Center for Critical Care Nephrology, Department of Critical Care Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
Department of Translational Medicine, Università degli Studi del Piemonte Orientale, Novara, Italy.
JAMA Netw Open. 2022 May 2;5(5):e2212709. doi: 10.1001/jamanetworkopen.2022.12709.
The 23rd Acute Disease Quality Initiative (ADQI-23) consensus conference proposed a framework to integrate biomarkers into the staging of acute kidney injury (AKI). It is unknown whether tissue inhibitor of metalloproteinases 2 (TIMP-2) and insulinlike growth factor binding protein 7 (IGFBP7) could be used for staging.
To test whether higher levels of urinary [TIMP-2] × [IGFBP7] are associated with lower survival among patients with the same functional stage of AKI.
DESIGN, SETTING, AND PARTICIPANTS: This cohort study was performed using data from the Protocolized Care for Early Septic Shock (ProCESS) trial, which enrolled critically ill patients with septic shock who presented at academic and community emergency departments and intensive care units in the US from March 2008 to May 2013. Patients with end-stage kidney disease, a reference serum creatinine level of 4 mg/dL or greater (to convert to μmol/L, multiply by 76.25), or missing data on serum creatinine levels or urinary levels of [TIMP-2] × [IGFBP7] were excluded. Data were analyzed from October 2020 to October 2021.
The presence of AKI, assessed using Kidney Disease: Improving Global Outcomes criteria within 24 hours after enrollment and the highest AKI stage as well as urinary [TIMP-2] × [IGFBP7] level at 6 hours after enrollment. A previously reported high-specificity cutoff level for [TIMP-2] × [IGFBP7] of 2.0 (ng/mL)2/1000 was used to categorize patients (including those without functional criteria of AKI) according to the new staging system proposed by the ADQI-23 as biomarker negative (urinary [TIMP-2] × [IGFBP7] level ≤2.0 [ng/mL]2/1000) or biomarker positive ([TIMP-2] × [IGFBP7] >2.0 [ng/mL]2/1000).
Survival (assessed using Kaplan-Meier plots and the log-rank test) and mortality (assessed using relative risk [RR] 30 days after enrollment).
The analysis included 999 patients with a median age of 61 years (IQR, 50-73 years); 554 (55.5%) were male. Biomarker-positive patients had lower survival and higher mortality at 30 days in the groups with AKI stage 1 (RR, 2.20; 95% CI, 1.02-4.72), stage 2 (RR, 1.53; 95% CI, 1.04-2.27), and stage 3 (RR, 1.61; 95% CI, 1.00-2.60). The associations were specific to patients with AKI. No difference in 30-day survival was found between biomarker-positive and biomarker-negative patients in the absence of functional criteria for AKI (RR, 1.16; 95% CI, 0.45-3.01).
The findings suggest that assessment of the cell-cycle arrest biomarkers TIMP-2 and IGFBP7 may augment AKI staging for patients with functional criteria for AKI.
重要性：第 23 届急性病质量倡议（ADQI-23）共识会议提出了一个将生物标志物整合到急性肾损伤（AKI）分期中的框架。目前尚不清楚组织抑制剂金属蛋白酶 2（TIMP-2）和胰岛素样生长因子结合蛋白 7（IGFBP7）是否可用于分期。
目的：检验尿液 [TIMP-2]×[IGFBP7] 水平较高的患者在 AKI 相同功能分期下的生存率是否更低。
设计、地点和参与者：这项队列研究使用 Protocolized Care for Early Septic Shock (ProCESS) 试验的数据进行，该试验纳入了在美国的学术和社区急诊部门以及重症监护病房就诊的患有败血症性休克的危重病患者，入组时间为 2008 年 3 月至 2013 年 5 月。排除终末期肾病患者、参考血清肌酐水平大于等于 4 mg/dL（换算为 μmol/L，乘以 76.25）患者、或缺失血清肌酐水平或尿液 [TIMP-2]×[IGFBP7] 数据的患者。数据分析于 2020 年 10 月至 2021 年 10 月进行。
暴露情况：采用肾脏疾病：改善全球预后标准在入组后 24 小时内评估 AKI，并根据 AKI 最高分期以及入组后 6 小时的尿液 [TIMP-2]×[IGFBP7] 水平进行评估。使用先前报道的 TIMP-2×IGFBP7 高特异性截断值 2.0（ng/mL）2/1000 对患者进行分类（包括那些没有 AKI 功能标准的患者），根据 ADQI-23 提出的新分期系统，将患者分为生物标志物阴性（尿液 [TIMP-2]×[IGFBP7] 水平≤2.0 [ng/mL]2/1000）或生物标志物阳性（TIMP-2×IGFBP7＞2.0 [ng/mL]2/1000）。
主要结局和测量指标：生存（采用 Kaplan-Meier 图和对数秩检验评估）和死亡率（采用 30 天后的相对风险 RR 评估）。
结果：共纳入 999 名中位年龄为 61 岁（IQR，50-73 岁）的患者；其中 554 名（55.5%）为男性。在 AKI 分期 1 级（RR，2.20；95%CI，1.02-4.72）、2 级（RR，1.53；95%CI，1.04-2.27）和 3 级（RR，1.61；95%CI，1.00-2.60）患者中，生物标志物阳性患者的 30 天生存率和死亡率更高。这些关联仅存在于 AKI 患者中。在没有 AKI 功能标准的情况下，生物标志物阳性和生物标志物阴性患者的 30 天生存率无差异（RR，1.16；95%CI，0.45-3.01）。
结论和相关性：研究结果表明，细胞周期阻滞生物标志物 TIMP-2 和 IGFBP7 的评估可能会增强 AKI 分期对具有 AKI 功能标准患者的适用性。
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