Fiorentino Marco, Xu Zhongying, Smith Ali, Singbartl Kai, Palevsky Paul M, Chawla Lakhmir S, Huang David T, Yealy Donald M, Angus Derek C, Kellum John A
Center for Critical Care Nephrology and.
Clinical Research, Investigation and Systems Modeling of Acute Illness Center, Department of Critical Care Medicine.
Am J Respir Crit Care Med. 2020 Nov 1;202(9):1262-1270. doi: 10.1164/rccm.201906-1197OC.
Urinary TIMP-2 (tissue inhibitor of metalloproteinases-2) and IGFBP7 (insulin-like growth factor-binding protein 7) can predict acute kidney injury (AKI) in patients with sepsis. To address critical questions about whether biomarkers can inform the response to treatment and whether they might be used to guide therapy, as most sepsis patients present with AKI. We measured [TIMP-2] · [IGFBP7] before and after a 6-hour resuscitation in 688 patients with septic shock enrolled in the ProCESS (Protocol-based Care for Early Septic Shock) trial. Our primary endpoint was stage 3 AKI, renal replacement therapy, or death within 7 days. The endpoint was reached in 113 patients (16.4%). In patients with negative [TIMP-2] · [IGFBP7] at baseline, those who became positive (>0.3 U) after resuscitation had three-times higher risk compared with those who remained negative (21.8% vs. 8.5%; = 0.01; odds ratio [OR], 3.0; 95% confidence interval [CI], 1.31-6.87). Conversely, compared with patients with a positive biomarker at baseline that were still positive at Hour 6, risk was reduced for patients who became negative (23.8% vs. 9.8%; = 0.01; OR, 2.15; 95% CI, 1.17-3.95). A positive [TIMP-2] · [IGFBP7] after resuscitation was associated with worse outcomes in both patients with and without AKI at that time point. The clinical response to resuscitation, as judged by the Acute Physiology and Chronic Health Evaluation II score, was weakly predictive of the endpoint (area under the curve, 0.68; 95% CI, 0.62-0.73) and improved with addition of [TIMP-2] · [IGFBP7] (0.72; 95% CI, 0.66-0.77; = 0.03). Different resuscitation protocols did not alter biomarker trajectories, nor did they alter outcomes in biomarker-positive or biomarker-negative patients. However, biomarker trajectories were associated with outcomes. Changes in urinary [TIMP-2] · [IGFBP7] after initial fluid resuscitation identify patients with sepsis who have differing risk for progression of AKI.Clinical trial registered with www.clinicaltrials.gov (NCT00510835).
尿组织金属蛋白酶抑制剂-2（TIMP-2）和胰岛素样生长因子结合蛋白7（IGFBP7）可预测脓毒症患者的急性肾损伤（AKI）。鉴于大多数脓毒症患者都伴有AKI，为解决有关生物标志物能否提示治疗反应以及是否可用于指导治疗的关键问题，我们在参与“脓毒症休克早期基于方案的治疗（ProCESS）”试验的688例脓毒症休克患者复苏6小时前后测量了[TIMP-2]·[IGFBP7]。我们的主要终点是3期AKI、肾脏替代治疗或7天内死亡。113例患者（16.4%）达到该终点。基线时[TIMP-2]·[IGFBP7]为阴性的患者中，复苏后变为阳性（>0.3 U）的患者与仍为阴性的患者相比，风险高3倍（21.8%对8.5%；P = 0.01；优势比[OR]，3.0；95%置信区间[CI]，1.31 - 6.87）。相反，与基线时生物标志物为阳性且在6小时时仍为阳性的患者相比，变为阴性的患者风险降低（23.8%对9.8%；P = 0.01；OR，2.15；95% CI，1.17 - 3.95）。复苏后[TIMP-2]·[IGFBP7]为阳性与当时有或无AKI的患者预后较差相关。根据急性生理学与慢性健康状况评估II评分判断的复苏临床反应对终点的预测作用较弱（曲线下面积，0.68；95% CI，0.62 - 0.73），加入[TIMP-2]·[IGFBP7]后有所改善（0.72；95% CI，0.66 - 0.77；P = 0.03）。不同的复苏方案未改变生物标志物轨迹，也未改变生物标志物阳性或阴性患者的预后。然而，生物标志物轨迹与预后相关。初始液体复苏后尿[TIMP-
