Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Medical Center of Kidney, Shanghai, China; Shanghai Key Laboratory of Kidney and Blood Purification, Shanghai, China.
Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Medical Center of Kidney, Shanghai, China; Shanghai Key Laboratory of Kidney and Blood Purification, Shanghai, China.
Nefrologia (Engl Ed). 2021 Mar-Apr;41(2):165-173. doi: 10.1016/j.nefro.2020.06.007. Epub 2020 Nov 4.
Chronic kidney disease (CKD) is a risk factor for the development of acute kidney injury (AKI). Recent studies have revealed numerous biomarkers eligible for AKI prediction. However, the expression and performance of AKI biomarkers in acute injury superimposed on preexisting CKD (AonC) remain elusive. The aim of this study was to evaluate whether biomarkers which robustly expressed in acute kidney injury could predict acute injury based on CKD.
Mice were classified into cohorts: AKI, CKD, AonC and sham. The AonC model mice were subjected to renal bilateral ischemia/reperfusion (I/R) injury fourteen days after intraperitoneally administrated with 20mg/kg aristolochic acid. Severity of acute ischemic injury was stratified by clamping the dissected bilateral renal arteries with non-traumatic microvascular clips for 20 or 35min. The AKI mice were induced with renal bilateral I/R injury and CKD mice were crafted with 20mg/kg aristolochic acid administrated intraperitoneally. Histology, genetic and protein expression of biomarkers were measured in three cohorts.
We found that serum creatinine dramatically increased in severe (sAonC) but not in moderate (mAonC) injury mice. Upregulation of Kidney injury molecule-1 (KIM-1) mRNA, tissue inhibitor of metalloproteinase-2 (TIMP-2), Syndecan-1 (SDC-1) mRNA and insulin-like growth factor binding protein-7 (IGFBP7) protein indicated the onset of mAonC. An increase in neutrophil gelatinase-associated lipocalin (NGAL), rhomboid-like protein 2 (RHBDL2), Syndecan-1 (SDC-1) mRNA and protein, and a decrease in IGFBP7 protein were associated with sAonC.
Our study revealed the variational expression of AKI biomarkers in AonC kidneys, and uncovered IGFBP7 protein can be used as a sensitive biomarker to predict and differentiate AonC severity. The performance of RHBDL2 and SDC-1 in predicting severe AonC was promising, providing new biomarkers for predicting AonC.
慢性肾脏病（CKD）是急性肾损伤（AKI）发展的一个危险因素。最近的研究表明，有许多生物标志物可用于 AKI 的预测。然而，急性肾损伤叠加预先存在的 CKD（AonC）中 AKI 生物标志物的表达和性能仍不清楚。本研究旨在评估在 CKD 基础上，是否能通过 AKI 生物标志物的表达来预测急性损伤。
将小鼠分为 AKI、CKD、AonC 和假手术组。AonC 模型组小鼠在腹腔注射 20mg/kg 马兜铃酸后 14 天接受双侧肾脏缺血/再灌注（I/R）损伤。通过非创伤性微血管夹夹闭分离的双侧肾动脉 20 或 35min 来分层急性缺血损伤的严重程度。AKI 组小鼠通过双侧肾脏 I/R 损伤诱导，CKD 组小鼠通过腹腔注射 20mg/kg 马兜铃酸制作。在三组中测量生物标志物的组织学、基因和蛋白表达。
我们发现，严重（sAonC）而非中度（mAonC）损伤小鼠的血清肌酐显著升高。Kidney injury molecule-1（KIM-1）mRNA、基质金属蛋白酶抑制剂-2（TIMP-2）、Syndecan-1（SDC-1）mRNA 和胰岛素样生长因子结合蛋白-7（IGFBP7）蛋白的上调表明 mAonC 的发生。中性粒细胞明胶酶相关脂质运载蛋白（NGAL）、菱形样蛋白 2（RHBDL2）、Syndecan-1（SDC-1）mRNA 和蛋白的增加，以及 IGFBP7 蛋白的减少与 sAonC 相关。
本研究揭示了 AonC 肾脏中 AKI 生物标志物的变异表达，并发现 IGFBP7 蛋白可作为预测和区分 AonC 严重程度的敏感生物标志物。RHBDL2 和 SDC-1 在预测严重 AonC 方面表现出良好的性能，为预测 AonC 提供了新的生物标志物。
