論文 - 伊藤　裕

Predictors of Clinical Success After Surgery for Primary Aldosteronism in the Japanese Nationwide Cohort.

Morisaki M, Kurihara I, Itoh H, Naruse M, Takeda Y, Katabami T, Ichijo T, Wada N, Yoshimoto T, Ogawa Y, Sone M, Tsuiki M, Shibata H, Kawashima J, Fujita M, Watanabe M, Matsuda Y, Kobayashi H, Suzuki T, JPAS Study Group

Journal of the Endocrine Society 3 （ 11 ） 2012 - 2022 2019年11月

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　概要を見る

Context: Aldosterone-producing adenomas are a curable subtype of primary aldosteronism (PA); however, hypertension persists in some patients after adrenalectomy. Objective: To identify factors associated with, and develop prediction models for, blood pressure (BP) normalization or improvement after adrenalectomy. Design: Retrospective analysis of patients treated between 2006 and 2018, with a 6-month follow-up. Setting: A nationwide, 29-center Japanese registry encompassing 15 university hospitals and 14 city hospitals. Patients: We categorized 574 participants in the Japan Primary Aldosteronism Study, who were diagnosed with PA and underwent adrenalectomy, as BP normalized or improved, on the basis of their presentations at 6 months postsurgery. Main Outcome Measure: The rate of complete, partial, and absent clinical success. Predictive factors related to BP outcomes after PA surgery were also evaluated. Results: Complete clinical success was achieved in 32.6% and partial clinical success was achieved in 53.0% of the patients at 6 months postsurgery. The following five variables were independent predictors for BP normalization: ≤7 years of hypertension, body mass index ≤25 kg/m2, no more than one antihypertensive medication, absence of medical history of diabetes, and female sex. The area under the receiver operator characteristic curve was 0.797 in the BP normalization model. Conclusion: We established models that predicted postoperative BP normalization in patients with PA. These should be useful for shared decision-making regarding adrenalectomy for PA.

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Application of Japanese guidelines for gestational weight gain to multiple pregnancy outcomes and its optimal range in 101,336 Japanese women

Nomura K, Nagashima K, Suzuki S, Itoh H

Scientific Reports 9 （ 1 ） 17310 2019年11月

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Effect of oral administration of nicotinamide mononucleotide on clinical parameters and nicotinamide metabolite levels in healthy Japanese men.

Irie J, Inagaki E, Fujita M, Nakaya H, Mitsuishi M, Yamaguchi S, Yamashita K, Shigaki S, Ono T, Yukioka H, Okano H, Nabeshima YI, Imai SI, Yasui M, Tsubota K, Itoh H

Endocrine journal 67 （ 2 ） 153 - 160 2019年11月

査読有り,  ISSN  0918-8959

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GLP-1受容体作動薬により過食の軽減が認められた2型糖尿病合併高度肥満症の一例

後藤 伸子, 入江 潤一郎, 清水 真美子, 喜田 素子, 伊藤 裕

肥満研究 （(一社)日本肥満学会）  25 （ Suppl. ） 310 - 310 2019年10月

査読有り,  ISSN  1343-229X

Efficacy and safety of once-weekly exenatide after switching from twice-daily exenatide in patients with type 2 diabetes.

Watanabe Y, Saisho Y, Inaishi J, Kou K, Yamauchi A, Kanazawa Y, Okubo Y, Tokui M, Imai T, Murakami R, Tsuchiya T, Sasaki H, Masaoka T, Irie J, Meguro S, Itoh H, Twin-exenatide Study Group

Journal of diabetes investigation 11 （ 2 ） 382 - 388 2019年09月

査読有り,  ISSN  2040-1116

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AIMS/INTRODUCTION: To evaluate the efficacy and safety of once-weekly (q.w.) extended-release exenatide after switching from twice-daily (b.i.d.) exenatide in patients with type 2 diabetes. MATERIALS AND METHODS: This was an investigator-initiated, prospective, single-arm, multicenter study. Individuals with type 2 diabetes who had been treated with exenatide b.i.d. for at least 3 months were enrolled and switched to exenatide q.w. for 24 weeks. The primary end-point was change in HbA1c at week 24 to test the glucose-lowering effect of exenatide q.w. versus exenatide b.i.d. RESULTS: A total of 58 Japanese individuals with type 2 diabetes completed the study. Glycated hemoglobin was reduced by 0.2% at week 24 (7.2 ± 1.2% vs 7.0 ± 1.2% [56 ± 13 vs 53 ± 13 mmol/mol], 95% confidence interval -0.4 to -0.03%, P < 0.005 for non-inferiority, P = 0.01 for superiority). Fasting plasma glucose was reduced by 12 mg/dL at week 24 (154 ± 46 vs 142 ± 46 mg/dL, P = 0.02). β-Cell function assessed by homeostasis model assessment of β-cell function and C-peptide index was significantly improved at week 24. The incidence of self-reported hypoglycemia was reduced, and treatment satisfaction assessed by the Diabetes Treatment Satisfaction Questionnaire and Diabetes Medication Satisfaction Questionnaire was improved at week 24, with no change in body weight. There was no serious adverse event related to the study drug. CONCLUSIONS: Switching from exenatide b.i.d. to exenatide q.w. resulted in a reduction in glycated hemoglobin, fasting plasma glucose and the incidence of hypoglycemia, and improvement in β-cell function and treatment satisfaction in patients with type 2 diabetes. These findings will be useful for selecting optimal treatment in individuals with type 2 diabetes.

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Low birth weight is associated with decline in renal function in Japanese male and female adolescents.

Murai-Takeda A, Kanda T, Azegami T, Hirose H, Inokuchi M, Tokuyama H, Wakino S, Tokumura M, Kawabe H, Mori M, Itoh H

Clinical and Experimental Nephrology 23 （ 12 ） 1364 - 1372 2019年09月

査読有り,  ISSN  1342-1751

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Association Between Acute Fall in Estimated Glomerular Filtration Rate After Treatment for Primary Aldosteronism and Long-Term Decline in Renal Function.

Kobayashi H, Abe M, Nakamura Y, Takahashi K, Fujita M, Takeda Y, Yoneda T, Kurihara I, Itoh H, Tsuiki M, Wada N, Ichijo T, Katabami T, Ogawa Y, Kawashima J, Yoshimoto T, Sone M, Inagaki N, Watanabe M, Kamemura K, Matsuda Y, Izawa S, Tanabe M, Tanabe A, Suzuki T, Naruse M, JPAS/JRAS, Study Group

Hypertension (Dallas, Tex. : 1979) 74 （ 3 ） 630 - 638 2019年09月

査読有り,  ISSN  0194-911X

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Primary aldosteronism causes renal structural damage after glomerular hyperfiltration, and primary aldosteronism-specific treatment leads to an acute fall in estimated glomerular filtration rate (eGFR). We investigated whether this change affected the long-term eGFR slope in a retrospective cohort from the multicenter Japan Primary Aldosteronism Study. We allocated patients with primary aldosteronism to the adrenalectomy (n=202) and MR (mineralocorticoid receptor) antagonist (n=303) groups based on their treatment history and analyzed the association between the initial eGFR fall and long-term eGFR slope. The increased age, low serum potassium levels, high eGFR, and high plasma aldosterone levels were independent predictors for a large initial eGFR fall in both groups. Our analysis of tertiles based on the initial eGFR fall revealed that in the MR antagonist group, patients with a small initial eGFR fall had a significantly steeper long-term eGFR slope than those with a large initial fall (tertile 1 versus 2, P=0.025; tertile 1 versus 3, P=0.017). These associations were not identified in the adrenalectomy group. Thus, the smaller the acute fall in eGFR by initiation of MR antagonists, the greater was the rate of long-term eGFR decline. While the acute fall in eGFR induced by primary aldosteronism-specific treatment is occasionally a clinical concern, our findings highlight the favorable implications of the acute fall with respect to long-term renal outcomes.

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Gut microbiota confers host resistance to obesity by metabolizing dietary polyunsaturated fatty acids.

Miyamoto J, Igarashi M, Watanabe K, Karaki SI, Mukouyama H, Kishino S, Li X, Ichimura A, Irie J, Sugimoto Y, Mizutani T, Sugawara T, Miki T, Ogawa J, Drucker DJ, Arita M, Itoh H, Kimura I

Nature Communications 10 （ 1 ） 4007 2019年09月

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Hypertension as a Metabolic Disorder and the Novel Role of the Gut

Tanaka M., Itoh H.

Current Hypertension Reports （Current Hypertension Reports）  21 （ 8 ）  2019年08月

ISSN  15226417

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© 2019, The Author(s). Purpose of Review: Hypertension is related to impaired metabolic homeostasis and can be regarded as a metabolic disorder. This review presents possible mechanisms by which metabolic disorders increase blood pressure (BP) and discusses the importance of the gut as a novel modulator of BP. Recent Findings: Obesity and high salt intake are major risk factors for hypertension. There is a hypothesis of “salt-induced obesity”; i.e., high salt intake may tie to obesity. Heightened sympathetic nervous system (SNS) activity, especially in the kidney and brain, increases BP in obese patients. Adipokines, including adiponectin and leptin, and renin-angiotensin-aldosterone system (RAAS) contribute to hypertension. Adiponectin induced by a high-salt diet may decrease sodium/glucose cotransporter (SGLT) 2 expression in the kidney, which results in reducing BP. High salt can change secretions of adipokines and RAAS-related components. Evidence has been accumulating linking the gastrointestinal tract to BP. Glucagon-like peptide-1 (GLP-1) and ghrelin decrease BP in both rodents and humans. The sweet taste receptor in enteroendocrine cells increases SGLT1 expression and stimulates sodium/glucose absorption. Roux-en-Y gastric bypass improves glycemic and BP control due to reducing the activity of SGLT1. Na/H exchanger isoform 3 (NHE3) increases BP by stimulating the intestinal absorption of sodium. Gastrin functions as an intestinal sodium taste sensor and inhibits NHE3 activity. Intestinal mineralocorticoid receptors also regulate sodium absorption and BP due to changing ENaC activity. Gastric sensing of sodium induces natriuresis, and gastric distension increases BP. Changes in the composition and function of gut microbiota contribute to hypertension. A high-salt/fat diet may disrupt the gut barrier, which results in systemic inflammation, insulin resistance, and increased BP. Gut microbiota regulates BP by secreting vasoactive hormones and short-chain fatty acids. BP-lowering effects of probiotics and antibiotics have been reported. Bariatric surgery improves metabolic disorders and hypertension due to increasing GLP-1 secretion, decreasing leptin secretion and SNS activity, and changing gut microbiome composition. Strategies targeting the gastrointestinal system may be therapeutic options for improving metabolic abnormalities and reducing BP in humans. Summary: SNS, brain, adipocytes, RAAS, the kidney, the gastrointestinal tract, and microbiota play important roles in regulating BP. Most notably, the gut could be a novel target for treatment of hypertension as a metabolic disorder.

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DNA Damage Repair and DNA Methylation in the Kidney

Hayashi K., Hishikawa A., Itoh H.

American Journal of Nephrology （American Journal of Nephrology）  50 （ 2 ） 81 - 91 2019年07月

ISSN  02508095

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© 2019 © 2019 S. Karger AG, Basel. Copyright: All rights reserved. The DNA repair system is essential for the maintenance of genome integrity and is mainly investigated in the areas of aging and cancer. The DNA repair system is strikingly cell-type specific, depending on the expression of DNA repair factors; therefore, different DNA repair systems may exist in each type of kidney cell. Importance of DNA repair in the kidney is suggested by renal phenotypes caused by both genetic mutations in the DNA repair pathway and increased stimuli of DNA damage. Recently, we reported the importance of DNA double-strand break repair in glomerular podocytes and its involvement in the alteration of DNA methylation status, which regulates podocyte phenotypes. In this review, we summarize the roles of the DNA repair system in the kidneys and possible associations with altered kidney DNA methylation, which have been infrequently reported together. Investigations of DNA damage repair and epigenetic changes in the kidneys may achieve a profound understanding of kidney aging and diseases.

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Influence of antihypertensive drugs in the subtype diagnosis of primary aldosteronism by adrenal venous sampling

Nagasawa M., Yamamoto K., Rakugi H., Takeda M., Akasaka H., Umakoshi H., Tsuiki M., Takeda Y., Kurihara I., Itoh H., Ichijo T., Katabami T., Wada N., Shibayama Y., Yoshimoto T., Ogawa Y., Kawashima J., Sone M., Inagaki N., Takahashi K., Fujita M., Watanabe M., Matsuda Y., Kobayashi H., Shibata H., Kamemura K., Otsuki M., Fujii Y., Ogo A., Okamura S., Miyauchi S., Yanase T., Suzuki T., Kawamura T., Naruse M.

Journal of Hypertension （Journal of Hypertension）  37 （ 7 ） 1493 - 1499 2019年07月

ISSN  02636352

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© 2019 Wolters Kluwer Health, Inc. All rights reserved. Objectives:Because of the influence on the renin-angiotensin-aldosterone system, it is recommended to avoid, if possible, the use of angiotensin-converting-enzyme inhibitors, angiotensin II type 1 receptor blockers, diuretics, β-blockers, and mineralocorticoid receptor antagonists during the diagnostic period of primary aldosteronism. A laterality index more than 4 in adrenocorticotropic hormone (ACTH)-stimulated adrenal venous sampling (ACTH-AVS) is a widely used classification of the unilateral subtype that can benefit from adrenalectomy. Here, we revealed clinical features of patients taking drugs that could affect the primary aldosteronism diagnosis (DAPD) and investigated whether the classification with laterality index more than 4 in ACTH-AVS is applicable to these patients.Patients and methods:Using a large database of primary aldosteronism patients in Japan, we analyzed 2122 patients with successful ACTH-AVS.Results:Patients who received any DAPD (n = 209) showed higher prevalence of comorbidity burdens and took more antihypertensive drugs compared with patients without DAPD. In patients taking DAPD, those with laterality index more than 4 had a higher prevalence of hypokalemia, a higher aldosterone-to-renin ratio and a higher prevalence of adrenal mass than those with laterality index of 4 or less. Adrenalectomy was performed in 76% patients with laterality index more than 4 and 20% with laterality index of 4 or less. Patients who underwent adrenalectomy showed biochemical cure in 89% with laterality index more than 4 and 50% with laterality index of 4 or less (P = 0.001). Multivariate regression analysis showed that laterality index more than 4 was an independent predictor of a biochemical cure. Biochemical cure rate in patients with laterality index more than 4 was consistently high, irrespective of the potential effect of individual DAPD on laterality index.Conclusion:Our findings suggest that in primary aldosteronism patients to whom DAPD were administrated due to severe clinical features, laterality index more than 4 in ACTH-AVS could accurately predict a biochemical cure after adrenalectomy.

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Efficacy and safety of esaxerenone (CS-3150) for the treatment of essential hypertension: a phase 2 randomized, placebo-controlled, double-blind study

Ito S., Itoh H., Rakugi H., Okuda Y., Yamakawa S.

Journal of Human Hypertension （Journal of Human Hypertension）  33 （ 7 ） 542 - 551 2019年07月

ISSN  09509240

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© 2019, Springer Nature Limited. This was a phase 2, multicenter, randomized, double-blind, placebo-controlled, open-label comparator study to investigate the efficacy and safety of esaxerenone (CS-3150), a novel non-steroidal mineralocorticoid receptor blocker, in Japanese patients with essential hypertension. Eligible patients (n = 426) received esaxerenone (1.25, 2.5, or 5 mg/day), placebo, or eplerenone (50–100 mg/day) for 12 weeks. The primary efficacy endpoint was the change from baseline in sitting systolic and diastolic blood pressure (BP). Safety endpoints included adverse events and serum K+ elevation. There were significant dose–response reductions in the 2.5 and 5 mg/day esaxerenone groups for sitting BP (both p < 0.001) and 24-h BP (both p < 0.0001) compared with placebo, with a mean (95% confidence interval) change in sitting BP of −7.0 (−9.5 to −4.6)/−3.8 (−5.2 to −2.4) mmHg in the placebo group, and −10.7 (−13.2 to −8.2)/−5.0 (−6.4 to −3.6) mmHg, −14.3 (−16.8 to −11.9)/−7.6 (−9.1 to −6.2) mmHg, and −20.6 (−23.0 to −18.2)/ −10.4 (−11.8 to −9.0) mmHg for the 1.25, 2.5, and 5 mg/day esaxerenone groups, respectively, while the change was −17.4 (−19.9 to −15.0)/−8.5 (−9.9 to −7.1) mmHg for eplerenone. The incidence of adverse events was similar in all treatment groups. Serum K+ levels initially increased in proportion with esaxerenone dose but were stable from week 2 until week 12. Plasma esaxerenone concentration increased in proportion with the dose. In conclusion, esaxerenone is an effective and tolerable treatment option for patients with essential hypertension.

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Clinical and biochemical outcomes after adrenalectomy and medical treatment in patients with unilateral primary aldosteronism.

Takuyuki Katabami, Hisashi Fukuda, Hidekazu Tsukiyama, Yasushi Tanaka, Yoshiyu Takeda, Isao Kurihara, Hiroshi Ito, Mika Tsuiki, Takamasa Ichijo, Norio Wada, Yui Shibayama, Takanobu Yoshimoto, Yoshihiro Ogawa, Junji Kawashima, Masakatsu Sone, Nobuya Inagaki, Katsutoshi Takahashi, Megumi Fujita, Minemori Watanabe, Yuichi Matsuda, Hiroki Kobayashi, Hirotaka Shibata, Kohei Kamemura, Michio Otsuki, Yuichi Fujii, Koichi Yamamoto, Atsushi Ogo, Toshihiko Yanase, Tomoko Suzuki, Mitsuhide Naruse

Journal of hypertension 37 （ 7 ） 1513 - 1520 2019年07月

査読有り,  ISSN  0263-6352

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OBJECTIVES: Current clinical guidelines of primary aldosteronism recommend adrenalectomy (AdX) for unilateral primary aldosteronism based on the studies showing the potential superiority of AdX over the medical treatment. However, since most medically treated cases consisted of bilateral primary aldosteronism and all surgically treated cases consisted of unilateral primary aldosteronism, the different subtype of primary aldosteronism could be a bias for their effects. This study compared the effects of AdX and medical therapy in patients with unilateral primary aldosteronism confirmed by adrenal vein sampling. METHODS: Of the 339 patients with unilateral primary aldosteronism in the Japan Primary Pldosteronism Study data base, unilateral AdX and treatment with mineral corticoid receptor antagonists (MRAs) was done in 276 patients (AdX group) and in 63 patients (MRAs group), respectively. The effects were compared by the clinical (improvement of blood pressure) and biochemical outcomes (improvement of hypokalemia). RESULTS: At baseline, use of potassium replacement, plasma aldosterone concentration, aldosterone-to-renin ratio, estimated glomerular filtration rate, and prevalence of adrenal mass on imaging were higher in the AdX group than in the MRAs group. At 6 months after commencement of specific treatment for primary aldosteronism, clinical outcome and biochemical outcome in the AdX group were superior than those in the MRAs group. The difference of the outcome between the two groups were the case even after adjusting for the different clinical backgrounds in the two groups before the specific treatment. CONCLUSION: Our study provides evidence that AdX is the first choice of treatment in the patients with unilateral primary aldosteronism in terms of clinical and biochemical outcome.

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Greeting Messages from President of Japanese Society of Hypertension (JSH) The challenge of JSH: moonshot for "Conquest of hypertension in Japan".

Itoh H

Hypertension research : official journal of the Japanese Society of Hypertension 42 （ 7 ） 925 - 927 2019年07月

ISSN  0916-9636

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Renal impairment is closely associated with plasma aldosterone concentration in patients with primary aldosteronism.

Kawashima A, Sone M, Inagaki N, Takeda Y, Itoh H, Kurihara I, Umakoshi H, Ichijo T, Katabami T, Wada N, Ogawa Y, Kawashima J, Fujita M, Miyauchi S, Okamura S, Fukuoka T, Yanase T, Izawa S, Yoshikawa Y, Hashimoto S, Yamada M, Kai T, Suzuki T, Naruse M

European journal of endocrinology 181 （ 3 ） 339 - 350 2019年07月

査読有り,  ISSN  0804-4643

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Acute Interstitial Nephritis With Karyomegalic Epithelial Cells After Nivolumab Treatment—Two Case Reports

Ryuzaki M., Tokuyama H., Uchiyama K., Nakaya H., Hasegawa K., Miyashita K., Konishi K., Hashiguchi A., Wakino S., Itoh H.

Clinical Medicine Insights: Case Reports （Clinical Medicine Insights: Case Reports）  12 2019年06月

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© The Author(s) 2019. Clinical application of immune checkpoint inhibitors (CPIs) including nivolumab is expanding in the field of oncology treatment. Nivolumab is an anti-programmed death 1 protein (PD-1) antibody designed to augment an immunologic reaction against cancer cells. On the contrary, CPIs are known to cause a unique variety of side effects termed as immune-related adverse events, which can affect any organ including kidney. However, the characteristics of renal disorders by nivolumab treatment are poorly described. We describe two cases of acute kidney injury that were treated with nivolumab. Two patients, one with renal-cell carcinoma and the other with lung cancer, exhibited progressive renal dysfunction after the initiation of nivolumab treatment. By kidney biopsy, each case was diagnosed as acute interstitial nephritis (AIN). Of note, tubular epithelial cells enlarged with hyperchromatic nuclei were focally observed, and this finding was consistent with karyomegalic tubular epithelial cells. In immunostaining, most of the enlarged tubular epithelial cells were positive for Ki-67, which suggested regeneration of tubular epithelial cells. Clinically, in one case, renal function was partially recovered with the discontinuation of nivolumab, while in another case renal function was fully recovered with additional corticosteroid treatment. We presented nivolumab-induced AIN with karyomegalic changes of tubular epithelia. We propose that immunosuppressive therapy may be necessary for the full recovery from renal impairment.

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2型糖尿病患者における短時間作用型GLP-1製剤から長時間作用型GLP-1製剤への切替えの有効性及び安全性についての検討

税所 芳史, 渡辺 雄祐, 稲石 淳, 侯 金成, 山内 晃, 金澤 寧彦, 大久保 佳昭, 徳井 幹也, 今井 孝俊, 村上 理恵, 土屋 多美, 佐々木 裕伸, 菊地 理恵子, 正岡 建洋, 入江 潤一郎, 目黒 周, 伊藤 裕

日本抗加齢医学会総会プログラム・抄録集 （(一社)日本抗加齢医学会）  19回   231 - 231 2019年06月

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CKDにおけるdysbiosisは、筋萎縮およびミトコンドリア機能低下を伴う運動耐容能の低下を惹起する

内山 清貴, 脇野 修, 入江 潤一郎, 伊藤 裕

日本抗加齢医学会総会プログラム・抄録集 （(一社)日本抗加齢医学会）  19回   194 - 194 2019年06月

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2型糖尿病患者に非定型抗精神病薬リスペリドンを使用し高血糖高浸透圧症候群を発症した1例

宇都 飛鳥, 税所 芳史, 入江 潤一郎, 田中 正巳, 目黒 周, 伊藤 裕

日本抗加齢医学会総会プログラム・抄録集 （(一社)日本抗加齢医学会）  19回   246 - 246 2019年06月

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2型糖尿病患者における血中総ビリルビン濃度と網膜症および大血管障害との関連

田中 正巳, 西村 健志, 目黒 周, 入江 潤一郎, 税所 芳史, 三石 正憲, 川野 義長, 伊藤 裕

日本抗加齢医学会総会プログラム・抄録集 （(一社)日本抗加齢医学会）  19回   249 - 249 2019年06月

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