Perioperative Role Of Vascular Endothelial Growth Factor In Cardiac Surgery-associated Acute Kidney Injury (PROVE-AKI)

Cardiac surgery-associated acute kidney injury (CSA-AKI) remains a common and serious complication affecting 20-30% of patients undergoing cardiac surgery, with significant implications for short- and long-term morbidity and mortality. The pathophysiology of CSA-AKI is multifactorial and incompletely understood. It involves hypoperfusion, ischemia-reperfusion injury, inflammation, and oxidative stress. Emerging evidence suggests that vascular endothelial dysfunction and microvascular injury play central roles in the development and progression of CSA-AKI. Vascular endothelial growth factor (VEGF) is a key regulator of endothelial cell survival, vascular permeability, inflammation, and angiogenesis. VEGF appears to play a critical role in maintaining renal microvascular homeostasis. While renal VEGF expression in vitro is induced by hypoxia, its renal expression and protein plasma levels have been shown to drop significantly following ischemia-reperfusion injury in a mouse model. These observations have been supported by an observational study that found an approximately 2-fold decrease in plasma concentrations of VEGF by 6 hours in patients that had underwent cardiac surgery with cardiopulmonary bypass (CPB). Conversely, higher early postoperative VEGF plasma concentrations have been independently associated with significantly reduced risk of AKI, shorter AKI duration and improved survival, suggesting a protective role for VEGF in the acute phase of CSA-AKI. However, while VEGF appears to be nephroprotective in the acute phase after cardiac surgery, it potentially contributes to chronic kidney disease (CKD) progression due to fibrosis and is associated with higher risk for progression to end stage kidney disease in patients with diabetic nephropathy. Despite these insights, the reliance of the only clinical study by Mansour et al. on plasma VEGF measurements may limit the precision with which renal VEGF dynamics can be characterized. Plasma VEGF reflects contributions from multiple non-renal sources, including platelets, leukocytes, vascular endothelium, and other tissues, all of which are substantially perturbed in the context of cardiac surgery. The resulting hemodilution, platelet activation and systemic inflammatory response inherent to extracorporeal circulation represent important confounders of circulating VEGF levels that are unrelated to renal pathophysiology. Consequently, the observed 2-fold decrease in plasma VEGF following cardiac surgery³ likely represents an attenuated and partially masked signal of what preclinical data suggest to be a far more pronounced local renal VEGF suppression. In contrast, urinary VEGF may provide a more specific representation of intrarenal VEGF (predominantly produced by glomerular podocytes) that is less susceptible to systemic confounders. Given the magnitude of renal VEGF suppression documented in the IRI model, urinary VEGF concentrations would be expected to demonstrate a substantially larger and more consistent signal in patients developing CSA-AKI compared to plasma-based measurements. The precise role of VEGF in the pathophysiology of CSA-AKI thus remains unclear. To date, urinary VEGF has not been systematically evaluated as a biomarker in the context of CSA-AKI, and direct comparative data with plasma VEGF in this setting are lacking. The temporal changes of VEGF expression, its relationship to specific injury mechanisms such as ischemia-reperfusion injury, oxidative stress, and inflammation and its potential utility as a predictive biomarker in the plasma/urine or therapeutic target require further investigation. The objective of this study is to comprehensively evaluate the role of VEGF in CSA-AKI by examining its urine and plasma concentration over time in relation to clinical outcomes. First, we aim to determine whether perioperative VEGF levels can serve as a predictive biomarker for CSA- AKI development, severity, and duration. Second, we aim to elucidate the mechanistic pathways through which VEGF influences AKI and recovery in the cardiac surgery setting. Understanding the significance of VEGF in CSA-AKI may identify novel opportunities for risk stratification and possibly therapeutic interventions to improve kidney outcomes in this high-risk patient population.