has little effect on uric acid metabolism; therefore, it is considered that natto, which is of marked health value, can be recommended even to patients with gout and hyperuricemia.