Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury.
Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury.
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DOI：
10.1186/cc12503
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发表时间：
2013-02-06
期刊：
影响因子：
--
通讯作者：
Kellum JA
中科院分区：
文献类型：
--
作者：
Kashani K;Al-Khafaji A;Ardiles T;Artigas A;Bagshaw SM;Bell M;Bihorac A;Birkhahn R;Cely CM;Chawla LS;Davison DL;Feldkamp T;Forni LG;Gong MN;Gunnerson KJ;Haase M;Hackett J;Honore PM;Hoste EA;Joannes-Boyau O;Joannidis M;Kim P;Koyner JL;Laskowitz DT;Lissauer ME;Marx G;McCullough PA;Mullaney S;Ostermann M;Rimmelé T;Shapiro NI;Shaw AD;Shi J;Sprague AM;Vincent JL;Vinsonneau C;Wagner L;Walker MG;Wilkerson RG;Zacharowski K;Kellum JA
急性肾损伤（阿基）可以迅速发展，并且在干预可能提供益处的时候，临床功能测量通常无法检测到阿基。由于人类阿基的复杂性质，其中存在多种病因，因此难以鉴定肾损伤的早期标志物。本研究的目的是鉴定和验证阿基的新生物标志物。我们在有阿基风险的重症患者中进行了两项多中心观察性研究-发现和验证。在第二项研究（Sapphire）中验证了来自发现的前两个标志物，并与许多先前描述的生物标志物进行了比较。在发现阶段，我们在三个不同的队列中招募了522名成年人，包括败血症，休克，大手术和创伤患者，并检查了300多个标志物。在Sapphire验证研究中，我们入组了744名患有危重病且在入组时没有阿基证据的成人受试者;最终分析队列是728名危重患者的异质样本。主要终点为样本采集后12小时内的中度至重度阿基（KDIGO 2 - 3期）。14%的Sapphire受试者发生中度至重度阿基。来自发现的两个顶级生物标志物得到验证。尿胰岛素样生长因子结合蛋白7（IGFBP 7）和金属蛋白酶组织抑制剂-2（TIMP-2）均为G1期细胞周期阻滞的诱导剂（阿基的关键机制），两者的AUC均为0.80（单独为0.76和0.79）。尿[TIMP-2]·[IGFBP 7]显著上级于所有先前描述的阿基标志物（P <0.002），其中没有一个达到AUC >0.72。此外，当使用考克斯比例风险模型、广义估计方程、综合区分改善或净重新分类改善进行分析时，[TIMP-2]·[IGFBP 7]在添加到9变量临床模型时显著改善了风险分层。最后，在敏感性分析中，[TIMP-2]·[IGFBP 7]仍然显著且上级所有其他标志物，无论参考肌酐方法的变化如何。两种新的阿基标志物已在独立的多中心队列中鉴定和验证。两种标记物均上级现有标记物，提供了临床变量的额外信息，并增加了对阿基的机制见解。ClinicalTrials.gov编号NCT 01209169。
Acute kidney injury (AKI) can evolve quickly and clinical measures of function often fail to detect AKI at a time when interventions are likely to provide benefit. Identifying early markers of kidney damage has been difficult due to the complex nature of human AKI, in which multiple etiologies exist. The objective of this study was to identify and validate novel biomarkers of AKI. We performed two multicenter observational studies in critically ill patients at risk for AKI - discovery and validation. The top two markers from discovery were validated in a second study (Sapphire) and compared to a number of previously described biomarkers. In the discovery phase, we enrolled 522 adults in three distinct cohorts including patients with sepsis, shock, major surgery, and trauma and examined over 300 markers. In the Sapphire validation study, we enrolled 744 adult subjects with critical illness and without evidence of AKI at enrollment; the final analysis cohort was a heterogeneous sample of 728 critically ill patients. The primary endpoint was moderate to severe AKI (KDIGO stage 2 to 3) within 12 hours of sample collection. Moderate to severe AKI occurred in 14% of Sapphire subjects. The two top biomarkers from discovery were validated. Urine insulin-like growth factor-binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases-2 (TIMP-2), both inducers of G1 cell cycle arrest, a key mechanism implicated in AKI, together demonstrated an AUC of 0.80 (0.76 and 0.79 alone). Urine [TIMP-2]·[IGFBP7] was significantly superior to all previously described markers of AKI (P <0.002), none of which achieved an AUC >0.72. Furthermore, [TIMP-2]·[IGFBP7] significantly improved risk stratification when added to a nine-variable clinical model when analyzed using Cox proportional hazards model, generalized estimating equation, integrated discrimination improvement or net reclassification improvement. Finally, in sensitivity analyses [TIMP-2]·[IGFBP7] remained significant and superior to all other markers regardless of changes in reference creatinine method. Two novel markers for AKI have been identified and validated in independent multicenter cohorts. Both markers are superior to existing markers, provide additional information over clinical variables and add mechanistic insight into AKI. ClinicalTrials.gov number NCT01209169.
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影响因子：
14.9
作者：
Rodier, Francis;Campisi, Judith;Bhaumik, Dipa
通讯作者：
Bhaumik, Dipa
急性肾脏损伤的步枪标准与重症患者的医院死亡率有关：一项队列分析。
影响因子：
15.1
作者：
Hoste, Eric A. J.;Clermont, Gilles;Kersten, Alexander;Venkataraman, Ramesh;Angus, Derek C.;De Bacquer, Dirk;Kellum, John A.
通讯作者：
Kellum, John A.
影响因子：
19.6
作者：
Price, Peter M.;Safirstein, Robert L.;Megyesi, Judit
通讯作者：
Megyesi, Judit
影响因子：
120.7
作者：
Uchino, S;Kellum, JA;Ronco, C
通讯作者：
Ronco, C
影响因子：
39.2
作者：
von Elm, Erik;Altman, Douglas G.;Vandenbroucke, Jan P.
通讯作者：
Vandenbroucke, Jan P.