The Emerging Role of VEGF-C and the Lymphatic System in Diuretic Resistance

Diuretic resistance (DR) amounts to a significant clinical hurdle in patients with heart failure (HF) and cardiorenal syndrome (CRS), as it is linked to persistent congestion and adverse clinical outcomes. Although impaired drug delivery, neurohormonal activation, renal hemodynamic alterations, and tubular adaptation contribute to a diminished natriuretic response, these mechanisms may not completely explain congestion, particularly in patients who appear to achieve an adequate natriuretic response. Current decongestive strategies focus mainly on increasing renal sodium and fluid excretion, leaving other mechanisms such as interstitial fluid mobilization relatively unexplored. The lymphatic system plays an important role in maintaining interstitial fluid and sodium homeostasis and adapts both functionally and structurally in response to elevated interstitial fluid load. Vascular endothelial growth factor-C (VEGF-C), acting primarily via its receptor VEGFR-3, may regulate lymphatic adaptation in response to different stimuli. Recent experimental and clinical observations, largely from observational studies, suggest that disturbances in lymphatic adaptation could cause persistent interstitial congestion; however, the extent of its direct involvement in pharmacological DR, and whether changes in circulating VEGF-C are causative, remain unclear. In this narrative review, we analyze DR mechanisms and evaluate current evidence linking lymphatic function and VEGF-C/VEGFR-3 signaling to congestion. We introduce an interstitial-lymphatic background in which ongoing congestion heightens lymphatic demand, while maladaptive responses may hinder interstitial fluid clearance and promote renal interstitial edema. Elevated renal interstitial pressure, in theory, influences renal hemodynamics and sodium handling through a renal tamponade-like effect, potentially causing lowered natriuretic responsiveness. This proposed mechanism remains hypothetical, and further empirical and clinical investigation is warranted. Determining whether VEGF-C acts as a mediator, a compensatory signal, or a biomarker of lymphatic dysfunction could help clarify the role of the interstitial-lymphatic compartment in cardiorenal decongestion and DR.