Clarification of molecular mechanisms of chronic allograft nephropathy focusing on adverse reaction of immunosuppressive drugs, and survey of noninvasive markers

2017 Fiscal Year Annual Research Report

• Project/Area Number: 15H04666
• Research Institution: Kyushu University
• Principal Investigator: 増田 智先 九州大学, 大学病院, 教授 (90303825)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Keywords: 臨床薬学 / 免疫抑制薬 / 副作用 / 移植 / バイオマーカー

Outline of Annual Research Achievements

腎臓移植患者の過半数は慢性移植腎症（Chronic Allograft Nephropathy, CAN）とよばれる移植腎組織の高度な線維化を伴う慢性腎臓病様の機能障害に陥るため、移植腎の生着は維持されるものの、機能低下による血液透析への再導入が問題とされている。CANの要因として、生化学データに反映されない軽微な拒絶反応（Subclinical Rejection）の遷延とカルシニューリン阻害薬（CNI）の副作用である腎毒性の蓄積が疑われるが、分子機構は未解明である。そこで、腎臓移植治療におけるCAN克服の手がかりとして、移植腎組織中の免疫抑制薬の濃度がsubclinicalな拒絶反応並びに薬剤成人毒性の遷延と障害の蓄積、組織線維化の進展につながると仮説を立てて系統的な解析を実施した。腎移植患者73名より尿並びに血液検体の回収を終え、尿中バイオマーカー候補タンパク質並びに免疫抑制薬の血中濃度推移、臨床経過との関連性について解析を進めた結果、尿中のneutrophil gelatinase-associated lipocalin (NGAL)、Monocyte Chemoattractant Protein 1 (MCP-1)とタクロリムスによる急性腎障害発現との関連性が示された。一方、Liver type-Fatty Acid Binding Protein (L-FABP)をはじめとする4種類の尿中バイオマーカー候補分子との関連性は認められなかった。従って、腎移植後のCNIによる腎障害発症を早期予測するための指標として尿中のNGALやMCP-1の有用性が示された。さらに、長期間のCNI暴露とsubclinicalな拒絶反応の継続に伴うCANの検出には尿中のKidney injury molecule 1漏出との関連性が示唆された。

Research Progress Status

29年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

29年度が最終年度であるため、記入しない。

Research Products

• [Int'l Joint Research] Harvard Institute od Medicine(米国)
  • Country Name: U.S.A.
  • Counterpart Institution: Harvard Institute od Medicine
• [Int'l Joint Research] Fischer-Bosch Institute(ドイツ)
  • Country Name: GERMANY
  • Counterpart Institution: Fischer-Bosch Institute
• [Journal Article] Excessive spinal glutamate transmission is involved in oxaliplatin-induced mechanical allodynia: a possibility for riluzole as a prophylactic drug (2017)
  • Author(s): Yamamoto S, Ushio S, Egashira N, Kawashiri T, Mitsuyasu S, Higuchi H, Ozawa N, Masuguchi K, Ono Y & Masuda S
  • Journal Title: Sci Rep Volume: 7 Pages: 9661
  • DOI: 10.1038/s41598-017-08891-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Evaluation of Teicoplanin Trough Values After the Recommended Loading Dose in Children With Associated Safety Analysis (2017)
  • Author(s): Yamada T, Kubota T, Yonezawa M, Nishio H, Kanno S, Yano T, Kobayashi D, Egashira N, Takada H, Hara T & Masuda S
  • Journal Title: Pediatr Infect Dis J Volume: 36 Pages: 398-400
  • DOI: 10.1097/inf.0000000000001456
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Analysis of the variable factors influencing tacrolimus blood concentration during the switch from continuous intravenous infusion to oral administration after allogeneic hematopoietic stem cell transplantation (2017)
  • Author(s): Suetsugu K, Ikesue H, Miyamoto T, Shiratsuchi M, Yamamoto-Taguchi N, Tsuchiya Y, Matsukawa K, Uchida M, Watanabe H, Akashi K & Masuda S
  • Journal Title: Int J Hematol Volume: 105 Pages: 361-368
  • DOI: 10.1007/s12185-016-2135-7
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Vancomycin induces reactive oxygen species-dependent apoptosis via mitochondrial cardiolipin peroxidation in renal tubular epithelial cells (2017)
  • Author(s): Sakamoto Y, Yano T, Hanada Y, Takeshita A, Inagaki F, Masuda S, Matsunaga N, Koyanagi S & Ohdo S
  • Journal Title: Eur J Pharmacol Volume: 800 Pages: 48-56
  • DOI: 10.1016/j.ejphar.2017.02.025
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Calcineurin inhibitors exacerbate coronary arteritis via the MyD88 signalling pathway in a murine model of Kawasaki disease (2017)
  • Author(s): Murata K, Motomura Y, Tanaka T, Kanno S, Yano T, Onimaru M, Shimoyama A, Nishio H, Sakai Y, Oh-Hora M, Hara H, Fukase K, Takada H, Masuda S, Ohga S, Yamasaki S & Hara T
  • Journal Title: Clin Exp Immunol Volume: 190 Pages: 54-67
  • DOI: 10.1111/cei.13002
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Intratumor analysis of trastuzumab distribution by pid staining, breakthrough method with high visuality and single cell quantification (2018)
  • Author(s): Ryosuke Matsukane, Mitsuhiro Hayashi, Masaru Takahashi, Hiroaki Hiroaki Aikawa, Mayu Ohuchi, Hisatake Okada, Satohiro Masuda, Akinobu Hamada
  • Organizer: American Society of Clinical Pharmacology and Therapeutics (ASCPT) 2018
  • Int'l Joint Research / Invited
• [Presentation] 薬物治療上の慎重投与例に対する薬学的関与 (2017)
  • Author(s): 増田 智先、渡邊 裕之
  • Organizer: 第38回日本臨床薬理学会学術総会
  • Invited
• [Presentation] Guidelines on therapeutic drug monitoring of immuno-suppressive drugs used in organ transplantation (2017)
  • Author(s): Satohiro Masuda
  • Organizer: 15th International Congress of Therapeutic Drug Monitoring and Clinical Toxicology (ICTDMCT) Post Congress Symposium
  • Int'l Joint Research / Invited
• [Presentation] Robotic anticancer drug compounding assist system for the preparation of injectable antineoplastic drugs (2017)
  • Author(s): Satohiro Masuda, Ph.D., Hiroyuki Watanabe, Ph.D., Toshihiro Irisa, MS, Kojiro Hata, MS, Ayako Kumagai, BS, Chika Tanaka, BS, Nana Ozawa, BS, Kazue Nakashima, MS
  • Organizer: ESMO2017
  • Int'l Joint Research
• [Presentation] 臓器移植後個別化免疫抑制療法の実施における薬剤師の役割 (2017)
  • Author(s): 増田 智先、福田 未音、上杉 美和、松原 和夫
  • Organizer: 第53回 日本移植学会総会
  • Invited
• [Presentation] Effect of angiotensin II on duodenal iron-transporting protein expression (2017)
  • Author(s): Soichiro Tajima, Kimitaka Suetsugu, Satohiro Masuda
  • Organizer: 10th BioMedical Transporters Conference
  • Int'l Joint Research
• [Presentation] 薬物による腎障害発現のメカニズム (2017)
  • Author(s): 増田智先
  • Organizer: 医療薬学フォーラム2017/第25回クリニカルファーマシーシンポジウム
  • Invited
• [Presentation] タクロリムス血中濃度測定システムの比較検討- 肝移植患者における検討 (2017)
  • Author(s): 松川公美、末次王卓、重松智博、山本奈々絵、田川慎二、土谷祐一、江頭伸昭、増田智先
  • Organizer: 第35回日本肝移植研究会
• [Presentation] Urinary biomarker for drug-induced nephrotoxicity (2017)
  • Author(s): Satohiro Masuda
  • Organizer: Predictive Safety Testing Consortium (PSTC) Japan Safety Biomarker Conference
  • Int'l Joint Research / Invited