Ocular and systemic vascular endothelial growth factor ligand inhibitor use and nephrotoxicity: an update

Abstract

Tumor growth is intricately linked to the process of angiogenesis, with a key role played by vascular endothelial growth factor (VEGF) and its associated signaling pathways. Notably, these pathways also play a pivotal "housekeeping" role in renal physiology. Over the past decade, the utilization of VEGF signaling inhibitors has seen a substantial rise in the treatment of diverse solid organ tumors, diabetic retinopathy, age-related macular degeneration, and various ocular diseases. However, this increased use of such agents has led to a higher frequency of encountering renal adverse effects in clinical practice. This review comprehensively addresses the incidence, pathophysiological mechanisms, and current evidence concerning renal adverse events associated with systemic and intravitreal antiangiogenic therapies targeting VEGF-A and its receptors (VEGFR) and their associated signaling pathways. Additionally, we briefly explore strategies for mitigating potential risks linked to the use of these agents and effectively managing various renal adverse events, including but not limited to hypertension, proteinuria, renal dysfunction, and electrolyte imbalances.

Keywords: Anti-angiogenic; Drug induced TMA; Drug induced nephrotoxicity; Vascular endothelial growth factor.

Fig. 1

Pathogenesis of nephrotoxicity related to anti-VEGF therapy. Anti-VEGF drugs interfere with multiple downstream tyrosine kinase pathways responsible for maintaining glomerular and podocyte integrity. A consequence of this disruption is the development of podocyte effacement and glomerular basement membrane thickening, both leading to proteinuria. In addition, there is development of microthrombi, endotheliosis, and reduction in complement factors that lead to thrombotic microangiopathy and hypertension. Reduced fractional excretion of sodium also contributes to the hypertension. VEGF vascular endothelial growth factor, VEGFR vascular endothelial growth factor receptor, AKT-PI3 phosphoinositide-3-kinase, MAPK mitogen-activated protein kinase, ERK extracellular signal-regulated kinase, mTOR mammalian target of rapamycin, eNOS endothelial nitric oxide synthase, GBM glomerular basement membrane, MCNS minimal change nephrotic syndrome, FSGS focal segmental glomerulosclerosis, TMA thrombotic microangiopathy, CFH complement factor-H

Fig. 2

A Glomerulus with features of chronic thrombotic microangiopathy. Diffuse and global duplication of glomerular basement membranes (arrows) is noted with segmental mesangial matrix expansion (PASM stain; 400×); B glomerulus showing segmental sclerosis with hyalinosis (arrow; PAS stain; 400×). Both images are representative images of lesions seen in patients with renal effects of anti-VEGF therapy and not actual patient images