"The role of IGFBP-1 in the clinical prognosis and pathophysiology of acute kidney injury".

Abstract

Introduction: 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. Methods: 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. Additionally, we investigated its role in the pathophysiology of AKI using a murine model of cisplatin-induced AKI (CIAKI). Results: Urinary IGFBP-1 concentration in samples collected from patients that developed stage 1 AKI following cardiothoracic surgery were significantly higher in patients that progressed to severe AKI compared to patients that did not progress to beyond stage 1 AKI (40.28 ng/mg vs 2.8 ng/mg, p<0.0001) and predicted the progression to the composite outcome (AUC: 0.85, p< 0.0001). IGFBP-1 knockout (KO) mice showed less renal injury, cell death, and apoptosis following CIAKI, possibly through increased activation of the insulin growth factor receptor 1 (IGF-1r). Conclusions: 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.