Palmowski Lars, Lindau Simone, Henk Laura Contreras, Marko Britta, Witowski Andrea, Nowak Hartmuth, Stoll Sandra E, Zacharowski Kai, Böttiger Bernd W, Peters Jürgen, Adamzik Michael, Dusse Fabian, Rahmel Tim
Department of Anesthesiology, Intensive Care Medicine and Pain Medicine, University Hospital Knappschaftskrankenhaus Bochum, In der Schornau 23-25, 44892, Bochum, Germany.
Department of Anesthesiology, Intensive Care Medicine and Pain Medicine, University Hospital Frankfurt, Goethe-University Frankfurt, Frankfurt, Germany.
Ann Intensive Care. 2024 Jul 13;14(1):111. doi: 10.1186/s13613-024-01349-4.
In sepsis, initial resuscitation with fluids is followed by efforts to achieve a negative fluid balance. However, patients with sepsis-associated acute kidney injury (SA-AKI) often need diuretic or renal replacement therapy (RRT). The dilemma is to predict whether early RRT might be advantageous or diuretics will suffice. Both the Furosemide Stress Test (FST) and measurements of the urinary biomarkers TIMP-2IGFBP-7, if applied solely, do not provide sufficient guidance. We tested the hypothesis that a combination of two tests, i.e., an upstream FST combined with downstream measurements of urinary TIMP-2IGFBP-7 concentrations improves the accuracy in predicting RRT necessity.
In this prospective, multicenter study 100 patients with sepsis (diagnosed < 48h), AKI stage ≥ 2, and an indication for negative fluid balance were included between 02/2020 and 12/2022. All patients received a standardized FST and urinary biomarkers TIMP-2*IGFBP-7 were serially measured immediately before and up to 12 h after the FST. The primary outcome was the RRT requirement within 7 days after inclusion.
32% (n = 32/99) of SA-AKI patients eventually required RRT within 7 days. With the FST, urine TIMP-2IGFBP-7 decreased within 2 h from 3.26 ng/mL/1000 (IQR: 1.38-5.53) to 2.36 ng/mL/1000 (IQR: 1.61-4.87) in RRT and 1.68 ng/mL/1000 (IQR: 0.56-2.94) to 0.27 ng/mL/1000 (IQR: 0.12-0.89) and non-RRT patients, respectively. While TIMP-2IGFBP-7 concentrations remained low for up to 12 h in non-RRT patients, we noted a rebound in RRT patients after 6 h. TIMP-2IGFBP-7 before FST (accuracy 0.66; 95%-CI 0.55-0.78) and the FST itself (accuracy 0.74; 95%-CI: 0.64-0.82) yielded moderate test accuracies in predicting RRT requirement. In contrast, a two-step approach, utilizing FST as an upstream screening tool followed by TIMP-2IGFBP-7 quantification after 2 h improved predictive accuracy (0.83; 95%-CI 0.74-0.90, p = 0.03) compared to the FST alone, resulting in a positive predictive value of 0.86 (95%-CI 0.64-0.97), and a specificity of 0.96 (95%-CI 0.88-0.99).
The combined application of an upstream FST followed by urinary TIMP-2*IGFBP-7 measurements supports highly specific identification of SA-AKI patients requiring RRT. Upcoming interventional trials should elucidate if this high-risk SA-AKI subgroup, identified by our predictive enrichment approach, benefits from an early RRT initiation.
在脓毒症中，首先进行液体复苏，随后致力于实现负液体平衡。然而，脓毒症相关急性肾损伤（SA-AKI）患者通常需要利尿剂或肾脏替代治疗（RRT）。困境在于预测早期RRT是否可能有益或利尿剂是否足够。单独应用速尿应激试验（FST）和尿生物标志物TIMP-2IGFBP-7的测量均不能提供足够的指导。我们检验了以下假设：两种检测方法相结合，即上游的FST与下游尿TIMP-2IGFBP-7浓度测量相结合，可提高预测RRT必要性的准确性。
在这项前瞻性多中心研究中，2020年2月至2022年12月期间纳入了100例脓毒症（诊断时间<48小时）、急性肾损伤（AKI）分期≥2且有负液体平衡指征的患者。所有患者均接受标准化的FST，并在FST前及FST后长达12小时连续测量尿生物标志物TIMP-2*IGFBP-7。主要结局是纳入后7天内的RRT需求。
32%（n = 32/99）的SA-AKI患者最终在7天内需要RRT。对于FST，RRT患者的尿TIMP-2IGFBP-7在2小时内从3.26 ng/mL/1000（四分位间距：1.38 - 5.53）降至2.36 ng/mL/1000（四分位间距：1.61 - 4.87），非RRT患者从1.68 ng/mL/1000（四分位间距：0.56 - 2.94）降至0.27 ng/mL/1000（四分位间距：0.12 - 0.89）。在非RRT患者中，TIMP-2IGFBP-7浓度在长达12小时内保持较低水平，而我们注意到RRT患者在6小时后出现反弹。FST前的TIMP-2IGFBP-7（准确性0.66；95%置信区间0.55 - 0.78）和FST本身（准确性0.74；95%置信区间：0.64 - 0.82）在预测RRT需求方面具有中等的检测准确性。相比之下，一种两步法，即利用FST作为上游筛查工具，随后在2小时后进行TIMP-2IGFBP-7定量分析，与单独使用FST相比，提高了预测准确性（0.83；95%置信区间0.74 - 0.90，p = 0.03），阳性预测值为0.86（95%置信区间0.64 - 0.97），特异性为0.96（95%置信区间0.88 - 0.99）。
上游FST与尿TIMP-2*IGFBP-7测量相结合的应用支持对需要RRT的SA-AKI患者进行高度特异性识别。即将开展的干预试验应阐明通过我们的预测性富集方法识别出的这一高风险SA-AKI亚组是否能从早期开始RRT中获益。
