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大学・研究所にある論文を検索できる 「肝臓移植術後の免疫抑制療法に関連する腎障害の要因分析ならびに腎障害対策の構築に関する研究」の論文概要。リケラボ論文検索は、全国の大学リポジトリにある学位論文・教授論文を一括検索できる論文検索サービスです。

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肝臓移植術後の免疫抑制療法に関連する腎障害の要因分析ならびに腎障害対策の構築に関する研究

福田, 未音 FUKUDA, Mio フクダ, ミオ 九州大学

2020.03.23

概要

【背景・目的】
タクロリムスは、肝臓移植領域において現在最も汎用される代表的な免疫抑制薬であり、血中濃度モニタリング (therapeutic drug monitoring, TDM) に基づく精密な用量調節が行われているが、腎障害を引き起こすことが問題となっている。そのため九州大学病院(当院)では、腎障害を軽減させる目的で、腎毒性の少ないミコフェノール酸モフェチル (MMF) を術後 1 日目より用いて、術後 2-3 日目よりタクロリムスを開始するプロトコルで診療を行っている。通常、腎機能の指標としては、血清クレアチニン (Scr) 値が用いられるが、薬剤性腎障害に対して特異性が高くないことが指摘されており、近年、タクロリムス誘発性腎障害を反映する指標として Neutrophil gelatinase-associated lipocalin (NGAL) の有用性が報告されている。しかし、当院のプロトコルにおいて NGAL が腎障害の指標となるかどうかは不明である。さらに、当院ではカプセルと懸濁散の 2 つの剤形の MMF 製剤が使用されているが、術後 1 日目の MMF 製剤の体内動態に関する十分な情報がないのが現状である。一方、タクロリムスの体内動態においては、その代謝酵素であるチトクロム P450 (CYP) 3A5や補酵素である POR の遺伝的多型性が個人差を考える上で有用な情報とされている。しかしながら、肝臓移植領域において患者・ドナー双方の CYP3A5 及び POR28 遺伝子多型のタクロリムスの代謝に 及ぼす影響については報告されていない。

以上の背景をふまえ、本研究では、肝臓移植後免疫抑制療法におけるタクロリムス誘発性腎障害の要因分析ならびに腎障害対策に関する検討を行った。

【方法、結果】
第1章 タクロリムス誘発性腎障害の早期検出に資する尿中バイオマーカーの探索
26 名の生体肝移植患者を対象に、タクロリムス誘発性 AKI(acute kidney injury)群と非 AKI 群に分け、AKI のバイオマーカーとして報告されている Neutrophil gelatinase-associated lipocalin (NGAL)、 Liver-type fatty acid binding protein (L-FABP)、Monocyte chemotactic protein-1 (MCP-1) に加え、 CKD を反映する尿中バイオマーカーとして報告されている human epididymis secretory protein 4 (HE4) の 4 分子の挙動についてタクロリムスの投与前後で比較検討を行った。その結果、NGAL、 L-FABP、MCP-1 は両群間で有意な差は認めなかったが、タクロリムス誘発性 AKI 群で HE4 が有意に上昇した。またタクロリムス誘発性 AKI の割合は 23%であった。

第2章 タクロリムス誘発性腎障害の回避を念頭にしたミコフェノール酸モフェチル導入プロトコルの検討
患者 14 名(セルセプト®カプセル使用患者 8 名 とセ ル セ プ ト ® 懸 濁 用 散 31.8% 使用患者 6 名)を対象に移植術後 1 日目の血中濃度を測定し、AUC0-12h を算出した。その結果、カプセル群において血中濃度のピークが認められたのに対し、懸濁用散群では血中濃度のピークが認められなかった。一方で AUC0-12h に有意な差は認められなかった。すべての群においてタクロリムス誘発性 AKI は認められなかった。

第 3 章 肝臓移植後患者におけるタクロリムスの体内動態に及ぼす CYP3A5 及び POR28 遺伝子多型の影響
患者・ドナー65 組(患者:65 名、ドナー:65 名)を対象とし、CYP3A5、POR28 の遺伝子型判定を行い、これらの情報がタクロリムスの体内動態に与える影響についてタクロリムスの血中濃度/投与量 (C/D, concentration/dose) 比 (以下、C/D) 比を用いて検討した。CYP3A5 機能型の患者において少なくとも 1 つの POR*28 対立遺伝子を有する患者は、POR*28 を伴わない患者に比して術後 2, 3 週目においてタクロリムスの C/D 比が有意に低かった。その一方で CYP3A5 機能型のドナーにおいては少なくとも 1 つの POR*28 対立遺伝子を有する患者は、POR*28 を伴わない患者に比してタクロリムスの C/D 比が有意に高かった。しかし、重回帰分析の結果、術後 1 ヶ月間においてタクロリムスの C/D 比に影響を与える因子として、患者の CYP3A5 遺伝子多型は認められたが、ドナーの CYP3A5 遺伝子多型ならびに患者・ドナーの POR28 遺伝子多型は認められなかった。

【考察・まとめ】
第 1 章では、当院の免疫抑制療法におけるタクロリムスによる急性腎障害時に変動する尿中バイオマーカーを探索したところ、尿中 NGAL ではなく HE4 の上昇が認められた。これらのことから、免疫抑制療法の違いによって、タクロリムス誘発性急性腎障害を反映するバイオマーカーが異なることが示唆された。第 2 章では、投与 1 日目の剤型が異なることで MMF の血中濃度の推移に違いがみられることが示された。その一方で剤型間において AUC0-12h に有意な差は認められなかったことから、AUC0-12h が臨床効果に影響するパラメータである可能性が示された。第 3 章では、術後 1 ヶ月間において、タクロリムスの薬物動態には患者の CYP3A5 遺伝子多型の寄与度が高いことが示唆された。また、POR28 遺伝子多型についても少なからず関連している可能性が示された。以上のことから、患者・ドナー双方の CYP3A5 及び POR28 の遺伝子多型情報を加えることが、生体肝移植後のタクロリムス個別化免疫抑制療法の適正化につながる可能性が示された。

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参考文献

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