JP4249612B2 - 初期腎機能障害の検査方法 - Google Patents
初期腎機能障害の検査方法 Download PDFInfo
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Description
−ヒトの体液又は組織サンプル中のアポA−IV量を測定し、そして
−アポA−IVの測定値とリファレンス値とを測定する、
ことを特徴とするヒトの初期の腎機能障害を診断する方法により達成される。
本発明の方法を用いて、普通の腎疾患の特定の病理に関わりなく、初期のいかなる腎機能障害も診断することができる。好ましくは、この初期の腎機能障害は、初期糸球体腎炎、初期腎嚢胞、初期慢性「腎盂腎炎」又は初期糖尿病性腎症である。
−腎機能障害に罹患するか又は腎機能障害の危険性を有するヒトから得た体液若しくは組織のサンプルを含有する容器、又はこのサンプルが満たされていると仮定した容器、
−体液又は組織サンプル中のアポA−IV量測定手段、そして
−このヒトの初期腎機能障害の診断を可能にするリファレンス値手段、
を含む。
−ヒトの体液又は組織サンプル中のアポA−IV量を測定し、そして
−アポA−IVの測定値とリファレンス値とを比較する、
ことにより特徴づけられる。
患者:
1997年に、ドイツ(Gottingen、Greifswald、Heidelberg、Homburg/Saar、Munich)、オーストリア(Feldkirch、Innsbruck)及び南チロル(Bozen)の8カ所の腎臓病部門から患者を召集した。患者の約3分の2は2つの部門(Heidelberg及びInnsbruck)から来ていた(23)。前年に少なくとも1回外来を訪れた19〜65歳の白人患者がこの研究に関与した。排除基準は、血清クレアチニンが>6mg/dl、召集時に糖尿病、悪性疾患、肝疾患、甲状腺疾患又は感染症であること、1日蛋白尿>3.5g/1.73m2として定義されるネフローゼ症候群、臓器移植、イオン性造影剤に対するアレルギー、及び妊娠であった。340人の患者が基準を満たし、そのうちの28人には連絡をとれず、85人が研究への参加を拒否した。残りの227人の患者がこの研究に関与した。彼らの特徴を表1に示す。本研究は倫理委員会組織により承認され、被験者は同意書面を提出している。
12時間の一晩絶食後、血清及びEDTA血漿を採取した。低速遠心後、サンプルを凍結させ、解析前に−80℃で保存した(25)。同一の外来訪問時、血清クレアチニンレベルに応じて、イオヘキソールの注入後2〜3の血液サンプルを得、イオヘキソール法によりGFRを測定した(26)。大部分腎機能障害が進行した18人の患者について、コッククロフトとゴールトの式を用いてGFRを計算した(27)。蛋白尿を測定するための24時間尿サンプルの採取に関し、患者は注意深く指示された。
社会科学のための統計パッケージ(SPSS)、ウインドウズ10.0用を用いて統計解析を行った。変数が正常に分散していない場合は、対応のないt検定又はノンパラメトリックウィルコクソン順位和検定により、対照と腎疾患患者とのあいだの連続変数の1変量比較を行った。2元変数はピアソンのχ2検定を用いて比較した。対照と、GFRの三分位値によりサブグループに分けられた腎疾患患者とのあいだの連続変数を、ANOVAを用いて比較した。正常に分散していない変数は、解析前に対数に変換した。スピアマンの相関検定を用いてアポA−IVと他の連続変数とを相関させた。患者の年齢及び蛋白尿についての血清アポA−IV濃度の補正を、直線回帰分析で行った。多重回帰分析を用いてそれぞれの変数と血清アポA−IV濃度との関連性を調査した。過去に発生した一般的な粥状硬化性事象についての予測変数を同定するためにロジスチック回帰分析を行った。
アポA−IV濃度に対する腎機能の影響:
腎疾患患者は、対照と比較して、全コレステロール濃度、トリグリセリド濃度及びLp(a)濃度が有意に高かったが、HDL及びLDLコレステロールレベルに変化はなかった(表2)。アポA−I及びアポBの濃度は、患者において有意に低かった。最も際立った変化の1つはアポA−IV濃度であり、患者では対照よりも約70%も高かった(24.6±8.6対14.6±4.2mg/dl、P<0.001)。
「ln蛋白尿」は変数が対数に変換されていることを意味する。
最後に、アポA−IV濃度と存在する粥状硬化性合併症との関連性について解析した。26人の患者は、36の粥状硬化性事象を体験しており、その中には17の冠事象(多くは心筋梗塞及び大動脈冠動脈バイパス)、9の卒中、及び末梢動脈系に影響する10の事象が含まれる。粥状硬化性合併症を有する患者は、GFRの3つの範囲全てにおいて、合併症のない患者と比較して、少なくともアポA−IV濃度が低下する傾向を示した(表6)。十中八九各範囲のサンプルサイズが小さいために、全ての群で差が有意なわけではなかった。この解析において、全患者群に対し、GFRを含むロジスチック回帰分析も行った。最も貧弱なモデルが、粥状硬化性合併症に関連する3つの変数を同定した:年齢、アポA−IV、及び性別である(表7)。アポA−IVがそれぞれ1mg/dl増加すると、粥状硬化性合併症に対するオッズ比が8%減少した(P=0.011)。低分子アポ(a)表現型及びGFRは粥状硬化性合併症との関連性が標準に満たなかった(表7)。
議論:
アポA−IV濃度に対する腎機能の影響:
ここで提示する研究は血清アポA−IV濃度に対する腎機能の強力な影響を証明している。初期の研究は、末期腎疾患患者アポA−IV濃度が顕著に増加することを示していた(18〜20、22)。しかしながら、ほとんどGFR値が正常な腎疾患によるわずかな障害でさえアポA−IV濃度の有意な増加を伴うことは全く知られていなかった。したがって、アポA−IVは腎機能障害の初期マーカーであると思われる。これはまたSun et al.による中高年の男性及び女性における最も最近の研究が、アポA−IV濃度の主要な決定要素として糖尿病を同定したことの理由であるかもしれない(29)。多くの糖尿病患者が腎機能障害を有しているため、そして腎機能の非常に軽度な障害がすでにアポA−IVの増加と関連しているため、糖尿病自体というよりも腎機能がアポA−IVの増加の原因であると考えられる。これは、糖尿病はアポA−IVの増加が生じていたにも関わらず本研究において排除基準であったため、本データによりさらに支持される。さらに、末期腎疾患患者における初期の研究において、189人の糖尿病患者と513人の非糖尿病患者を比較して、アポA−IVレベルに差は観察されなかった(22)。しかしながら、糖尿病患者における他の研究は、これらの患者のアポA−IV上昇について報告しているが、腎機能について注意深く評価していない(30、31)。Verges et al.は腎不全患者のみを排除したが、彼らは排除基準についての詳細な情報を提供しなかった(30、31)。しかしながら、およそ40%の患者はミクロアルブミン尿症であり(31)、少なくとも、アポA−IV濃度に有意に影響することが予想される腎疾患の併発を示している。
最近、血管造影的に明示されたCADを有する114人の白人試験男性において、年齢を調整した114人の男性対照と比較して、有意に低いアポA−IVレベルが初めて報告された。(10.2±3.8mg/dl対15.1±4.0mg/dl、P<0.001)。これはアポA−IVレベル間の関係を反対にし、血管造影的に示されたCADを有する68人のアジアのインド人男性及び年齢が一致する68人の対照の独立サンプルにおいてCADの存在が確認された。この知見と一致して、事象のない対象と比較し、より低濃度のアポA−IVがすでに粥状硬化性事象を体験している患者において観察された。これは3つの範囲のGFR全てにおいて観察されたが、最も低いGFRの範囲においてのみ、通常の有意レベルに達した。これは、1つの個別範囲における事象を有する少人数の患者により説明されるであろう(表6)。統計モデルに対してGFRが提示されているロジスチック回帰分析において全群が検討されたとき、GFRにかかわらず、アポA−IVは事象に対する信頼できる予測変数であることを証明した(表7)。この関係が非常に起こり得る証拠は強力である:コレステロール逆輸送のいくつかの工程へのアポA−IVの関与を示す細胞培養研究(9〜14)、並びに抗酸化特性(33);粥状動脈硬化症を減少させたマウスにおけるヒト及びマウスアポA−IVの過剰発現(16、17);そして最後に、血管造影的に証明されたCADを有する男性におけるより低濃度のアポA−IVについての最初の結果(34)。
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Claims (18)
- ヒトにおいて初期の腎機能障害を検査する方法であって、以下の行程:
−ヒトの体液又は組織サンプル中のアポA−IVの量を測定し、そして
−アポA−IVの測定値とリファレンス値とを比較する、
ことを特徴とし、初期腎機能障害が、初期糸球体腎炎、初期腎嚢胞、又は初期慢性腎盂腎炎である、前記方法。 - このリファレンス値が腎機能障害のないヒトから得られることを特徴とする、請求項1に記載の方法。
- 初期の腎機能障害が、体液又は組織サンプル中のアポA−IVの増加レベルとして検査されることを特徴とする、請求項1又は2に記載の方法。
- この増加値が、リファレンス値よりも少なくとも50%高いことを特徴とする、請求項3に記載の方法。
- このリファレンス値が、10〜18mgのアポA−IV/dl血清であることを特徴とする、請求項3又は4に記載の方法。
- 初期の腎機能障害が、22mgのアポA−IV/dl血清よりも高値として検査されることを特徴とする、請求項3〜5のいずれか1項に記載の方法。
- 初期の腎機能障害が、28mgのアポA−IV/dl血清よりも高値として検査されることを特徴とする、請求項6項に記載の方法。
- 冠動脈疾患に罹患するヒト又は粥状硬化性合併症に罹患するヒトに対し、腎機能障害がなく且つ冠動脈疾患も粥状硬化性合併症もないヒトよりも低い、腎機能障害の欠如を示すリファレンス値が提供されることを特徴とする、請求項1〜7のいずれか1項に記載の方法。
- 初期腎機能障害の欠如を示すこのより低いリファレンス値が、腎機能障害がなく且つ冠動脈疾患も粥状硬化性合併症もないヒトのリファレンス値よりも少なくとも20%低いことを特徴とする、請求項8に記載の方法。
- 初期腎機能障害の欠如を示すこのより低いリファレンス値が、腎機能障害がなく且つ冠動脈疾患も粥状硬化性合併症もないヒトのリファレンス値よりも少なくとも40%低いことを特徴とする、請求項8に記載の方法。
- このより低いリファレンス値が、6〜14mgのアポA−IV/dl血清であることを特徴とする、請求項8〜10のいずれか1項に記載の方法。
- 冠動脈疾患又は粥状硬化性合併症に罹患するこのヒトの初期腎機能障害が、14mgのアポA−IV/dl血清よりも高いレベルとして検査されることを特徴とする、請求項8〜11のいずれか1項に記載の方法。
- 初期腎機能障害の進行を観察するための、請求項1〜12に記載の方法の使用。
- 冠動脈疾患に罹患するヒト又は粥状硬化性合併症に罹患するヒトの鑑別検査のための、請求項13に記載の使用。
- −腎機能障害に罹患するか若しくは腎機能障害の危険性を有するヒトから得た体液若しくは組織サンプルを含有する容器、又はこのサンプルが満たされていると仮定した容器、
−体液又は組織サンプル中のアポA−IV量測定手段、そして
−このヒトの初期腎機能障害の検査を可能にするリファレンス値手段、
を含む、請求項1〜12のいずれか1項に記載の方法を実施するためのキットの使用。 - このアポA−IV量測定手段が、抗アポA−IV抗体、2次抗体、アポA−IV−RNA特異的核酸、アポA−IV特異的酵素試験、アポA−IV特異的ELISA又はそれらの組合せから選択されることを特徴とする、請求項15に記載の使用。
- このリファレンス値が、予め決められた量のアポA−IVを含有する容器、健常人の体液若しくは組織サンプルを含有する容器、腎機能障害に罹患するヒトの体液若しくは組織サンプルを含有する容器、検量線、キットの使用説明書、又はそれらの組合せから選択されることを特徴とする、請求項15又は16に記載の使用。
- 初期腎機能障害に罹患するヒトにおいて冠動脈性心疾患を検査する方法であって、以下の工程:
−ヒトの体液又は組織サンプル中のアポA−IV量を測定し、そして
−アポA−IVの測定値をリファレンス値と比較する、
ことを特徴とし、初期腎機能障害が、初期糸球体腎炎、初期腎嚢胞、又は初期慢性腎盂腎炎である、前記方法。
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PCT/AT2002/000219 WO2003010544A2 (de) | 2001-07-26 | 2002-07-23 | Verfahren zur diagnose von nierenschädigungen im frühstadium |
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