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

• Project/Area Number: 15H04666
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Medical pharmacy
• Research Institution: Kyushu University
• Principal Investigator: Masuda Satohiro 九州大学, 大学病院, 教授 (90303825)
• Co-Investigator(Kenkyū-buntansha): 北田 秀久 九州大学, 大学病院, 助教 (10403958)
• Co-Investigator(Renkei-kenkyūsha): YANO Takahisa 九州大学, 大学病院, 薬剤主任 (90532846)
• Research Collaborator: KAJIWARA Moto ; TAJIMA Soichiro ; YAMAMOTO Nanae
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥17,030,000 (Direct Cost: ¥13,100,000、Indirect Cost: ¥3,930,000); Fiscal Year 2017: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2016: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2015: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000)
• Keywords: 臨床薬学 / 免疫抑制薬 / 副作用 / 移植 / バイオマーカー / 安全性バイオマーカー / 非侵襲

Outline of Final Research Achievements

Chronic allograft nephropathy (CAN) after kidney transplantation results in dysfunction like chronic kidney disease with advanced fibrosis. In order to overcome CAN in kidney transplantation therapy, urinary biomarkers leading to fibrosis of transplanted kidney tissue were examined. By use of urine and blood samples from 73 patients after renal transplantation, and analyzed the relationship between urinary biomarker candidate protein and clinical course and analyzed with tissue damage mainly including acute rejection and tubularitis found after 3 months postoperative course were shown. As a result, the urinary NGAL, MCP-1 and LC3 were shown as an useful index for early prediction of CNI-induced renal impairment after renal transplantation.

Research Products

• [Int'l Joint Research] Harvard Institute od Medicine(米国)
• [Int'l Joint Research] Fischer-Bosch Institute(ドイツ)
• [Int'l Joint Research] Harvard Institute of Medicine(米国)
• [Int'l Joint Research] Fischer-Bosch Institute(ドイツ)
• [Int'l Joint Research]
• [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 Shota、Ushio Soichiro、Egashira Nobuaki、Kawashiri Takehiro、Mitsuyasu Shohei、Higuchi Hitomi、Ozawa Nana、Masuguchi Ken、Ono Yuko、Masuda Satohiro
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 9661-9661
  • 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 Issue: 4 Pages: 398-400
  • DOI: 10.1097/inf.0000000000001456
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Analysis of the variable factors influencing tacrolimus blood concentration during the switch (2017)
  • Author(s): Suetsugu K, Ikesue H, Miyamoto T, Shiratsuchi M, Yamamoto-Taguchi N, Tsuchiya Y, Matsukawa K,
  • Journal Title: Int J Hematol Volume: 105 Issue: 3 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: European Journal of Pharmacology Volume: 800 Pages: 48-56
  • DOI: 10.1016/j.ejphar.2017.02.025
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [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: Clinical & Experimental Immunology Volume: 190 Issue: 1 Pages: 54-67
  • DOI: 10.1111/cei.13002
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Disruption of Slc52a3 gene causes neonatal lethality with riboflavin deficiency in mice (2016)
  • Author(s): Yoshimatsu H, Yonezawa A, Yamanishi K, Yao Y, Sugano K, Nakagawa S, Imai S, Omura T, Nakagawa T, Yano I, Masuda S, Inui K & Matsubara K
  • Journal Title: Sci Rep Volume: 6 Issue: 1 Pages: 27557-27557
  • DOI: 10.1038/srep27557
  • NAID: 120005818230
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Involvement of intracellular cAMP in epirubicin-induced vascular endothelial cell injury (2016)
  • Author(s): Yamada T, Ueda M, Egashira N, Zukeyama N, Kuwahara J & Masuda S
  • Journal Title: J Pharmacol Sci Volume: 130 Issue: 1 Pages: 33-37
  • DOI: 10.1016/j.jphs.2015.12.010
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Efficacy of aprepitant for the prevention of chemotherapy-induced nausea and vomiting with a moderately emetogenic chemotherapy regimen: a multicenter, placebo-controlled, double-blind, randomized study in patients with gynecologic cancer receiving paclitaxel and carboplatin (2016)
  • Author(s): Yahata H, Kobayashi H, Sonoda K, Shimokawa M, Ohgami T, Saito T, Ogawa S, Sakai K, Ichinoe A, Ueoka Y, Hasuo Y, Nishida M, Masuda S & Kato K
  • Journal Title: Int J Clin Oncol Volume: 21 Issue: 3 Pages: 491-497
  • DOI: 10.1007/s10147-015-0928-y
  • Peer Reviewed
• [Journal Article] Protective Effects of Imatinib on Ischemia/Reperfusion Injury in Rat Lung (2016)
  • Author(s): Tanaka S, Chen-Yoshikawa TF, Kajiwara M, Menju T, Ohata K, Takahashi M, Kondo T, Hijiya K, Motoyama H, Aoyama A, Masuda S & Date H
  • Journal Title: Ann Thorac Surg Volume: 102 Issue: 5 Pages: 1717-1724
  • DOI: 10.1016/j.athoracsur.2016.05.037
  • Peer Reviewed
• [Journal Article] Therapeutic Drug Monitoring of Everolimus: A Consensus Report. (2016)
  • Author(s): Shipkova M, Hesselink DA, Holt DW, Billaud EM, van Gelder T, Kunicki PK, Brunet M, Budde K, Barten MJ, De Simone P, Wieland E, Lopez OM, Masuda S, Seger C, Picard N, Oellerich M, Langman LJ, Wallemacq P, Morris RG, Thompson C & Marquet P
  • Journal Title: Ther Drug Monit Volume: 38 Issue: 2 Pages: 143-169
  • DOI: 10.1097/ftd.0000000000000260
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Role of mTOR Inhibitors in Kidney Disease. (2016)
  • Author(s): Kajiwara M & Masuda S
  • Journal Title: Int J Mol Sci Volume: 17 Issue: 6 Pages: 975-975
  • DOI: 10.3390/ijms17060975
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Urinary Dopamine as a Potential Index of the Transport Activity of Multidrug and Toxin Extrusion in the Kidney (2016)
  • Author(s): Kajiwara M, Ban T, Matsubara K, Nakanishi Y & Masuda S
  • Journal Title: Int J Mol Sci Volume: 17 Issue: 8 Pages: 1228-1228
  • DOI: 10.3390/ijms17081228
  • NAID: 120005838149
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Molecular Markers of Tubulointerstitial Fibrosis and Tubular Cell Damage in Patients with Chronic Kidney Disease (2015)
  • Author(s): Nakagawa S, Nishihara K, Miyata H, Shinke H, Tomita E, Kajiwara M, Matsubara T, Iehara N, Igarashi Y, Yamada H, Fukatsu A, Yanagita M, Matsubara K & Masuda S
  • Journal Title: PLoS One Volume: 10 Issue: 8 Pages: 1-14
  • DOI: 10.1371/journal.pone.0136994
  • NAID: 120005763422
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Urinary kidney injury molecule-1 and monocyte chemotactic protein-1 are noninvasive biomarkers of cisplatin-induced nephrotoxicity in lung cancer patients (2015)
  • Author(s): Shinke H, Masuda S, Togashi Y, Ikemi Y, Ozawa A, Sato T, Kim YH, Mishima M, Ichimura T, Bonventre JV & Matsubara K
  • Journal Title: Cancer Chemother Pharmacol Volume: 76 Issue: 5 Pages: 989-996
  • DOI: 10.1007/s00280-015-2880-y
  • NAID: 120005689175
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Risk Factors for Predicting Severe Neutropenia Induced by Pemetrexed Plus Carboplatin Therapy in Patients with Advanced Non-small Cell Lung Cancer (2015)
  • Author(s): Ikesue H, Watanabe H, Hirano M, Chikamori A, Suetsugu K, Ryokai Y, Egashira N, Yamada T, Ikeda M, Iwama E, Harada T, Takayama K, Nakanishi Y & Masuda S
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 38 Issue: 8 Pages: 1192-1198
  • DOI: 10.1248/bpb.b15-00162
  • NAID: 130005090645
  • ISSN: 0918-6158, 1347-5215
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Association of decreased mRNA expression of multidrug and toxin extrusion protein 1 in peripheral blood cells with the development of flutamide-induced liver injury. (2015)
  • Author(s): Nakano K, Ando H, Kurokawa S, Hosohata K, Ushijima K, Takada M, Tateishi M, Yonezawa A, Masuda S, Matsubara K, Inui KI, Morita T, Fujimura A.
  • Journal Title: Cancer Chemother Pharmacol. Volume: ｉｎ ｐｒｅｓｓ Issue: 6 Pages: 1191-1197
  • DOI: 10.1007/s00280-015-2743-6
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Effect of CYP2C19 polymorphisms on the clinical outcome of low-dose clobazam therapy in Japanese patients with epilepsy (2014)
  • Author(s): Hashi S, Yano I, Shibata M, Masuda S, Kinoshita M, Matsumoto R, Ikeda A, Takahashi R, Matsubara K.
  • Journal Title: Eur J Clin Pharmacol Volume: 37 Issue: 1 Pages: 51-58
  • DOI: 10.1007/s00228-014-1773-z
  • NAID: 120005657893
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [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] Evaluation of the factors affecting teicoplanin serum concentration in neonates and children (2017)
  • Author(s): Takaaki Yamada, Hisanori Nishio, Masayuki Ochiai, Shigeru Ishida, Youko Wakasugi, Kimitaka Suetsugu, Toshikazu Tsuji, Akiko Kanaya, Toshiro Hara, Satohiro Masuda
  • Organizer: American Society of Clinical Pharmacology and Therapeutics (ASCPT) 2017
  • Place of Presentation: 米国ワシントンDC
  • Year and Date: 2017-03-15
  • Int'l Joint Research
• [Presentation] 免疫抑制薬血中濃度測定の 全国サーベイ事業結果報告 (2017)
  • Author(s): 増田智先
  • Organizer: 第50回 日本臨床腎移植学会
  • Place of Presentation: 神戸市
  • Year and Date: 2017-02-15
  • 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
• [Presentation] 臓器移植医療における免疫抑制薬のTDM (2016)
  • Author(s): 増田智先
  • Organizer: 第56回 日本臨床化学会 年次学術集会
  • Place of Presentation: 熊本市
  • Year and Date: 2016-12-01
  • Invited
• [Presentation] Role of pharmacists in the safe and efficient care of patients receiving cancer treatment (2016)
  • Author(s): Hiroaki Ikesue, Hiroyuki Watanabe, Satohiro Masuda
  • Organizer: FIP World Congress
  • Place of Presentation: ブエノスアイレス（アルゼンチン）
  • Year and Date: 2016-08-28
  • Int'l Joint Research / Invited
• [Presentation] The standardization guideline and quality control surveillance in TDM of immunosuppressants in Japan (2016)
  • Author(s): Satohiro Masuda
  • Organizer: 2016 IATDMCT (International Association of Therapeutic Drug Monitoring and Clinical Toxicology) Regional Meeting
  • Place of Presentation: 広州市（中国）
  • Year and Date: 2016-08-16
  • Int'l Joint Research / Invited
• [Presentation] がん薬物治療における腎障害の尿中バイオマーカー（Urinary biomarkers of acute kidney injury in anti-cancer drug treatment） (2016)
  • Author(s): Satohiro Masuda, Moto Kajiwara, Hiroyuki Watanabe
  • Organizer: 第14回日本臨床腫瘍学会学術集会
  • Place of Presentation: 神戸市
  • Year and Date: 2016-07-28
  • Invited
• [Presentation] 薬毒物による腎障害検出のための尿中バイオマーカーの探索 (2016)
  • Author(s): 増田智先
  • Organizer: 医療薬学フォーラム2016/第24回クリニカルファーマシーシンポジウム
  • Place of Presentation: 大津市
  • Year and Date: 2016-06-25
  • Invited
• [Presentation] 臓器移植医療における免疫抑制剤のTDM (2016)
  • Author(s): 増田智先
  • Organizer: 第33回日本TDM学会・学術大会
  • Place of Presentation: 宇都宮市
  • Year and Date: 2016-05-28
  • Invited
• [Presentation] カルシニューリン阻害薬：肝移植領域 (2015)
  • Author(s): 増田智先
  • Organizer: 第25回日本医療薬学会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2015-11-22
  • Invited
• [Presentation] Impact of renal system mediating detoxification and onco-nephrology （がん化学療法における腎異物排泄機構の重要性） (2015)
  • Author(s): 増田智先
  • Organizer: 第30回日本薬物動態学会
  • Place of Presentation: タワーホール船堀
  • Year and Date: 2015-11-12
  • Invited
• [Presentation] Identification of a useful biomarker for tacrolimus-induced nephrotoxicity in liver transplant patients (2015)
  • Author(s): S. Masuda, M. Kajiwara, A Tsuchimoto, H. Shinke, M. Uesugi. Uemoto, K. Matsubara
  • Organizer: Urine Omics & 2nd International Caparica Conference In Translational Nephrology
  • Place of Presentation: Caparica, Lisbon
  • Year and Date: 2015-09-28
  • Int'l Joint Research / Invited
• [Presentation] Role of OCT2/MATEs interplay in drug-induced nephrontoxicity (2015)
  • Author(s): Satohiro Masuda
  • Organizer: BioMedical Transporters Conference 2015
  • Place of Presentation: Lugano, Switzerland
  • Year and Date: 2015-08-09
  • Int'l Joint Research / Invited
• [Presentation] 臓器移植領域における エベロリムスのTDM (2015)
  • Author(s): 増田智先
  • Organizer: 第32回日本TDM学会・学術大会
  • Place of Presentation: キッセイ文化ホール（長野県松本文化会館）
  • Year and Date: 2015-05-23
  • Invited