Investigation of the Suppressing Effect on Post-Kidney Transplantation Malignancy Due to KIR Ligand Mismatch

• Project/Area Number: 17K16773
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Urology
• Research Institution: Akita University
• Principal Investigator: Fujiyama Nobuhiro 秋田大学, 医学部附属病院, 講師 (90603275)
• Project Period (FY): 2017-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 移植医療 / 腎移植 / 組織適合性 / HLA / KIR / 移植免疫 / 腫瘍免疫 / 移植後悪性腫瘍 / NK細胞 / 移植免疫学 / 発がん抑制

Outline of Final Research Achievements

Histocompatibility assessment is essential for kidney transplantation between the recipient and the organ donor. This predicts the immunological alloreactivity between the recipient and the donor. There exists a diverse repertoire for the HLA receptor-KIR involved in innate immunity, but pre-transplant compatibility assessments are hardly ever conducted. Therefore, we retrospectively explored the impact on the prognosis of kidney transplantation by assessing the tissue compatibility between the recipient and donor in the innate immune system. As a result, we found a difference in the frequency of carcinogenesis depending on the presence or absence of KIR ligand mismatch, that innate immunity is maintained when there is a KIR ligand mismatch, and we propose that it is involved in suppressing the onset of viral infections.

Academic Significance and Societal Importance of the Research Achievements

近年の腎移植医療は良好な治療成績を示し、長期QOLを得ることが大きな課題となっている。しかし、腎移植後の悪性腫瘍による死亡率は15%と高く（罹患率は健常人3 倍いじょうとされ）、増加傾向にある。本研究はレシピエントKIR遺伝子ハプロタイプが悪性腫瘍発症リスクを客観的に把握できる極めて重要な指標となりえることを示唆した。また、特定のウイルス感染リスクとも強く関連する可能性もある。現在の腎移植における免疫学的な適合性評価にKIR遺伝子は含まれていない。移植後重大合併症を回避するための治療戦略としてKIR-HLA適合性の重要性を提唱する。

Research Products

• [Int'l Joint Research] シンガポール国立大学(シンガポール)
• [Int'l Joint Research] シンガポール国立大学(シンガポール)
• [Journal Article] Development and nation-wide validation of kidney graft injury markers using urinary exosomes and microvesicles (complete English translation of the Japanese version) (2022)
  • Author(s): Harada Hiroshi、Fukuzawa Nobuyuki、Abe Toyofumi、Imamura Ryoichi、Masaki Noriyuki、Fujiyama Nobuhiro、Sato Shigeru、Hatakeyama Shingo、Nishimura Kenji、Kishikawa Hidefumi、Iwami Daiki、Hotta Kiyohiko、Miura Masayoshi、Ide Kentaro、Nakamura Michio、Kosoku Akihiro、Uchida Junji、Murakami Taku、Tsuji Takahiro
  • Journal Title: BMC Nephrology Volume: In press
  • DOI: 10.21203/rs.3.rs-2094408/v1
  • Peer Reviewed
• [Journal Article] Advanced Tertiary Lymphoid Tissues in Protocol Biopsies are Associated with Progressive Graft Dysfunction in Kidney Transplant Recipients (2021)
  • Author(s): Lee Yu Ho、Sato Yuki、Saito Mitsuru、Fukuma Shingo、Saito Masaya、Yamamoto Shigenori、Komatsuda Atsushi、Fujiyama Nobuhiro、Satoh Shigeru、Lee Sang-Ho、Boor Peter、Habuchi Tomonori、Floege J?rgen、Yanagita Motoko
  • Journal Title: Journal of the American Society of Nephrology Volume: 33 Issue: 1 Pages: 186-200
  • DOI: 10.1681/asn.2021050715
  • NAID: 120007181755
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Loss of antibodies to hepatitis E virus in organ transplant patients with hepatitis E (2021)
  • Author(s): Oshiro Y, Harada H, Hasegawa K, Akutsu N, Yoshizumi T, Kawagishi N, Nanmoku K, Ichimaru N, Okamura K, Ohira M, Itabashi Y, Fujiyama N, Ide K, Okajima H, Ogawa K, Takagi K, Eguchi H, Shinoda M, Nishida K, Shimazaki J, Shimoda M, Takahashi M, Okamoto H, Suzuki S.
  • Journal Title: Hepatol Res Volume: in press Issue: 5 Pages: 538-547
  • DOI: 10.1111/hepr.13637
  • Peer Reviewed
• [Journal Article] Association of immunosuppressive agents and cytomegalovirus infection with de novo donor-specific antibody development within 1 year after renal transplantation (2019)
  • Author(s): Fujiyama Nobuhiro、Satoh Shigeru、Saito Mitsuru、Numakura Kazuyuki、Inoue Takamitsu、Yamamoto Ryohei、Saito Takuro、Nara Taketoshi、Kanda Sohei、Narita Shintaro、Kagaya Hideaki、Miura Masatomo、Habuchi Tomonori
  • Journal Title: International Immunopharmacology Volume: 76 Pages: 105881-105881
  • DOI: 10.1016/j.intimp.2019.105881
  • Peer Reviewed
• [Journal Article] Impact of persistent preformed and de novo donor-specific antibodies detected at 1?year after kidney transplantation on long-term graft survival in Japan: a retrospective study (2019)
  • Author(s): Fujiyama Nobuhiro、Satoh Shigeru、Saito Mitsuru、Numakura Kazuyuki、Inoue Takamitsu、Yamamoto Ryuhei、Saito Takuro、Kanda Sohei、Narita Shintaro、Mitobe Yoko、Habuchi Tomonori
  • Journal Title: Clinical and Experimental Nephrology Volume: 23 Issue: 12 Pages: 1398-1406
  • DOI: 10.1007/s10157-019-01780-z
  • Peer Reviewed
• [Journal Article] A Nationwide Survey of Hepatitis E Virus Infection and Chronic Hepatitis in Heart and Kidney Transplant Recipients in Japan (2019)
  • Author(s): Yohei Owada, Yukio Oshiro, Yuki Inagaki, Hiroshi Harada, Nobuhiro Fujiyama, Naoki Kawagishi, Takashi Yagisawa, Joichi Usui, Naotake Akutsu, Yoshihiro Itabashi, Kazuhide Saito, Yoshihiko Watarai, Naotsugu Ichimaru, Ryoichi Imamura, Miyaji Kyakuno, Kentaro Ide, Yuichi Shibuya, Yasuhiro Okabe, Minoru Ono, Konosuke Sasaki
  • Journal Title: Transplantaion Volume: In press
  • NAID: 120007132798
  • Peer Reviewed
• [Journal Article] Clinical implications of pharmacokinetics of sunitinib malate and N-desethyl-sunitinib plasma concentrations for treatment outcome in metastatic renal cell carcinoma patients (2018)
  • Author(s): Numakura Kazuyuki、Fujiyama Nobuhiro、Takahashi Makoto、Igarashi Ryoma、Tsuruta Hiroshi、Maeno Atsushi、Huang Mingguo、Saito Mitsuru、Narita Shintaro、Inoue Takamitsu、Satoh Shigeru、Tsuchiya Norihiko、Niioka Takenori、Miura Masatomo、Habuchi Tomonori
  • Journal Title: Oncotarget Volume: 9 Issue: 38 Pages: 25277-25284
  • DOI: 10.18632/oncotarget.25423
  • Peer Reviewed / Open Access
• [Journal Article] Contribution of UGT1A1 genetic polymorphisms related to axitinib pharmacokinetics to safety and efficacy in patients with renal cell carcinoma. (2018)
  • Author(s): Igarashi R, Inoue T, Fujiyama N, Tsuchiya N, Numakura K, Kagaya H, Saito M, Narita S, Satoh S, Niioka T, Miura M, Habuchi T.
  • Journal Title: Med Oncol. Volume: 35(51) Issue: 4 Pages: 51-58
  • DOI: 10.1007/s12032-018-1113-8
  • Peer Reviewed / Open Access
• [Journal Article] Clinical implications of pharmacokinetics of sunitinib malate and N-desethyl-sunitinib plasma concentrations for treatment outcome in metastatic renal cell carcinoma patients (2018)
  • Author(s): Kazuyuki Numakura, Nobuhiro Fujiyama, Makoto Takahashi, Ryoma Igarashi, Hiroshi Tsuruta, Atsushi Maeno, Mingguo Huang, Mitsuru Saito, Shintaro Narita, Takamitsu Inoue, Shigeru Satoh, Norihiko Tsuchiya, Takenori Niioka, Masatomo Miura, Tomonori Habuchi
  • Journal Title: Oncotarget Volume: -
  • Peer Reviewed
• [Presentation] 腎移植におけるネフロオンコロジー (2022)
  • Author(s): 藤山信弘
  • Organizer: 第8回日本医薬品安全性学会
• [Presentation] 腎移植後悪性腫瘍の特徴 (2022)
  • Author(s): 藤山信弘
  • Organizer: 第22回日本臨床腫瘍薬学会
• [Presentation] 長期フォロー腎移植患者CNI血中濃度によるde novo DSA発生への影響 (2022)
  • Author(s): 藤山信弘、齋藤満、山本竜平、提箸隆一郎、斎藤拓郎、青山有、沼倉一幸、羽渕友則
  • Organizer: 第16回日本腎臓病薬物療法学会
• [Presentation] Effect of tacrolimus trough level on de novo donor-specific antibody production in long-term renal transplant patients (2022)
  • Author(s): Nobuhiro Fujiyama, Mitsuru Saito, Ryouhei Yamamoto, Ryuichiro Sagehashi, Takuro Saito, Yu Aoyama, Kazuyuki Numakura, Shintaro Narita, Tomonori Habuchi
  • Organizer: TSS Asian Regional Meeting 2022
  • Int'l Joint Research
• [Presentation] Association between de novo donor specific antibody and tacrolimus trough levels in long-term follow-up renal transplantation (2022)
  • Author(s): Nobuhiro Fujiyama, Mitsuru Saito, Ryouhei Yamamoto, Ryuichiro Sagehashi, Takuro Saito, Soki Kashima, Kazuyuki Numakura, Shintaro Narita, Tomonori Habuchi, Shigeru Satoh
  • Organizer: American Transplant Congress 2022
  • Int'l Joint Research
• [Presentation] 腎移植後長期フォロー中のde novo DSA発生とCNIトラフ値の関連 (2022)
  • Author(s): 藤山信弘、齋藤満、山本竜平、提箸隆一郎、斎藤拓郎、青山有、沼倉一幸、羽渕友則、佐藤滋
  • Organizer: 第55回日本臨床腎移植学会
• [Presentation] Influence of HLA compatibility on BK polyomavirus associated nephropathy among living-donor kidney transplant recipient (2021)
  • Author(s): Nobuhiro Fujiyama, Mitsuru Saito, Ryouhei Yamamoto, Ryuichiro Sagehashi, Takuro Saito, Soki Kashima, Kazuyuki Numakura, Shintaro Narita, Tomonori Habuchi, Shigeru Satoh
  • Organizer: American Transplant Congress 2021
  • Int'l Joint Research
• [Presentation] 腎移植後長期フォロー患者におけるde novo DSAの特異性と傾向 (2021)
  • Author(s): 藤山信弘、齋藤満、山本竜平、提箸隆一郎、斎藤拓郎、青山有、沼倉一幸、羽渕友則、佐藤滋
  • Organizer: 第29回日本組織適合性学会
• [Presentation] 腎移植後帯状疱疹の発症リスク因子と移植腎予後への影響 (2021)
  • Author(s): 藤山信弘、齋藤満、山本竜平、提箸隆一郎、斎藤拓郎、青山有、沼倉一幸、羽渕友則、佐藤滋
  • Organizer: 第57回日本移植学会総会
• [Presentation] Evaluation of complement-related factors in TMA post-kidney transplantation: A retrospective multicenter study (interim analysis) (2019)
  • Author(s): Nobuhiro Fujiyama, Masayuki Tasaki, Hiroshi Harada, Koichi Tsutahara, Akihiko Matsumoto, Yuta Hara, Masayoshi Okumi, Kazuhide Saito, Yoshihiko Watarai, Norimitsu inoue, Nobutaka Wakamiya, and Shigeru Satoh
  • Organizer: 2019 American Transplant Congress
  • Int'l Joint Research
• [Presentation] 腎移植後サイトメガロウイルス感染とHLAの相関性 (2019)
  • Author(s): 藤山信弘、三浦アヤ子、齊藤満、山本竜平、齋藤拓郎、沼倉一幸、井上高光、奥山慎、羽渕友則、佐藤滋
  • Organizer: 第52回日本臨床腎移植学会
• [Presentation] Immunosuppressant related to de novo donor specific HLA antibody production in post kidney transplantation (2018)
  • Author(s): Nobuhiro Fujiyama, Mitsuru Saito, Ryohei Yamamoto, Kazuyuki Numakura, Shin Okuyama, Takamitsu Inoue, Tomonori Habuchi, Shigeru Satoh
  • Organizer: The Transplantation Society (2018) Madrid
  • Int'l Joint Research
• [Presentation] 腎移植後TMA患者の補体関連因子を評価する後向き多施設研究（中間報告） (2018)
  • Author(s): 藤山信弘、田崎正行、蔦原宏一、松本明彦、原悠太、奥見雅由、齋藤和英、原田浩、渡井 至彦、井上徳光、若宮伸隆、佐藤滋
  • Organizer: 第55 回 日本補体学会学術集会
• [Presentation] 秋田大学における既存抗体および新生抗体に対する取り組み (2018)
  • Author(s): 齋藤 満，佐藤 滋，藤山信弘，山本竜平，齋藤拓郎，米田真也，忠地一輝，下田次郎，奈良健平，千葉修治，神田壮平，沼倉一幸，成田伸太郎，井上高光，羽渕友則
  • Organizer: 第54回日本移植学会総会
• [Presentation] 腎移植後TMA患者における補体関連因子を評価する多施設共同研究(中間報告) (2018)
  • Author(s): 4)藤山信弘、田崎正行、蔦原宏一、松本明彦、原 悠太、奥見雅由、齋藤和英、原田 浩、渡井至彦、井上徳光、若宮伸隆、佐藤 滋
  • Organizer: 第54回日本移植学会総会
• [Presentation] 腎移植後TMA患者の補体関連検査：多施設共同研究の進捗と自験例 (2018)
  • Author(s): 藤山信弘、齋藤 満、沼倉一幸、山本竜平、井上高光、羽渕友則、佐藤 滋
  • Organizer: 第51回日本臨床腎移植学会
• [Presentation] Prediction of de novo Donor Specific HLA Antibody Production in The Follow-up Period of Kidney Transplantation (2017)
  • Author(s): Nobuhiro Fujiyama, Shin Okuyama, Mitsuru Saito, Ryohei Yamamoto, Kazuyuki Numakura, Takamitsu Inoue, Tomonori Habuchi, Shigeru Satoh
  • Organizer: 43rd American Society for Histocompatibility and Immunogenetics
  • Int'l Joint Research
• [Presentation] 生体腎移植前DSA検査の比較とTCR/ABMRへの影響 (2017)
  • Author(s): 藤山信弘、齋藤 満、山本竜平、沼倉一幸、井上高光、奥山 慎、羽渕友則、佐藤 滋
  • Organizer: 第26回日本組織適合性学会大会
• [Presentation] 腎移植患者におけるタクロリムス変動係数と服薬アドヒアランス、拒絶反応との関連性 (2017)
  • Author(s): 山本竜平、齋藤 満、藤山信弘、奈良健平、神田壮平、沼倉一幸 、鶴田大、成田伸太郎、井上高光、佐藤 滋、羽渕友則
  • Organizer: 第53回日本移植学会総会
• [Presentation] 秋田大学における腎移植後患者のがん検診受診状況と今後の課題 (2017)
  • Author(s): 瀬田川美香、立原恵里子、佐々木聖子、千田千亜希、齋藤 満、井上高光、加賀谷英彰、奥山 慎、藤山信弘、水戸部陽子、羽渕友則、佐藤 滋
  • Organizer: 第33回腎移植・血管外科研究会
• [Book] 腎臓病薬物療法ガイドブック (2022)
  • Author(s): 腎臓病薬物療法ガイドブック ワーキンググループ、日本腎臓病薬物療法学会（分担執筆）
  • Total Pages: 608
  • Publisher: じほう
  • ISBN: 9784840754422