2021 Fiscal Year Final Research Report

Development of renal protection-oriented immunosuppressive therapy after organ transplantation utilizing mTOR inhibitor

Research Project

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Project/Area Number	18H02588
Research Category	Grant-in-Aid for Scientific Research (B)
Allocation Type	Single-year Grants
Section	一般
Review Section	Basic Section 47060:Clinical pharmacy-related
Research Institution	Himeji Dokkyo University (2020-2021) International University of Health and Welfare (2019) Kyushu University (2018)
Principal Investigator	Masuda Satohiro 姫路獨協大学, 薬学部, 教授 (90303825)
Co-Investigator(Kenkyū-buntansha)	吉住朋晴九州大学, 医学研究院, 准教授 (80363373) 岡部安博九州大学, 大学病院, 助教 (90444819) 田島壮一郎九州大学, 大学病院, 薬剤師 (10579460)
Project Period (FY)	2018-04-01 – 2021-03-31
Keywords	免疫抑制薬 / 副作用 / 有害反応 / 移植 / バイオマーカー / mTOR / カルシニューリン阻害薬 / 遺伝子多型
Outline of Final Research Achievements	Chronic allograft nephrotoxicity induced by calcineurin inhibitors has been also raised as a severe problem in the transplant patients receiving these drugs. The renal fibrosis model rats using the treatment of ischemia-reperfusion injury with daily administration of tacrolimus, coadministration of mTOR inhibitor everolimus suppressed the progression of interstitial fibrosis in comparison with the tacrolimus alone. In clinical cases, the pharmacokinetic monitoring of the sum of the trough concentrations of tasrolimus and everolimus seems to be easier than that of the conventional separate monitoring of tacrolimus and everolimus, respectively. These results suggest that the present pharmacokinetic monitoring such as sum of each trough measurement of tacrolimus and everolimus is useful in posttransplant immunosuppressive therapy obtaining the decreasing tacrolimus-induced CNI-induced renal interstitial fibrosis by the pharmacological effect of mTOR inhibitor after organ transplantation.
Free Research Field	臨床薬理学、医療薬学
Academic Significance and Societal Importance of the Research Achievements	臓器移植後の免疫抑制療法において、カルシニューリン阻害薬（タクロリムス、シクロスポリン）は移植臓器の生着率を著しく向上させてきたが、組織の線維化という病理像を示す毒性を引き起こすことが問題とされてきた。今回、新しいクラスのmTOR阻害薬を併用することにより、タクロリムスの用量を抑制し、移植術後の腎毒性を軽減するための新たなモニタリング戦略を構築することができた。さらに、mTOR阻害薬の併用はタクロリムスによって引き起こされた組織の線維化領域の削減にも効果を示した。これらの結果は、臓器移植術を受けた患者の術後腎機能低下という合併症を回避し、QOL向上に役立つものと考える。