Details of a Researcher - Hashiguchi, Akinori

Papers - Hashiguchi, Akinori

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DNA-damaged podocyte-CD8 T cell crosstalk exacerbates kidney injury by altering DNA methylation

Nakamichi R, Hishikawa A, Chikuma S, Yoshimura A, Sasaki T, Hashiguchi A, Abe T, Tokuhara T, Yoshimoto N, Nishimura E.S, Hama E.Y, Azegami T, Nakayama T, Hayashi K, Itoh H

Cell Reports (Cell Reports) 42 ( 4 ) 112302 - 112302 2023.04

Joint Work

Recent epigenome-wide studies suggest an association between blood DNA methylation and kidney function. However, the pathological importance remains unclear. Here, we show that the homing endonuclease I-PpoI-induced DNA double-strand breaks in kidney glomerular podocytes cause proteinuria, glomerulosclerosis, and tubulointerstitial fibrosis with DNA methylation changes in blood cells as well as in podocytes. Single-cell RNA-sequencing analysis reveals an increase in cytotoxic CD8+ T cells with the activating/costimulatory receptor NKG2D in the kidneys, which exhibit a memory precursor effector cell phenotype, and the CD44high memory CD8+ T cells are also increased in the peripheral circulation. NKG2D blockade attenuates the renal phenotype caused by podocyte DNA damage. Blood methylome shows increased DNA methylation in binding sites for STAT1, a transcription factor contributing to CD8+ T cell homeostasis. Collectively, podocyte DNA damage alters the blood methylome, leading to changes in CD8+ T cells, which contribute to sustained renal injury in chronic kidney disease.

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Significance of podocyte DNA damage and glomerular DNA methylation in CKD patients with proteinuria

Yoshimoto N, Hayashi K, Hishikawa A, Hashiguchi A, Nakamichi R, Sugita-Nishimura E, Yoshida-Hama E, Azegami T, Nakayama T, Itoh H

Hypertension Research (Hypertension Research) 46 ( 4 ) 1000 - 1008 2023.04

Joint Work, ISSN 09169636

The number of chronic kidney disease (CKD) patients is increasing worldwide, and it is necessary to diagnose CKD patients in earlier stages to improve their prognosis. Previously, in a study using human samples, we reported that DNA methylation and DNA damage in podocytes are potential markers for kidney function decline in IgA nephropathy; however, these candidate markers have not been adequately investigated in other glomerular diseases. Here, we report that the association of podocyte DNA damage and DNA methylation with eGFR decline and proteinuria differs depending on the type of glomerular disease. Patients diagnosed with minor glomerular abnormality (MGA, n = 33), membranous nephropathy (MN, n = 9) or diabetic nephropathy (DN, n = 10) following kidney biopsy at Keio University Hospital from 2015 to 2017 were included. In MGA patients, both podocyte DNA damage and glomerular DNA methylation were associated with the severity of proteinuria. In DN patients, podocyte DNA double-strand breaks (DSBs) and glomerular DNA methylation were associated with an eGFR decline. When patients with urinary protein levels of more than 1 g/gCr were examined, fewer podocyte DNA DSBs were detected in MN patients than in MGA patients, and the level of glomerular DNA methylation was lower in MN patients than in MGA or DN patients. These results indicate that investigating podocyte DNA DSBs and DNA methylation changes may be useful for understanding the pathogenesis of CKD with proteinuria in humans. [Figure not available: see fulltext.].

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Case report: Importance of early and continuous tocilizumab therapy in nephrotic syndrome associated with idiopathic multicentric Castleman disease: A case series.

Daiki Kojima, Shintaro Yamaguchi, Akinori Hashiguchi, Kaori Hayashi, Kiyotaka Uchiyama, Norifumi Yoshimoto, Keika Adachi, Takashin Nakayama, Ken Nishioka, Takaya Tajima, Kohkichi Morimoto, Jun Yoshino, Tadashi Yoshida, Toshiaki Monkawa, Takeshi Kanda, Hiroshi Itoh

Frontiers in medicine (Frontiers in Medicine) 9 1037032 - 1037032 2023.01

Joint Work, ISSN 2296-858X

Idiopathic multicentric Castleman disease (iMCD) is a systemic and polyclonal lymphoproliferative disease involving multiple organs, including the kidneys, due to the overproduction of interleukin-6 (IL-6). Recently, several reports have suggested that excessive IL-6 actions in iMCD could have a causal relationship with the development of diverse histopathological renal manifestations that cause nephrotic syndrome. However, the treatment for such cases remains unclear. We report a series of three cases of nephrotic syndrome due to iMCD that helps to delineate the importance of early and continuous therapy with the anti-interleukin-6 receptor antibody tocilizumab. First, treatment was suspended for infectious control, and the patient presented with nephrotic syndrome due to diffuse mesangial and endocapillary hypercellularity without immune deposits complicating acute kidney injury. Second, iMCD was treated with prednisolone alone. The patient suddenly developed nephrotic syndrome due to immune-complex glomerulonephritis, not otherwise specified, complicated with acute kidney injury. In the third case, nephrotic syndrome secondary to membranous glomerulonephritis was diagnosed, with a skin rash and IgE antibodies to tocilizumab, and was therefore treated with prednisolone alone. In contrast to the first two cases, the third progressed to end-stage renal disease on hemodialysis. Taken together, this series suggests that clinicians should maintain clinical vigilance for iMCD as a possible underlying component of nephrotic syndrome, since iMCD presents with a variety of renal pathologies. Prompt initiation and continuous administration of tocilizumab are likely key determinants of renal outcomes in such cases. In particular, when tocilizumab is suspended due to infection or in the perioperative period, consideration of its expeditious resumption should be made, taking into account both the withdrawal period and systemic conditions.

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Antineutrophil cytoplasmic antibody-associated vasculitis predominantly manifesting tubulointerstitial nephritis: A case report.

Ken Nishioka, Shintaro Yamaguchi, Akinori Hashiguchi, Norifumi Yoshimoto, Takaya Tajima, Itaru Yasuda, Kiyotaka Uchiyama, Kenji Kaneko, Mitsuhiro Aso, Jun Yoshino, Toshiaki Monkawa, Takeshi Kanda, Kaori Hayashi, Hiroshi Itoh

SAGE open medical case reports (SAGE Open Medical Case Reports) 11 2050313X231197324 2023.01

Joint Work, ISSN 2050-313X

The common histopathology of antineutrophil cytoplasmic antibody-associated vasculitis comprises pauci-immune crescentic glomerulonephritis with concomitant tubulointerstitial nephritis. Tubulointerstitial nephritis in the absence of glomerular involvement in patients with antineutrophil cytoplasmic antibody-associated vasculitis is uncommon. We report a case of antineutrophil cytoplasmic antibody-associated vasculitis-associated acute kidney injury manifesting as tubulointerstitial nephritis without glomerulonephritis. A 75-year-old woman with fever, cough, and myalgia developed kidney dysfunction with inflammatory reactions and tubular-type proteinuria, without glomerular hematuria. A kidney biopsy revealed tubulointerstitial nephritis with arteritis. We ruled out important underlying etiologies of tubulointerstitial nephritis, including infection, drug reactions, and autoimmune diseases. Since chest high-resolution computed tomography demonstrated mild interstitial pneumonia in bilateral lower lung fields, myeloperoxidase antineutrophil cytoplasmic antibody was measured and found to be positive. Therefore, we diagnosed the patient with antineutrophil cytoplasmic antibody-associated vasculitis-associated tubulointerstitial nephritis but not glomerulonephritis, and interstitial pneumonia. The patient's kidney function and symptoms markedly improved with prednisolone treatment. Clinicians should maintain high-level vigilance for antineutrophil cytoplasmic antibody-associated vasculitis as a possible underlying component of tubulointerstitial nephritis, particularly when kidney function deteriorates with tubulointerstitial injuries without glomerular features.

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Granulomatous interstitial nephritis with CTLA-4 haploinsufficiency: a case report

Kohatsu K, Suzuki T, Takimoto M, Matsui K, Hashiguchi A, Koike J, Shirai S

BMC Nephrology (BMC Nephrology) 23 ( 1 ) 367 2022.12

Joint Work

Background: Cytotoxic T lymphocyte antigen-4 (CTLA-4) is an essential inhibitory regulator of immune activation. CTLA-4 haploinsufficiency is known to be associated with dysregulation of FOXP3+ regulatory T cells, hyperactivation of effector T cells, and lymphocytic infiltration of multiple organs. However, there have only been a few reports of renal involvement with CTLA-4. Herein, we present a case of acute granulomatous tubulointerstitial nephritis (TIN) in a patient with CTLA-4 haploinsufficiency. Case presentation: A 44-year-old man presented with a 3-week history of fever and malaise, and subsequently developed acute kidney injury (AKI) a few days after treatment with levofloxacin (LVFX). A kidney biopsy and immunohistochemical staining revealed granulomatous TIN with dominantly infiltrating CD4+ T cells. General symptoms and renal impairment showed improvement after discontinuation of LVFX and initiation of oral steroids. However, they worsened following steroid tapering. Further, a colon biopsy analysis showed similar findings to the renal tissue analysis. We suspected that granulomatous TIN was possibly associated with CTLA-4 haploinsufficiency. Therefore, the patient was transferred to another hospital for further treatment of CTLA-4 haploinsufficiency using immunosuppressive agents. Conclusions: There have been few reports regarding renal involvement of CTLA-4 haploinsufficiency. In the present case, granulomatous TIN could have arisen due to instability of immune regulatory functions, such as CTLA-4 haploinsufficiency, and treatment with LVFX could have triggered immunologic activation and severe inflammation as well as renal dysfunction.

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尿細管・間質病変主体のANCA関連血管炎の一例

西岡謙, 山口慎太郎, 安田格, 吉本憲史, 田島敬也, 林香, 吉野純, 橋口明典, 神田武志, 伊藤裕

日本腎臓学会誌 ((一社)日本腎臓学会) 64 ( 6-E ) 549 - 549 2022.10

Joint Work, ISSN 0385-2385

A girl with membranous nephropathy associated with ventriculoperitoneal shunt infection.

Awazu M, Miyahara M, Chiga M, Hashiguchi A, Takahashi H

CEN case reports (CEN case reports) 12 ( 1 ) 130 - 134 2022.09

Joint Work

Glomerulopathy associated with shunt infection is commonly membranoproliferative glomerulonephritis, whereas the causative organisms of secondary membranous nephropathy are usually viruses. We report a case of membranous nephropathy associated with shunt infection. The patient was born at 29-week gestation with a birth weight of 1178 g. Ventriculoperitoneal shunt surgery had been performed for congenital hydrocephalus. Thereafter, she had experienced seven shunt infections. At the age 13 years, proteinuria was detected in a school urinary screening. Urinalysis at our hospital demonstrated 3 + protein and 3 + blood. Laboratory testing demonstrated a serum creatinine 0.5 m/dl, albumin 2.5 g/dl, C-reactive protein (CRP) 13.7 mg/dl, and C3 182 mg/dl. Prior to repeat urinalysis, the patient developed vomiting and was admitted with suspected shunt infection. On admission, her body temperature was 36.0 ºC. Physical examination was unremarkable other than small stature and a palpable mass in the left upper quadrant. Urinalysis demonstrated 2 + protein and 1 + blood with no cells or casts. The urinary protein excretion was 3 g/day. Abnormal laboratory tests included erythrocyte sedimentation rate 102 mm/hr, CRP 11.67 mg/dl, IgG 2442 mg/dl, C3 177 mg/dl, and C4 44 mg/dl. Antibiotic therapy was initiated for a presumptive diagnosis of shunt infection and the shunt catheter was removed. Cultures obtained after antibiotic administration were negative. Proteinuria persisted after control of the shunt infection. Histology of a renal biopsy demonstrated membranous nephropathy with diffuse granular IgG staining and subepithelial deposits. Three possible pathomechanisms for her membranous nephropathy were considered.

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Structural modeling for Oxford histological classifications of immunoglobulin A nephropathy

Kensuke Joh, Takashi Nakazato, Akinori Hashiguchi, Akira Shimizu, Ritsuko Katafuchi, Hideo Okonogi, Kentaro Koike, Keita Hirano, Nobuo Tsuboi, Tetsuya Kawamura, Takashi Yokoo, Ichiei Narita, Yusuke Suzuki

PLoS ONE (PLoS ONE) 17 ( 9 September ) e0268731 2022.09

Joint Work

In immunoglobulin A nephropathy (IgAN), Cox regression analysis can select independent prognostic variables for renal functional decline (RFD). However, the correlation of the selected histological variables with clinical and/or treatment variables is unknown, thereby making histology-based treatment decisions unreliable. We prospectively followed 946 Japanese patients with IgAN for a median of 66 mo. and applied structural equation modeling (SEM) to identify direct and indirect effects of histological variables on RFD as a regression line of estimated glomerular filtration rate (eGFR) via clinical variables including amount of proteinuria, eGFR, mean arterial pressure (MAP) at biopsy, and treatment variables such as steroid therapy with/without tonsillectomy (ST) and renin-angiotensin system blocker (RASB). Multi-layered correlations between the variables and RFD were identified by multivariate linear regression analysis and the model's goodness of fit was confirmed. Only tubular atrophy/interstitial fibrosis (T) had an accelerative direct effect on RFD, while endocapillary hypercellularity and active crescent (C) had an attenuating indirect effect via ST. Segmental sclerosis (S) had an attenuating indirect effect via eGFR and mesangial hypercellularity (M) had accelerative indirect effect for RFD via proteinuria. Moreover, M and C had accelerative indirect effect via proteinuria, which can be controlled by ST. However, both T and S had additional indirect accelerative effects via eGFR or MAP at biopsy, which cannot be controlled by ST. SEM identified a systemic path links between histological variables and RFD via dependent clinical and/or treatment variables. These findings lead to clinically applicable novel methodologies that can contribute to predict treatment outcomes using the Oxford classifications.

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キャッスルマン病で治療中に壊死性筋膜炎及び急性腎障害を呈した2型糖尿病患者の1例

山口慎太郎, 安達京華, 吉本憲史, 安田格, 内山清貴, 田島敬也, 吉野純, 橋口明典, 神田武志, 目黒周, 伊藤裕

糖尿病 ((一社)日本糖尿病学会) 65 ( 7 ) 395 - 395 2022.07

Joint Work, ISSN 0021-437X

Diagnosis of monoclonal immunotactoid glomerulopathy with positive λ chain by immunoelectron microscopy.

Sugita E, Sonoda H, Ryuzaki M, Hashiguchi A, Tokuyama H, Wakino S, Kanda T, Itoh H

CEN case reports (Springer Science and Business Media LLC) 12 ( 1 ) 7 - 13 2022.06

Joint Work

We report the case of a 73-year-old-man who developed immunotactoid glomerulopathy (ITG). ITG is a rare disease characterized by proliferative glomerulonephritis and capillary wall deposits with a 10-60 nm diameter microtubular substructure. In monoclonal ITG, immunofluorescence analysis typically exhibits IgG with light chain restriction. Recent reviews recommend distinguishing monoclonal ITG from polyclonal ITG because monoclonal ITG is associated with a higher incidence of hematological disorders and better responsiveness to clone-directed therapy and renal prognosis. In our case, IgG, IgA, and IgM were negative by routine immunofluorescence; however, immunoelectron microscopy revealed positive λ chain. At 6 months after renal biopsy, the IgG λ chain was detected in the serum and urine, reflecting possible monoclonality. Therefore, it is useful to perform immunoelectron microscopy and follow-up with serum and urine protein electrophoresis and immunofixation to diagnose monoclonal ITG, even when routine immunofluorescence shows negative or nonspecific findings.

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MPO-ANCA、抗GBM抗体共陽性かつ膜性腎症を合併した急速進行性糸球体腎炎に対して選択的血漿交換(SePE)を行った一例

星健太, 浦井秀徳, 渡部統, 中村彰良, 橋口明典, 村上円人

日本急性血液浄化学会雑誌 ((NPO)日本急性血液浄化学会) 13 ( 1 ) 48 - 51 2022.06

Joint Work, ISSN 2185-1085

当院において、半月体形成性糸球体腎炎を呈したMPO-ANCA、抗糸球体基底膜(glomerular basement membrane:GBM)抗体共陽性かつ膜性腎症を合併した急速進行性糸球体腎炎(rapidly progressive glomerulonephritis:RPGN)を経験した。血清Crの上昇がみられた早期に副腎皮質ステロイド、静注シクロホスファミドパルス療法(intravenous cyclophosphamide:IVCY)に加え選択的血漿交換(selective plasma exchange:SePE)を行ったところ、2抗体の陰性化を得られ肺障害を生じることなく腎機能障害も改善した。発症早期に、免疫抑制療法に加えて凝固因子補充不要なSePEを行うことが新規抗体産生抑制および抗体除去に有用であると考えられた。(著者抄録)

Clinical and pathological characteristics of patients with acute kidney injury in Japan in whom kidney biopsy was performed: a cross-sectional analysis of the Japan Renal Biopsy Registry (J‑RBR).

Moniwa N, Tanaka M, Sato H, Shimizu A, Sugiyama H, Yokoyama H, Tsuruya K, Hashiguchi A, Committee for, Renal Biopsy, Disease Registry of the, Japanese, Society of Nephrology

Clinical and experimental nephrology (Clinical and Experimental Nephrology) 26 ( 10 ) 963 - 973 2022.05

Joint Work, ISSN 1342-1751

INTRODUCTION: Acute kidney injury (AKI) is a worldwide concern and it leads to a poor prognosis or end-stage kidney disease. The purpose of this study was to clarify the characteristics of patients with AKI in whom kidney biopsy was performed using data of the Japan Renal Biopsy Registry (J-RBR). METHODS: We screened 38,351 cases that were registered in the J-RBR from 2007 to 2018. We obtained data for 383 patients with AKI based on clinical diagnosis for analysis 1 and data for 714 patients with acute interstitial nephritis (AIN) or acute tubular necrosis (ATN) based on pathological diagnosis for analysis 2. RESULTS: Of the cases screened, 383 patients with AKI (1.0%) were included in analysis 1. The main pathological diagnoses of AKI were AIN, ATN, chronic interstitial nephritis, nephro-sclerosis and crescentic glomerulonephritis. Of the cases screened, 589 patients with AIN (1.5%) and 110 patients with ATN (0.3%) were included in analysis 2. The main clinical diagnoses of AIN were AKI, rapidly progressive glomerulonephritis (RPGN), chronic nephritic syndrome (CNS) and drug-induced nephropathy (DIN), whereas those of ATN were AKI, RPGN, DIN and CNS. ATN patients had a higher serum creatinine level than that of AIN patients. CONCLUSION: Our results revealed that cases in the J-RBR included 1.0% of AKI cases based on clinical diagnosis and 1.5% and 0.3% of AIN and ATN cases, respectively, based on pathological diagnosis. In patients with suspected intrinsic AKI, kidney biopsy should be performed for diagnosis of the precise etiology and selection of appropriate treatment.

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異なる撮像機のデジタルスライドに対して抗酸菌検出AIの再現性を得るための検討

江本桂, 松田紘典, 阿部時也, 橋口明典, 坂元亨宇

日本病理学会会誌 ((一社)日本病理学会) 111 ( 1 ) 240 - 240 2022.03

Joint Work, ISSN 0300-9181

当院で施行した移植腎生検病理組織の検討

坂巻裕介, 香野日高, 橋口明典, 環聡, 萩生田純, 桝田司, 宍戸偉海, 井上博之, 徳山博文, 中川健

日本臨床腎移植学会プログラム・抄録集 ((一社)日本臨床腎移植学会) 55回 288 - 288 2022.02

Joint Work

Quantitative evaluation of color difference between actual specimens and whole-slide imaging-scanned images calibrated with commercial color charts

Murayama Y, Sugiyama T, Ogino Y, Furuta H, Kambara T, Kamisono K, Abe T, Emoto K, Hashiguchi A, Kajimura Y, Sakamoto M

Progress in Biomedical Optics and Imaging - Proceedings of SPIE (Progress in Biomedical Optics and Imaging - Proceedings of SPIE) 12039 2022

Joint Work, ISSN 16057422

When using different cameras and displays in the shot and display of one subject, different color images are often showed. To solve this problem, we have developed a color chart in which the constituent colors dyed with dyes are evenly distributed in the color space. We have also developed a tool that creates an International Color Consortium (ICC) profile from the captured image of this color chart. In this report, we will describe the color difference correction accuracy when our method is applied to actual stained pathological specimens taken with multiple whole-slide imaging (WSI). We confirmed color correction accuracy of Lab values in major parts such as the cell nucleus. The Lab value of the specimen itself measured by a spectrocolorimeter was compared with that of the captured image. As a result, the color difference ?E in H&E-stained cell nucleus was improved from 32.2 to 6.4 for Nanozoomer and from 13.5 to 7.2 for ultra-fast scanner (UFS) by our color correction. The results of the evaluations for other areas and other stain methods (PAS, EVG, MT, and PAM) were good. In the future, high-accuracy color correction of teacher data/evaluation data in AI diagnosis using pathological images will be important.

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DNA repair factor KAT5 prevents ischemic acute kidney injury through glomerular filtration regulation

Hishikawa A, Hayashi K, Kubo A, Miyashita K, Hashiguchi A, Kinouchi K, Yoshimoto N, Nakamichi R, Akashio R, Sugita E, Azegami T, Monkawa T, Suematsu M, Itoh H

iScience (iScience) 24 ( 12 ) 103436 - 103436 2021.12

Research paper (scientific journal), Joint Work, Accepted, ISSN 2589-0042

The “preconditioning effect” in AKI is a phenomenon in which an episode of ischemia-reperfusion results in tolerance to subsequent ischemia-reperfusion injury. However, its relationship between DNA damage repair has not been elucidated. Here, we show the role of KAT5 in the preconditioning effect. Preconditioning attenuated DNA damage in proximal tubular cells with elevated KAT5 expression. Ischemia-reperfusion (IR) injuries were exacerbated, and preconditioning effect vanished in proximal tubular-cell-specific KAT5 knockout mice. Investigation of tubuloglomerular feedback (TGF) by MALDI-IMS and urinary adenosine revealed that preconditioning caused attenuated TGF at least in part via KAT5. In addition, K-Cl cotransporter 3 (KCC3) expression decreased in damaged proximal tubular cells, which may be involved in accelerated TGF following IR. Furthermore, KAT5 induced KCC3 expression by maintaining chromatin accessibility and binding to the KCC3 promoter. These results suggest a novel mechanism of the preconditioning effect mediated by the promotion of DNA repair and attenuation of TGF through KAT5.

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A Case of Fibronectin Glomerulopathy Confused with Glomerular Endothelial Injury in a Patient with Takotsubo Cardiomyopathy.

Azegami T, Hashiguchi A, Nakayama T, Hayashi K, Kanda T, Itoh H

Internal medicine (Tokyo, Japan) (Internal Medicine) 61 ( 13 ) 2027 - 2032 2021.12

Research paper (scientific journal), Joint Work, Accepted, ISSN 0918-2918

A 46-year-old woman developed takotsubo cardiomyopathy and nephrotic syndrome. The first kidney biopsy suggested non-immune-complex-mediated membranoproliferative glomerulonephritis (MPGN), and she was diagnosed with glomerular endothelial injury associated with takotsubo cardiomyopathy. A second biopsy was performed two years later because of persistent proteinuria despite renin-angiotensin system inhibition. This biopsy indicated non-immune-complex-mediated MPGN, but a mesangial and subendothelial substance of a higher electron density than that in the first biopsy was detected, suggesting the possibility of glomerular disease with non-immune deposits rather than endothelial injury. Finally, she was diagnosed with fibronectin nephropathy. Although rare, fibronectin glomerulopathy should be considered in non-immune-complex-mediated MPGN.

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Diabetic condition induces hypertrophy and vacuolization in glomerular parietal epithelial cells.

Takahisa Kawaguchi, Kazuhiro Hasegawa, Itaru Yasuda, Hirokazu Muraoka, Hiroyuki Umino, Hirobumi Tokuyama, Akinori Hashiguchi, Shu Wakino, Hiroshi Itoh

Scientific reports (Scientific Reports) 11 ( 1 ) 1515 - 1515 2021.12

Research paper (scientific journal), Joint Work, Accepted

Diabetic nephropathy (DN) is accompanied by characteristic changes in the glomerulus, but little is known about the effect of diabetes on parietal epithelial cells (PECs). In this study, a descriptive analysis of PECs was undertaken in diabetic db/db mice and in diabetic patients. PEC hypertrophy was significantly more prominent in diabetic mice than in nondiabetic mice, and this was evident even at the early stage. Additionally, the number of vacuoles in PECs was markedly increased in diabetic mice, suggesting the presence of cellular injury in PECs in DN. Although rare, binuclear cells were observed in mice with early diabetes. In cultured PECs, a high glucose condition, compared with normal glucose condition, induced cellular hypertrophy and apoptosis. Flow cytometry showed that some PECs in the G0 phase reentered the cell cycle but got arrested in the S phase. Finally, in human diabetic subjects, hypertrophy and vacuolization were observed in the PECs. Our data showed that PECs undergo substantial changes in DN and may participate in rearrangement for differentiation into podocytes.

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手術標本および生検標本のH&E染色組織画像を用いた畳み込みニューラルネットワークによる肝細胞癌の識別

高木弦, 山口雅浩, 阿部時也, 橋口明典, 坂元亨宇

日本医用画像工学会大会予稿集 ((一社)日本医用画像工学会) 40回 133 - 137 2021.10

Research paper (scientific journal), Joint Work, Accepted

本研究では,H&E染色病理標本のデジタルスライド画像に対して畳み込みニューラルネットワーク(CNN)による肝細胞癌と非癌の識別を行った.CNNとしてEfficientNetB3を採用し,高解像度の病理画像を分割して学習させ,その結果を統合する方法について検討するとともに,学習率などについて改善行い精度向上を図った.2048×2048画素の手術標本及び生検標本の画像それぞれ約1,000枚に対して5-foldの交差検証を行った結果,先行研究において特徴量ベースのSVMで約90%の精度であったデータに対して,正解率約97%と極めて高い精度を得ることかができた.このとき,生検標本と手術標本の両者の画像を合わせて教師データとした際に,高精度でロバストな識別器が作成できることが示された.さらに,生検標本と手術標本の両方を学習させた際に,CNNが両者に共通する特徴を抽出しているのかについても考察を行った.(著者抄録)

Fabry disease associated with multiple myeloma: a case report.

Keika Adachi, Hirobumi Tokuyama, Yoichi Oshima, Tomoaki Itoh, Akinori Hashiguchi, Hiroyuki Yamakawa, Tadayasu Togawa, Hitoshi Sakuraba, Shu Wakino, Hiroshi Itoh

CEN case reports (CEN case reports) 11 ( 1 ) 146 - 153 2021.09

Research paper (scientific journal), Joint Work, Accepted

Fabry disease (FD) is an X-linked genetic lysosomal disorder caused by alpha-galactosidase A (GLA) deficiency. Multiple myeloma (MM) predominately affects older adults, which ranks as the second commonest hematological malignancy. Their overlap has rarely been reported. We present a case of the coexistence of FD and MM in a patient. We report the case of a 68-year-old woman who was referred to our hospital for the evaluation of thoracic spine tumor with bone destruction. On admission, her serum creatinine (Cr) level was elevated to 12.70 mg/dL from the baseline value of 0.91 mg/dL. Bone marrow aspiration revealed MM. Renal biopsy showed myeloma cast nephropathy, which was the primary cause of acute kidney injury. Renal pathology also showed podocyte swelling and tubule myeloid bodies in a mosaic pattern compatible with female FD. Consequently, the patient was diagnosed as FD based on the germ line mutation in GLA. The patient was treated with bortezomib and dexamethasone therapy, which significantly improved the renal function. This is the second case demonstrating a potential pathogenic relationship between FD and MM. Since FD is one of the few genetic diseases for which there are therapeutic agents with fewer side effects, diagnostic value of FD is high. If an MM patient has multiple organ abnormalities or any familial history, the physician should suspect FD.

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