Establishment and elucidation of the mechanisms of new renal pathological entity "IgM-positive plasma cell tubulointerstitial nephritis''

• Project/Area Number: 17K09692
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Kidney internal medicine
• Research Institution: University of Fukui
• Principal Investigator: Takahashi Naoki 福井大学, 学術研究院医学系部門(附属病院部), 助教 (30377460)
• Co-Investigator(Kenkyū-buntansha): 岩野 正之 福井大学, 学術研究院医学系部門, 教授 (20275324) ; 木村 秀樹 福井大学, 学術研究院医学系部門(附属病院部), 准教授 (20283187) ; 糟野 健司 福井大学, 学術研究院医学系部門, 准教授 (60455243)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: IgM / 形質細胞 / 尿細管性アシドーシス / 原発性胆汁性胆管炎 / 尿細管間質性腎炎 / ファンコニー症候群 / 腎病理 / Fancnoni症候群

Outline of Final Research Achievements

In 2017, we reported the clinical and histological features of tubulointerstitial nephritis with IgM-positive plasma cells (IgMPC-TIN) in J Am Soc Nephrol. The clinical features were 100% distal renal tubular acidosis, 92% urinary glucose (Fanconi syndrome), 82% anti-mitochondrial antibody positivity, and 46% primary biliary cholangitis. The histological features were marked infiltration of IgMPC into the interstitium and tubulitis with CD3-positive T lymphocytes in the proximal tubules and collecting ducts. In order to establish the diagnostic criteria for IgMPC-TIN, we have started a multi center clinical study in which more than 20 institutions newly parrticipated and we are currently analyzing the data.

Academic Significance and Societal Importance of the Research Achievements

本研究成果として、IgM陽性形質細胞が腎臓に多く存在している腎炎 (IgMPC-TIN) を発見し、この病気の症状や顕微鏡所見の特徴を明らかにし、我が国から先行して世界に報告することができた。これは学術的に非常に意義の高いことである。また、この病気は全国では腎生検の0.06％と頻度は多くないが、われわれの施設では0.7％と10倍以上の頻度で認めており、原因不明の腎炎として見逃されてきた可能性が高い。これまで原因不明とされていた病気が新たに見いだされ、その病気の病態解明が進めば、次のステップとして副作用の少ない新しい治療の開発の道が開けるため、社会的意義も高いと考えられる。

Research Products

• [Journal Article] IgA Vasculitis Developed as an Adverse Effect of Tofacitinib Taken for Rheumatoid Arthritis (2020)
  • Author(s): Itoh I, Kasuno K, Yamamoto C, Takahashi N, Shimizu H, Ojima T, Hayashi S, Kimura H, Iwano M.
  • Journal Title: Internal Medicine Volume: 59 Issue: 6 Pages: 817-821
  • DOI: 10.2169/internalmedicine.3668-19
  • NAID: 130007808723
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2020-03-15
  • Peer Reviewed
• [Journal Article] Analytical and clinical validation of rapid chemiluminescence enzyme immunoassay for urinary thioredoxin, an oxidative stress-dependent early biomarker of acute kidney injury. (2020)
  • Author(s): Yokoi S, Kasuno K, Nishimori K, Nishikawa S, Nishikawa Y, Morita S, Kobayashi M, Fukushima S, Mikami D, Takahashi N, Oota Y, Kimura H, Soya Y, Kimata S, Nishimura K, Ono T, Muso E, Yoshida H, Yodoi J, Iwano M.
  • Journal Title: Clin Chim Acta. Volume: 507 Pages: 271-279
  • DOI: 10.1016/j.cca.2020.04.025
  • Peer Reviewed
• [Journal Article] Chronic hypoxia exacerbates diabetic glomerulosclerosis through mesangiolysis and podocyte injury in db/db mice (2020)
  • Author(s): Naoki Takahashi, Haruyoshi Yoshida, Hideki Kimura, Kazuko Kamiyama, Tomomi Kurose, Hidehiro Sugimoto, Toshio Imura, Seiji Yokoi, Daisuke Mikami, Kenji Kasuno, Hiroyuki Kurosawa, Yoshiaki Hirayama, Hironobu Naiki, Masanori Hara, Masayuki Iwano.
  • Journal Title: Nephrol Dial Transplant Volume: - Issue: 10 Pages: 1678-1688
  • DOI: 10.1093/ndt/gfaa074
  • Peer Reviewed
• [Journal Article] Elevated Levels of Urinary Extracellular Vesicle Fibroblast-Specific Protein 1 in Patients with Active Crescentic Glomerulonephritis. (2019)
  • Author(s): Morikawa Y, Takahashi N, Kamiyama K, Nishimori K, Nishikawa Y, Morita S, Kobayashi M, Fukushima S, Yokoi S, Mikami D, Kimura H, Kasuno K, Yashiki T, Naiki H, Hara M, Iwano M.
  • Journal Title: Nephron Volume: 141 Issue: 3 Pages: 177-187
  • DOI: 10.1159/000495217
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] β-Hydroxybutyrate, a ketone body, reduces the cytotoxic effect of cisplatin via activation of HDAC5 in human renal cortical epithelial cells. (2019)
  • Author(s): Mikami D, Kobayashi M, Uwada J, Yazawa T, Kamiyama K, Nishimori K, Nishikawa Y, Morikawa Y, Yokoi S, Takahashi N, Kasuno K, Taniguchi T, Iwano M.
  • Journal Title: Life Sci Volume: 222 Pages: 125-132
  • DOI: 10.1016/j.lfs.2019.03.008
  • Peer Reviewed / Open Access
• [Journal Article] Tubulointerstitial Nephritis with IgM-Positive Plasma Cells. (2017)
  • Author(s): Takahashi N, Kimura H et al
  • Journal Title: J Am Soc Nephrol. Volume: 28 Issue: 12 Pages: 3688-3698
  • DOI: 10.1681/asn.2016101074
  • Peer Reviewed / Open Access
• [Presentation] Difference between urinary vesicle fibroblast specific protein1 and urinary soluble CD 163 as a marker of crescent formation (2019)
  • Author(s): Yukie Morikawa, Naoki Takahashi, Kazuko Kamiyama, Sho Nishikawa, Kazuhisa Nishimori, Yudai Nishikawa, Sayu Morita, Mamiko Kobayashi, Sachiko Fukushima, Seiji Yokoi, Daisuke Mikami, Hideki Kimura, Kenji Kasuno, Masayuki Iwano
  • Organizer: ASN Kidney Week 2019 Annual Meeting
  • Int'l Joint Research
• [Presentation] Fanconi syndrome in an elderly patient with membranous nephropathy during treatment with immunosuppressant mizoribine (2019)
  • Author(s): Sho Nishikawa, Naoki Takahashi, Yudai Nishikawa, Sayu Morita, Kazuhisa Nishimori, Mamiko Kobayashi, Sachiko Fukushima, Seiji Yokoi, Daisuke Mikami, Hideki Kimura, Kenji Kasuno, Masayuki Iwano
  • Organizer: ASN Kidney Week 2019 Annual Meeting
  • Int'l Joint Research
• [Presentation] 免疫グロブリン沈着症 IgM陽性形質細胞浸潤を伴った尿細管間質性腎炎(IgMPC-TIN)の発見 (2019)
  • Author(s): 髙橋直生、岩野正之
  • Organizer: 日本腎臓学会東部学術大会
  • Invited
• [Presentation] PLA2R陽性膜性腎症はPLA2R陰性膜性腎症に比べ尿蛋白選択性が低い (2019)
  • Author(s): 髙橋 直生, 西川 翔, 西森 一久, 福島 佐知子, 森川 幸恵, 西川 雄大, 小林 麻美子, 横井 靖二, 三上 大輔, 木村 秀樹, 糟野 健司, 岩野 正之
  • Organizer: 日本腎臓学会学術総会
• [Presentation] 腎組織の特徴的線維化が乏しいIgG4関連腎臓病(IgG4-RKD)の一例 (2019)
  • Author(s): 福島 佐知子, 髙橋 直生, 西川 翔, 横井 靖二, 西森 一久, 小林 麻美子, 森田 紗由, 西川 雄大, 三上 大輔, 木村 秀樹, 糟野 健司, 岩野 正之
  • Organizer: 日本腎臓学会西部学術大会
• [Presentation] A unique form of tubulointerstitial nephritis with IgM-positive plasma cells (2018)
  • Author(s): Naoki Takahashi, Takako Saeki, Atsushi Komatsuda, Chishio Munemura, Tsuguru Hatta, Ken-ichi Samejima, Yudai Nishikawa, Mamiko Kobayashi, Daisuke Mikami, Kenji Kasuno, Hideki Kimura, Hironobu Naiki, Haruyoshi Yoshida, Ichiei Narita and Masayuki Iwano
  • Organizer: ISN Frontier 2018
  • Int'l Joint Research
• [Presentation] Elevated levels of urinary extracellular vesicle fibroblast-specific protein 1 in patients with active crescentic glomerulonephritis (2018)
  • Author(s): Yukie Morikawa, Naoki Takahashi, Kazuko Kamiyama, Kazuhisa Nishimori, Yudai Nishikawa, Mamiko Kobayashi, Sachiko Fukushima, Seiji Yokoi, Daisuke Mikami, Hideki Kimura, Kenji Kasuno, Masanori Hara and Masayuki Iwano
  • Organizer: ASN Kidney Week 2018 Annual Meeting
  • Int'l Joint Research
• [Presentation] A unique form of tubulointerstitial nephritis with IgM-positive plasma cells (2018)
  • Author(s): Naoki Takahashi, Takako Saeki, Atsushi Komatsuda, Chishio Munemura, Tsuguru Hatta, Ken-ichi Samejima, Yudai Nishikawa, Mamiko Kobayashi, Daisuke Mikami, Kenji Kasuno, Hideki Kimura, Hironobu Naiki, Haruyoshi Yoshida, Ichiei Narita and Masayuki Iwano
  • Organizer: ISN Frontier Meeting 2018
  • Int'l Joint Research
• [Presentation] Tubulointerstitial nephritis with IgM-positive plasma cells (2017)
  • Author(s): Naoki Takahashi, Takako Saeki, Atsushi Komatsuda, Ken-ichi Samejima, Yudai Nishikawa, Kazuhisa Nishimori, Sayu Morita, Mamiko Kobayashi, Yukie Morikawa, Sachiko Fukushima, Seiji Yokoi, Daisuke Mikami, Kenji Kasuno, Hideki Kimura, Ichiei Narita and Masayuki Iwano
  • Organizer: American Society of Nephrology 2017 Annual Meeting
  • Int'l Joint Research
• [Book] 腎と透析 (2019)
  • Author(s): 髙橋直生、岩野正之
  • Total Pages: 6
  • Publisher: 東京医学社
• [Book] Hospitalist (2018)
  • Author(s): 高橋直生 岩野正之
  • Total Pages: 10
  • Publisher: メディカル・サイエンス・インターナショナル
  • ISBN: 9784895929530
• [Remarks] 髙橋直生先生「これまで見逃されてきた新しいタイプの腎炎を発見」JASNに掲載
  • URL: http://www-n.med.u-fukui.ac.jp/information/2266/
• [Remarks] 新タイプの腎炎発見、福井大など研究チーム「治療法確立を目指す」
  • URL: http://www.fukuishimbun.co.jp/articles/-/235952
• [Remarks] 福井大 新たな腎炎発見 見逃された発掘も
  • URL: https://mainichi.jp/articles/20170919/k00/00e/040/152000c