Search for causative antigens of pediatric membranous nephropathy

• Project/Area Number: 20K08237
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• Research Institution: The University of Tokyo
• Principal Investigator: Yabuuchi Tomoo 東京大学, 医学部附属病院, 届出研究員 (60791936)
• Co-Investigator(Kenkyū-buntansha): 張田 豊 東京大学, 医学部附属病院, 准教授 (10451866) ; 神田 祥一郎 東京大学, 医学部附属病院, 講師 (60632651) ; 服部 元史 東京女子医科大学, 医学部, 教授 (50192274)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 膜性腎症

Outline of Research at the Start

膜性腎症は、糸球体基底膜上皮下に免疫複合体が沈着し補体の活性化により惹起される疾患である。長らくその原因となる抗原は不明であったが、近年成人の特発性膜性腎症の原因となる二つの抗原が発見され、特異的な治療に向け臨床的取り組みが進みつつある。申請者らはこれまでに小児期に発症する膜性腎症では成人の膜性腎症と異なる病因が関与することを明らかにしてきた。
本研究では候補分子及びそれに対する自己抗体について検討を進め、小児膜性腎症の原因を確立する。本研究の成果は、病因の解明だけでなく、抗体価による病勢モニタリングや特異的治療法の開発に直接つながる可能性がある。

Outline of Final Research Achievements

The purpose of this study is to identify antigens that react with autoantibodies present in the blood of pediatric membranous nephropathy patients. Using a protein array, we comprehensively analyzed antibodies contained in pediatric membranous nephropathy patients and control sera.
As a result, more than 60 specific autoantigen candidates were identified in the IgG4-positive group and IgG3-positive group of pediatric membranous nephropathy patients, and autoantigens common to both groups were identified. The obtained candidate molecules suggested a pathogenic mechanism different from the known cause. Antigen candidates include molecules that are specifically expressed in glomerular epithelial cells. As a new antigen candidate, we are investigating the expression changes in the blood and tissues of patients with membranous nephropathy and the antibody titer against the candidate molecule.

Academic Significance and Societal Importance of the Research Achievements

膜性腎症患者の抗原として、近年PLA2R以外にも次々と新規抗原が同定されている(THSD7A, NELL1, SEMA3B, PCDH7, HTRA1, EXT1/EXT2, NCAM1, FAT1, NDNF等)。これらの多くの解析では患者の腎組織において原因となる抗原が増加しているという変化をスクリーニングに使用している。本研究では組織ではなく血中の自己抗体をスクリーニングするため、既存の研究で検討されていなかった情報を捉えられていると考えている。また疾患群で複数の抗原に対する抗体が検出されることから、エピトープスプレディングの可能性についても検討する必要があると考えられた。

Research Products

• [Journal Article] Urinary extracellular vesicles signature for diagnosis of kidney disease (2022)
  • Author(s): Takizawa Keiichi、Ueda Koji、Sekiguchi Masahiro、Nakano Eiji、Nishimura Tatsuya、Kajiho Yuko、Kanda Shoichiro、Miura Kenichiro、Hattori Motoshi、Hashimoto Junya、Hamasaki Yuko、Hisano Masataka、Omori Tae、Okamoto Takayuki、Kitayama Hirotsugu、Fujita Naoya、Kuramochi Hiromi、Ichiki Takanori、Oka Akira、Harita Yutaka
  • Journal Title: iScience Volume: 25 Issue: 11 Pages: 105416-105416
  • DOI: 10.1016/j.isci.2022.105416
  • Peer Reviewed / Open Access
• [Journal Article] Precise clinicopathologic findings for application of genetic testing in pediatric kidney transplant recipients with focal segmental glomerulosclerosis/steroid-resistant nephrotic syndrome (2022)
  • Author(s): Miura Kenichiro、Kaneko Naoto、Hashimoto Taeko、Ishizuka Kiyonobu、Shirai Yoko、Hisano Masataka、Chikamoto Hiroko、Akioka Yuko、Kanda Shoichiro、Harita Yutaka、Yamamoto Toshiyuki、Hattori Motoshi
  • Journal Title: Pediatric Nephrology Volume: 38 Issue: 2 Pages: 417-429
  • DOI: 10.1007/s00467-022-05604-3
  • Peer Reviewed
• [Journal Article] A case of right hypodysplastic kidney and ectopic ureter associated with bicornuate uterus in a prepubertal girl (2022)
  • Author(s): Nakamura Misako、Kanda Shoichiro、Kajiho Yuko、Hinata Munetoshi、Tomonaga Kotaro、Fujishiro Jun、Harita Yutaka
  • Journal Title: CEN Case Reports Volume: 12 Issue: 1 Pages: 122-129
  • DOI: 10.1007/s13730-022-00730-1
  • Peer Reviewed
• [Journal Article] Circulating nephrin autoantibodies and post‐transplant recurrence of primary focal segmental glomerulosclerosis (2022)
  • Author(s): Hattori Motoshi、Shirai Yoko、Kanda Shoichiro、Ishizuka Kiyonobu、Kaneko Naoto、Ando Taro、Eguchi Makoto、Miura Kenichiro
  • Journal Title: American Journal of Transplantation Volume: 未定 Issue: 10 Pages: 2478-2480
  • DOI: 10.1111/ajt.17077
  • Peer Reviewed / Open Access
• [Journal Article] Cumulative dialytic glucose exposure is a risk factor for peritoneal fibrosis and angiogenesis in pediatric patients undergoing peritoneal dialysis using neutral-pH fluids. (2022)
  • Author(s): Shirai Y, Miura K, Ike T, Sasaki K, Ishizuka K, Horita S, Taneda S, Hirano D, Honda K, Yamaguchi Y, Masaki T, Hattori M.
  • Journal Title: Kidney Int Rep Volume: 7 Issue: 11 Pages: 2431-2445
  • DOI: 10.1016/j.ekir.2022.08.013
  • Peer Reviewed / Open Access
• [Journal Article] A case of Dent disease type 2 with large deletion of OCRL diagnosed after close examination of a school urinary test (2022)
  • Author(s): Motoyoshi Yaeko、Yabuuchi Tomoo、Miura Kenichiro、Hattori Motoshi、Kiyohara Koji
  • Journal Title: CEN Case Reports Volume: 11 Issue: 3 Pages: 366-370
  • DOI: 10.1007/s13730-022-00685-3
  • Peer Reviewed
• [Journal Article] Any modality of renal replacement therapy can be a treatment option for Joubert syndrome (2021)
  • Author(s): Takagi Yoko、Miura Kenichiro、Yabuuchi Tomoo、Kaneko Naoto、Ishizuka Kiyonobu、Takei Mariko、Yajima Chikage、Ikeuchi Yuka、Kobayashi Yasuko、Takizawa Takumi、Hisano Masataka、Tsurusaki Yoshinori、Matsumoto Naomichi、Hattori Motoshi
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 462-462
  • DOI: 10.1038/s41598-020-80712-4
  • NAID: 120007183295
  • Peer Reviewed / Open Access
• [Journal Article] Valganciclovir prophylaxis for cytomegalovirus infection in pediatric kidney transplant recipients: a single-center experience (2021)
  • Author(s): Iida Takaya、Miura Kenichiro、Ban Hideki、Ando Taro、Shirai Yoko、Ishiwa Sho、Shiratori Atsutoshi、Kaneko Naoto、Yabuuchi Tomoo、Ishizuka Kiyonobu、Takaiwa Masanori、Suyama Kazuhide、Hisano Masataka、Hattori Motoshi
  • Journal Title: Clinical and Experimental Nephrology Volume: - Issue: 5 Pages: 531-536
  • DOI: 10.1007/s10157-021-02020-z
  • Peer Reviewed
• [Journal Article] Cancer After Pediatric Kidney Transplantation: A Long-term Single-center Experience in Japan (2021)
  • Author(s): Yabuuchi Tomoo, Miura Kenichiro, Shimizu Satoru, Kaneko Naoto, Ishizuka Kiyonobu, Kanda Sshoichiro, Chikamoto Hiroko, Akioka Yuko, Fujieda Mikiya, Hattori Motoshi
  • Journal Title: Transplantation Direct Volume: 7 Issue: 4 Pages: e687-e687
  • DOI: 10.1097/txd.0000000000001137
  • NAID: 120007183297
  • Peer Reviewed / Open Access
• [Journal Article] Degree of foot process effacement in patients with genetic focal segmental glomerulosclerosis: a single-center analysis and review of the literature (2021)
  • Author(s): Ishizuka K, Miura K, Hashimoto T, Kaneko N, Harita Y, Yabuuchi T, Hisano M, Fujinaga S, Omori T, Yamaguchi Y, Hattori M.
  • Journal Title: Sci Rep Volume: 11 Issue: 1 Pages: 12008-12008
  • DOI: 10.1038/s41598-021-91520-9
  • NAID: 120007183298
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Amount and selectivity of proteinuria may predict the treatment response in post-transplant recurrence of focal segmental glomerulosclerosis: a single-center retrospective study (2021)
  • Author(s): Ban Hideki、Miura Kenichiro、Kaneko Naoto、Shirai Yoko、Yabuuchi Tomoo、Ishizuka Kiyonobu、Chikamoto Hiroko、Akioka Yuko、Shimizu Satoru、Ishida Hideki、Tanabe Kazunari、Hattori Motoshi
  • Journal Title: Pediatric Nephrology Volume: - Pages: 2433-2442
  • DOI: 10.1007/s00467-021-04951-x
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Response to steroid and immunosuppressive therapies may predict post‐transplant recurrence of steroid‐resistant nephrotic syndrome (2021)
  • Author(s): Miura Kenichiro、Ando Taro、Kanda Shoichiro、Hashimoto Taeko、Kaneko Naoto、Ishizuka Kiyonobu、Hamada Riku、Hataya Hiroshi、Hotta Kiyohiko、Gotoh Yoshimitsu、Nishiyama Kei、Hamasaki Yuko、Shishido Seiichiro、Fujita Naoya、Hattori Motoshi
  • Journal Title: Pediatric Transplantation Volume: - Issue: 8 Pages: 14103-14103
  • DOI: 10.1111/petr.14103
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Analysis of water and electrolyte imbalance in a patient with adipsic hypernatremia associated with subfornical organ-targeting antibody (2021)
  • Author(s): Shirai Yoko、Miura Kenichiro、Nakamura-Utsunomiya Akari、Ishizuka Kiyonobu、Hattori Miku、Hattori Motoshi
  • Journal Title: CEN Case Reports Volume: 11 Issue: 1 Pages: 110-115
  • DOI: 10.1007/s13730-021-00638-2
  • Peer Reviewed / Open Access
• [Journal Article] Laminin β2 variants associated with isolated nephropathy that impact matrix regulation (2021)
  • Author(s): Kikkawa Yamato、Hashimoto Taeko、Takizawa Keiichi、Urae Seiya、Masuda Haruka、Matsunuma Masumi、Yamada Yuji、Hamada Keisuke、Nomizu Motoyoshi、Liapis Helen、Hisano Masataka、Akioka Yuko、Miura Kenichiro、Hattori Motoshi、Miner Jeffrey H.、Harita Yutaka
  • Journal Title: JCI Insight Volume: 6 Issue: 6 Pages: 145908-145908
  • DOI: 10.1172/jci.insight.145908
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A novel de novo truncating TRIM8 variant associated with childhood-onset focal segmental glomerulosclerosis without epileptic encephalopathy: a case report (2021)
  • Author(s): Shirai Yoko、Miura Kenichiro、Kaneko Naoto、Ishizuka Kiyonobu、Endo Amane、Hashimoto Taeko、Kanda Shoichiro、Harita Yutaka、Hattori Motoshi
  • Journal Title: BMC Nephrology Volume: 22 Issue: 1 Pages: 417-417
  • DOI: 10.1186/s12882-021-02626-1
  • NAID: 120007181370
  • Peer Reviewed / Open Access
• [Journal Article] A case of 17q12 deletion syndrome that presented antenatally with markedly enlarged kidneys and clinically mimicked autosomal recessive polycystic kidney disease (2021)
  • Author(s): Nakamura Misako、Kanda Shoichiro、Kajiho Yuko、Morisada Naoya、Iijima Kazumoto、Harita Yutaka
  • Journal Title: CEN Case Reports Volume: 10 Issue: 4 Pages: 543-548
  • DOI: 10.1007/s13730-021-00604-y
  • Peer Reviewed / Open Access
• [Journal Article] Long-term outcome of renal transplantation in childhood-onset anti-neutrophil cytoplasmic antibody-associated vasculitis. (2020)
  • Author(s): Nagasawa T, Miura K, Kaneko N, Yabuuchi T, Ishizuka K, Chikamoto H, Akioka Y, Hisano M, Hattori M.
  • Journal Title: Pediatr Nephrol. Volume: Mar;24(2) Issue: 2
  • DOI: 10.1111/petr.13656
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Individualized concept for the treatment of autosomal recessive polycystic kidney disease with end-stage renal disease. (2020)
  • Author(s): Miura K, Sato Y, Yabuuchi T, Kaneko N, Ishizuka K, Chikamoto H, Akioka Y, Nawashiro Y, Hisano M, Imamura H, Miyai T, Sakamoto S, Kasahara M, Fuchinoue S, Okumi M, Ishida H, Tanabe K, Hattori M.
  • Journal Title: Pediatr Nephrol Volume: Mar 3 Issue: 3
  • DOI: 10.1111/petr.13690
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Renal hypoplasia can be the cause of membranous nephropathy-like lesions. (2020)
  • Author(s): Keiichi Takizawa, Kenichiro Miura, Naoto Kaneko, Tomoo Yabuuchi, Kiyonobu Ishizuka, Shoichiro Kanda, Yutaka Harita, Yuko Akioka, Shigeru Horita, Sekiko Taneda, Kazuho Honda, Motoshi Hattori
  • Journal Title: Clin Exp Nephrol Volume: 24 Issue: 9 Pages: 813-820
  • DOI: 10.1007/s10157-020-01902-y
  • Peer Reviewed / Open Access
• [Journal Article] Incomplete cryptic splicing by an intronic mutation of OCRL in patients with partial phenotypes of Lowe syndrome (2020)
  • Author(s): Nakano Eiji、Yoshida Amine、Miyama Yudai、Yabuuchi Tomoo、Kajiho Yuko、Kanda Shoichiro、Miura Kenichiro、Oka Akira、Harita Yutaka
  • Journal Title: Journal of Human Genetics Volume: 65 Issue: 10 Pages: 831-839
  • DOI: 10.1038/s10038-020-0773-3
  • Peer Reviewed
• [Journal Article] Rapid progression to end-stage renal disease in a child with IgA-dominant infection-related glomerulonephritis associated with parvovirus B19. (2020)
  • Author(s): Yoko Shirai, Kenichiro Miura, Tomoo Yabuuchi, Takeshi Nagasawa, Kiyonobu Ishizuka, Kazuhiro Takahashi, Sekiko Taneda, Kazuho Honda, Yutaka Yamaguchi, Hitoshi Suzuki, Yusuke Suzuki, Motoshi Hattori
  • Journal Title: CEN Case Rep Volume: 9 Issue: 4 Pages: 423-430
  • DOI: 10.1007/s13730-020-00501-w
  • Peer Reviewed / Open Access
• [Journal Article] Chronic Active Antibody-Mediated Rejection with Linear IgG Deposition on Glomerular Capillaries in a Kidney Transplant Recipient (2020)
  • Author(s): Miura Kenichiro、Shirai Yoko、Kaneko Naoto、Yabuuchi Tomoo、Ishizuka Kiyonobu、Horita Shigeru、Furusawa Miyuki、Unagami Kohei、Okumi Masayoshi、Ishida Hideki、Tanabe Kazunari、Koike Junki、Honda Kazuho、Yamaguchi Yutaka、Hattori Motoshi
  • Journal Title: Nephron Volume: 144 Issue: Suppl. 1 Pages: 97-101
  • DOI: 10.1159/000511322
  • Peer Reviewed / Open Access
• [Presentation] 移植後FSGS再発例における抗ネフリン抗体に関連した病態の解析 (2023)
  • Author(s): 白井陽子, 三浦健一郎, 神田祥一郎, 小池淳樹, 渡井至彦, 武田朝美, 後藤芳充, 堀田記世彦, 齋藤和英, 成田一衛, 石田英樹, 服部元史
  • Organizer: 第56回日本臨床腎移植学会
• [Presentation] 巣状分節性糸球体硬化症の移植後再発例における1時間生検検体でのスリット膜関連分子の発現変化 (2022)
  • Author(s): 白井陽子, 服部元史, 石塚喜世伸, 金子直人, 三浦健一郎, 安藤太郎, 小池淳樹, 種田積子, 本田一穂, 山口裕
  • Organizer: 第125回日本小児科学会学術集会
• [Presentation] Precise clinicopathologic findings for application of genetic testing in pediatric kidney transplant recipients with focal segmental glomerulosclerosis/steroid-resistant nephrotic syndrome. (2022)
  • Author(s): MIURA Kenichiro, AKIOKA Yuko, Chikamoto Hiroko, ISHIZUKA Kiyonobu, HISANO Masataka, KANDA Shoichiro, KANEKO Naoto, SHIRAI Yoko, HASHIMOTO TAEKO, HARITA Yutaka, YAMAMOTO Toshiyuki, Toshiyuki Yamamoto, HATTORI Motoshi
  • Organizer: IPNA
  • Int'l Joint Research
• [Presentation] 小児腹膜透析患者における酸性透析液と腹膜病理像との関連性の検討 (2021)
  • Author(s): 白井陽子, 服部元史, 石塚喜世伸, 薮内智朗, 金子直人, 三浦健一郎, 飯田貴也, 安藤太郎, 石和翔, 白鳥孝俊, 種田積子, 本田一穂
  • Organizer: 第55回日本小児腎臓病学会学術集会
• [Presentation] 巣状分節性糸球体硬化症の移植後再発例における 1 時間生検検体で のスリット膜関連分子のエンドサイトーシスの関与 (2021)
  • Author(s): 白井陽子, 服部元史, 石塚喜世伸, 池野かおる, 金子直人, 三浦健一郎, 安藤太郎, 種田積子, 本田一穂, 小池淳樹
  • Organizer: 第42回日本小児腎不全学会学術集会
• [Presentation] エプスタイン症候群の腎生検初見と臨床経過 (2021)
  • Author(s): 三浦健一郎, 服部元史, 白井陽子, 大塚泰史, 大和田葉子, 吉田晃, 東義人, 西山慶, 此元隆雄, 諸橋環, 濱田陸, 石倉健司
  • Organizer: 第56回日本小児腎臓病学会学術集会
• [Presentation] Lowe症候群の長期的な腎予後に関する検討 (2021)
  • Author(s): 服部元史, 石塚喜世伸, 神田祥一郎, 薮内智朗, 三浦健一郎, 張田豊, 佐藤享志, 磯島豪, 濱田陸, 石倉健司, 五十嵐隆
  • Organizer: 第55回日本小児腎臓病学会学術集会
• [Presentation] 利尿レノグラフィ後に閉塞性腎盂腎炎を発症した先天性水腎症（腎盂尿管移行部通過障害）の乳児例 (2021)
  • Author(s): 服部元史, 石塚喜世伸, 薮内智朗, 金子直人, 三浦健一郎, 白井陽子, 飯田貴也, 安藤太郎, 石和翔, 白鳥孝俊, 鈴木万里
  • Organizer: 第55回日本小児腎臓病学会学術集会
• [Presentation] 新生児仮死により腹膜透析にい至り、栄養管理に工夫を必要としている1乳児例 (2020)
  • Author(s): 服部元史, 石塚喜世伸, 薮内智朗, 金子直人, 三浦健一郎, 白井陽子, 安藤太郎, 石和翔, 白鳥孝俊, 世川修
  • Organizer: 第26回日本腹膜透析医学会 学術集会・総会
• [Presentation] 小児腹膜透析患者における中性透析液使用下の腹膜病理像の検討 (2020)
  • Author(s): 服部元史, 石塚喜世伸, 薮内智朗, 金子直人, 三浦健一郎, 白井陽子, 石和翔, 白鳥孝俊, 種田積子, 本田一穂
  • Organizer: 第26回日本腹膜透析医学会 学術集会・総会
• [Presentation] 腎移植後再発性巣状分節性糸球体硬化症の治療反応性の予測 (2020)
  • Author(s): 服部元史, 石塚喜世伸, 薮内智朗, 金子直人, 三浦健一郎, 白井陽子, 伴英樹, 安藤太郎, 石和翔, 白鳥孝俊, 石田英樹, 田邉一成
  • Organizer: 第41回日本アフェレシス学会学術大会