VEGF inhibition, hypertension, and renal toxicity

Abstract

The use of anti-angiogenic agents as part of the therapeutic armamentarium for advanced stage solid tumors has become the standard of care in several instances, particularly for renal cell carcinoma, non-small cell lung carcinoma, colorectal carcinoma, and gastrointestinal stromal tumors. These agents primarily target vascular endothelial growth factor (VEGF) and/or its receptors, and include bevacizumab, a humanized monoclonal antibody against VEGF, as well as tyrosine kinase inhibitors that target several receptor tyrosine kinases (RTK), including VEGF receptors. These therapies, as a general class of anti-angiogenic medications, have been shown to have common adverse vascular effects attributable directly or indirectly to their anti-VEGF effects, including hypertension, renal vascular injury, often manifested by proteinuria and thrombotic microangiopathy, and congestive heart failure. Knowledge of these common side effects and their underlying mechanisms may allow for more accurate and prompt diagnoses, timely clinical interventions, and the development of rational and standard treatments. These measures may minimize patient morbidity and mortality, not only by the treatment of side effects, but also by minimizing the disruption of treatment of the underlying malignancy, as well as improving patient quality of life.

Figure 1

Anti-VEGF therapy, by causing low free VEGF levels, may cause endothelial dysfunction and podocyte dysregulation, leading to hypertension and proteinuria, respectively.

Figure 2

64 year old male with metastatic liver angiosarcoma treated with bevacizumab, who, after 35 months of treatment, developed nephrotic range proteinuria and an active urinary sediment. A renal biopsy (silver stain) showing double contouring (arrow), consistent with thrombotic microangiopathy.