NGAL、KIM-1、TIMP-2对脓毒症所致AKI早期诊断价值的前瞻性临床队列研究

目的评估血浆中性粒细胞明胶酶相关载脂蛋白（pNGAL）、尿中性粒细胞明胶酶相关载脂蛋白（uNGAL）、尿肾损伤分子-1（KIM-1）和尿金属蛋白酶抑制物-2（TIMP-2）对脓毒症急性肾损伤（AKI）的早期诊断价值。 方法收集2015年6月至2016年1月期间入住苏北人民医院重症医学科（ICU）的脓毒症患者,连续观察72 h,以是否出现AKI进行分组,即脓毒症AKI组及脓毒症非AKI组,收集各组患者的一般资料,入ICU时（0 h）,入ICU后6、12、24、48、72 h时的外周静脉血及尿液样本,并采用酶联免疫吸附试验（ELISA）测定各时刻pNGAL、uNGAL、尿KIM-1、尿TIMP-2的表达水平,绘制受试者工作特征（ROC）曲线,计算曲线下面积（AUC）,评价pNGAL、uNGAL、尿KIM-1、尿TIMP-2对脓毒症AKI的早期诊断价值。 结果研究期间共有522例患者入住我院ICU,最终纳入符合研究标准的脓毒症患者共90例,其中38例发生AKI,占42.22%。脓毒症AKI组患者pNGAL、uNGAL水平在入住ICU后6 h开始升高（P<0.05）,12 h开始明显升高,24 h达到峰值,在6、12、24、48、72 h时pNGAL浓度明显高于同时刻脓毒症非AKI组患者,差异具有统计学意义（P<0.05）。脓毒症AKI组患者尿KIM-1、尿TIMP-2水平在入住ICU后6 h开始升高（P<0.05）,12 h开始明显升高并达到峰值,在6、12、24、48、72 h时尿KIM-1水平明显高于同时刻脓毒症非AKI组患者,差异具有统计学意义（P<0.05）。ROC曲线显示pNGAL、uNGAL、尿KIM-1、尿TIMP-2的ROC的AUC分别为0.862、0.858、0.788、0.771,其诊断截断值分别为119.30、120.36、90.07、3299.50 ng/L。各时间点绘制ROC曲线显示,在T-12 h时,pNGAL、尿KIM-1及尿TIMP-2的ROC的AUC分别为1.00、0.96、0.92,在T-18 h时,uNGAL的ROC的AUC为0.95。 结论脓毒症AKI患者pNGAL、uNGAL、尿KIM-1、尿TIMP-2表达水平明显早于血肌酐升高,早于AKI临床诊断标准,有望用于脓毒症AKI的早期诊断。     

舌下微循环监测对脓毒症休克患者并发急性肾损伤的预测价值

目的探讨舌下微循环监测对脓毒症休克患者并发急性肾损伤（AKI）的预测价值。 方法采用前瞻性研究方法,选择2020年5月至2021年5月我院重症医学科连续收治的55例脓毒症休克患者,使用旁流暗视野成像技术（SDF）观察其0、6、24 h舌下微循环图像,根据是否并发AKI分为AKI组（29例）和非AKI组（26例）。比较2组间体循环指标包括心率（HR）、平均动脉压（MAP）、中心静脉压（CVP）,以及舌下微循环指标包括乳酸（Lac）、中心静脉血氧饱和度（ScvO₂）、小血管总密度（TVDs）、灌注小血管密度（PVDs）、小血管灌注比例（PPVs）、变异指数（HI）的变化,采用多因素二元logistic回归分析脓毒症休克并发AKI的危险因素;通过受试者工作特征曲线（ROC）的曲线下面积（AUC）评价舌下微循环指标对脓毒症休克患者并发AKI的预测价值。 结果在0、6、24 h,与非AKI组相比,AKI组Lac、HI均明显高于非AKI组,PPVs低于非AKI组,差异均有统计学意义（P均＜0.05）。多因素logistic回归分析显示,在0 h HI、PPVs是脓毒症休克患者并发AKI的独立危险因素（P＜0.05）。ROC曲线分析显示,以HI=0.8为临界值时,其预测脓毒症休克患者并发AKI的敏感度为86.21%,特异度为96.15%,AUC为0.917（95%CI：0.811~0.974,P＜0.001）,以PPVs=81.2%为临界值时,敏感度为72.42%,特异度为96.15%,AUC为0.902（95%CI：0.791~0.966,P＜0.001）,HI联合PPVs预测脓毒症休克患者并发AKI的AUC为0.928（95%CI：0.827~0.981,P＜0.001）。 结论舌下微循环指标HI联合PPVs对于脓毒症休克患者并发AKI的早期预测有一定的临床参考意义。     

尿金属蛋白酶组织抑制剂-2·胰岛素样生长因子结合蛋白-7对脓毒血症患者急性肾损伤和肾替代治疗的早期预测价值

目的探讨尿金属蛋白酶组织抑制剂-2(TIMP-2)·胰岛素样生长因子结合蛋白-7(IGFBP-7)对脓毒血症患者急性肾损伤(AKI)和肾替代治疗(RRT)的早期预测价值。方法选取121例脓毒血症患者和24例体检健康者,后者作为对照组。记录上述人群一般资料,检测并比较入院时的血肌酐(sCr)、乳酸脱氢酶(LDH)、C-反应蛋白(CRP)、降钙素原(PCT)、白细胞计数(WBC)、D-二聚体(D-D)、纤维蛋白原(Fib)、TIMP-2、IGFBP-7水平。检测脓毒血症患者入住ICU后6、12、24、36 h尿TIMP-2、尿IGFBP-7,计算尿TIMP-2·IGFBP-7。将所有脓毒血症患者根据是否发生AKI分为AKI组和非AKI组,采用受试者工作特征曲线(ROC)及曲线下面积(AUC)判断不同时间点尿TIMP-2·IGFBP-7对AKI的预测价值,确定最佳临界值,分析尿TIMP-2·IGFBP-7与AKI的关系。将AKI患者分为肾替代治疗(RRT)组和非RRT组,比较两组间尿TIMP-2·IGFBP-7,利用ROC曲线及AUC判断不同时间点尿TIMP-2·IGFBP-7对RRT的预测价值,确定最佳临界值。结果121例脓毒血症患者中发生AKI 45例。AKI组、非AKI组LDH、CRP、PCT、WBC、D-D、Fib水平均高于对照组(P<0.05),非AKI组序贯器官衰竭评估(SOFA)评分、血浆输注量、RBC输注量均低于AKI组,发病至入住ICU时间长于AKI组,差异均有统计学意义(P<0.05);入住ICU后6、12、24、36 h尿TIMP-2·IGFBP-7与AKI的发生呈正相关(r=0.206、0.383、0.415、0.462,均P<0.05),随着时间推移r增大。入住ICU后6、12、24、36 h尿TIMP-2·IGFBP-7用于预测AKI的AUC分别为0.740、0.788、0.795、0.877,最佳临界值分别为0.415、0.485、0.591、0.825 ng/(mL^2·10^3);RRT组尿TIMP-2·IGFBP-7高于非RRT组,入住ICU后6、12、24、36 h尿TIMP-2·IGFBP-7用于预测RRT的AUC分别为0.575、0.804、0.883、0.809,最佳临界值分别为0.518、0.825、0.917、1.015 ng/(mL^2·10^3)。结论尿TIMP-2·IGFBP-7是脓毒血症患者AKI发生和AKI患者行RRT的独立预测指标,具有较好的早期预测价值。     

超声造影在脓毒症相关急性肾损伤诊断及预后预测中的临床价值

目的 应用超声造影诊断脓毒症相关急性肾损伤（AKI）并预测其预后，探讨其临床价值。方法 前瞻性连续纳入2021年8月至2022年4月我院重症医学科收治的脓毒症患者51例，分别于入院24 h内（D1）及第3天（D3）行超声造影，获取峰值强度（PI）、达峰时间（TTP）、曲线下面积（AUC）。以是否发生AKI将患者分为AKI组27例和非AKI组24例，进一步以是否为持续性AKI将AKI组患者分为AKI持续组8例和AKI恢复组19例，以是否死亡将AKI组患者分为存活组22例和死亡组5例，比较各组间超声造影定量参数的差异。应用单因素Logistic回归分析脓毒症相关AKI的影响因素；绘制受试者工作特征（ROC）曲线分析超声造影定量参数预测脓毒症相关AKI的诊断效能。结果 AKI组与非AKI组AUC、PI比较差异均有统计学意义（均P<0.05）。与AKI持续组比较，AKI恢复组D3时AUC、PI均增加，TTP减少，差异均有统计学意义（均P<0.05）;AKI恢复组D3时AUC、PI均较D1时增加，TTP较D1时减少，差异均有统计学意义（均P<0.05）。存活组与死亡组不同时间超...     

肾脏超声联合指标对非脓毒症危重患者急性肾损伤的预测价值

目的:探讨肾动脉阻力指数（renal resistive index,RRI）和肾能量多普勒超声（power Doppler ultrasound,PDU）半定量评分联合指标对入住重症监护室（intensive care unit,ICU）的非脓毒症患者发生急性肾损伤（acute kidney injury,AKI）的预测价值。方法:采用前瞻性观察性研究的方法,纳入2018年1月至2019年8月期间于沧州市中心医院急诊ICU住院的非脓毒症危重患者作为研究对象。记录一般资料;于入ICU 6 h内应用医学超声仪完成RRI和PDU半定量评分测量。入ICU第5天依据改善全球肾脏病预后组织（KDIGO）标准评估肾功能,按肾功能情况分为AKI 3期组（入ICU 5 d内进展为AKI 3期）和AKI 0~2期组（未发生AKI或发生AKI 1或2期）。分别在非脓毒症和急性心力衰竭患者中比较不同AKI分期两组间各指标的差异。计量资料两组间比较采用独立样本 t检验或Mann-Whiney秩和检验。计数资料两组间比较采用卡方检验。绘制受试者工作特征曲线（receiver operator characteristic,ROC）分析RRI、PDU评分、RRI-RDU/10、RRI/PDU和RRI+PDU对AKI 3期的预测价值。使用Delong检验方法比较每个预测因子之间ROC曲线下面积的差异。 结果:共纳入110例非脓毒症危重患者（无AKI 51例,AKI 1期21例,AKI 2期11例,AKI 3期27例）,其中急性心力衰竭患者63例（无AKI 21例,AKI 1期15例,AKI 2期7例,AKI 3期20例）。在非脓毒症患者及急性心力衰竭患者中,AKI 3期患者的急性生理学与慢性健康状况（APACHEⅡ）评分、序贯器官衰竭（sequential organ failure assessment,SOFA）评分、动脉乳酸水平、机械通气比例、血管活性药物比例、28 d病死率、肌酐、RRI、RRI-PDU/10、RRI/PDU、RRI+PDU及连续性肾脏替代治疗（continuous renal replacement therapy,CRRT）比例均明显高于AKI 0~2期患者（ P<0.05）;而尿量和PDU评分明显低于AKI 0~2期患者（ P<0.05）。非脓毒症患者中,RRI/PDU[曲线下面积(AUC)=0.915,95%可信区间( CI)：0.846~0.959, P<0.01）及RRI+PDU（AUC=0.914,95% CI：0.845~0.959, P<0.01）对AKI 3期的预测价值最高,且两者与RRI（AUC=0.804,95% CI：0.718~0.874, P<0.01）和PDU评分（AUC=0.868,95% CI：0.791~0.925, P<0.01）,差异均有统计学意义（均 P<0.05）;RRI/PDU预测AKI 3期的最佳临界值为0.355（灵敏度92.6%,特异度81.9%,约登指数0.745）;RRI-PDU/10（AUC=0.899,95% CI：0.827~0.948, P<0.01）对AKI 3期的预测价值亦优于RRI和PDU评分,但较RRI/PDU和RRI+PDU略差,仅RRI与RRI-PDU/10之间差异有统计学意义（ P<0.05）。在急性心力衰竭患者中,RRI/PDU（AUC=0.962,95% CI：0.880~0.994, P<0.01）及RRI+PDU（AUC=0.962,95% CI：0.880~0.994, P<0.01）对AKI 3期的预测价值亦最高,且两者与RRI（AUC=0.845,95% CI：0.731~0.924, P<0.01）和PDU评分（AUC=0.913,95% CI：0.814~0.969, P<0.01）两两间均差异有统计学意义（均 P<0.05）;RRI/PDU预测AKI 3期的最佳临界值为0.360（灵敏度95.0%,特异度90.7%,约登指数0.857）;RRI-PDU/10（AUC=0.950,95% CI:0.864~0.989, P<0.01）对AKI 3期的预测价值亦优于RRI和PDU评分,但较RRI/PDU和RRI+PDU略差,仅RRI与RRI-PDU/10之间差异有统计学意义（ P<0.05）。 结论:RRI和PDU评分的联合指标可有效预测非脓毒症患者发生AKI 3期,尤其在急性心力衰竭患者中表现更优。RRI与PDU评分的比值对AKI 3期的预测价值以及实用价值最好,建议临床推广应用。     

外周血Th17细胞对脓毒症急性肾损伤的早期诊断价值

目的探讨外周血Th17细胞水平在脓毒症急性肾损伤(AKI)早期诊断中的临床意义。方法选取该院2012年8月至2016年8月收治的脓毒症患者300例作为研究对象,其中65例患者合并AKI;另选取80例健康体检者作为对照组。检测研究对象外周血Th17细胞、白细胞介素(IL)-17、IL-6及胱抑素C(Cys C)水平,记录急性生理与慢性健康状况(APACHEⅡ)评分情况;对外周血Th17细胞与IL-17、IL-6、Cys C水平及APACHEⅡ评分进行相关性分析,通过受试者工作特征曲线(ROC曲线)评价外周血Th17细胞水平在早期诊断脓毒症AKI中的诊断价值。结果脓毒症AKI组患者外周血Th17细胞、IL-17、IL-6及Cys C水平明显高于非AKI组和对照组,差异均有统计学意义(P0.05)。给予相应治疗后,AKI组患者外周血Th17细胞、IL-17、IL-6及Cys C水平均较治疗前明显下降,差异有统计学意义(P0.05);相关性分析显示,外周血Th17细胞水平与IL-17、IL-6、Cys C及APACHEⅡ评分均呈正相关(r=0.81、0.65、0.72、0.76,P0.01)。ROC曲线分析显示,外周血Th17细胞对诊断脓毒症AKI的敏感度和特异度分别为86.1%和83.5%,ROC曲线下面积(AUC)为0.850(95%CI:0.771~0.912),明显高于IL-17、IL-6及Cys C。结论外周血Th17细胞水平在脓毒症AKI患者中明显升高,可作为脓毒症AKI的早期诊断标志物。     

血浆可溶性髓样细胞触发受体1对成人脓毒症患者诊断价值的Meta分析

目的评价血浆可溶性髓样细胞触发受体1（sTREM-1）对成人脓毒症患者的诊断价值。 方法检索PubMed、Embase、Cochrane图书馆、中国生物医学文献数据库（CBM）、中国期刊全文数据库（CNKI）、万方数据库和中文科技期刊全文库（VIP）数据库从建库至2017年5月发表的有关血浆sTREM-1对成人脓毒症患者诊断价值的文献。采用双变量模型计算合并诊断比值比（DOR）、合并敏感度、合并特异度、合并阳性似然比（PLR）及合并阴性似然比（NLR）。进行合并受试者工作特征（SROC）曲线，获得曲线下面积（AUC）。 结果最终纳入30篇文献，共3 349例患者。Meta分析显示，合并DOR为20.03[95%置信区间（CI）（12.20，32.87）]、合并敏感度为0.82[95% CI（0.77，0.86）]、合并特异度为0.81 [95% CI（0.76，0.85）]、合并PLR为4.36 [95% CI（3.37，5.64）]、合并NLR为0.22[95%CI（0.16，0.29）]。SROC曲线显示合并AUC为0.89[95%CI（0.85，0.91）]。 结论血浆sTREM-1对诊断成人脓毒症患者具有中度诊断价值。     

肾脏超声联合指标对非脓毒症危重患者急性肾损伤的预测价值

目的:探讨肾动脉阻力指数（renal resistive index,RRI）和肾能量多普勒超声（power Doppler ultrasound,PDU）半定量评分联合指标对入住重症监护室（intensive care unit,ICU）的非脓毒症患者发生急性肾损伤（acute kidney injury,AKI）的预测价值。方法:采用前瞻性观察性研究的方法,纳入2018年1月至2019年8月期间于沧州市中心医院急诊ICU住院的非脓毒症危重患者作为研究对象。记录一般资料;于入ICU 6 h内应用医学超声仪完成RRI和PDU半定量评分测量。入ICU第5天依据改善全球肾脏病预后组织（KDIGO）标准评估肾功能,按肾功能情况分为AKI 3期组（入ICU 5 d内进展为AKI 3期）和AKI 0~2期组（未发生AKI或发生AKI 1或2期）。分别在非脓毒症和急性心力衰竭患者中比较不同AKI分期两组间各指标的差异。计量资料两组间比较采用独立样本 t检验或Mann-Whiney秩和检验。计数资料两组间比较采用卡方检验。绘制受试者工作特征曲线（receiver operator characteristic,ROC）分析RRI、PDU评分、RRI-RDU/10、RRI/PDU和RRI+PDU对AKI 3期的预测价值。使用Delong检验方法比较每个预测因子之间ROC曲线下面积的差异。 结果:共纳入110例非脓毒症危重患者（无AKI 51例,AKI 1期21例,AKI 2期11例,AKI 3期27例）,其中急性心力衰竭患者63例（无AKI 21例,AKI 1期15例,AKI 2期7例,AKI 3期20例）。在非脓毒症患者及急性心力衰竭患者中,AKI 3期患者的急性生理学与慢性健康状况（APACHEⅡ）评分、序贯器官衰竭（sequential organ failure assessment,SOFA）评分、动脉乳酸水平、机械通气比例、血管活性药物比例、28 d病死率、肌酐、RRI、RRI-PDU/10、RRI/PDU、RRI+PDU及连续性肾脏替代治疗（continuous renal replacement therapy,CRRT）比例均明显高于AKI 0~2期患者（ P<0.05）;而尿量和PDU评分明显低于AKI 0~2期患者（ P<0.05）。非脓毒症患者中,RRI/PDU[曲线下面积(AUC)=0.915,95%可信区间( CI)：0.846~0.959, P<0.01）及RRI+PDU（AUC=0.914,95% CI：0.845~0.959, P<0.01）对AKI 3期的预测价值最高,且两者与RRI（AUC=0.804,95% CI：0.718~0.874, P<0.01）和PDU评分（AUC=0.868,95% CI：0.791~0.925, P<0.01）,差异均有统计学意义（均 P<0.05）;RRI/PDU预测AKI 3期的最佳临界值为0.355（灵敏度92.6%,特异度81.9%,约登指数0.745）;RRI-PDU/10（AUC=0.899,95% CI：0.827~0.948, P<0.01）对AKI 3期的预测价值亦优于RRI和PDU评分,但较RRI/PDU和RRI+PDU略差,仅RRI与RRI-PDU/10之间差异有统计学意义（ P<0.05）。在急性心力衰竭患者中,RRI/PDU（AUC=0.962,95% CI：0.880~0.994, P<0.01）及RRI+PDU（AUC=0.962,95% CI：0.880~0.994, P<0.01）对AKI 3期的预测价值亦最高,且两者与RRI（AUC=0.845,95% CI：0.731~0.924, P<0.01）和PDU评分（AUC=0.913,95% CI：0.814~0.969, P<0.01）两两间均差异有统计学意义（均 P<0.05）;RRI/PDU预测AKI 3期的最佳临界值为0.360（灵敏度95.0%,特异度90.7%,约登指数0.857）;RRI-PDU/10（AUC=0.950,95% CI:0.864~0.989, P<0.01）对AKI 3期的预测价值亦优于RRI和PDU评分,但较RRI/PDU和RRI+PDU略差,仅RRI与RRI-PDU/10之间差异有统计学意义（ P<0.05）。 结论:RRI和PDU评分的联合指标可有效预测非脓毒症患者发生AKI 3期,尤其在急性心力衰竭患者中表现更优。RRI与PDU评分的比值对AKI 3期的预测价值以及实用价值最好,建议临床推广应用。     

金属蛋白酶组织抑制剂-2联合胰岛素样生长因子结合蛋白-7对于急性肾损伤早期诊断及预后评估的临床意义

急性肾损伤（AKI）是重症患者常见的临床综合征,早期诊断可显著降低患者病死率。血肌酐和尿量作为传统诊断指标存在滞后性,近年来研究发现的一批新型生物标志物中,联合应用表达于肾小管细胞的与细胞损伤相关的细胞周期标志物金属蛋白酶组织抑制剂-2（TIMP-2）与胰岛素样生长因子结合蛋白-7（IGFBP-7）早期预测AKI的发生风险并对患者预后进行早期评估。本文将主要叙述细胞周期标志物TIMP-2和IGFBP-7用于AKI早期诊断及预后评估的相关内容。     

脓毒症患者血清 YKL-40 水平检测与急性肾损伤早期诊断的相关性研究

目的　探究脓毒症患者血清人类软骨糖蛋白 -39(YKL-40) 水平检测与急性肾损伤 (acute kidney injury, AKI) 早期诊断的相关性研究。方法　选择 2018 年 7 月～ 2020 年 2 月西安高新医院急诊科收治的 170 例脓毒症患者为研究对象，根据患者入住 ICU 后 24 h 内是否发生 AKI 分为 AKI 组和非 AKI 组。采用酶联免疫吸附法 (ELISA) 检测血清 YKL40 的水平。结果 AKI 组和非 AKI 组的平均年龄、吸烟史、饮酒史、白细胞计数 (white blood cell count, WBC) 比较差异均无统计学意义 (t=0.37,χ2=1.71,χ2=0.90,t=0.67, 均 P ＞ 0.05)，AKI 组的血肌酐 (serum creatinine, SCr) 和 YKL-40 水平均高于非 AKI 组，其差异均有统计学意义 (χ2=5.97，10.11，均 P ＜ 0.05)。脓毒症伴 AKI- Ⅲ期患者血清 YKL-40 水平高于脓毒症伴 AKI- Ⅱ期和 AKI- Ⅰ期，脓毒症伴 AKI- Ⅱ期显著高于 AKI- Ⅰ期，其组间差异具有统计学意义 (F=1.37，P=0.00)。Pearson 相关法分析结果显示，血清 YKL-40 水平与 SCr 和 AKI 分期呈正相关关系 (r= 0.19，0.25，P=0.00)。ROC 曲线分析结果显示，区别诊断 AKI 及非 AKI 患者时，血清 YKL-40 的 AUC 为 0.88(95%CI 0.81~0.94)，当 cut-off值为 4.20 ng/mg 时，特异度和灵敏度分别为 0.75 和 0.78。区别诊断脓毒症伴 AKI- Ⅲ期与 AKI-Ⅰ/Ⅱ期患者时，血清YKL-40 的 AUC 为 0.82(95%CI 0.71~0.94)，当 cut-off 值为 6.79 ng/mg 时，特异度和灵敏度分别为 0.83 和 0.72。结论血清 YKL-40 在脓毒症伴 AKI 患者中高表达，可用于诊断 AKI 和判断 AKI 的严重程度。     

Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury

Introduction

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.

Methods

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.

Results

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.

Conclusions

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.

Trial registration

ClinicalTrials.gov number {"type":"clinical-trial","attrs":{"text":"NCT01209169","term_id":"NCT01209169"}}NCT01209169.     

Is plasma neutrophil gelatinase-associated lipocalin a predictive biomarker for acute kidney injury in sepsis patients? A systematic review and meta-analysis

PurposeNeutrophil gelatinase-associated lipocalin (NGAL) is a useful biomarker for early diagnosis of acute kidney injury (AKI). However, the diagnostic value of NGAL for predicting AKI in sepsis patients is unclear.MethodsMEDLINE, EMBASE, and Cochrane Library databases were searched to identify research publications.ResultsTwelve studies from 9 countries including a total of 1582 patients, of whom 315 (19.9%) developed AKI, were included in the study; plasma NGAL levels were significantly higher in adult sepsis patients with AKI than in those without AKI (mean difference, 274.65; 95% confidence interval [CI], 106.16-443.15; I² = 94%). Urine NGAL levels were not significantly different. The diagnostic odds ratio of plasma NGAL for predicting AKI in sepsis patients was 6.64 (95% CI, 3.80-11.58). The diagnostic accuracy of plasma NGAL was 0.881 (95% CI, 0.819-0.923) for sensitivity, 0.474 (95% CI, 0.367-0.582) for specificity, 0.216 (95% CI, 0.177-0.261) for positive predictive value and 0.965 (95% CI, 0.945-0.977) for negative predictive value.ConclusionPlasma NGAL has a high sensitivity and a high negative predictive value for detection of AKI in adult sepsis patients. However, its low specificity and low positive predictive value could limit its clinical utility. The usefulness of urine NGAL was not revealed in this study.     

Evaluation of urinary tissue inhibitor of metalloproteinase-2 in acute kidney injury: a prospective observational study

Introduction

Tissue inhibitor of metalloproteinase-2 (TIMP-2) is an emerging acute kidney injury (AKI) biomarker. We evaluated the performance of urinary TIMP-2 in an adult mixed ICU by comparison with other biomarkers that reflect several different pathways of AKI.

Methods

In this study, we prospectively enrolled 98 adult critically ill patients who had been admitted to the adult mixed ICU. Urinary TIMP-2 and N-acetyl-β-d-glucosaminidase (NAG) and plasma neutrophil gelatinase-associated lipocalin (NGAL), interleukin-6 (IL-6) and erythropoietin (EPO) were measured on ICU admission. We evaluated these biomarkers’ capability of detecting AKI and its severity as determined by using the Kidney Disease Improving Global Outcomes serum creatinine criteria, as well as its capacity to predict in-hospital mortality. The impact of sepsis, the leading cause of AKI in ICUs, was also evaluated.

Results

We found AKI in 42 patients (42.9%). All biomarkers were significantly higher in AKI than in non-AKI. In total, 27 patients (27.6%) developed severe AKI. Urinary TIMP-2 was able to distinguish severe AKI from non-severe AKI with an area under the receiver operating characteristic curve (AUC-ROC) of 0.80 (95% confidence interval, 0.66 to 0.90). A total of 41 cases (41.8%) were complicated with sepsis. Although plasma NGAL and IL-6 were increased by sepsis, urinary TIMP-2 and NAG were increased not by sepsis, but by the presence of severe AKI. Plasma EPO was increased only by septic AKI. In-hospital mortality was 15.3% in this cohort. Urinary TIMP-2 and NAG, and plasma NGAL, were significantly higher in non-survivors than in survivors, although plasma IL-6 and EPO were not. Among the biomarkers, only urinary TIMP-2 was able to predict in-hospital mortality significantly better than serum creatinine.

Conclusion

Urinary TIMP-2 can detect severe AKI with performance equivalent to plasma NGAL and urinary NAG, with an AUC-ROC value higher than 0.80. Furthermore, urinary TIMP-2 was associated with mortality. Sepsis appeared to have only a limited impact on urinary TIMP-2, in contrast to plasma NGAL.

Electronic supplementary material

The online version of this article (doi:10.1186/s13054-014-0716-5) contains supplementary material, which is available to authorized users.     

A promising marker in early diagnosis of septic acute kidney injury of critically ill patients: urine insulin like growth factor binding protein-7

Aim: An ideal biomarker for early diagnosis of septic acute kidney injury (AKI) should reflect renal stress or damage at initiation point, at cellular level. The aim of this study was to assess the role of a urinary cell cycle arrest marker, insulin-like growth factor-binding protein 7 (IGFBP7) in early diagnosis of septic AKI in adult critical care patients.

Methods: This was a single-center prospective cohort study. Patients without AKI, admitted to a medical intensive care unit (ICU) between January 2010 and March 2013, were included. According to ‘sepsis’ and ‘AKI’ development during their ICU stay, they were grouped as ‘sepsis-non AKI’, ‘sepsis-AKI’ and ‘non-sepsis-non AKI (control)’. Among these groups, urine IGFBP7 was studied and compared with Human ELISA Kit/96 Test/USCNK^® first on admission and then on daily collected serial urine samples.

Results: A total of 118 patients formed the cohort; 52 in sepsis-non AKI, 43 in sepsis-AKI, 23 in control group. Admission urine IGFBP7 predicted septic AKI development with 72% sensitivity and 70% specificity for a threshold level of 2.5?ng/mL with an area under the receiver operating characteristics curve (AUC) of 0.79 (95% CI: 0.70–0.88). No impact of sepsis was observed on urine IGFBP7 levels in the absence of AKI. In the septic AKI group urine IGFBP7 levels continuously increased up to the day of AKI development and high levels were suspended for 10 days further.

Conclusion: Admission urine IGFBP7 levels and following its course in ICUs can be used as a promising new biomarker for the early diagnosis of septic AKI development without being affected by sepsis itself.     

Urinary output and fractional excretion of sodium and urea as indicators of transient versus intrinsic acute kidney injury during early sepsis

Introduction

The pathophysiology of acute kidney injury (AKI) in sepsis is ill defined. We investigated parameters associated with low glomerular filtration, and their predictive value to discriminate transient from intrinsic septic AKI.

Methods

In 107 sepsis patients, AKI was defined by the Risk, Injury, Failure, Loss of Kidney Function, End-stage renal disease (RIFLE) urinary output or serum creatinine criterion, or both. Transient AKI (TAKI) versus intrinsic AKI was defined as RIFLE R, I, or F on the first day evolving to no AKI or not, respectively, over the following 5 days. Fractional excretion of sodium (FENa), urea (FEUrea), and NGAL (FENGAL) at admission (d0t0), 4 (d0t4), and 24 hours (d1) was determined.

Results

Including versus not including the urinary-output criterion of RIFLE increased AKI from 43% to 64.5%. Median uNGAL levels and FENGAL were lower in no AKI versus transient AKI when AKI was defined based on creatinine (P = 0.002 and P = 0.04, respectively), but not when based on urinary output (P = 0.9 and P = 0.49, respectively). FENa < 1% and FEUrea <35% was present in 77.3% and 63.2% of patients. Urinary NGAL was higher (P < 0.001) in those with high versus low fractional sodium excretion, but this was only in patients with transient or intrinsic AKI (P < 0.001 in subgroups), and not in patients without AKI. The negative predictive value for either intrinsic AKI or not restoring diuresis in patients with FENa > 0.36% and FEUrea > 31.5% was 92% and 94.5% respectively.

Conclusions

A low FENa and FEUrea is highly prevalent in the first hours of sepsis. In sepsis, oliguria is an earlier sign of impending AKI than increase in serum creatinine. A combination of a high FENa and a low FEUrea is associated with intrinsic AKI, whereas a combined high FENa and FEUrea is strongly predictive of transient AKI.     

Diagnostic and prognostic value of neutrophil gelatinase-associated lipocalin,matrix metalloproteinase-9, and tissue inhibitor of matrix metalloproteinases-1 for sepsis in the Emergency Department: an observational study

Introduction

The aim of this study was to evaluate the early diagnostic, risk stratification and prognostic value of neutrophil gelatinase-associated lipocalin (NGAL), matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of matrix metalloproteinases-1 (TIMP-1), compared with procalcitonin (PCT) and the Mortality in Emergency Department Sepsis (MEDS) score in septic patients in the emergency department (ED).

Methods

In total, 480 consecutive adult patients were enrolled in this study. They fulfilled the systemic inflammatory response syndrome (SIRS) criteria and were admitted to the ED of Beijing Chaoyang Hospital from February 2013 to August 2013. A total of 40 healthy controls comprised the control group. The patients were classified into four groups: SIRS, sepsis, severe sepsis, and septic shock. Serum NGAL, MMP-9, TIMP-1 and PCT were measured, and MEDS score was calculated at enrollment. The prognostic values of NGAL, MMP-9 and TIMP-1 were compared with PCT and MEDS score. A 28-day follow-up was performed for all patients.

Results

The median levels of serum NGAL and TIMP-1 increased with sepsis severity. The areas under the receiver operating characteristic (AUC) curves of NGAL or TIMP-1 were greater than those of PCT and MEDS score in diagnosing and predicting 28-day mortality, and the AUC of a combination of NGAL and MEDS score or TIMP-1 and MEDS score was more significant. Serum NGAL, MMP-9 and TIMP-1 levels were significantly higher in non-survivors than survivors at 28 days’ follow-up. In addition, the level of NGAL was much higher in septic patients with acute kidney injury (AKI) than those without AKI. NGAL, TIMP-1, MMP-9 and MEDS score were found to be independent predictors of 28-day mortality in septic patients. The levels of serum NGAL and TIMP-1 were positively correlated with PCT and MEDS score in every septic group.

Conclusions

NGAL and TIMP-1 are valuable for the risk stratification, early diagnosis and prognostication of sepsis in the ED. NGAL is also a valuable biomarker for prognosis of septic patients with AKI in the ED.     

可溶性CD73联合SOFA评分对脓毒症相关急性肾损伤患者28 d死亡风险的预测价值

目的探讨血清可溶性CD73(sCD73)联合序贯器官衰竭评分(SOFA)对脓毒症相关急性肾损伤(SA-AKI)患者28d死亡风险的预测价值。方法前瞻性收集184例SA-AKI患者和50例健康志愿者临床资料。根据28 d转归将SA-AKI患者分为存活组(n=142)和死亡组(n=42)。按AKI分期标准分为AKIⅠ期(n=90)、AKIⅡ期(n=50)和AKIⅢ期(n=44)。单因素和多因素Logistic回归分析临床资料,确定SA-AKI患者28 d死亡的独立影响因素。Spearman相关性分析探讨SA-AKI患者血清sCD73水平与SOFA评分的相关性。利用受试者工作特征(ROC)曲线评估血清sCD73水平、SOFA评分及两者联合检测对SA-AKI患者28 d死亡风险的预测价值。结果SA-AKI患者血清sCD73水平明显高于健康志愿者[μg/L:7.42(4.29,11.23)vs.5.37(3.14,7.27),P<0.001]。SA-AKI患者28 d病死率为22.8%(42/184)。死亡组血清sCD73水平明显低于存活组[μg/L:2.76(1.78,7.32)vs.8.07(5.81,11.75),P<0.001],SOFA评分明显高于存活组(分:10.67±3.03 vs.7.53±2.89,P<0.001)。随AKI分期的增加,SA-AKI患者血清sCD73水平依次降低,SOFA评分依次升高,差异均有统计学意义(P<0.05)。多因素Logistic回归分析显示,年龄(OR=1.088,95%CI 1.039~1.139,P<0.001)、SOFA评分(OR=1.341,95%CI 1.127~1.597,P=0.001)、AKIⅡ期(OR=8.719,95%CI 1.665~45.651,P=0.010)、AKIⅢ期(OR=29.920,95%CI 5.009~178.709,P<0.001)、连续性肾脏替代治疗(OR=0.138,95%CI 0.027~0.693,P=0.016)和sCD73(OR=0.910,95%CI 0.833~0.993,P=0.034)是SA-AKI患者28 d死亡的独立影响因素。血清sCD73水平与SOFA评分呈负相关(rs=-0.319,P<0.001)。ROC曲线分析结果显示,血清sCD73水平与SOFA评分联合检测预测SA-AKI患者28 d死亡风险的AUC明显高于两个指标单独预测(0.854 vs.0.766,Z=2.160,P<0.05;0.854 vs.0.785,Z=2.925,P<0.05)。血清sCD73最佳截断值为5.84μg/L时,诊断敏感度为71.43%,特异度为72.54%;SOFA评分最佳截断值为8分时,诊断敏感度为80.96%,特异度为66.90%。两者联合检测的敏感度为83.33%,特异度为78.87%。结论血清sCD73水平降低、SOFA评分升高是SA-AKI患者28 d死亡的独立危险因素,两者联合检测对SA-AKI患者的28 d死亡风险具有良好的预测价值。     

Renal injury study in critical ill patients in accordance with the new definition given by the Acute Kidney Injury Network

Objective

This research aims to apply the definition proposed by the Acute Kidney Injury Network (AKIN) research group to assess the incidence, risk factors, and outcomes in acute kidney injury (AKI) patients admitted at the intensive care unit (ICU).

Design

This is a retrospective cohort study. Patients who were admitted to the ICU from January 1, 2003 to December 31, 2004 were studied.

Interventions

Medical records of all patients were reviewed. Demographic information, diagnoses, risk factors for AKI, laboratory data, urinary output, frequency and days of exposure to mechanical ventilation, ICU and hospital stay, and outcomes were recorded.

Measurements and Main Results

A total of 794 patients were studied. There were 39.8% of patients who presented AKI (stage 1: 13.9%, stage 2: 12%, stage 3: 13.9%). The variables that were associated with the presence of AKI in the multivariable analysis were as follows: sepsis (odds ratio [OR], 5.29; 95% confidence interval [CI], 3.36-8.33), heart failure (OR, 3.01; 95% CI, 1.59-5.67), vasopressor use (OR, 1.89; 95% CI, 1.26-2.83), and age (β = 1.02; 95% CI, 1.01-1.03).The mean hospital stay increased with renal commitment: patients without AKI, 10.9 days; AKIN stage 1, 17.8; AKIN stage 2, 21.1; and AKIN stage 3, 22.1 days (P < .0001).Mortality rate increased as more advanced the AKI stage was (no AKI, 7.3%; AKI 1, 16.4%; AKI 2, 34.7%; and AKIN 3, 45.5%; P < .0001).

Conclusions

All of the result indicators—stay days in ICU, hospital stay days, frequency and days of mechanical ventilation, and mortality—considerably increased with more acute AKI stage. The most important risk factor of AKI was the sepsis.