VEGF inhibitor-induced proteinuria: the role of hypertension and vascular endothelial dysfunction

Vascular endothelial growth factor (VEGF) inhibitors are widely used anticancer agents that suppress tumor angiogenesis and improve outcomes in various solid tumors. However, these therapies are frequently associated with adverse renal and vascular events, particularly hypertension and proteinuria, which may compromise treatment continuity and patient quality of life. Although hypertension has long been considered a major contributor to VEGF inhibitor-induced proteinuria, the precise relationship between these complications remains incompletely understood. In addition, accumulating evidence suggests that endothelial dysfunction-characterized by impaired nitric oxide bioavailability, increased endothelin-1 signaling, and microvascular injury-plays a central role in the pathogenesis of these adverse events, potentially linking hypertension and proteinuria through a shared underlying mechanism. This review summarizes current evidence regarding the role of blood pressure and vascular endothelial dysfunction in the development of proteinuria during VEGF inhibitor therapy. Multiple clinical studies have demonstrated that both baseline and on-treatment blood pressure are associated with an increased risk of proteinuria. However, the causal relationship between hypertension and proteinuria remains uncertain. Hypertension may contribute to glomerular injury by increasing intraglomerular pressure, but it may also represent a parallel manifestation of endothelial injury caused by VEGF signaling blockade. Emerging evidence suggests that vascular endothelial dysfunction plays a key role in this process. Studies using flow-mediated dilation and reactive hyperemia index measurements have demonstrated impaired endothelial function during VEGF inhibitor therapy. In addition, alterations in endothelial-derived vasoactive mediators, including reduced nitric oxide bioavailability and increased endothelin-1 signaling, have been reported. Taken together, VEGF inhibitor-induced proteinuria likely results from complex interactions between systemic hypertension, endothelial dysfunction, and glomerular microvascular injury. Further translational and prospective clinical studies are needed to clarify the causal mechanisms and optimize strategies for prediction, prevention, and management of this complication.