Supplementary Material for: Serum IGFBP7 deriving from spleen and lung could be used for early recognition of cardiac surgery-associated acute kidney injury

Introduction: 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. Methods: In mice, gene transcription and protein levels of IGFBP7/TIMP2 in the heart, liver, spleen, lung, and kidney were measured in both ischaemia-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, blood urea nitrogen (BUN), estimated glomerular filtration rate (eGFR) and serum uric acid (UA). Results: 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 (s[IGFBP7]-2 h) was significantly higher in patients who developed AKI. The relationships between s[IGFBP7]-2 h in AKI patients and log2(SCr), log2(BUN), log2(eGFR), and log2(UA) were statistically significant. The diagnostic performance of s[IGFBP7]-2 h measured by the macro-averaged area under the receiver operating characteristic curve (AUC) was 0.948 ([95% CI], 0.853 to 1.000; P<0.001). Discussion/Conclusion: 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、肝、脾、肺、肾组织中IGFBP7与TIMP2的基因转录水平及蛋白表达水平。同时纳入心脏手术患者，分别于术前、重症监护病房（ICU）入住时（0 h）、入住后2 h、6 h及12 h采集血清样本，检测IGFBP7与TIMP2水平，并与血清肌酐、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的表达水平无明显变化，但脾脏与肺组织中二者的表达水平显著上调。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ICU入住后2 h时的血清IGFBP7水平（s[IGFBP7]-2 h）即已显著升高。AKI患者的s[IGFBP7]-2 h水平与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下面积（macro-averaged AUC）评估的s[IGFBP7]-2 h诊断性能为0.948（95%置信区间：0.853~1.000；P<0.001）。讨论与结论：急性肾损伤发生时，脾脏与肺可能是血清IGFBP7与TIMP2的主要分泌来源。在心脏手术患者中，ICU入住后2 h内检测的血清IGFBP7水平对术后急性肾损伤具有良好的预测效能。