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

Abstract

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, P < 0.0001) and predicted the progression to the composite outcome (area under the curve: 0.85, P < 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.NEW & NOTEWORTHY 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.