論文 - 古橋　眞人

Significance of urinary fatty acid-binding protein 4 level as a possible biomarker for the identification of minimal change disease in patents with nephrotic-range proteinuria

Marenao Tanaka, Masato Furuhashi, Norihito Moniwa, Takuto Maeda, Hideki Takizawa, Megumi Matsumoto, Akiko Sakai, Yukimura Higashiura, Yufu Gocho, Masayuki Koyama, Yayoi Ogawa, Tetsuji Miura

BMC Nephrology ( Springer Science and Business Media {LLC} )  21 ( 1 )  2020年12月

　概要を見る

Abstract Background Fatty acid-binding protein 4 (FABP4), but not FABP1 (liver-type FABP), is ectopically induced in injured glomerular endothelial cells, and urinary FABP4 (U-FABP4) level is associated with proteinuria and renal dysfunction in a general population. Methods The clinical significance of U-FABP4 was investigated in 81 patients (male/female: 43/38, age: 57 ± 17 years) who underwent kidney biopsy. Results U-FABP4 was negatively correlated with estimated glomerular filtration rate (eGFR) (r = − 0.56, P < 0.01) and was positively correlated with age, blood pressure, triglycerides, proteinuria (r = 0.58, P < 0.01), plasma FABP4 and urinary FABP1 (U-FABP1) (r = 0.52, P < 0.01). Multivariable regression analysis showed that eGFR, proteinuria and U-FABP1 were independent predictors of U-FABP4. The level of U-FABP4, but not that of proteinuria, eGFR or U-FABP1, in minimal change nephrotic syndrome (MCNS) was significantly lower than the level in membranous nephropathy (MN) and that in diabetic nephropathy. Receiver operating characteristic curve analysis indicated that U-FABP4 level ≤ 0.78 μg/gCr predicted MCNS in patients who had nephrotic-range proteinuria with a high level of accuracy. When divided by the median value of U-FABP4 at baseline in 33 of the 81 patients who could be followed up, the yearly change (post–pre) in eGFR in the low U-FABP4 group was significantly greater than that in the high U-FABP4 group (median: 11.0 vs. -5.0 mL/min/1.73m2/year). Conclusions U-FABP4 level is independently associated with proteinuria and renal dysfunction in patients with glomerular kidney disease. A low U-FABP4 level may predict MCNS in patients with nephrotic syndrome and would be a useful biomarker for differential diagnosis of MCNS and MN, which are common causes of nephrotic syndrome.

DOI

New insights into purine metabolism in metabolic diseases: role of xanthine oxidoreductase activity

Masato Furuhashi

American Journal of Physiology-Endocrinology and Metabolism ( American Physiological Society )  319 ( 5 ) E827 - E834  2020年11月

　概要を見る

Xanthine oxidoreductase (XOR) consists of two different forms, xanthine dehydrogenase and xanthine oxidase (XO), and is a rate-limiting enzyme of uric acid production from hypoxanthine and xanthine. Uric acid is the end product of purine metabolism in humans and has a powerful antioxidant effect. The lack of ascorbic acid, known as vitamin C, in hominoids has been thought to cause a compensatory increase in uric acid as an antioxidant by unfunctional gene mutation of uricase to a pseudogene. Because XO is involved in an increase in reactive oxygen species (ROS) by generating superoxide and hydrogen peroxide, inadequate activation of XOR promotes oxidative stress-related tissue injury. Plasma XOR activity is associated with obesity, smoking, liver dysfunction, hyperuricemia, dyslipidemia, insulin resistance, and adipokines, indicating a novel biomarker of metabolic disorders. However, XOR activity in adipose tissue is low in humans unlike in rodents, and hypoxanthine is secreted from human adipose tissue. The concentration of hypoxanthine, but not xanthine, is independently associated with obesity in a general population, indicating differential regulation of hypoxanthine and xanthine. Treatment with an XOR inhibitor can decrease uric acid for preventing gout, reduce production of XO-related ROS, and promote reutilization of hypoxanthine and ATP production through the salvage pathway. It has recently been suggested that discontinuation of an XOR inhibitor causes adverse cardiovascular outcomes as XOR inhibitor withdrawal syndrome, possibly due to cardiac disturbance of conduction and contraction by reduced ATP production. New insights into purine metabolism, including the role of XOR activity in the past 5 yr, are mainly discussed in this review.

DOI

Independent and Distinct Associations of FABP4 and FABP5 With Metabolic Parameters in Type 2 Diabetes Mellitus

Masato Furuhashi, Ichiro Sakuma, Takeshi Morimoto, Yukimura Higashiura, Akiko Sakai, Megumi Matsumoto, Mio Sakuma, Michio Shimabukuro, Takashi Nomiyama, Osamu Arasaki, Koichi Node, Shinichiro Ueda

Frontiers in Endocrinology ( Frontiers Media {SA} )  11   575557 - 575557  2020年09月  [国際誌]

　概要を見る

Objective: Among fatty acid-binding proteins (FABPs), secreted forms of FABP4 and FABP5, which are expressed in adipocytes and macrophages, act as bioactive molecules. We investigated concentrations of FABP4 and FABP5 in patients with type 2 diabetes mellitus. Methods: As a sub-analysis study of the Randomized Evaluation of Anagliptin vs. Sitagliptin On low-density lipoproteiN cholesterol in diabetes (REASON) trial, 256 patients (male/female: 146/110, age: 68 ± 10 years) with type 2 diabetes mellitus and dyslipidemia who were receiving statin therapy were recruited. Patients who had been treated with a thiazolidinedione were excluded. Results: Several drugs which may modulate FABP4 levels including statins, dipeptidyl peptidase-4 inhibitors and angiotensin II receptor blockers had been administered in 100, 81, and 51% of the recruited patients, respectively. The level of FABP4, but not that of FABP5, was significantly higher in females than in males. Multivariable linear regression analysis demonstrated that waist circumference (β = 0.21), estimated glomerular filtration rate (β = -0.31), triglycerides (β = 0.16), and FABP5 (β = 0.39) were independent predictors of FABP4 level after adjusting age and sex. On the other hand, FABP5 level was independently associated with levels of FABP4 (β = 0.57) and high-density lipoprotein (HDL) cholesterol (β = -0.12). Conclusions: Concentrations of FABP4 and FABP5 are independent predictors of each other in patients with type 2 diabetes mellitus. There are distinct independent associations of FABP4 with renal dysfunction, adiposity and hypertriglyceridemia and there is a distinct independent association of FABP5 with a low HDL cholesterol level in type 2 diabetic patients with dyslipidemia at high risks for cardiovascular disease who are receiving statin therapy.

DOI PubMed

U-shaped relationship between serum uric acid level and decline in renal function during a 10-year period in female subjects: BOREAS-CKD2.

Kazuma Mori, Masato Furuhashi, Marenao Tanaka, Keita Numata, Takashi Hisasue, Nagisa Hanawa, Masayuki Koyama, Arata Osanami, Yukimura Higashiura, Masafumi Inyaku, Megumi Matsumoto, Norihito Moniwa, Hirofumi Ohnishi, Tetsuji Miura

Hypertension research : official journal of the Japanese Society of Hypertension ( Springer Science and Business Media {LLC} )  44 ( 1 ) 107 - 116  2020年08月  [査読有り]  [国際誌]

　概要を見る

While hyperuricemia is recognized as a risk factor for chronic kidney disease (CKD), the risk of CKD in subjects with a low level of serum uric acid (UA) remains controversial. Here, we examined whether the association of CKD risk with serum UA level differs depending on the sex and age of subjects in a general population. Of subjects who received annual health checkups, we enrolled 6,779 subjects (male/female: 4,454/2,325; age: 45 ± 9 years) with data from a 10-year follow-up after excluding subjects taking anti-hyperuricemic drugs and those with CKD at baseline. During the follow-up period, 11.4% of the males and 11.7% of the females developed CKD. A significant interaction of sex, but not age, with the effect of baseline UA level on CKD risk was found. A restricted cubic spline analysis showed a U-shaped association of the baseline UA level with the risk of CKD in females. Multivariable Cox proportional hazard analyses for females showed that baseline UA levels in the 5th quintile (Q5, ≥5 mg/dL; HR: 1.68) and the 1st quintile (Q1, ≤3.5 mg/dL; HR: 1.73) were independent risk factors for CKD when compared with UA levels in the 4th quintile (Q4, 4.5-4.9 mg/dL). In males, restricted cubic spline analysis indicated increased CKD risk in subjects with a higher baseline UA level but not in those with a low UA level. In conclusion, a low UA level is a significant risk factor for CKD in females, while an elevated UA level increases the risk of CKD in both sexes.

DOI PubMed

Potential differential effects of renin-angiotensin system inhibitors on SARS-CoV-2 infection and lung injury in COVID-19.

Masato Furuhashi, Norihito Moniwa, Hideki Takizawa, Nobuyuki Ura, Kazuaki Shimamoto

Hypertension research : official journal of the Japanese Society of Hypertension    2020年05月  [査読有り]  [国際誌]

DOI PubMed

糖尿病外来診療における慢性合併症評価の実態調査

小川 俊史, 佐藤 達也, 東浦 幸村, 伊野 祥哉, 矢野 俊之, 古橋 眞人, 丹野 雅也, 三木 隆幸, 斎藤 重幸, 三浦 哲嗣

糖尿病 ( (一社)日本糖尿病学会 )  63 ( 5 ) 356 - 356  2020年05月

Low urine pH predicts new onset of diabetes mellitus during a 10-year period in men: BOREAS-DM1 study.

Yukimura Higashiura, Marenao Tanaka, Masato Furuhashi, Masayuki Koyama, Hirofumi Ohnishi, Keita Numata, Takashi Hisasue, Nagisa Hanawa, Norihito Moniwa, Tetsuji Miura

Journal of diabetes investigation   11 ( 6 ) 1490 - 1497  2020年04月  [査読有り]  [国内誌]

　概要を見る

AIMS/INTRODUCTION: A low level of urine pH (U-pH) has been reported to be associated with metabolic disorders. However, the relationship between the incidence of diabetes mellitus and U-pH has not yet been fully addressed. MATERIALS AND METHODS: We investigated the relationship between U-pH and the development of diabetes mellitus during a 10-year period in a general population of individuals who received annual health examinations in 2006 (n = 28,990). After exclusion of individuals with missing data, and those with diabetes mellitus and/or chronic kidney disease at baseline, a total of 12,476 individuals (men/women: 8,027/4,449) who received health examinations at least once during the period from 2007 to 2016 were recruited. The recruited individuals were divided into four groups according to their U-pH levels: groups of U-pH ≤5.0, 5.5, 6.0 and ≥6.5. RESULTS: During a 10-year period, 521 men (6.5%) and 132 women (3.0%) had new onset of diabetes mellitus. The cumulative incidence of diabetes mellitus was 7.5% (men/women: 9.3%/4.4%) per 100 person-years. The hazard ratios (HRs) in the U-pH ≤5.0 (HR 1.93) and U-pH 5.5 groups (HR 1.46) were significantly higher than that in the U-pH ≥6.5 group as a reference for men, but not for women. After adjustment of age, obesity, fasting glucose, smoking and alcohol drinking habits, family history of diabetes mellitus, and use of drugs for hypertension and dyslipidemia, HR in the U-pH ≤5.0 group (HR 1.39) was significantly higher than that in the U-pH ≥6.5 group for men, but not for women. CONCLUSIONS: Low U-pH predicts new onset of diabetes mellitus in a general population of men.

DOI PubMed

ALT、γGTPの組み合わせによる糖尿病発症リスク評価の向上

宮森 大輔, 田中 希尚, 古橋 眞人, 茂庭 仁人, 三浦 哲嗣, 小山 雅之, 大西 浩文, 沼田 啓太, 久末 章史, 塙 なぎさ

日本内科学会雑誌 ( (一社)日本内科学会 )  109 ( Suppl. ) 241 - 241  2020年02月

ALT、γGTPの組み合わせによる糖尿病発症リスク評価の向上

宮森 大輔, 田中 希尚, 古橋 眞人, 茂庭 仁人, 三浦 哲嗣, 小山 雅之, 大西 浩文, 沼田 啓太, 久末 章史, 塙 なぎさ

日本内科学会雑誌 ( (一社)日本内科学会 )  109 ( Suppl. ) 241 - 241  2020年02月

Differential regulation of hypoxanthine and xanthine by obesity in a general population.

Masato Furuhashi, Masayuki Koyama, Yukimura Higashiura, Takayo Murase, Takashi Nakamura, Megumi Matsumoto, Akiko Sakai, Hirofumi Ohnishi, Marenao Tanaka, Shigeyuki Saitoh, Norihito Moniwa, Kazuaki Shimamoto, Tetsuji Miura

Journal of diabetes investigation   11 ( 4 ) 878 - 887  2020年01月  [査読有り]  [国内誌]

　概要を見る

AIMS/INTRODUCTION: Uric acid is synthesized by oxidation of hypoxanthine and xanthine using a catalyzing enzyme, xanthine oxidoreductase (XOR), which can be a source of reactive oxygen species. Plasma XOR activity is a metabolic biomarker associated with obesity, hyperuricemia, liver dysfunction and insulin resistance. However, it has recently been reported that XOR activity in fat tissue is low in humans, unlike in rodents, and that hypoxanthine is secreted from human fat tissue. MATERIALS AND METHODS: The associations of obesity with hypoxanthine, xanthine and plasma XOR activity were investigated in 484 participants (men/women: 224/260) of the Tanno-Sobetsu Study. RESULTS: Levels of hypoxanthine, xanthine and plasma XOR activity were significantly higher in men than in women. In 59 participants with hyperuricemia, 11 (men/women: 11/0) participants were being treated with an XOR inhibitor and had a significantly higher level of xanthine, but not hypoxanthine, than that in participants without treatment. In all of the participants, hypoxanthine concentration in smokers was significantly higher than that in non-smokers. Stepwise and multivariate regression analyses showed that body mass index, smoking habit and xanthine were independent predictors of hypoxanthine after adjustment of age, sex and use of antihyperuricemic drugs. Whereas, alanine transaminase, hypoxanthine and plasma XOR activity were independent predictors for xanthine, and alanine transaminase, triglycerides and xanthine were independent predictors for plasma XOR activity. CONCLUSIONS: The concentration of hypoxanthine, but not that of xanthine, is independently associated with obesity and smoking habit, indicating differential regulation of hypoxanthine and xanthine in a general population.

DOI PubMed

高intact PTH血症、高Ca血症から副甲状腺癌の遠隔再発の診断を得た一例

寺沢 誠, 後町 結, 小山 雅之, 茂庭 仁人, 古橋 眞人, 三浦 哲嗣

日本内分泌学会雑誌 ( (一社)日本内分泌学会 )  95 ( 3 ) 864 - 864  2020年01月

一般住民においてヒポキサンチンとキサンチンの血中濃度は肥満によって異なった制御を受ける

古橋 眞人, 東浦 幸村, 小山 雅之, 村瀬 貴代, 中村 敬志, 酒井 晶子, 田中 希尚, 茂庭 仁人, 大西 浩文, 斎藤 重幸, 三浦 哲嗣

日本痛風・核酸代謝学会総会プログラム抄録集 ( (一社)日本痛風・尿酸核酸学会 )  53回   74 - 74  2020年01月

Reply to the comment of Hirota et al. on "Accuracy of flash glucose monitoring in insulin-treated patients with type 2 diabetes".

Tatsuya Sato, Hiroto Oshima, Kei Nakata, Yukishige Kimura, Toshiyuki Yano, Masato Furuhashi, Masaya Tannno, Takayuki Miki, Tetsuji Miura

Journal of diabetes investigation   11 ( 1 ) 256 - 256  2020年01月  [国内誌]

DOI PubMed

SAP療法下に多量飲酒を誘因に発症した糖尿病性ケトアシドーシスの1例

東浦 幸村, 中田 圭, 西川 諒, 矢野 俊之, 古橋 眞人, 三木 隆幸, 三浦 哲嗣

糖尿病 ( (一社)日本糖尿病学会 )  62 ( 12 ) 776 - 776  2019年12月

一般住民において血漿ヒポキサンチン濃度は肥満度および喫煙と関連する

東浦 幸村, 古橋 眞人, 松本 めぐみ, 酒井 晶子, 小山 雅之, 村瀬 貴代, 中村 敬志, 田中 希尚, 茂庭 仁人, 大西 浩文, 斎藤 重幸, 三浦 哲嗣

肥満研究 ( (一社)日本肥満学会 )  25 ( Suppl. ) 279 - 279  2019年10月

一般住民におけるキサンチン酸化還元酵素(XOR)活性と高血圧との関連

東浦 幸村, 古橋 眞人, 小山 雅之, 田中 希尚, 茂庭 仁人, 松本 めぐみ, 酒井 晶子, 村瀬 貴代, 中村 敬志, 大西 浩文, 齋藤 重幸, 島本 和明, 三浦 哲嗣

日本高血圧学会総会プログラム・抄録集 ( (NPO)日本高血圧学会 )  42回   279 - 279  2019年10月

北海道都市部健診受診者コホートにおける初年度の血圧カテゴリ別の血清尿酸値と高血圧発症との関連

小山 雅之, 樋室 伸顕, 田中 希尚, 茂庭 仁人, 古橋 眞人, 沼田 啓太, 久末 章史, 塙 なぎさ, 齋藤 重幸, 三浦 哲嗣, 大西 浩文

日本高血圧学会総会プログラム・抄録集 ( (NPO)日本高血圧学会 )  42回   300 - 300  2019年10月

Annual change in plasma xanthine oxidoreductase activity is associated with changes in liver enzymes and body weight.

Masato Furuhashi, Masayuki Koyama, Megumi Matsumoto, Takayo Murase, Takashi Nakamura, Yukimura Higashiura, Marenao Tanaka, Norihito Moniwa, Hirofumi Ohnishi, Shigeyuki Saitoh, Kazuaki Shimamoto, Tetsuji Miura

Endocrine journal   66 ( 9 ) 777 - 786  2019年09月  [査読有り]  [国内誌]

　概要を見る

Xanthine oxidoreductase (XOR), an enzyme of uric acid formation from hypoxanthine and xanthine, is recognized as a source of oxidative stress. Plasma activity of XOR has been reported to be a biomarker of metabolic disorders associated with obesity, liver dysfunction, insulin resistance, hyperuricemia and adipokines. We investigated longitudinal change in plasma XOR activity, which was determined by using mass spectrometry and liquid chromatography to detect [13C2, 15N2]-uric acid using [13C2, 15N2]-xanthine as a substrate, in 511 subjects (male/female: 244/267) of the Tanno-Sobetsu Study in the years 2016 and 2017. Plasma XOR activity in a basal state was significantly higher in men than in women, but no significant sex difference was observed in annual change in plasma XOR activity. Annual change in plasma activity of XOR was positively correlated with changes in each parameter, including body weight (r = 0.203, p < 0.001), body mass index, diastolic blood pressure, aspartate transaminase (AST) (r = 0.772, p < 0.001), alanine transaminase (r = 0.647, p < 0.001), γ-glutamyl transpeptidase, total cholesterol, triglycerides, uric acid, fasting glucose and HbA1c. Multivariate regression analysis demonstrated that change in AST and that in body weight were independent predictors of change in plasma XOR activity after adjustment of age, sex and changes in each variable with a significant correlation without multicollinearity. In conclusion, annual change in plasma XOR activity is independently associated with changes in liver enzymes and body weight in a general population. Improvement of liver function and reduction of body weight would decrease plasma XOR activity and its related oxidative stress as a therapeutic strategy.

DOI PubMed

Anorexia nervosaによるCKDの3症例

後町 結, 茂庭 仁人, 木村 歩, 長南 新太, 菅原 浩仁, 高橋 聖子, 田中 希尚, 古橋 眞人, 小川 弥生, 三浦 哲嗣

日本腎臓学会誌 ( (一社)日本腎臓学会 )  61 ( 6 ) 739 - 739  2019年08月

潜在性甲状腺機能亢進症による二次性膜性腎症と診断した1例

茂庭 仁人, 大嶋 優, 後町 結, 高橋 聖子, 田中 希尚, 古橋 眞人, 黒田 せつ子, 浜 武継, 島 友子, 小川 弥生, 三浦 哲嗣

日本腎臓学会誌 ( (一社)日本腎臓学会 )  61 ( 6 ) 699 - 699  2019年08月