Holthoff Joseph Hunter, Karakala Nithin, Basnakian Alexei G, Edmondson Ricky D, Fite Todd Wesley, Gokden Neriman, Harville Yanping, Herzog Christian, Holthoff Kaegan G, Juncos Luis A, Reynolds Katlyn L, Shelton Randall S, Arthur John M
Department of Nephrology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States.
Section of Nephrology, Central Arkansas Veterans Healthcare System, Little Rock, Arkansas, United States.
Am J Physiol Renal Physiol. 2025 May 1;328(5):F647-F661. doi: 10.1152/ajprenal.00173.2024. Epub 2025 Apr 2.
The ability to predict progression to severe acute kidney injury (AKI) remains an unmet challenge. Contributing to the inability to predict the course of AKI is a void of understanding of the pathophysiological mechanisms of AKI. The identification of novel prognostic biomarkers could both predict patient outcomes and unravel the molecular mechanisms of AKI. We performed a multicenter retrospective observational study from a cohort of patients following cardiac surgery. We identified novel urinary prognostic biomarkers of severe AKI among subjects with early AKI. Of 2,065 proteins identified in the discovery cohort, insulin-like growth factor binding protein 1 (IGFBP-1) was the most promising. We validated IGFBP-1 as a prognostic biomarker of AKI in 213 patients. In addition, we investigated its role in the pathophysiology of AKI using a murine model of cisplatin-induced AKI (CIAKI). Urinary IGFBP-1 concentration in samples collected from patients with stage 1 AKI following cardiothoracic surgery was significantly higher in patients who progressed to severe AKI compared with patients who did not progress beyond stage 1 AKI (40.28 ng/ml vs. 2.8 ng/ml, < 0.0001) and predicted the progression to the composite outcome (area under the curve: 0.85, < 0.0001). IGFBP-1 knockout mice showed less renal injury, cell death, and apoptosis following CIAKI, possibly through increased activation of the insulin growth factor receptor 1. IGFBP-1 is a clinical prognostic biomarker of AKI and a direct mediator of the pathophysiology of AKI. Therapies that target the IGFBP-1 pathways may help alleviate the severity of AKI. The ability to predict progression to severe AKI remains an unmet challenge. Early prognostic biomarkers of AKI hold promise to improve patient outcomes by early implementation of clinical therapy, as well as unravel the pathophysiological mechanisms of AKI. Here, we present a novel urinary biomarker, IGFBP-1, that predicts the progression to severe AKI following cardiac surgery. In addition, we show that IGFBP-1 mice are protected against CIAKI, suggesting a mechanistic role for IGFBP-1 in AKI.
预测进展为严重急性肾损伤（AKI）的能力仍然是一个尚未解决的挑战。导致无法预测AKI病程的原因是对AKI病理生理机制缺乏了解。新型预后生物标志物的识别既能预测患者的预后，又能揭示AKI的分子机制。我们对一组心脏手术后的患者进行了一项多中心回顾性观察研究。我们在早期AKI患者中识别出了严重AKI的新型尿液预后生物标志物。在发现队列中鉴定出的2065种蛋白质中，胰岛素样生长因子结合蛋白1（IGFBP-1）最具前景。我们在213名患者中验证了IGFBP-1作为AKI的预后生物标志物。此外，我们使用顺铂诱导的急性肾损伤（CIAKI）小鼠模型研究了其在AKI病理生理学中的作用。与未进展至1期以上AKI的患者相比，心胸手术后1期AKI患者中进展为严重AKI的患者，其样本中的尿液IGFBP-1浓度显著更高（40.28 ng/ml对2.8 ng/ml，<0.0001），并预测了复合结局的进展（曲线下面积：0.85，<0.0001）。IGFBP-1基因敲除小鼠在CIAKI后肾损伤、细胞死亡和凋亡较少，可能是通过增加胰岛素生长因子受体1的激活。IGFBP-1是AKI的临床预后生物标志物，也是AKI病理生理学的直接介质。针对IGFBP-1途径的治疗可能有助于减轻AKI的严重程度。预测进展为严重AKI的能力仍然是一个尚未解决的挑战。AKI的早期预后生物标志物有望通过早期实施临床治疗改善患者预后，并揭示AKI的病理生理机制。在此，我们提出一种新型尿液生物标志物IGFBP-1，它可预测心脏手术后进展为严重AKI的情况。此外，我们表明IGFBP-1基因敲除小鼠对CIAKI具有保护作用，提示IGFBP-1在AKI中具有机制性作用。
