研究者詳細 - 橋口　明典

論文 - 橋口　明典

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Urinary Biomarkers Associated With Pathogenic Pathways Reflecting Histologic Findings in Lupus Nephritis

Hiramoto K., Saito S., Hanaoka H., Kikuchi J., Fukui H., Hashiguchi A., Suzuki K., Takeuchi T., Kaneko Y.

Arthritis and Rheumatology 77 （ 3 ） 298 - 310 2025年03月

共著, ISSN 23265191

Objective: There is a pressing need to understand the pathogenesis of histologic findings and identify the biomarkers for predicting the histologic severity in lupus nephritis (LN). This study aimed to identify the pathogenic signal pathway and elucidate urinary biomarkers for predicting the presence or severity of histologic findings in LN. Methods: Urine samples from patients with biopsy-proven active LN were screened for 1,305 proteins using an aptamer-based proteomic assay. The diversity and expansion of individual renal histologic features in LN were quantified to identify the urinary proteins associated with the histologic findings found in each score. Candidate urinary proteins were validated in a validation cohort. Immunohistochemical staining of the renal tissues was performed to clarify the localization of the candidate proteins. Results: Cluster analysis extracted five histologic subgroups according to their correlations with each histologic finding in LN. Protein groups that correlated with each histologic subgroup revealed a distinct pathogenesis in LN using pathway analyses. Enzyme-linked immunosorbent assay validation revealed that urinary calgranulin B (S100A9), monocyte chemotactic protein 1 (MCP-1), and insulin-like growth factor binding protein 5 (IGFBP-5) levels could specifically predict the presence and severity of active glomerular lesions, interstitial inflammation, and interstitial fibrosis, respectively. Immunohistochemical staining revealed the localization of these proteins in each lesion. Conclusion: Renal histologic findings may reflect the different pathogeneses involved in each lesion, and estimating the urinary calgranulin B, MCP-1, and IGFBP-5 levels may be useful in predicting the presence and severity of histologic findings in LN.

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A Case of Membranous Nephropathy Associated with Syphilis: Correlative Light and Electron Microscopy Revealing the Localization of Neuron-derived Neurotrophic Factor within Subepithelial Electron Dense Deposits.

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

Internal medicine (Tokyo, Japan) 2024年12月

共著, ISSN 0918-2918

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The proteinuria selectivity index value predicts the remission of IgA nephropathy: a retrospective cohort study.

Mitsuno R, Nakayama T, Ito W, Maruki T, Nakamichi R, Adachi K, Yoshimoto N, Hishikawa A, Hagiwara A, Yamaguchi S, Monkawa T, Yoshino J, Hashiguchi A, Azegami T, Hayashi K

Renal failure 46 （ 2 ） 2423839 2024年12月

共著, ISSN 0886-022X

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Clinical relevance of proteinuria selectivity index and fractional excretion of sodium in patients with nephrotic syndrome.

Nakayama T, Azegami T, Yamaguchi S, Hirano K, Komatsu M, Fujii K, Futatsugi K, Urai H, Kawaguchi T, Itoh T, Yoshimoto N, Hagiwara A, Hishikawa A, Matsuda H, Ando T, Yamaji Y, Murakami M, Hashiguchi A, Kaneko Y, Yokoo T, Hayashi K

Scientific reports 14 （ 1 ） 23755 2024年10月

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Primary breast lymphoma mimicking triple-negative breast cancer: a case report with clinical and pathological implications.

Sawano T, Wada M, Ozaki A, Hashiguchi A, Hirooka S, Tanimoto T

Surgical case reports 10 （ 1 ） 234 2024年10月

共著, ISSN 2198-7793

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機能性表示食品「紅麹コレステヘルプ」およびNSAIDs服用中に発症した完全型Fanconi症候群を伴う急性腎障害の1例

星健太, 村上円人, 佐藤芳紀, 杉浦康平, 船木裕規, 橋口明典

日本腎臓学会誌（(一社)日本腎臓学会） 66 （ 7 ） 1207 - 1214 2024年10月

共著, ISSN 0385-2385

薬剤性腎障害の原因は多岐にわたるが,漢方薬やサプリメントなど医薬品以外の物質の関与も多く,病歴を漏れなく聴取することが重要である。近年,機能性表示食品「紅麹コレステヘルプ」(小林製薬,大阪,日本)による健康被害の報告が多数のぼり,腎機能障害や尿所見異常などを呈し,一部の症例では末期腎不全に至るなどの臨床像が報告されているが,原因物質は未詳である。今回われわれは,以前より軽度の推算糸球体濾過量(estimated glomerular filtration rate:eGFR)低下を指摘されていたところへ同サプリメントを3年間内服継続し,発症2ヵ月前から非ステロイド性抗炎症薬(non-steroidal anti-inflammatory drugs:NSAIDs)を使用していたところに発症した急性腎障害(acute kidney injury:AKI),後天性完全型Fanconi症候群を伴った急性尿細管障害(acute tubular injury:ATI)の1例を経験した。初診時には尿中β2ミクログロブリン(β2 microglobulin:β2MG)および好中球ゼラチナーゼ結合リポカリン(neutrophil gelatinase-associated lipocalin:NGAL)の上昇と,汎アミノ酸尿,尿糖陽性,高カルシウム尿症,高リン尿症,高尿酸尿症,II型尿細管性アシドーシスといった近位尿細管機能異常を認め,Fanconi症候群を呈したATIによるAKIと考えられた。腎生検組織所見では尿細管上皮の傷害像はみられたが,炎症性細胞浸潤は乏しかった。足突起消失(foot process effacement)は部分的であった。ステロイドを含めた免疫抑制治療は行わず保存的治療のみで腎機能障害やFanconi症候群は軽快し,現在経過観察中である。全国的に使用されているサプリメントであり,原因物質の究明が待たれるが,同サプリメントにより惹起される腎機能障害や蛋白尿などの尿所見異常の病態を中心に,文献的考察を踏まえて報告する。(著者抄録)

False-positive Serum Antiglomerular Basement Membrane Antibody due to Bovine Serum Albumin-containing Surgical Adhesive: A Case Report.

Yoshida R, Azegami T, Yamaguchi S, Hagiwara A, Hishikawa A, Yoshimoto N, Hashiguchi A, Hayashi K

Kidney medicine 6 （ 10 ） 100880 2024年10月

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Effective calcineurin inhibitor treatment in adult-onset steroid-resistant nephrotic syndrome with a novel splice donor site variant of TRPC6: a case report.

Nagasaka T, Uchiyama K, Hama EY, Kojima D, Kaneko K, Yoshimoto N, Yasuda I, Yamada M, Miya F, Suzuki H, Tajima T, Yamaguchi S, Hayashi K, Kanda T, Hashiguchi A, Kosaki K, Itoh H

CEN case reports 2024年09月

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Complement Receptor 1 Enhancement in Recurrent Membranous Nephropathy Following Kidney Transplantation: A Case Report.

Kounoue N, Oguchi H, Hashiguchi A, Honda K, Kang D, Mikami T, Tochigi N, Kawamura T, Itabashi Y, Yonekura T, Sakurabayashi K, Sakai K

Kidney medicine 6 （ 9 ） 100876 2024年09月

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多発病変の中の小さな最高grade病変は,MRIで検出できるのか

松本一宏, 秋田大宇, 橋口明典, 武田利和, 小坂威雄, 福本桂資郎, 安水洋太, 田中伸之, 森田伸也, 水野隆一, 浅沼宏, 大家基嗣, 陣崎雅弘

泌尿器外科（医学図書出版(株)） 37 （ 8 ） 942 - 944 2024年08月

共著, ISSN 0914-6180

Intestinal epithelium dysfunctions cause IgA deposition in the kidney glomeruli of intestine-specific Ap1m2-deficient mice

Kinashi Y., Tanaka K., Kimura S., Hirota M., Komiyama S., Shindo T., Hashiguchi A., Takahashi D., Shibata S., Karaki S.I., Ohno H., Hase K.

eBioMedicine 106 105256 2024年08月

共著

Background: Intestinal epithelial cells (IECs) serve as robust barriers against potentially hostile luminal antigens and commensal microbiota. Epithelial barrier dysfunction enhances intestinal permeability, leading to leaky gut syndrome (LGS) associated with autoimmune and chronic inflammatory disorders. However, a causal relationship between LGS and systemic disorders remains unclear. Ap1m2 encodes clathrin adaptor protein complex 1 subunit mu 2, which facilitates polarized protein trafficking toward the basolateral membrane and contributes to the establishment of epithelial barrier functions. Methods: We generated IEC-specific Ap1m2-deficient (Ap1m2ΔIEC) mice with low intestinal barrier integrity as an LSG model and examined the systemic impact. Findings: Ap1m2ΔIEC mice spontaneously developed IgA nephropathy (IgAN)-like features characterized by the deposition of IgA–IgG immune complexes and complement factors in the kidney glomeruli. Ap1m2 deficiency markedly enhanced aberrantly glycosylated IgA in the serum owing to downregulation and mis-sorting of polymeric immunoglobulin receptors in IECs. Furthermore, Ap1m2 deficiency caused intestinal dysbiosis by attenuating IL-22-STAT3 signaling. Intestinal dysbiosis contributed to the pathogenesis of IgAN because antibiotic treatment reduced aberrantly glycosylated IgA production and renal IgA deposition in Ap1m2ΔIEC mice. Interpretation: IEC barrier dysfunction and subsequent dysbiosis by AP-1B deficiency provoke IgA deposition in the mouse kidney. Our findings provide experimental evidence of a pathological link between LGS and IgAN. Funding: AMED, AMED-CREST, JSPS Grants-in-Aid for Scientific Research, JST CREST, Fuji Foundation for Protein Research, and Keio University Program for the Advancement of Next Generation Research Projects.

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Detection of the Highest-Grade Lesion in Multifocal Discordant Prostate Cancer by Multiparametric Magnetic Resonance Imaging

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

Clinical Genitourinary Cancer （Clinical Genitourinary Cancer） 22 （ 3 ） 102084 - 102084 2024年06月

共著, ISSN 15587673

Purpose: Prostate cancer generally occurs multifocally. The lesions of the largest size and highest-grade are often concordant, and defined as an index tumor. However, these factors sometimes do not coincide within one lesion. In such discordant cases, not the largest size lesion but the highest-grade lesion is known to determine the prognosis. We focused on the multiparametric magnetic resonance imaging (mpMRI) detectability of the highest-grade tumors in discordant cases. Materials and Methods: We investigated the detectability of the highest-grade tumor using preoperative mpMRI in 50 discordant patients who underwent radical prostatectomy. The radiologist was informed of the tumor location on the pathological tumor map, and mpMRI interpretation for each tumor was performed. Results: Prostate Imaging-Reporting and Data System (PI-RADS) scores of 1, 2, 3, 4, and 5 on preoperative mpMRI were assigned to 13, 1, 9, 16, and 11 of the largest tumors, respectively. On the other hand, scores of 1, 2, 3, 4, and 5 were assigned to 23, 0, 7, 19, and 1 of the highest-grade tumors, respectively. The difference between them was statistically significant (p=0.007). We also found that the largest anterior tumor frequently hid the ipsilateral posterior highest-grade tumor; the detection rate of the highest-grade tumor in this pattern was 42.1% (8 of 19 cases) Conclusion: We found that mpMRI detectability of the highest-grade tumor in discordant cases was inferior to that of the largest tumor with low malignant potential. Our results suggest that the risk of high-grade tumors which determine patient prognosis being overlooked.

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慢性腎臓病患者における腎洞脂肪量と腎血行動態の関連の検証

金子賢司, 満野竜之介, 児島大輝, 畔上達彦, 小杉将太郎, 中村俊文, 橋口明典, 山田祥岳, 陣崎雅弘, 山口慎太郎, 伊藤裕, 吉野純, 林香

日本腎臓学会誌（(一社)日本腎臓学会） 66 （ 4 ） 586 - 586 2024年06月

共著, ISSN 0385-2385

Establishment of artificial intelligence model for precise histological subtyping of lung adenocarcinoma and its application to quantitative and spatial analysis.

Miura E, Emoto K, Abe T, Hashiguchi A, Hishida T, Asakura K, Sakamoto M

Japanese journal of clinical oncology 54 （ 9 ） 1009 - 1023 2024年05月

共著, ISSN 0368-2811

Background: The histological subtype of lung adenocarcinoma is a major prognostic factor. We developed a new artificial intelligence model to classify lung adenocarcinoma images into seven histological subtypes and adopted the model for whole-slide images to investigate the relationship between the distribution of histological subtypes and clinicopathological factors. Methods: Using histological subtype images, which are typical for pathologists, we trained and validated an artificial intelligence model. Then, the model was applied to whole-slide images of resected lung adenocarcinoma specimens from 147 cases. Result: The model achieved an accuracy of 99.7% in training sets and 90.4% in validation sets consisting of typical tiles of histological subtyping for pathologists. When the model was applied to whole-slide images, the predominant subtype according to the artificial intelligence model classification matched that determined by pathologists in 75.5% of cases. The predominant subtype and tumor grade (using the WHO fourth and fifth classifications) determined by the artificial intelligence model resulted in similar recurrence-free survival curves to those determined by pathologists. Furthermore, we stratified the recurrence-free survival curves for patients with different proportions of high-grade components (solid, micropapillary and cribriform) according to the physical distribution of the high-grade component. The results suggested that tumors with centrally located high-grade components had a higher malignant potential (P < 0.001 for 5-20% high-grade component). Conclusion: The new artificial intelligence model for histological subtyping of lung adenocarcinoma achieved high accuracy, and subtype quantification and subtype distribution analyses could be achieved. Artificial intelligence model therefore has potential for clinical application for both quantification and spatial analysis.

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慢性腎臓病患者における腎洞脂肪量と腎血行動態の関連の検証

金子賢司, 満野竜ノ介, 児島大輝, 畔上達彦, 中村俊文, 橋口明典, 山田祥岳, 陣崎雅弘, 山口慎太郎, 伊藤裕, 吉野純, 林香

日本内分泌学会雑誌（(一社)日本内分泌学会） 100 （ 1 ） 348 - 348 2024年05月

共著, ISSN 0029-0661

慢性腎臓病患者における腎洞脂肪量と腎血行動態の関連の検証

金子賢司, 満野竜ノ介, 児島大輝, 畔上達彦, 中村俊文, 橋口明典, 山田祥岳, 陣崎雅弘, 山口慎太郎, 伊藤裕, 吉野純, 林香

日本内分泌学会雑誌（(一社)日本内分泌学会） 100 （ 1 ） 348 - 348 2024年05月

共著, ISSN 0029-0661

Renal sinus fat is associated with intrarenal hemodynamic abnormalities independent of visceral fat in patients with chronic kidney disease

Kaneko K., Mitsuno R., Kojima D., Azegami T., Kosugi S., Nakamura T., Hashiguchi A., Yamada Y., Jinzaki M., Yamaguchi S., Itoh H., Yoshino J., Hayashi K.

Obesity Research and Clinical Practice （Obesity Research and Clinical Practice） 18 （ 2 ） 118 - 123 2024年03月

共著, ISSN 1871403X

Objective: Obesity is a risk factor of chronic kidney disease (CKD), contributing to the rising incidence of cardiometabolic diseases. Renal sinus fat (RSF) is an ectopic fat depot located at the renal cavity that could impair renal function and hemodynamic through compression of renal structures. The major purpose of this study was to explore the relationship between RSF accumulation and renal dysfunction in CKD patients. Methods: We evaluated the associations between computed tomography measured RSF volume and key clinical and histologic parameters involved in renal function and hemodynamics in 132 well-characterized CKD patients who underwent renal biopsy (median age: 62 years; 63.6% men). Results: RSF volume normalized by renal volume (RSF%) positively correlated with obesity-related traits such body mass index and visceral fat volume (VFV) (all P < 0.001) whereas it negatively correlated with estimated glomerular filtration rate (eGFR) (ρ = −0.42, P < 0.001) and 24-h urinary creatinine clearance (CCr) (ρ = −0.34, P < 0.001). Notably, we found robust positive correlations between RSF% and renal resistive index (RRI) measured by the Doppler ultrasound (ρ = 0.40, P < 0.001), and the histological severity of global glomerular sclerosis (ρ = 0.48, P < 0.001) and interstitial fibrosis and tubular atrophy (IFTA) (ρ = 0.35, P < 0.001). In the multivariate linear regression models, after accounting for potential confounders including VFV, RSF% remained significantly associated with CCr (β = −0.26, P < 0.001), RRI (β = 0.17, P = 0.022), global glomerular sclerosis (β = 0.21, P = 0.002), and IFTA (β = 0.17, P = 0.012). Conclusion: RSF accumulation is associated with renal dysfunction and hemodynamic abnormalities independent of visceral adiposity. Our results suggest that RSF may have a potential unique role in the pathogenesis of CKD.

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Morphological and etiological analyses of C3 and non-C3 glomerulonephritis in primary membranoproliferative glomerulonephritis using periodic acid-methenamine silver stain electron microscopy: a retrospective multicentered study

Honma S., Sato N., Sakaguchi R., Hashiguchi A., Uesugi N., Nakamura Y., Sasano H., Joh K.

Medical Molecular Morphology （Medical Molecular Morphology） 57 （ 1 ） 23 - 34 2024年03月

共著, ISSN 18601480

This study elucidated the etiology of C3 glomerulonephritis (C3GN) and non-C3GN with primary membranoproliferative glomerulonephritis (MPGN) using transmission electron microscopy (TEM) and periodic acid-methenamine silver stain (PAM-EM). Thirty-one primary MPGN cases were analyzed by TEM and PAM-EM to distinguish among MPGN I, MPGN II, MPGN III Burkholder subtype (MPGN IIIB), and Anders and Strife subtype (MPGN IIIA/S). Each case was also classified into C3GN or non-C3GN according to the standard C3GN definition using immunostaining. Four cases of MPGN II met C3 glomerulopathy; whereas, four cases of MPGN IIIB did not meet C3 glomerulopathy. Seven of 11 cases (64%) of MPGN I without GBM disruption and 7 of 12 cases (58%) of MPGN IIIA/S with GBM disruption met the non-C3GN criteria with significant immunoglobulins’ deposition. Regardless of the C3GN or non-C3GN diagnosis, the deposits in primary MPGN I and MPGN IIIA/S exhibited ill-defined, amorphous, and foggy characteristics similar to those found in postinfectious GN but were different from immune complex (IC) deposits seen in MPGN IIIB. Not only C3GN but also non-C3GN was due to mechanisms other than IC deposition as found in postinfectious GN. Consequently, GBM disruption of MPGN IIIA/S was not due to IC deposition.

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Clinicopathological prognostic stratification for proteinuria and kidney survival in IgA nephropathy: a Japanese prospective cohort study

Koike K., Kawamura T., Hirano K., Nishikawa M., Shimizu A., Joh K., Katafuchi R., Hashiguchi A., Yano Y., Matsuzaki K., Matsushima M., Tsuboi N., Maruyama S., Narita I., Yokoo T., Suzuki Y.

Clinical Kidney Journal （Clinical Kidney Journal） 17 （ 1 ） sfad294 2024年01月

共著, ISSN 20488505

Background. We require a clinicopathological risk stratification method for immunoglobulin A nephropathy (IgAN) to predict kidney outcomes. We examined a renal failure risk group (RF-RG) classification system created following a prior multicentre, retrospective study to determine if RF-RG could predict kidney outcomes. Methods. We collected data from Japanese patients with IgAN registered between 1 April 2005 and 31 August 2015. The primary outcome was a composite 50% increase in serum creatinine from baseline or dialysis induction. The secondary outcomes were times to proteinuria remission (ProR) and haematuria remission (HemR). Results. The enrolled 991 patients from 44 facilities were followed for a median of 5.5 years (interquartile range 2.5-7.5), during which 87 composite events (8.8%) occurred. RF-RG was significantly associated with the primary outcome {hazard ratio [HR] II 2.78 [95% confidence interval (CI) 1.12-6.93], III 7.15 (2.90-17.6), IV 33.4 (14.1-79.0), I as a reference, P < .001}. The discrimination performance was good [C-statistic 0.81 (95% CI 0.76-0.86)] and the time-dependent C-statistics exceeded 0.8 over 10 years. Among the 764 patients with proteinuria and 879 patients with haematuria at baseline, 515 and 645 patients showed ProR and HemR, respectively. ProR was significantly less frequent in patients with advanced disease [subdistribution HR: II 0.79 (95% CI 0.67-0.94), III 0.53 (0.41-0.66), IV 0.15 (0.09-0.23), I as a reference, P < .001]. We also observed an association between HemR and RF-RG. Conclusions. RF-RG demonstrated good predictive ability for kidney outcomes.

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Associations of corticosteroid therapy and tonsillectomy with kidney survival in a multicenter prospective study for IgA nephropathy

Kawamura T., Hirano K., Koike K., Nishikawa M., Shimizu A., Joh K., Katafuchi R., Hashiguchi A., Matsuzaki K., Maruyama S., Tsuboi N., Narita I., Yano Y., Yokoo T., Suzuki Y.

Scientific Reports （Scientific Reports） 13 （ 1 ） 18455 - 18455 2023年12月

共著

Efficacy of systemic corticosteroid therapy (CS) for long-term kidney survival in patients with IgA nephropathy (IgAN) is controversial. Therefore, prospective studies evaluating targeted therapies to lymphatic tissues in mucosal immune system responsible for production of nephritogenic IgA have been desired worldwide. Here, we aimed to evaluate the associations of CS and combination therapy of CS and tonsillectomy (CS + Tx) with kidney survival, using database from a nationwide multicenter prospective cohort study on IgAN. Primary outcome was a 50% increase in serum creatinine from baseline or dialysis induction. The analysis included 941 patients (CS/CS + Tx/non-CS 239/364/338), 85 (9.0%) of whom reached outcomes during median follow-up of 5.5 (interquartile range 2.0–8.0) years. On overlap weighting analysis with balanced baseline characteristics, CS and CS + Tx were associated with lower risk of kidney events when compared with non-CS (hazard ratio [HR] 0.51, 95% confidence interval [CI] 0.29–0.88 and HR 0.20, 95%CI 0.09–0.44, respectively). Notably, when compared with the CS, CS + Tx was associated with a lower risk of kidney events (HR 0.40, 95%CI 0.18–0.91). Present study demonstrated, keeping with favorable association of systemic CS with kidney survival, concurrent tonsillectomy as one of targeted interventions to lymphatic tissues may provide additional improvement to kidney survival in patients with IgAN.

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