Clinical research for the development of graft biomarkers after kidney transplantation from donors after cardiac death

• Project/Area Number: 19591874
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Urology
• Research Institution: Fujita Health University
• Principal Investigator: KUSAKA Mamoru Fujita Health University, 医学部, 講師 (40309141)
• Co-Investigator(Kenkyū-buntansha): HOSHONAGA Kiyotaka 藤田保健衛生大学, 医学部, 教授 (30229174) ; SHIROKI Ryouichi 藤田保健衛生大学, 医学部, 准教授 (70226330) ; HAYAKAWA Kunihiro 藤田保健衛生大学, 医学部, 准教授 (00198821) ; KUROYANAGI Yuko 藤田保健衛生大学, 研究補助員, 研究補助員 (60449460)
• Project Period (FY): 2007 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2008: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2007: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 腎移植 / バイオマーカー / 心停止下献腎移植 / 慢性拒絶反応 / 献腎移植 / 移植腎機能発現遅延 / ELISA / microarray

Research Abstract

我が国の献腎移植成績は短期ならびに長期においても世界に誇る良好な成績を報告しているが、移植後早期は、移植腎機能発現遅延に伴い平均約2週間の維持透析期間を必要とし、primary non-functionとともに臨床上この間のレシピエント管理が極めて重要となる。DCD腎における移植後変化は、一般的に組織学的特徴として急性尿細管壊死(ATN)に代表される腎機能発現遅延により引き起こされるが、発生機序はさまざまな要因を含み、確立した予防法がなく、移植腎の長期予後にも影響を及ぼし、慢性移植腎症(CAN)のリスクファクターとしても知られている。我々は動物実験と臨床検体のmicroarray解析から共通の発現亢進遺伝子として分泌蛋白NGAL(neutrophil gelatinase-associated lipocalin)、 TIMP-1, REG1A, Lactotransferin, SLPIに注目した。移植腎機能回復のバイオマーカーとして尿ならびに血清中のNGAL濃度を測定し、意義を検討した。NGALの移植後の血清を用いたELISA解析では、移植前の血清NGAL値は963±33 ng/mlであり、生体腎移植例では移植後直ちに減少した。一方献腎移植症例では術後のNGAL変化は二峰性を示し徐々に減少した。後半のピークを過ぎて数日で利尿が始まり移植腎機能は回復しはじめた。献腎移植における血清NGAL値の変化は無尿期における移植腎機能の回復を示すバイオマーカーの一つと考えられた。また、移植腎機能回復のバイオマーカーとして、血清中のTIMP-1についても意義を検討したところ、生体腎移植症例では移植後も血清TIMP-1値は変化しなかった。一方献腎移植症例では、移植後長期に透析期間を要した症例で、移植後のpeak TIMP-1値が高く、immediate functionであった症例では血清中のTIMP-1値は上昇しなかった。移植後のpeak TIMP-1値と移植前のTIMP-1値の差を検討したところ、移植後透析を要した期間と相関関係を示していた。NGAL(neutrophil gelatinase-associated lipocalin)と同様、移植後の血清TIMP-1値は、献腎移植における無尿期の移植腎機能の回復を示すバイオマーカーの一つと考えられ、本研究により、血清NGAL値と血清TIMP-1値の有効性を報告できた。本研究の成果の一部は、欧州移植学会ならびに国際移植学会で報告を行い、microarray解析のデータとNGAL, TIMP-1に関しての研究の成果は、ともにCell Transplantationに投稿し掲載された。

Research Products

• [Journal Article] Global expression profiles in one hour biopsy specimens of human kidney transplantation from donors after cardiac death (2009)
  • Author(s): Kusaka M., Kuroyanagi Y., Mori T., Nagaoka K., Sasaki H., Maruyama T., Hayakawa K., Shiroki R., Kurahashi H., Hoshinaga K.
  • Journal Title: Cell Transplantation (in press)
• [Journal Article] Global expression profiles in one hour biopsy specimens of human kid ney transplantation from donors after cardiac death (2009)
  • Author(s): M. Kusaka, Y. Kuroyanagi, et al.
  • Journal Title: Cell Transplantation (in press)
  • Peer Reviewed
• [Journal Article] Serum tissue inhibitor of metalloproteinases 1 (TIMP-1) predicts organ recovery from delayed graft function after kidney transplantation from donors after cardiac death (2009)
  • Author(s): M. Kusaka, Y. Kuroyanagi, et al.
  • Journal Title: Cell Transplantation (in press)
  • Peer Reviewed
• [Journal Article] Serum neutrophil gelatinase-associated lipocalin as a predictor of organ recovery from delayed graft function after kidney transplantation from donors after cardiac death (2008)
  • Author(s): Kusaka M., Kuroyanagi Y., Mori T., Nagaoka K., Sasaki H., Maruyama T., Hayakawa K., Shiroki R., Kurahashi H., Hoshinaga K.
  • Journal Title: Cell Transplantation 17 Pages: 129-134
• [Journal Article] Serum neutrophil gelatinase-associated lipocalin as a predictor of organ recovery from delayed graft function after kidney transplantation from donors after cardiac death. (2008)
  • Author(s): M. Kusaka, Y. Kuroyanagi, et al.
  • Journal Title: Cell Transplantation 17 Pages: 129-134
  • Peer Reviewed
• [Journal Article] Serum neutrophil gelatinase-associated lipocalin as a predictor of organ recovery from delayed graft function after kidney transplantation applying donation after cardiac death. (2008)
  • Author(s): M. Kusaka, Y. Kuroyanagi, et. al.
  • Journal Title: Cell Transplantation (in press)
  • Peer Reviewed
• [Journal Article] Serum tissue inhibitor of metalloproteinases 1(TIMP-1)predicts organ recovery from delayed graft function after kidney transplantation from donors after cardiac death
  • Author(s): Kusaka M., Kuroyanagi Y., Ichino M., Sasaki H., Maruyama T., Hayakawa K., Shiroki R., Kurahashi H., Hoshinaga K.
  • Journal Title: Cell Transplantation (in press)
• [Presentation] Global expression profiles in one hour biopsy specimens of human kidney transplantation from donors after cardiac death (2008)
  • Author(s): Kusaka M., Kuroyanagi Y., Mori T., Nagaoka K., Sasaki H., Maruyama T., Hayakawa K., Shiroki R., Kurahashi H., Hoshinaga K.
  • Organizer: XXII International Congress of the Transplantation Society
  • Place of Presentation: Sydney Australia
• [Presentation] Serum tissue inhibitor of metalloproteinases 1(TIMP-1)as a predictor of organ recovery from delayed graft function after kidney transplantation from donors after cardiac death (2008)
  • Author(s): Kusaka M., Kuroyanagi Y., Ichino M., Sasaki H., Maruyama T., Hayakawa K., Shiroki R., Kurahashi H., Hoshinaga K.
  • Organizer: XXII International Congress of the Transplantation Society
  • Place of Presentation: Sydney Australia
• [Presentation] Serum tissue inhibitor of metalloproteinases 1 (TIMP-1) as a predictor of organ recovery from delayed graft function after kidney transplantation from donors after cardiac death (2008)
  • Author(s): M. Kusaka, Y. Kuroyanagi, et al.
  • Organizer: Sydney Exhibition and Convention Center
  • Place of Presentation: Sydney Australia
• [Presentation] Serum neutrophil gelatinase-associated lipocalin as a predictor of organ recovery from delayed graft function after kidney transplantation applying donation after cardiac death (2007)
  • Author(s): Kusaka M., Kuroyanagi Y., Mori T., Nagaoka K., Sasaki H., Maruyama T., Hayakawa K., Shiroki R., Kurahashi H., Hoshinaga K.
  • Organizer: 13th Congress of the European Society for Organ Transplantation
  • Place of Presentation: Prague, Czech Republic
• [Presentation] Serum neutrophil gelatinase-associated lipocalin as a predictor of organ recovery from delayed graft function after kidney transplantation applying donation after cardiac death. (2007)
  • Author(s): M. Kusaka, Y. Kuroyanagi, et. al.
  • Organizer: 13th Congress of the European Society for Organ Transplantation
  • Place of Presentation: Prague, Czech Republic
• [Remarks] Fujita Health University Microarray Database
  • URL: http://www.fujita-hu.ac.jp/~genome/ma/index.html
• [Remarks] and the Gene Expression Omnibus (GEO; accession number GSE10419)
• [Remarks] Fujita Health University Microarray Database and the Gene Expression Omnibus(GEO; accession number GSE 10419)
  • URL: http://www.fuita-hu.ac.jp/~genome/ma/index.html