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Papers - ITOH Hiroshi

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CD44 variant inhibits insulin secretion in pancreatic β cells by attenuating LAT1-mediated amino acid uptake

Kobayashi N., Okazaki S., Sampetrean O., Irie J., Itoh H., Saya H.

Scientific Reports (Scientific Reports) 8 ( 1 ) 2018.12

© 2018 The Author(s). CD44 variant (CD44v) contributes to cancer stemness by stabilizing the xCT subunit of system xc(-) and thereby promoting its glutamate-cystine antiporter activity. CD44 has also been implicated in autoimmune insulitis and inflammation in diabetic islets, but whether CD44v regulates insulin secretion has remained unclear. Here we show that CD44v inhibits insulin secretion by attenuating amino acid transport mediated by the L-type amino acid transporter LAT1. CD44v expression level was inversely related to insulin content in islets of normal and diabetic model mice. Knockdown of CD44 increased insulin secretion, the intracellular insulin level, and the transport of neutral amino acids mediated by LAT1 in Min6 cells. Attenuation of the uptake of neutral amino acids with a LAT inhibitor reduced insulin secretion and insulin content in Min6 cells, whereas overexpression of LAT1 increased insulin secretion. Moreover, inhibition of LAT1 prevented the increase in insulin secretion and content induced by CD44 depletion in Min6 cells. Our results thus implicate CD44v in the regulation of insulin secretion and reveal that amino acid transport is rate limiting for such secretion. They further suggest that amino acid transport mediated by LAT1 is a potential therapeutic target for diabetes.

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NNMT activation can contribute to the development of fatty liver disease by modulating the NAD <sup>+</sup> metabolism

Komatsu M., Kanda T., Urai H., Kurokochi A., Kitahama R., Shigaki S., Ono T., Yukioka H., Hasegawa K., Tokuyama H., Kawabe H., Wakino S., Itoh H.

Scientific Reports (Scientific Reports) 8 ( 1 ) 2018.12

© 2018 The Author(s). Nicotinamide N-methyltransferase (NNMT) catalyses the reaction between nicotinamide (NAM) and S-adenosylmethionine to produce 1-methylnicotinamide and S-adenosylhomocysteine. Recently, this enzyme has also been reported to modulate hepatic nutrient metabolism, but its role in the liver has not been fully elucidated. We developed transgenic mice overexpressing NNMT to elucidate its role in hepatic nutrient metabolism. When fed a high fat diet containing NAM, a precursor for nicotinamide adenine dinucleotide (NAD)+, these NNMT-overexpressing mice exhibit fatty liver deterioration following increased expression of the genes mediating fatty acid uptake and decreased very low-density lipoprotein secretion. NNMT overactivation decreased the NAD+ content in the liver and also decreased gene activity related to fatty acid oxidation by inhibiting NAD+-dependent deacetylase Sirt3 function. Moreover, the transgenic mice showed liver fibrosis, with the induction of inflammatory and fibrosis genes. Induced NNMT expression decreased the tissue methylation capacity, thereby reducing methylation of the connective tissue growth factor (CTGF) gene promoter, resulting in increased CTGF expression. These data indicate that NNMT links the NAD+ and methionine metabolic pathways and promotes liver steatosis and fibrosis. Therefore, targeting NNMT may serve as a therapeutic strategy for treating fatty liver and fibrosis.

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High Basolateral Glucose Increases Sodium-Glucose Cotransporter 2 and Reduces Sirtuin-1 in Renal Tubules through Glucose Transporter-2 Detection

Umino H., Hasegawa K., Minakuchi H., Muraoka H., Kawaguchi T., Kanda T., Tokuyama H., Wakino S., Itoh H.

Scientific Reports (Scientific Reports) 8 ( 1 ) 2018.12

© 2018 The Author(s). Under diabetic conditions, sodium-glucose cotransporter 2 (SGLT2) for glucose uptake in proximal tubules (PTs) increases, whereas NAD+-dependent protein deacetylase silent mating type information regulation 2 homolog 1 (Sirtuin-1; SIRT1) for PT survival decreases. Therefore, we hypothesized that increased glucose influx by SGLT2 reduces SIRT1 expression. To test this hypothesis, db/db mice with diabetes and high-glucose (HG)-cultured porcine PT LLC-PK1 cells in a two-chamber system were treated with the SGLT2 inhibitor canagliflozin. We also examined SIRT1 and SGLT2 expression in human kidney biopsies. In db/db mice, SGLT2 expression increased with concomitant decreases in SIRT1, but was inhibited by canagliflozin. For determination of the polarity of SGLT2 and SIRT1 expression, LLC-PK1 cells were seeded into Transwell chambers (pore size, 0.4 μm; Becton Dickinson, Oxford, UK). HG medium was added to either or to both of the upper and lower chambers, which corresponded to the apical and basolateral sides of the cells, respectively. In this system, the lower chamber with HG showed increased SGLT2 and decreased SIRT1 expression. Canagliflozin reversed HG-induced SIRT1 downregulation. Gene silencing and inhibitors for glucose transporter 2 (GLUT2) blocked HG-induced SGLT2 expression upregulation. Gene silencing for the hepatic nuclear factor-1α (HNF-1α), whose nuclear translocation was enhanced by HG, blocked HG-induced SGLT2 expression upregulation. Similarly, gene silencing for importin-α1, a chaperone protein bound to GLUT2, blocked HG-induced HNF-1α nuclear translocation and SGLT2 expression upregulation. In human kidney, SIRT1 immunostaining was negatively correlated with SGLT2 immunostaining. Thus, under diabetic conditions, SIRT1 expression in PTs was downregulated by an increase in SGLT2 expression, which was stimulated by basolateral HG through activation of the GLUT2/importin-α1/HNF-1α pathway.

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2型糖尿病患者におけるweekly DPP4阻害薬トレラグリプチンの有効性・安全性の検討

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

日本内分泌学会雑誌 ((一社)日本内分泌学会) 94 ( 4 ) 1577 - 1577 2018.12

Accepted, ISSN 0029-0661

2型糖尿病患者における収縮期血圧、総ビリルビン濃度と網膜症との関連

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

日本内分泌学会雑誌 ((一社)日本内分泌学会) 94 ( 4 ) 1577 - 1577 2018.12

Accepted, ISSN 0029-0661

GLP-1受容体作動薬は抗CD3抗体誘導マウス非アルコール性脂肪肝を抑制する

入江潤一郎, 伊藤新, 加藤まり, 田中久美子, 菊地理恵子, 藤田真隆, 中島裕也, 山田悟, 河合俊英, 伊藤裕

日本内分泌学会雑誌 ((一社)日本内分泌学会) 94 ( 4 ) 1575 - 1575 2018.12

Accepted, ISSN 0029-0661

Penile calciphylaxis in a patient on combined peritoneal dialysis and hemodialysis

Kasai T., Washida N., Muraoka H., Fujii K., Uchiyama K., Shinozuka K., Morimoto K., Tokuyama H., Wakino S., Itoh H.

CEN case reports (CEN case reports) 7 ( 2 ) 204 - 207 2018.11

Calciphylaxis presents with painful purpura and intractable skin ulcers on the trunk and particularly the distal extremities, and it mainly occurs in patients on chronic dialysis. A 66-year-old man with renal failure due to diabetic nephropathy was on peritoneal dialysis alone for 1 year, followed by peritoneal dialysis combined with hemodialysis for 3 years. He developed calciphylaxis of the penis, which was diagnosed from the skin biopsy findings and clinical observation. To treat this condition, PD was stopped and HD was performed three times a week. In addition, warfarin therapy was discontinued and infusion of sodium thiosulfate was performed. The penile ulcers decreased in size and pain was markedly improved, so the patient was discharged from hospital. Following discharge, PD was resumed after changing the peritoneal dialysis fluid to bicarbonate-buffered dialysate. The penile ulcers eventually resolved completely. There have been very few reports about calciphylaxis in patients on combined dialysis modalities. In our patient, penile calciphylaxis progressed when lactate-buffered peritoneal dialysis fluid was used and resolved after switching to bicarbonate-buffered fluid together with cessation of warfarin therapy and infusion of sodium thiosulfate.

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The impact of a remote monitoring system of healthcare resource consumption in patients on automated peritoneal dialysis (APD): A simulation study

Uchiyama K., Washida N., Yube N., Kasai T., Shinozuka K., Morimoto K., Hishikawa A., Inoue H., Urai H., Hagiwara A., Fujii K., Wakino S., Deenitchina S., Itoh H.

Clinical Nephrology (Clinical Nephrology) 90 ( 5 ) 334 - 340 2018.11

ISSN 03010430

©2018 Dustri-Verlag Dr. K. Feistle Aims: Remote monitoring (RM) can improve management of chronic diseases. We evaluated the impact of RM in automated peritoneal dialysis (APD) in a simulation study. Materials and methods: We simulated 12 patient scenarios with common clinical problems and estimated the likely healthcare resource consumption with and without the availability of RM (RM+ and RM- groups, respectively). Scenarios were evaluated 4 times by randomly allocated nephrologist-nurse teams or nephrologist-alone assessors. Results: The RM+ group was assessed as having significantly lower total healthcare resource consumption compared with the RM- group (36.8 vs. 107.5 total episodes of resource consumption, p = 0.002). The RM+ group showed significantly lower “unplanned hospital visits” (2.3 vs. 11.3, p = 0.005), “emergency room visits” (0.5 vs. 5.3, p = 0.003), “home visits” (0.5 vs. 5.8, p = 0.016), “exchanges over the telephone” (18.5 vs. 57.8, p = 0.002), and “change to hemodialysis” (0.5 vs. 2.5, p = 0.003). Evaluations did not differ between nephrologist-nurse teams vs. nephrologist-alone assessors. Conclusion: RM can be expected to reduce healthcare resource consumption in APD patients.

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Achieving LDL-C target levels less than 70 mg/dL may provide extra cardiovascular protection in high-risk patients: exploratory analysis of the Standard Versus Intensive Statin Therapy for Patients With Hypercholesterolemia and Diabetic Retinopathy Study

Itoh H, Komuro I, Takeuchi M, Akasaka T, Daida H, Egashira Y, Fujita H, Higaki J, Hirata KI, Ishibashi S, Isshiki T, Ito S, Kashiwagi A, Kato S, Kitagawa K, Kitakaze M, Kitazono T, Kurabayashi M, Miyauchi K, Murakami T, Murohara T, Node K, Ogawa S, Saito Y, Seino Y, Shigeeda T, Shindo S, Sugawara M, Sugiyama S, Terauchi Y, Tsutsui H, Ueshima K, Utsunomiya K, Yamagishi M, Yamazaki T, Yo S, Yokote K, Yoshida K, Yoshimura M, Yoshimura N, Nakao K, Nagai R, EMPATHY Investigators

Diabetes Obes Metab 2018.11

Accepted

Clinical characteristics and postoperative outcomes of primary aldosteronism in the elderly

Takeda M., Yamamoto K., Akasaka H., Rakugi H., Naruse M., Takeda Y., Kurihara I., Itoh H., Umakoshi H., Tsuiki M., 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.

Journal of Clinical Endocrinology and Metabolism (Journal of Clinical Endocrinology and Metabolism) 103 ( 10 ) 3620 - 3629 2018.10

ISSN 0021972X

© 2018 Oxford University Press. All rights reserved. Context: Primary aldosteronism (PA) in the elderly has increased in importance in association with population aging. Objective: To investigate the characteristics and outcomes of elderly patients with PA undergoing adrenalectomy. Patients and Methods: Using a database of patients with PA who underwent adrenal venous sampling (AVS),wecompared elderly patients (65 years old)with nonelderly patients (,65 years old) in terms of characteristics, subtype classification in ACTH-stimulated AVS, and outcomes after adrenalectomy. Results: The elderly group had a higher prevalence of comorbidities than the nonelderly group. The proportion of the unilateral subtype [defined as a lateralization index (LI) .4] was comparable between the age groups. In patients who received adrenalectomy, biochemical cure was comparable between the groups, whereas persistent hypertension was more common in the elderly group. The prevalences of hyperkalemia and renal impairment (chronic kidney disease stage 3b or higher) were higher in the elderly group. Multiple regression analysis showed that the duration of hypertension predicted persistent hypertension and hyperkalemia and that preoperative estimated glomerular filtration rate predicted renal impairment in the elderly group. LI .4 in AVS was an independent predictor of biochemical cure after adrenalectomy in the elderly group but not in the nonelderly group. Age was negatively associated with biochemical cure in patients with LI #4. Conclusion: Adrenalectomy contributes to biochemical improvement in elderly patients if determined in accordance with AVS. The treatment strategy should be determined considering the high postoperative incidence of persistent hypertension and hyperkalemia in elderly patients with a long history of hypertension or renal impairment in those with reduced renal function.

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Organ memory: a key principle for understanding the pathophysiology of hypertension and other non-communicable diseases

Itoh H., Kurihara I., Miyashita K.

Hypertension Research (Hypertension Research) 41 ( 10 ) 771 - 779 2018.10

ISSN 09169636

© 2018, The Japanese Society of Hypertension. In recent years, several post-interventional analyses of large-scale randomized controlled clinical trials have given us a new concept regarding the risk management of hypertension and cardiovascular diseases. The beneficial effects of intensive treatments were extended even after the interventions ended. This phenomenon is known as “metabolic memory” or “legacy effect”, and we recognized its clinical significance. A certain level of evidence in human and animal studies employing organ transplantation techniques has indicated that this type of “memory” resides in each organ and could be transferrable, erasable, and rewritable, which is similar to neuronal and immune “memory”. In this review, we define this memory as “organ memory” and summarize the current picture and future direction of this concept. “Organ memory” can be observed in many clinical settings, including in the control of hypertension, diabetes mellitus, and dyslipidemia. Several intensive treatments were demonstrated to have the potential to rewrite “organ memory”, leading to the curability of targeted diseases. “Organ memory” is the engraved phenotype of altered organ responsiveness acquired by a time-dependent accumulation of organ stress responses. Not only is the epigenetic change of key genes involved in the formation of “organ memory” but the alteration of multiple factors, including low molecular weight energy metabolites, immune mediators, and tissue structures, is involved as well. These factors intercommunicate during every stress response and carry out incessant remodeling in a certain direction in a spiral fashion through positive feedback mechanisms. Future studies should be directed toward the identification of the core unit of “organ memory” and its manipulation.

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Oral adsorbent AST-120 ameliorates gut environment and protects against the progression of renal impairment in CKD rats

Yoshifuji A., Wakino S., Irie J., Matsui A., Hasegawa K., Tokuyama H., Hayashi K., Itoh H.

Clinical and Experimental Nephrology (Clinical and Experimental Nephrology) 22 ( 5 ) 1069 - 1078 2018.10

ISSN 13421751

© 2018, The Author(s). Background: Oral charcoal adsorbent AST-120 (AST) is reported to ameliorate renal dysfunction by the absorption of toxic substance in the gut. Recent study revealed that, in CKD, gut environment is disturbed including the decrease in tight junctions and Lactobacillus (Lact). In this study, we examined whether AST improves the renal dysfunction through gut environment. Method: Six-week-old spontaneously hypertensive rats (SHR) were rendered CKD by 5/6th nephrectomy (Nx). SHRs were divided into SHR (Sham), SHR with Nx (Nx), and Nx given AST (Nx + AST) (n = 10, each). After 12 weeks, rats were killed and biochemical parameters were explored. The gut flora was analyzed. Furthermore, gut molecular changes in tight junctions and toll-like receptors were examined. We also investigated the effects of the combination therapy with AST and Lact. Results: The increase in serum urea nitrogen and urinary protein excretion in Nx was restored in Nx + AST. The increased renal glomerulosclerosis in Nx was ameliorated in Nx + AST. Increases in serum uremic toxins and IL-6 in Nx were ameliorated in Nx + AST. The gut flora analysis revealed that the decrease in Lact in Nx was restored in Nx + AST. The downregulation in the tight junction and TLR2 in Nx was mitigated by AST. However, combination therapy failed to exhibit additional effects. Conclusion: AST ameliorated renal function with the restoration of Lact and tight junction through TLR pathway, which would mitigate systemic inflammation and contributed to their renoprotective effects. Our study provides a novel mechanism of the renoprotective effects by AST.

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Epidermal growth factor receptor/extracellular signal-regulated kinase pathway enhances mineralocorticoid receptor transcriptional activity through protein stabilization

Mitsuishi Y., Shibata H., Kurihara I., Kobayashi S., Yokota K., Murai-Takeda A., Hayashi T., Jo R., Nakamura T., Morisaki M., Itoh H.

Molecular and Cellular Endocrinology (Molecular and Cellular Endocrinology) 473 89 - 99 2018.09

ISSN 03037207

© 2018 Elsevier B.V. Activation of mineralocorticoid receptor (MR) is evoked by aldosterone, and it induces hypertension and cardiovascular disease when it's concomitant with excessive salt loading. We have proposed the notion of “MR-associated hypertension” in which add-on therapy of MR blockers is effective even though serum aldosterone level is within normal range. To elucidate its underlying molecular mechanism, we focused on the effect of epidermal growth factor receptor (EGFR)/extracellular signal-regulated kinase (ERK) activation on MR activity. Epidermal growth factor (EGF) administration increased MR transcriptional activity through EGFR/ERK pathway and increased protein level by counteracting MR ubiquitylation in vitro. EGF administration in vivo also increased MR protein level and target gene expression in kidney, which were decreased by EGFR inhibitor. In addition, the administration of EGFR inhibitor lowered systolic blood pressure and MR activity in DOCA/salt-treated mice. In conclusion, EGFR/ERK pathway activation is considered as one of the underlying mechanisms of aberrant MR activation and EGFR/ERK pathway blockade could be an alternative approach for the prevention of MR-related cardiovascular events.

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Difference of seasonal variation between glycated albumin and glycated haemoglobin

Tanaka K., Meguro S., Tanaka M., Irie J., Saisho Y., Itoh H.

Annals of Clinical Biochemistry (Annals of Clinical Biochemistry) 55 ( 5 ) 583 - 587 2018.09

ISSN 00045632

© The Author(s) 2018. Background: Glycated albumin reflects 2–3-week glycaemic controls, and in addition to glycated haemoglobin, it has been used as a glycaemic control indicator. We presumed that glycated albumin also has seasonal variations and is related to temperature, similar to glycated haemoglobin. Methods: The subjects were diabetic outpatients from April 2007 to March 2013. This resulted in the enrolment of 2246 subjects and the collection of a total of 53,968 measurements. Mean glycated haemoglobin, glycated albumin, and plasma glucose were calculated for each month over six years. The associations of the measures with each other and the average temperature for each month in Tokyo were assessed using Spearman rank correlation coefficients. Results: Plasma glucose was highest in January and lowest in May. Glycated haemoglobin was highest in March and lowest in September. Glycated albumin was highest in May and lowest in December. Glycated albumin tended to have a disjunction with plasma glucose in winter. Glycated haemoglobin had seasonal variation, but glycated albumin did not. Plasma glucose and glycated haemoglobin showed significant negative correlations with temperature (rs = −0.359, P < 0.001, rs = −0.449, P < 0.001, respectively), but glycated albumin did not. However, glycated albumin was inter-correlated with plasma glucose (rs = 0.396, P < 0.001) and glycated haemoglobin (rs = 0.685, P < 0.001), and glycated haemoglobin was inter-correlated with plasma glucose (rs = 0.465, P < 0.001). Conclusion: Glycated albumin and glycated haemoglobin showed different seasonal variations from each other over the six-year study period. Thus, further studies to identify factors that contribute to glycated albumin are needed.

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Pulmonary nocardiosis mimicking small cell lung cancer in ectopic ACTH syndrome associated with transformation of olfactory neuroblastoma: A case report

Kobayashi K., Asakura T., Ishii M., Ueda S., Irie H., Ozawa H., Saitoh K., Kurihara I., Itoh H., Betsuyaku T.

BMC Pulmonary Medicine (BMC Pulmonary Medicine) 18 ( 1 ) 2018.08

© 2018 The Author(s). Background: Pulmonary nocardiosis frequently develops as an opportunistic infection in cell-mediated immunosuppressive patients, and sometimes requires differentiation from pulmonary malignancy. Ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS) is a neoplastic disorder which leads to impaired cell-mediated immunity, and is commonly associated with small cell lung cancer (SCLC). Because pulmonary infection and causative malignancy can appear as pulmonary lesions with EAS, differentiation of these diseases remains a critical issue for physicians. Case presentation: A 52-year-old woman with progressive lower limb paralysis and general fatigue was referred to us. She had been diagnosed with olfactory neuroblastoma (ONB) and treated with surgery and radiation therapy 10 years before the referral and had required stereotactic radiosurgery and chemotherapy 4 years later for a relapse of the ONB. On referral, she presented with Cushing's syndrome with elevated cortisol and ACTH levels. Potassium supplement improved her symptoms; however, a month later, she was urgently hospitalized due to acute pleuritic chest pain on inspiration. Chest computed tomography revealed left lower lobular consolidations and a contralateral nodule in the right middle lobe. The clinical history and laboratory work-up suggested that her Cushing's syndrome had most likely arisen from EAS. Additionally, the lungs were suspected as the ACTH source due to high levels of progastrin-releasing peptide and progressive pulmonary consolidation with a contralateral nodule, suggesting SCLC. However, histological examination from bronchoscopy revealed no evidence of malignancy, and Nocardia cyriacigeorgica was isolated from bronchoalveolar lavage fluid. Sulfamethoxazole/trimethoprim improved her pulmonary lesions. Somatostatin receptor scintigraphy revealed strong tracer uptake in the ONB lesions, indicating that the origin of the EAS was the olfactory tumor. However, histological examination of ONB specimens resected 10 years earlier showed no intracytoplasmic immunopositivity for ACTH. Conclusions: We highlight a rare case of pulmonary nocardiosis, which was associated with EAS mimicking SCLC, and was related to ONB transformation. Nocardiosis has to be considered even though anamnestic, clinical, and radiological aspects suggest the presence of metastasis. Additionally, physicians should carefully monitor patients with ONB for the development of Cushing's symptoms because the tumor can transform into an ACTH-producing form, even after long-term follow-up.

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Expanding Phenotype of Nephronophthisis-Related Ciliopathy: An Elderly Patient with Homozygous RPGRIP1L Mutation

Kawaguchi T., Yoshida T., Hirahashi J., Uehara T., Takenouchi T., Kosaki K., Itoh H., Hayashi M.

Nephron (Nephron) 140 ( 1 ) 74 - 78 2018.08

ISSN 16608151

© 2018 S. Karger AG, Basel. Nephronophthisis-related ciliopathies (NPHP-RC) are autosomal recessive disorders characterized by renal corticomedullary cysts with the extrarenal symptoms. Typically, patients with NPHP-RC reach end-stage kidney disease (ESKD) before the age of 30 years. We herein report a Japanese woman with NPHP-RC who had unusually delayed progression to ESKD after 6 decades. She exhibited liver dysfunction at the age of 23 years. She also showed mild renal dysfunction at the age of 43 years. Ultrasonography revealed bilateral multiple renal cysts with loss of corticomedullary differentiation. Her liver and renal functions gradually deteriorated. She was diagnosed with liver fibrosis as a result of biopsy, and initiated the maintenance hemodiafiltration therapy for ESKD at the age of 61 years. Because of a unique combination of multiple renal cysts and liver fibrosis, ciliopathy was suspected and medical exome analysis was performed. A novel homozygous missense mutation was identified in RPGRIP1L (c.1810G>A p.Glu604Lys), a causative gene for NPHP-RC. To the best of our knowledge, this patient is the oldest one who progressed to ESKD in NPHP-RC. Our case illustrates that NPHP-RC should be included in the differential diagnosis of the patient with corticomedullary polycystic kidneys accompanied by the extrarenal organ involvements, even if the patient is elderly.

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Correlation Between Lateralization Index of Adrenal Venous Sampling and Standardized Outcome in Primary Aldosteronism.

Hironobu Umakoshi, Mika Tsuiki, Maki Yokomoto-Umakoshi, Yoshiyu Takeda, Yoneda Takashi, Isao Kurihara, Hiroshi Itoh, Takuyuki Katabami, Takamasa Ichijo, Norio Wada, Yui Shibayama, Takanobu Yoshimoto, Kenji Ashida, Yoshihiro Ogawa, Junji Kawashima, Masakatsu Sone, Nobuya Inagaki, Katsutoshi Takahashi, Minemori Watanabe, Yuichi Matsuda, Hiroki Kobayashi, Hirotaka Shibata, Kohei Kamemura, Michio Otsuki, Yuichi Fujii, Koichi Yamamto, Atsushi Ogo, Shintaro Okamura, Shozo Miyauchi, Tomikazu Fukuoka, Shoichiro Izawa, Toshihiko Yanase, Shigeatsu Hashimoto, Masanobu Yamada, Yuichiro Yoshikawa, Tatsuya Kai, Tomoko Suzuki, Takashi Kawamura, Mitsuhide Naruse

Journal of the Endocrine Society 2 ( 8 ) 893 - 902 2018.08

Accepted

Objectives: The aim of this study was to investigate the impact of adrenal venous sampling (AVS) lateralization cutoffs on surgical outcomes. Patients and Methods: Cosyntropin-stimulated AVS was used to guide surgical management of 377 patients with primary aldosteronism (PA) who were evaluated 6 months after surgery. Main Outcome Measures: The proportion of patients that achieved clinical benefit and complete biochemical success based on the AVS aldosterone lateralization index (LI) was determined. Results: Clinical benefit was achieved in 29 of 47 patients with an LI between 2 and 4, in 66 of 101 with an LI between 4 and 10, and in 158 of 203 with an LI > 10 (P < 0.01 for trend). Complete biochemical success was achieved in 27 of 42 with an LI between 2 and 4, in 60 of 76 with an LI between 4 and 10, and in 127 of 155 with an LI > 10 (P = 0.024 for trend). After adjustment for confounders and using those patients with an LI between 2 and 4 as a reference, a clinical benefit was associated only with those with an LI > 10 (OR, 2.30; 95% CI, 1.03 to 5.16), whereas complete biochemical success was associated with those with an LI between 4 and 10 (OR, 2.83; 95% CI, 1.14 to 7.01) or LI > 10 (OR, 3.55; 95% CI, 1.47 to 8.55). Conclusions: Difference of clinical outcome was relatively small when strict LI diagnostic threshold was used; biochemical cure was sufficiently achieved when an LI > 4 was used. Our study by standardized outcome measures validated that an LI > 4 may be appropriate for determining unilateral disease in PA.

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Intestinal mineralocorticoid receptor contributes to epithelial sodium channel–mediated intestinal sodium absorption and blood pressure regulation

Nakamura T., Kurihara I., Kobayashi S., Yokota K., Murai-Takeda A., Mitsuishi Y., Morisaki M., Kohata N., Oshima Y., Minami Y., Shibata H., Itoh H.

Journal of the American Heart Association (Journal of the American Heart Association) 7 ( 13 ) 2018.07

© 2018 The Authors. Background-—Mineralocorticoid receptor (MR) has pathological roles in various cell types, including renal tubule cells, myocytes, and smooth muscle cells; however, the role of MR in intestinal epithelial cells (IECs) has not been sufficiently evaluated. The intestine is the sensing organ of ingested sodium; accordingly, intestinal MR is expected to have essential roles in blood pressure (BP) regulation. Methods and Results-—We generated IEC-specific MR knockout (IEC-MR-KO) mice. With a standard diet, fecal sodium excretion was 1.5-fold higher in IEC-MR-KO mice, with markedly decreased colonic expression of b- and c-epithelial sodium channel, than in control mice. Urinary sodium excretion in IEC-MR-KO mice decreased by 30%, maintaining sodium balance; however, a low-salt diet caused significant reductions in body weight and BP in IEC-MR-KO mice, and plasma aldosterone exhibited a compensatory increase. With a high-salt diet, intestinal sodium absorption markedly increased to similar levels in both genotypes, without an elevation in BP. Deoxycorticosterone/salt treatment elevated BP and increased intestinal sodium absorption in both genotypes. Notably, the increase in BP was significantly smaller in IEC-MR-KO mice than in control mice. The addition of the MR antagonist spironolactone to deoxycorticosterone/salt treatment eliminated the differences in BP and intestinal sodium absorption between genotypes. Conclusions-—Intestinal MR regulates intestinal sodium absorption in the colon and contributes to BP regulation. These regulatory effects are associated with variation in epithelial sodium channel expression. These findings suggest that intestinal MR is a new target for studying the molecular mechanism of hypertension and cardiovascular diseases.

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Adhesive intestinal obstruction increases the risk of intestinal perforation in peritoneal dialysis patients: A case report

Fujii K., Washida N., Arai E., Tsuruta M., Wakino S., Itoh H.

BMC Nephrology (BMC Nephrology) 19 ( 1 ) 2018.06

© 2018 The Author(s). Background: Peritonitis secondary to bowel perforation is a rare and potentially fatal complication in peritoneal dialysis (PD) patients. However, the early diagnosis of bowel perforation is difficult in PD patients because the initial symptoms and signs of bowel perforation are similar to those of PD-associated peritonitis. Furthermore, the risk of bowel perforation in PD patients is unclear. Here, we present a case of intestinal perforation located at the site of adhesive intestinal obstruction in a PD patient. Case presentation: A 73-year-old man on PD presented with progressive worsening of abdominal pain and cloudy peritoneal fluid. The peritoneal fluid cell count was increased to 980/ml and peritoneal dialysis-associated peritonitis was diagnosed. Computed tomography showed local adhesions causing agglomeration of the dilated intestine. He initially responded to antibiotic treatment; however, his abdominal pain was rapidly worsened after resumption of oral intake. On hospital day 23, computed tomography showed loss of contents from the dilated intestine and discharge of fecal material from the PD tube was noted. Thus, small bowel perforation was diagnosed, and he underwent ileocecal resection with colostomy creation. As indicators of EPS was not evident, PD catheter was removed. Since then, he has been on maintenance of hemodialysis since then. Conclusion: The findings of the present case suggest that adhesive intestinal obstruction in PD patients can increase the risk of intestinal perforation. Careful monitoring for the early detection of intestinal perforation is required in such cases.

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Greater reductions in plasma aldosterone with aliskiren in hypertensive patients with higher soluble (Pro)renin receptor level article

Bokuda K., Morimoto S., Seki Y., Yatabe M., Watanabe D., Yatabe J., Ando T., Shimizu S., Itoh H., Ichihara A.

Hypertension Research (Hypertension Research) 41 ( 6 ) 435 - 443 2018.06

ISSN 09169636

© 2018 The Japanese Society of Hypertension. The (pro)renin receptor is important in the regulation of the tissue renin-angiotensin-aldosterone system. The benefits and safety of single-aliskiren treatment without other renin-angiotensin-aldosterone system inhibitors remain unclear. The serum level of the soluble form of the (pro)renin receptor is thought to be a biomarker reflecting the activity of the tissue renin-angiotensin-aldosterone system. We investigated the effects of single renin-angiotensin-aldosterone system blockade with aliskiren on renal and vascular functions and determined if serum level of the soluble (pro)renin receptor was a predictor of aliskiren efficacy in hypertensive patients with chronic kidney disease. Thirty-nine essential hypertensive patients with chronic kidney disease in our outpatient clinic were randomly assigned to receive either aliskiren or amlodipine. The parameters associated with renal and vascular functions and indices of renin-angiotensin-aldosterone system components, including serum levels of the soluble form, were evaluated before and after 12-week and 24-week treatment. Blood pressure was not significantly different between the groups. No significant changes in serum levels were observed in the soluble (pro)renin receptor in either group. Urinary albumin, protein excretion, and cardio-ankle vascular index significantly decreased in the aliskiren group. In the aliskiren group, there was a significant negative correlation between the basal level of the soluble (pro)renin receptor and the change in plasma aldosterone concentration. Single renin-angiotensin-aldosterone system blockade with aliskiren showed renal and vascular protective effects independent of blood pressure reduction. Serum levels of the soluble (pro)renin receptor may indicate aldosterone production via the (pro)renin receptor in the adrenal gland.

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