研究者詳細 - 橋口　明典

論文 - 橋口　明典

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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年03月

共著, 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年02月

共著

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年

共著, 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年12月

研究論文（学術雑誌）, 共著, 査読有り, 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年12月

研究論文（学術雑誌）, 共著, 査読有り, 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

Kawaguchi T., Hasegawa K., Yasuda I., Muraoka H., Umino H., Tokuyama H., Hashiguchi A., Wakino S., Itoh H.

Scientific Reports （Scientific Reports） 11 （ 1 ） 1515 - 1515 2021年12月

研究論文（学術雑誌）, 共著, 査読有り

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年10月

研究論文（学術雑誌）, 共著, 査読有り

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年09月

研究論文（学術雑誌）, 共著, 査読有り

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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Undifferentiated carcinoma of the mandible detected simultaneously with the liver: A case report

Asoda S., Morita M., Soma T., Sato H., Hasegawa T., Nakagawa T., Hashiguchi A., Kawana H.

Oral and Maxillofacial Surgery Cases （Oral and Maxillofacial Surgery Cases） 7 （ 3 ） 100228 - 100228 2021年09月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 2214-5419

We herein report a rare case of undifferentiated carcinoma that originated in the mandible with the same pathological findings as seen in the liver. A 64-year-old man underwent surgery for a hepatic tumor in October 2006, and the pathological diagnosis was undifferentiated carcinoma. The patient was referred to our department in January 2007, when whole-body positron emission tomography/computed tomography showed the uptake of fluorodeoxyglucose in the right mandibular ramus. The patient underwent right hemimandibulectomy in April 2007. The resected tumor was also undifferentiated carcinoma. In May 2014, seven years after the lower mandibular operation, the tumor recurred at the site corresponding to the right mandibular ramus after resection, and tumor resection and right neck dissection were performed. As a result of the histopathological examination, the undifferentiated carcinoma findings were the same as before. There have been no signs of local recurrence or metastases for over six years since the second mandibular surgery.

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MPGN様の病理像を呈したλ鎖単独陽性イムノタクトイド腎症の一例

杉田絵里那, 神田武志, 竜崎正毅, 橋口明典, 林香, 徳山博文, 脇野修, 伊藤裕

日本腎臓学会誌（(一社)日本腎臓学会） 63 （ 6-E ） 739 - 739 2021年09月

共著, ISSN 0385-2385

A girl with a mutation of the ciliary gene CC2D2A presenting with FSGS and nephronophthisis.

Awazu M, Yamada M, Asada N, Hashiguchi A, Kosaki K, Matsumura K

CEN case reports （CEN case reports） 11 （ 1 ） 116 - 119 2021年08月

研究論文（学術雑誌）, 共著, 査読有り

Mutations in the ciliary gene TTC21B, NPHP4, and CRB2 cause familial focal and segmental glomerulosclerosis (FSGS). We report a girl with a mutation of the ciliary gene CC2D2A presenting with FSGS and nephronophthisis. The patient had mental retardation, postaxial polydactyly, and ataxic breathing, and was diagnosed as having compound heterozygous CC2D2A missense mutations at age 5. Retrospectively, azotemia at 1 year and proteinuria at 5 years were recorded but not investigated. At age 6, she was referred to the pediatric nephrology service because of hypertension, pretibial pitting edema, heavy proteinuria, and hematuria. eGFR was 66 ml/min/1.73 m2, total protein 5.3 g/dl, albumin 2.4 g/dl, and cholesterol 317 mg/dl. Ultrasonography showed normal-sized kidneys with a cyst in the right. Losartan was started. On renal biopsy, 8 out of 24 glomeruli were globally sclerosed, and three showed segmental sclerosis and/or hyalinosis with no immune deposits. Mild tubular dilatation, tubular atrophy, and interstitial fibrosis were observed. On electron microscopy, glomeruli showed focal foot process effacement with no electron dense deposits. Since losartan did not exert an obvious effect, treatment with prednisolone was tried. Urine protein decreased from 6.6 to 3.7 g/gCr. Prednisolone was discontinued after 10 days, however, because she developed duodenal ulcer perforation that necessitated omentoplasty. Subsequently, she was treated with losartan only. Her renal function deteriorated and peritoneal dialysis was initiated 8 months later. FSGS in this patient could be primary glomerular associated with CC2D2A mutation, rather than the consequences of tubulointerstitial fibrosis.

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Grading of Multifocal Prostate Cancer Cases in which the Largest Volume and the Highest Grade Do Not Coincide within One Lesion

Matsumoto K., Omura M., Takeda T., Kosaka T., Hashiguchi A., Takamatsu K., Yasumizu Y., Tanaka N., Morita S., Mizuno R., Asanuma H., Oya M.

The Journal of urology （The Journal of urology） 206 （ 2 ） 338 - 345 2021年08月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0022-5347

PURPOSE: In general, the index lesion of prostate cancer has the largest tumor volume, the highest Grade Group (GG), and the highest stage (concordant cases). However, these factors sometimes do not coincide within one lesion (discordant cases). In such discordant cases, the largest tumor may not be of biological significance and the secondary tumor may more greatly impact the prognosis. MATERIALS AND METHODS: We retrospectively reviewed the medical records of patients who underwent radical prostatectomy, and we identified 580 (85.3%) concordant cases and 100 (14.7%) discordant cases. The end point of this study was biochemical recurrence, and median followup was 4.2 years. RESULTS: Among discordant cases in which GGs of the largest tumor and the highest GG tumor differed, the majority (67 patients) had the largest tumor of GG 2, and we set them as the study cohort. On the other hand, we regarded 212 concordant cases with an index tumor of GG 2 as the control cohort. The study cohort comprised 48 (71.6%) patients with a secondary tumor of GG 3 and 19 (28.4%) with a secondary tumor of GG 4/5. Kaplan-Meier curves revealed that the 5-year biochemical recurrence-free survival rates were 76%, and 67%, respectively. The 5-year biochemical recurrence-free survival rate of the control cohort was 91%, which was significantly better than that of the study cohort (p=0.013 and p=0.014, respectively). CONCLUSIONS: Our study suggests that the prognosis of discordant cases is better determined by the secondary cancer lesion with the highest GG instead of the largest lesion.

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Development of nephropathy in an adult patient after Fontan palliation for cyanotic congenital heart disease

Hayashi K., Hashiguchi A., Ikemiyagi M., Tokuyama H., Wakino S., Itoh H.

CEN case reports （CEN case reports） 10 （ 3 ） 354 - 358 2021年08月

研究論文（学術雑誌）, 共著, 査読有り

Cyanotic congenital heart disease is occasionally associated with kidney dysfunction, which is known as cyanotic nephropathy or cyanotic glomerulopathy. The clinical presentation of cyanotic nephropathy includes proteinuria, decreased estimated glomerular filtration rate, hyperuricemia, thrombocytopenia, or polycythemia. Although advances in surgical procedures have improved the prognosis of cyanotic congenital heart diseases, adult cases of cyanotic nephropathy are still rare, and there are few reports of kidney biopsy in adults with cyanotic nephropathy. Here, we present the case of a 41-year-old patient with Fontan palliation who developed nephrotic range proteinuria and had a kidney biopsy, which showed glomerular hypertrophy with segmental glomerulosclerosis around vascular poles, suggesting adaptive focal segmental glomerulosclerosis. This case provides further understanding of kidney dysfunction due to cyanotic congenital heart disease and shows the need for attention in the management for prevention of progression to end-stage renal disease and in the selection of renal replacement therapy.

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C3腎症を基準とした一次性MPGNの再分類:電顕PAMを用いたType 3 Anders-Strife型の鑑別のもとに

本間志功, 佐藤直実, 橋口明典, 上杉憲子, 中村保宏, 城謙輔

日本腎臓学会誌（(一社)日本腎臓学会） 63 （ 4 ） 436 - 436 2021年06月

共著, ISSN 0385-2385

DNA修復因子KAT5を介した尿細管糸球体フィードバック制御

菱川彰人, 林香, 久保亜紀子, 宮下和季, 橋口明典, 吉本憲史, 中道蘭, 杉田絵里那, 赤塩理起, 門川俊明, 末松誠, 伊藤裕

日本腎臓学会誌（(一社)日本腎臓学会） 63 （ 4 ） 488 - 488 2021年06月

共著, ISSN 0385-2385

Malignancy-associated membranous nephropathy with PLA2R double-positive for glomeruli and carcinoma

Yasuda I., Tokuyama H., Hashiguchi A., Hasegawa K., Uchiyama K., Ryuzaki M., Yasuda M., Mizuno R., Ishidoya S., Wakino S., Itoh H.

CEN case reports （CEN case reports） 10 （ 2 ） 281 - 286 2021年05月

研究論文（学術雑誌）, 共著, 査読有り

Phospholipase A2 receptor (PLA2R) is the most common primary target antigen of idiopathic membranous nephropathy (MN) although PLA2R antibodies are also reported to be present in malignancy-associated MN. However, a case of PLA2R-positive MN secondary to PLA2R-positive carcinoma has not been reported. A 26-year-old Japanese woman presented with general fatigue, fever, and nonproductive cough. Computed tomography demonstrated a left kidney mass with pathologic diagnosis of Xp11.2 translocation renal cell carcinoma (RCC). After the second time of administration with Sunitinib, the patients exhibited significant proteinuria and hypoalbuminemia. Renal biopsy revealed a diagnosis of diffuse MN secondary to RCC. Immunofluorescence staining showed granular patterns positive for immunoglobulin (Ig) G, IgA, and C3c. PLA2R and IgG1-3 were positive, while IgG4 was negative. For the treatment of severe nephrotic syndrome, we attempted steroid therapy without any clinical improvement. Open nephrectomy was performed and surprisingly, RCC was stained for PLA2R with polarity for the basal side. At outpatient follow-up, 4 months after the operation, urinary protein had still persisted, although serum albumin was slightly increased. We report a case of PLA2R-positive MN secondary to PLA2R-positive RCC.

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デジタル画像解析を用いたIgA腎症糸球体病変定量化

橋口明典, 石川雅浩, 城謙輔, 坂本直樹, 山内暁, 大塚武, 福西宗憲, 清水章, 片渕律子, 川村哲也

日本病理学会会誌（(一社)日本病理学会） 110 （ 1 ） 327 - 327 2021年03月

共著, ISSN 0300-9181

A cross-sectional study in patients with IgA nephropathy of correlations between clinical data and pathological findings at the time of renal biopsy: a Japanese prospective cohort study

Kamano C., Shimizu A., Joh K., Hashiguchi A., Hisano S., Katafuchi R., Kawamura T.

Clinical and Experimental Nephrology （Clinical and Experimental Nephrology） 25 （ 5 ） 509 - 521 2021年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 13421751

Background: The correlations between clinical data and pathological findings at the time of renal biopsy were investigated in IgA nephropathy patients. Methods: 771 patients diagnosed with IgA nephropathy by renal biopsy were enrolled. The correlations between clinical variables including eGFR, daily proteinuria, mean arterial pressure (MAP), serum uric acid (UA) values, and pathological parameters were examined. These patients were further divided into three groups: children (< 19 years old), young adults (19–60 years), and elderly patients (> 60 years). Results: Daily proteinuria was moderately correlated with all pathological parameters (Rs = 0.23–0.49). The mesangial score, the percentage of glomeruli that contained endocapillary hypercellularity, cellular/fibrocellular crescents or tuft necrosis, and segmental glomerulosclerosis (GS) affected daily proteinuria most on multiple linear regression analysis (MLRA). eGFR, MAP, and serum UA levels were mainly correlated with the degree of GS and interstitial lesions. In children, the degree of cellular/fibrocellular crescents or tuft necrosis was correlated with not only daily proteinuria, but also decreased eGFR (Rs = 0.51, − 0.24). Endocapillary hypercellularity was the only independent variable related to daily proteinuria on MLRA. Conclusion: In all age cohorts of IgA nephropathy patients, daily proteinuria was correlated with all histological parameters, including both acute and chronic glomerular lesions, and the mesangial score. Independent variables for daily proteinuria were the meangial score, acute histological lesions, and segmental GS on MLRA, whereas the remaining independent variable in the pediatric group was endocapillary hypercellurality. The clinical pathological correlation at the time of biopsy varied depending on the age group.

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Glomerulonephritis caused by bartonella spp. infective endocarditis: The difficulty and importance of differentiation from anti-neutrophil cytoplasmic antibody-related rapidly progressive glomerulonephritis

Yoshifuji A., Hibino Y., Komatsu M., Yasuda S., Hosoya K., Kobayashi E., Baba Y., Hirose S., Hashiguchi A., Kanno Y., Ryuzaki M.

Internal Medicine （Internal Medicine） 60 （ 12 ） 1899 - 1906 2021年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 09182918

A 65-year-old man with valvular disorder presented to his physician because of widespread purpura in both lower extremities. Blood tests showed elevated serum creatinine levels and proteinase 3-anti-neutrophil cytoplasmic antibody (ANCA) with hematuria, suggesting ANCA-related rapidly progressive glomerulonephritis (RPGN). Although multiple blood cultures were negative, transthoracic echocardiography revealed warts in the valves, and a renal biopsy also showed findings of glomerular infiltration by mononuclear leukocytes and C3 deposition in the glomeruli, suggesting infection-related glomerulonephritis. Later, Bartonella antibody turned positive. Antimicrobial treatment improved the purpura and renal function without any recurrence. ANCA-positive RPGN requires the exclusion of infective endocarditis, especially that induced by Bartonella spp.

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Association of glomerular DNA damage and DNA methylation with one-year eGFR decline in IgA nephropathy

Hayashi K., Hishikawa A., Hashiguchi A., Azegami T., Yoshimoto N., Nakamichi R., Tokuyama H., Itoh H.

Scientific Reports （Scientific Reports） 10 （ 1 ） 237 - 237 2020年12月

研究論文（学術雑誌）, 共著, 査読有り

© 2020, The Author(s). Accumulation of DNA double-strand breaks (DSBs) is linked to aging and age-related diseases. We recently reported the possible association of DNA DSBs with altered DNA methylation in murine models of kidney disease. However, DSBs and DNA methylation in human kidneys was not adequately investigated. This study was a cross-sectional observational study to evaluate the glomerular DNA DSB marker γH2AX and phosphorylated Ataxia Telangiectasia Mutated (pATM), and the DNA methylation marker 5-methyl cytosine (5mC) by immunostaining, and investigated the association with pathological features and clinical parameters in 29 patients with IgA nephropathy. To evaluate podocyte DSBs, quantitative long-distance PCR of the nephrin gene using laser-microdissected glomerular samples and immunofluorescent double-staining with WT1 and γH2AX were performed. Glomerular γH2AX level was associated with glomerular DNA methylation level in IgA nephropathy. Podocytopathic features were associated with increased number of WT1(+)γH2AX(+) cells and reduced amount of PCR product of the nephrin gene, which indicate podocyte DNA DSBs. Glomerular γH2AX and 5mC levels were significantly associated with the slope of eGFR decline over one year in IgA nephropathy patients using multiple regression analysis adjusted for age, baseline eGFR, amount of proteinuria at biopsy and immunosuppressive therapy after biopsy. Glomerular γH2AX level was associated with DNA methylation level, both of which may be a good predictor of renal outcome in IgA nephropathy.

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