論文 - 橋口　明典

Polyclonal immunoglobulin G deposits with distinctive appearance in the tubular basement membrane: a report of two cases

Sakamaki Y., Hashiguchi A., Konishi K., Araki T., Tokuyama H.

BMC Nephrology 26 （ 1 ） 591 2025年12月

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Background: Tubulointerstitial diseases arise from various etiologies, including infections, medications, autoimmune conditions, and systemic disorders. The histological presentation of the tubulointerstitium in renal biopsies can vary considerably. When tubulointerstitial alterations are identified through light microscopy, additional evaluation with immunofluorescence and electron microscopy may assist in diagnosis. This report describes two slowly progressive atypical cases of tubulointerstitial disease. Renal biopsy in both cases revealed tubular atrophy and interstitial fibrosis with limited inflammatory cell infiltration, along with polyclonal linear immunoglobulin G (IgG) staining pattern along the thickened tubular basement membrane (TBM) and distinctive electron-dense deposits. Case 1: Case presentation: A 65-year-old Japanese man with a history of chronic obstructive pulmonary disease, benign prostatic hyperplasia, and hypertension presented with anorexia and malaise 1 week prior to admission. Blood tests demonstrated marked renal impairment. Renal biopsy findings included relatively preserved glomeruli, widespread tubular atrophy, and significant interstitial fibrosis. Immunofluorescence showed linear deposition of IgG as well as kappa and lambda light chains along the TBM. Complement components C3 was also positive, and C1q were weakly positive. IgG subclass staining revealed positivity for IgG1, IgG2, and IgG4. Electron microscopy revealed electron-dense deposits within the TBM and on the epithelial side of the TBM, exhibiting a mottled and speckled appearance. Case 2: A 52-year-old Japanese man who had undergone allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia developed mild proteinuria and renal dysfunction 7 years after transplant. Renal biopsy indicated thrombotic microangiopathy, with glomeruli showing diffuse mesangial expansion and focal mesangiolysis. There was also diffuse TBM thickening and interstitial fibrosis with scattered cellular infiltration. Immunofluorescence demonstrated linear staining of polyclonal IgG and both light chains along the TBM. C3 was also positive while C1q was negative. IgG subclass staining revealed positivity for IgG1 and IgG4. Electron microscopy again identified electron-dense deposits within the reticulated TBM. Conclusions: These two cases demonstrated linear IgG immunofluorescence and distinctive electron-dense deposits in the TBM characterized by a mottled and speckled pattern. Although the underlying pathophysiological mechanisms remain unclear, further research is necessary to elucidate the nature of this form of tubulointerstitial disease.

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DNA damage in proximal tubules triggers systemic metabolic dysfunction through epigenetically altered macrophages

Nishimura E.S., Hishikawa A., Nakamichi R., Akashio R., Chikuma S., Hashiguchi A., Yoshimoto N., Hama E.Y., Maruki T., Itoh W., Yamaguchi S., Yoshino J., Itoh H., Hayashi K.

Nature Communications 16 （ 1 ） 3958 2025年12月

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DNA damage repair is a critical physiological process closely linked to aging. The accumulation of DNA damage in renal proximal tubular epithelial cells (PTEC) is related to a decline in kidney function. Here, we report that DNA double-strand breaks in PTECs lead to systemic metabolic dysfunction, including weight loss, reduced fat mass, impaired glucose tolerance with mitochondrial dysfunction, and increased inflammation in adipose tissues and the liver. Single-cell RNA sequencing analysis reveals expansion of CD11c+ Ccr2+ macrophages in the kidney cortex, liver, and adipose tissues and Ly6C^hi monocytes in peripheral blood. DNA damage in PTECs is associated with hypomethylation of macrophage activation genes, including Gasdermin D, in peripheral blood cells, which is linked to reduced DNA methylation at KLF9-binding motifs. Macrophage depletion ameliorates metabolic abnormalities. These findings highlight the impact of kidney DNA damage on systemic metabolic homeostasis, revealing a kidney-blood-metabolism axis mediated by epigenetic changes in macrophages.

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Human chorionic gonadotropin-positive cystic duct carcinoma with trophoblastic differentiation that exhibited an aggressive clinical course.

Takemura Y, Matsuda K, Abe Y, Hashiguchi A, Kitago M, Nakano Y, Sonoda K, Kitagawa Y

BMJ case reports 18 （ 11 ）  2025年11月

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Quantification-based explainable artificial intelligence for deep learning decisions: clustering and visualization of quantitative morphometric features in hepatocellular carcinoma discrimination.

Takagi G, Takeyama S, Abe T, Hashiguchi A, Sakamoto M, Suzuki K, Yamaguchi M

Journal of medical imaging (Bellingham, Wash.) 12 （ 6 ） 061407 2025年11月

共著,  ISSN  2329-4302

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Purpose: Deep learning (DL) is rapidly advancing in computational pathology, offering high diagnostic accuracy but often functioning as a “black box” with limited interpretability. This lack of transparency hinders its clinical adoption, emphasizing the need for quantitative explainable artificial intelligence (QXAI) methods. We propose a QXAI approach to objectively and quantitatively elucidate the reasoning behind DL model decisions in hepatocellular carcinoma (HCC) pathological image analysis. Approach: The proposed method utilizes clustering in the latent space of embeddings generated by a DL model to identify regions that contribute to the model’s discrimination. Each cluster is then quantitatively characterized by morphometric features obtained through nuclear segmentation using HoverNet and key feature selection with LightGBM. Statistical analysis is performed to assess the importance of selected features, ensuring an interpretable relationship between morphological characteristics and classification outcomes. This approach enables the quantitative interpretation of which regions and features are critical for the model’s decision-making, without sacrificing accuracy. Results: Experiments on pathology images of hematoxylin-and-eosin-stained HCC tissue sections showed that the proposed method effectively identified key discriminatory regions and features, such as nuclear size, chromatin density, and shape irregularity. The clustering-based analysis provided structured insights into morphological patterns influencing classification, with explanations evaluated as clinically relevant and interpretable by a pathologist. Conclusions: Our QXAI framework enhances the interpretability of DL-based pathology analysis by linking morphological features to classification decisions. This fosters trust in DL models and facilitates their clinical integration.

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Association Between Urinary Fractional Excretion of Potassium and Proteinuria Remission in Adult Nephrotic Syndrome.

Yoshida R, Nakayama T, Mitsuno R, Komatsu M, Oshima Y, Iwabuchi S, Itoh T, Matsumoto D, Kusahana E, Hoshi K, Nakamura K, Fujii K, Hara Y, Kawaguchi T, Futatsugi K, Yamaji Y, Tokuyama H, Murakami M, Takimoto C, Matsuda H, Ando T, Hashiguchi A, Kaneko Y, Azegami T, Hayashi K

Kidney360 2025年10月

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Tubulointerstitial nephritis with predominant monotypic plasma cell infiltration in three cases of Sjögren's syndrome: case reports and literature review

Miyauchi H., Azegami T., Hashiguchi A., Misaki M., Kawaguchi T., Hanaoka H., Muramatsu M., Soga T., Ando T., Kubota E., Nakayama T., Yoshimoto N., Hishikawa A., Hagiwara A., Kaneko Y., Hayashi K.

Cen Case Reports 14 （ 5 ） 774 - 780 2025年10月

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Tubulointerstitial nephritis (TIN) is a common kidney manifestation of Sjögren's syndrome, typically characterized by interstitial infiltration of T and B cells, with plasma cells being more prominent than in other etiologies. While most plasma cell infiltration in TIN is polytypic and the importance of the immunoglobulin isotypes expressed by the infiltrating plasma cells in the pathogenesis is unknown, recent reports have identified rare cases with monotypic IgA-positive plasma cell infiltration accompanied by monoclonal gammopathy of undetermined significance (MGUS). Here, we present three cases of Sjögren syndrome-associated TIN characterized by monotypic plasma cell infiltration. In all cases, the isotype of the infiltrating plasma cells was consistent with that of the predominant serum immunoglobulin. One patient exhibited IgA-type MGUS, one had IgM-type MGUS, and one showed elevated serum IgG levels along with IgG-positive plasma cell infiltration, but without detectable paraproteinemia. Notably, serum immunoglobulin levels decreased in parallel with improvement in kidney function. These findings suggest a potential link between the systemic immunoglobulin profile and local immunopathology of the kidneys in Sjögren's syndrome. Further case accumulation is needed to clarify the clinical significance and pathophysiology of monotypic plasma cell infiltration in TIN associated with Sjögren's syndrome.

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Phenotype-dependent heterogeneity of THSD7A expression in gastric cancer tissue in a patient with THSD7A-associated membranous nephropathy

Minezaki C., Azegami T., Hashiguchi A., Nakayama T., Yoshimoto N., Hishikawa A., Hagiwara A., Hayashi K.

Cen Case Reports 14 （ 5 ） 693 - 699 2025年10月

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An 88-year-old Japanese man with benign prostatic hyperplasia was presented to our hospital because of proteinuria and generalized edema. He was diagnosed with nephrotic syndrome and underwent a kidney biopsy, which revealed thickening of the capillary wall, spike formation, and subepithelial deposits, leading to histopathological diagnosis of membranous nephropathy. IgG4-dominant deposits were observed in IgG subclass staining, and immunostaining for thrombospondin type 1 domain-containing 7A (THSD7A) demonstrated granular staining along the capillary wall. A malignancy screening was performed, which led to the detection of gastric cancer. Malignancy-associated membranous nephropathy secondary to gastric cancer was suspected, and priority was given to the treatment of gastric cancer. Three months after undergoing radical surgery for gastric cancer, his nephrotic syndrome achieved remission. The histopathological diagnosis of gastric cancer was papillary adenocarcinoma. In the surgical specimen of the gastric cancer, THSD7A was positive in the tumor cells with intestinal phenotype and negative in gastric foveolar phenotype. These findings suggest that the acquisition of the ability to express THSD7A by cancer transformation in multi-step carcinogenesis of gastric cancer may be involved in the development of malignancy-associated membranous nephropathy.

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関節リウマチに対してアダリムマブ使用中にMPO-ANCA陽性を呈したIgA腎症の1例

中村 共生, 千種 尚紀, 中山 尭振, 吉本 憲史, 菱川 彰人, 萩原 あいか, 橋口 明典, 畔上 達彦, 林 香

日本腎臓学会誌 （(一社)日本腎臓学会）  67 （ 6-E ） 823 - 823 2025年09月

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骨髄異形成/骨髄増殖性腫瘍(MDS/MPN)に併発したリゾチーム腎症の一例

貫井 紀宏, 日鼻 瑛, 畔上 達彦, 橋口 明典, 徳山 博文

日本腎臓学会誌 （(一社)日本腎臓学会）  67 （ 6-E ） 796 - 796 2025年09月

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著明な肉芽腫性間質性腎炎を認めた腎サルコイドーシスの一例

渡邉 一生, 大島 洋一, 中山 尭振, 加藤 亜唯, 橋口 明典, 小松 素明

日本腎臓学会誌 （(一社)日本腎臓学会）  67 （ 6-E ） 866 - 866 2025年09月

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抗GBM抗体型腎炎に膜性腎症が合併した一例

堤 遼太郎, 川口 隆久, 山内 遥, 橋口 明典, 安藤 孝

日本腎臓学会誌 （(一社)日本腎臓学会）  67 （ 6-E ） 822 - 822 2025年09月

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家族性地中海熱にIgA腎症を合併した2症例

貫井 紀宏, 畔上 達彦, 中山 尭振, 吉本 憲史, 菱川 彰人, 萩原 あいか, 橋口 明典, 林 香

日本腎臓学会誌 （(一社)日本腎臓学会）  67 （ 6-E ） 813 - 813 2025年09月

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前立腺癌を伴う膜性腎症においてPLA2R・THSD7Aが共陽性となった一例

藤岡 怜史, 日鼻 瑛, 徳山 博文, 橋口 明典, 環 聡, 中川 健

日本腎臓学会誌 （(一社)日本腎臓学会）  67 （ 6-E ） 861 - 861 2025年09月

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初診時に高度腎機能障害と多発転移性腫瘍を呈し,病理解剖に至った1例

中村 共生, 中山 尭振, 吉本 憲史, 菱川 彰人, 萩原 あいか, 大坪 進矢, 村本 玄紀, 橋口 明典, 畔上 達彦, 林 香

日本腎臓学会誌 （(一社)日本腎臓学会）  67 （ 6-E ） 814 - 814 2025年09月

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免疫蛍光抗体法の結果から最終診断に至った抗ネフリン抗体陽性難治性MCDの一例

船木 裕規, 大島 洋一, 白井 陽子, 橋口 明典, 圓谷 泰章, 加藤 亜唯, 三浦 健一郎, 服部 元史, 小松 素明

日本腎臓学会誌 （(一社)日本腎臓学会）  67 （ 6-E ） 859 - 859 2025年09月

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人工血管感染の治療中に腎機能障害と検尿異常を認めた一例

熊谷 聡佑, 伊藤 亘, 中山 尭振, 吉本 憲史, 菱川 彰人, 萩原 あいか, 畔上 達彦, 橋口 明典, 林 香

日本腎臓学会誌 （(一社)日本腎臓学会）  67 （ 6-E ） 791 - 791 2025年09月

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ペンブロリズマブ投与後に腎機能障害が進行し,半月体形成を伴うIgA優位沈着型の糸球体腎炎を認めた症例

中山 生成, 川口 隆久, 橋口 明典, 堤 遼太郎, 山内 遥, 大原 弘喜, 安藤 孝

日本腎臓学会誌 （(一社)日本腎臓学会）  67 （ 6-E ） 794 - 794 2025年09月

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ベバシズマブとドキソルビシンを投与後に二峰性の腎障害を呈した1例

千種 尚紀, 中山 尭辰, 吉本 憲史, 菱川 彰人, 萩原 あいか, 橋口 明典, 畔上 逹彦, 林 香

日本腎臓学会誌 （(一社)日本腎臓学会）  67 （ 6-E ） 844 - 844 2025年09月

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サルコイドーシスによる非典型的腎障害としてリゾチーム関連腎症を認めた1例

中村 共生, 安井 雅晴, 中山 尭振, 吉本 憲史, 菱川 彰人, 萩原 あいか, 橋口 明典, 畔上 達彦, 林 香

日本腎臓学会誌 （(一社)日本腎臓学会）  67 （ 6-E ） 797 - 797 2025年09月

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IgM優勢の粗大な沈着物を伴う糸球体傷害を認めたネフローゼ症候群に対しプレドニゾロンを導入した1例

小野田 怜依, 星 健太, 熊谷 光祐, 佐藤 芳紀, 杉浦 康平, 橋口 明典, 村上 円人

日本腎臓学会誌 （(一社)日本腎臓学会）  67 （ 6-E ） 801 - 801 2025年09月

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