Supplementary Material for: Serum Insulin-Like Growth Factor-Binding Protein 7 Deriving from Spleen and Lung Could Be Used for Early Recognition of Cardiac Surgery-Associated Acute Kidney Injury

<b><i>Introduction:</i></b> The utility of arithmetic product of urinary tissue metalloproteinase inhibitor 2 (TIMP2) and insulin-like growth factor-binding protein 7 (IGFBP7) concentrations has been widely accepted on early diagnosis of acute kidney injury (AKI). However, which organ is the main source of those two factors and how the concentration of IGFBP7 and TIMP2 changed in serum during AKI still remain to be defined. <b><i>Methods:</i></b> In mice, gene transcription and protein levels of IGFBP7/TIMP2 in the heart, liver, spleen, lung, and kidney were measured in both ischemia-reperfusion injury (IRI)- and cisplatin-induced AKI models. Serum IGFBP7 and TIMP2 levels were measured and compared in patients before cardiac surgery and at inclusion (0 h), 2 h, 6 h, and 12 h after intensive care unit (ICU) admission, and compared with serum creatinine (SCr), blood urea nitrogen (BUN), estimated glomerular filtration rate (eGFR), and serum uric acid (UA). <b><i>Results:</i></b> In mouse IRI-AKI model, compared with the sham group, the expression levels of IGFBP7 and TIMP2 did not change in the kidney, but significantly upregulated in the spleen and lung. Compared with patients who did not develop AKI, the concentration of serum IGFBP7 at as early as 2 h after ICU admission (sIGFBP7-2 h) was significantly higher in patients who developed AKI. The relationships between sIGFBP7-2 h in AKI patients and log₂ (SCr), log₂ (BUN), log₂ (eGFR), and log₂ (UA) were statistically significant. The diagnostic performance of sIGFBP7-2 h measured by the macro-averaged area under the receiver operating characteristic curve was 0.948 (95% CI, 0.853–1.000; <i>p</i> &lt; 0.001). <b><i>Conclusion:</i></b> The spleen and lung might be the main source of serum IGFBP7 and TIMP2 during AKI. The serum IGFBP7 value demonstrated good predictive accuracy for AKI following cardiac surgery within 2 h after ICU admission.

引言：尿组织金属蛋白酶抑制剂2（TIMP2）与胰岛素样生长因子结合蛋白7（IGFBP7）浓度的算术乘积在急性肾损伤（AKI）早期诊断中的应用价值已得到广泛认可。然而，这两种因子的主要分泌器官为何，以及急性肾损伤发生时血清中IGFBP7与TIMP2的浓度变化规律仍有待明确。
方法：本研究在小鼠缺血再灌注损伤（IRI）和顺铂诱导的急性肾损伤模型中，检测了心脏、肝脏、脾脏、肺脏及肾脏组织中IGFBP7与TIMP2的基因转录水平与蛋白表达水平。同时纳入心脏手术患者，分别于术前、入住重症监护病房（ICU）即刻（0 h）、入住后2 h、6 h及12 h检测血清IGFBP7与TIMP2水平，并与血清肌酐（SCr）、血尿素氮（BUN）、估算肾小球滤过率（eGFR）及血尿酸（UA）进行对比分析。
结果：在小鼠IRI-AKI模型中，与假手术组相比，肾脏组织中IGFBP7与TIMP2的表达水平无显著变化，但脾脏与肺脏组织中的表达显著上调。与未发生急性肾损伤的患者相比，发生急性肾损伤的患者在入住ICU后2 h时的血清IGFBP7浓度（sIGFBP7-2 h）已显著升高。AKI患者的sIGFBP7-2 h与log₂(SCr)、log₂(BUN)、log₂(eGFR)及log₂(UA)均存在显著统计学相关性。采用受试者工作特征曲线宏观平均曲线下面积评估的sIGFBP7-2 h诊断效能为0.948（95%CI：0.853~1.000；p<0.001）。
结论：急性肾损伤发生时，脾脏与肺脏可能是血清IGFBP7与TIMP2的主要分泌来源。在入住ICU后2 h内检测的血清IGFBP7水平，对心脏手术后急性肾损伤具有良好的预测准确性。