研究者詳細 - 橋口　明典

論文 - 橋口　明典

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維持透析後のリツキシマブ寛解維持療法継続により血液透析を離脱した重症難治型ANCA関連血管炎の1例

星健太, 村上英人, 小野田怜依, 熊谷光祐, 佐藤由佳, 渡部統, 中村彰良, 橋口明典, 浦井秀徳

日本透析医学会雑誌（(一社)日本透析医学会） 56 （ 10 ） 377 - 384 2023年10月

共著, ISSN 1340-3451

当院において,コントロール不良の2型糖尿病および間質性肺炎を併存する高齢男性に生じた急速進行性糸球体腎炎(rapidly progressive glomerulonephritis:RPGN)で腎生検組織所見から感染後糸球体腎炎合併ANCA関連糸球体腎炎と診断した症例を経験した.プレドニゾロン(prednisolone:PSL)およびリツキシマブ(rituximab:RTX)で寛解導入療法を行うも腎機能が改善せず,維持血液透析療法導入となった.その後の寛解維持療法の継続により重篤な感染症を呈することなくステロイドを投与終了し残存腎機能の回復を認め,RTXの寛解維持治療中に透析導入後11ヵ月で透析離脱となった.高齢かつ合併症の多いANCA関連血管炎におけるRPGNにおいても,腎予後良好な徴候がみられた場合には適切な感染症予防を行ったうえでRTX療法を継続することで透析離脱が可能となる場合がある.(著者抄録)

当院における腎移植後5年の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, 桝田司, 高橋遼平, 萩生田純, 徳山博文, 中川健

移植（(一社)日本移植学会） 58 （総会臨時） 336 - 336 2023年09月

共著, ISSN 0578-7947

慢性糸球体腎炎の臨床経過で腎生検によりmasked IgG kappa depositsを伴う膜性腎症と診断し保存的加療を行った一例

満野竜ノ介, 吉本憲史, 橋口明典, 内山清貴, 山口慎太郎, 林香

日本腎臓学会誌（(一社)日本腎臓学会） 65 （ 6-E ） 638 - 638 2023年09月

共著, ISSN 0385-2385

Hepatitis B Virus-related Membranous Nephropathy with Crescentic Formation in an Inactive Carrier of Positive Hepatitis B Surface Antigen with Undetectable DNA under Anti-viral Treatment: A Case Report.

Kounoue N, Oguchi H, Mikami T, Yamaguchi Y, Hashiguchi A, Nagai H, Watanabe K, Furukawa S, Hisamatsu K, Sakai K

Internal medicine (Tokyo, Japan) 63 （ 1 ） 101 - 106 2023年05月

共著, ISSN 0918-2918

A man who was an inactive hepatitis B virus (HBV) carrier with positive hepatitis B surface antigen (HBs antigen) and undetectable HBV-DNA under anti-viral treatment developed nephrotic syndrome at 52 years old, and a renal biopsy revealed advanced membranous nephropathy (MN) with focal cellular crescents, interstitial hemorrhaging, and peritubular capillaritis. Immunofluorescence studies demonstrated granular IgG deposition and HBs antigen-positivity along the capillaries. Glomeruli were negative for phospholipase A2 receptor 1. There were no clinical findings of systemic vasculitis. We considered MN combined with small-vessel vasculitis due to HBV infection. These results suggest that HBV-related kidney disease should be considered even in patients with an inactive HBV carrier status under treatment.

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J-IGACSを用いたIgA腎症Oxford分類を構成する病変の組み合わせと治療反応性との関連の検討

坂口涼子, 城謙輔, 小此木英男, 中里毅, 橋口明典, 片渕律子, 清水章, 小池健太郎, 平野景太, 坪井伸夫, 川村哲也, 横尾隆, 成田一衛, 鈴木祐介

日本腎臓学会誌（(一社)日本腎臓学会） 65 （ 3 ） 320 - 320 2023年05月

共著, ISSN 0385-2385

J-IGACSを用いたIgA腎症Oxford分類を構成する病変の組み合わせと治療反応性との関連の検討

坂口涼子, 城謙輔, 小此木英男, 中里毅, 橋口明典, 片渕律子, 清水章, 小池健太郎, 平野景太, 坪井伸夫, 川村哲也, 横尾隆, 成田一衛, 鈴木祐介

日本腎臓学会誌（(一社)日本腎臓学会） 65 （ 3 ） 320 - 320 2023年05月

共著, ISSN 0385-2385

IgA腎症におけるステロイド療法,扁摘と腎予後の関連性

平野景太, 川村哲也, 小池健太郎, 西川正子, 清水章, 城謙輔, 片渕律子, 橋口明典, 松崎慶一, 丸山彰一, 坪井伸夫, 成田一衛, 矢野裕一朗, 横尾隆, 鈴木祐介

日本腎臓学会誌（(一社)日本腎臓学会） 65 （ 3 ） 272 - 272 2023年05月

共著, ISSN 0385-2385

IgA腎症におけるステロイド療法,扁摘と腎予後の関連性

日本腎臓学会誌（(一社)日本腎臓学会） 65 （ 3 ） 272 - 272 2023年05月

共著, ISSN 0385-2385

Immunohistochemistry May Not Replace Immunofluorescence in Paraffin-embedded Tissue for Detecting Masked Monoclonal Immunoglobulin Deposits: A Case Report.

Oda Y, Ikeda Y, Abe H, Hashiguchi A, Hatanaka K, Sawai T, Ushiku T, Nangaku M

Internal medicine (Tokyo, Japan) 62 （ 24 ） 3657 - 3661 2023年04月

共著, ISSN 0918-2918

An 84-year-old man developed a membranoproliferative glomerulonephritis pattern of injury, and the most likely cause detected during a workup was monoclonal IgG-λ in the urine and serum. Predominant IgG and λ light chain deposition was confirmed only by immunofluorescence using formalin-fixed, paraffin-embedded tissue and not by immunohistochemistry. A smaller and non-linear dynamic range of immunohistochemistry makes it less quantitative than immunofluorescence staining and may explain why immunohistochemistry failed to detect the light chain restriction. This case suggests that immunohistochemistry may not serve as a substitute for immunofluorescence on formalin-fixed, paraffin-embedded tissue in detecting masked monoclonal immunoglobulin deposits, although further research is warranted.

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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年04月

共著

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年04月

共著, 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

Kojima D., Yamaguchi S., Hashiguchi A., Hayashi K., Uchiyama K., Yoshimoto N., Adachi K., Nakayama T., Nishioka K., Tajima T., Morimoto K., Yoshino J., Yoshida T., Monkawa T., Kanda T., Itoh H.

Frontiers in Medicine （Frontiers in Medicine） 9 1037032 - 1037032 2023年01月

共著, 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

Nishioka K., Yamaguchi S., Hashiguchi A., Yoshimoto N., Tajima T., Yasuda I., Uchiyama K., Kaneko K., Aso M., Yoshino J., Monkawa T., Kanda T., Hayashi K., Itoh H.

SAGE Open Medical Case Reports （SAGE Open Medical Case Reports） 11 2050313X231197324 2023年01月

共著, 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年12月

共著

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年10月

共著, 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年09月

共著

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

Joh K., Nakazato T., Hashiguchi A., Shimizu A., Katafuchi R., Okonogi H., Koike K., Hirano K., Tsuboi N., Kawamura T., Yokoo T., Narita I., Suzuki Y.

PLoS ONE （PLoS ONE） 17 （ 9 September ） e0268731 2022年09月

共著

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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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 （CEN case reports） 12 （ 1 ） 7 - 13 2022年06月

共著

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年06月

共著, 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 and Disease Registry of the Japanese Society of Nephrology.

Clinical and experimental nephrology （Clinical and Experimental Nephrology） 26 （ 10 ） 963 - 973 2022年05月

共著, 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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