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

Evaluation of NGAL, KIM-1, and TIMP-2 as early biomarkers in sepsis-associated acute kidney injury: a prospective clinical cohort study

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72h,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(0h),入ICU后6、12、24、48、72h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6h开始升高(P<0.05),12h开始明显升高,24h达到峰值,在6、12、24、48、72h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6h开始升高(P<0.05),12h开始明显升高并达到峰值,在6、12、24、48、72h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、3299.50ng/L。各时间点绘制ROC曲线显示,在T-12h时,pNGAL、尿KIM-1及尿TIMP-2的ROC的AUC分别为1.00、0.96、0.92,在T-18h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。

Objective To evaluate the diagnostic value of plasma neutrophil gelatinase-associated lipocalin(pNGAL),urinary neutrophil gelatinase-associated lipocalin(uNGAL),kidney injury molecule-1(KIM-1),and tissue inhibitor of metalloproteinase-2(TIMP-2)in early sepsis-associated acute kidney injury(AKI).Methods From June 2015 to January 2016,patients with sepsis admitted to our hospital ICU were included in this study.They were continuously observed for 72 hours to observe the presence of AKI.The urine and plasma samples were collected upon admission and at 6,12,24,48,and 72 h after admission.The levels of plasma and urine biomarkers were determined by enzyme-linked immunosorbent assay(ELISA)and compared among groups.Furthermore,receiver operating characteristic(ROC)curves were plotted and the areas under the curve(AUCs)were calculated to evaluate the early diagnostic value of NGAL,KIM-l,and TIMP-2 in sepsis with AKI.Results Of 90 patients included,38(42.22%)were diagnosed to be complicated with AKI.In the AKI group,the levels of plasm and urine NGAL began to significantly increase at 6 h after admission(P<0.05)and reached the peak at 24 h(P<0.05).Compared with the non-AKI group,the AKI group had significantly higher levels of plasm and urine NGAL levels at 12,24,48,and 72 h(P<0.05).In the AKI group,the levels of urine KIM-1 and TIMP-2 began to significantly increase at 6 h after admission(P<0.05)and reached the peak at 12 h(P<0.05).Compared with the non-AKI group,the AKI group had significantly higher levels of urine KIM-1 and TIMP-2 at 12,24,48,and 72 h(P<0.05).ROC curve analysis showed that the AUCs of pNGAL,uNGAL,urinary KIM-1,and urinary TIMP-2 were 0.862,0.858,0.788,and 0.771,respectively,and the cutoff values were 119.30,120.36,90.07 and 3299.50 ng/L,respectively.ROC curve analysis at each time point showed that the AUCs of pNGAL,urine KIM-1,and urine TIMP-2 at 12 h were 1.00,0.96 and 0.92,respectively,and the AUC of uNGAL at 18 h was 0.95.Conclusion Plasma and urine NGAL,KIM-1,and TIMP-2 increase markedly in early renal injury in septic patients complicated with AKI.Plasma and urine NGAL,KIM-1,and TIMP-2 can be used as diagnostic and predictive biomarkers for AKI in critically ill patients with sepsis.