Supplementary Material for: Tissue inhibitor metalloproteinase-2 (TIMP-2) • IGF-binding protein 7 (IGFBP7) for the prediction of acute kidney injury following cardiac surgery

Introduction: Cardiac surgery-associated acute kidney injury (CSA-AKI) is a common complication associated with increased morbidity and mortality. Tissue inhibitor metalloproteinases-2 • insulin-like growth factor-binding protein 7 (TIMP-2•IGFBP7) determines tubular stress markers, which may occur prior to tubular damage. Previous studies on the use of TIMP-2•IGFBP7 for the prediction of CSA-AKI showed divergent results. Therefore, this study aimed to explore the predictive value of TIMP-2•IGFBP7 measurements for the early detection of acute kidney injury (AKI) and short-term adverse outcomes after cardiac surgery. Methods: In the prospective cohort study, blood and urine samples were collected 6–12 h after cardiac surgery. Blood samples to monitor serum creatinine levels were additionally extracted from days 1 to 7. AKI was defined based on the KDIGO consensus guidelines. AKI within 7 days following surgery was the primary outcome. The initiation of renal replacement therapy, in intensive care unit mortality, and the combination of both were secondary outcomes. Results: A total of 557 patients were enrolled, 134 (24.06%) of them developed AKI and 33 (5.9%) had moderate or severe AKI. AKI developed more frequently in elderly patients with diabetes or with higher baseline serum creatinine levels. Patients with AKI had higher EuroSCORE II, Cleveland clinical score, and simplified renal index than those without AKI. Urinary TIMP-2•IGFBP7 was significantly higher in patients with AKI. The area under the curve was 0.66 in predicting all AKI and 0.70 in predicting stages 2 and 3 AKI. The resulting sensitivity and specificity were 44.0% and 83.9%, respectively, for a calculated threshold TIMP-2•IGFBP7 value of 0.265 (ng/ml)2/1,000. The TIMP-2•IGFBP7 values, simplified renal index (SRI) Score and age were significantly associated with AKI within 7 days postoperatively. A total of 33 patients reached the composite endpoint, the percentage of patients who reached the composite end-point in the TIMP-2•IGFBP7 of >0.265 (ng/ml)2/1,000 group was significantly higher than that of ≤0.265 (ng/ml)2/1,000 group. Conclusions: Postoperative implementation of TIMP-2•IGFBP7 improved prediction of CSA-AKI and may aid in identifying patients at risk of short-term adverse outcomes. We identified an ideal calculated cutoff value of 0.265 (ng/ml))2/1,000 for the prediction of CSA-AKI among all AKI patients.

引言
心脏手术相关急性肾损伤（Cardiac surgery-associated acute kidney injury, CSA-AKI）是一类常见并发症，其伴随发病率与死亡率均显著升高。组织金属蛋白酶抑制剂-2•胰岛素样生长因子结合蛋白7（Tissue inhibitor metalloproteinases-2 • insulin-like growth factor-binding protein 7, TIMP-2•IGFBP7）属于肾小管应激标志物，可在肾小管损伤发生前出现异常表达。既往针对TIMP-2•IGFBP7预测CSA-AKI的相关研究结果存在分歧。因此本研究旨在探讨TIMP-2•IGFBP7检测对心脏手术后急性肾损伤（AKI）的早期筛查价值，以及对术后短期不良预后的预测效能。

研究方法
本项前瞻性队列研究于心脏手术后6~12小时采集患者血液与尿液样本。另于术后第1至7天额外采集血样以监测血清肌酐水平。AKI的诊断符合改善全球肾脏病预后组织（KDIGO）发布的共识指南标准。本研究的主要结局为术后7天内发生AKI；次要结局包括肾脏替代治疗启动率、重症监护病房（intensive care unit, ICU）病死率及二者联合的复合终点。

研究结果
本研究共纳入557例患者，其中134例（24.06%）发生AKI，33例（5.9%）为中重度AKI。AKI更易发生于合并糖尿病、基线血清肌酐水平较高的老年患者。AKI患者的欧洲心脏手术风险评估系统Ⅱ（EuroSCORE II）评分、克利夫兰临床评分及简化肾脏指数均显著高于非AKI患者。AKI患者的尿液TIMP-2•IGFBP7水平显著升高。其预测所有级别AKI的曲线下面积为0.66，预测2、3级AKI的曲线下面积为0.70。当TIMP-2•IGFBP7的计算临界值为0.265 (ng/ml)²/1000时，其对应的灵敏度为44.0%，特异度为83.9%。TIMP-2•IGFBP7水平、简化肾脏指数（SRI）评分及年龄均与术后7天内发生AKI显著相关。共有33例患者达到复合终点，TIMP-2•IGFBP7＞0.265 (ng/ml)²/1000组患者达到复合终点的比例显著高于≤0.265 (ng/ml)²/1000组。

研究结论
术后检测TIMP-2•IGFBP7可提升CSA-AKI的预测效能，有助于识别存在短期不良预后风险的患者。本研究确定了针对所有AKI患者的CSA-AKI预测理想临界值：0.265 (ng/ml)²/1000。