Angiogenesis Inhibitor Therapies: Focus on Kidney Toxicity and Hypertension

Angiogenesis inhibitors that target the epidermal growth factor (EGF) receptor (EGFR) and vascular endothelial growth factor (VEGF) constitute an important addition to the therapeutic armamentarium for the treatment of patients with metastatic disease. However, because the same growth factors are expressed in the kidneys, these treatment molecules have renal side effects. EGFR is expressed mainly in tubules (mainly distal and collecting segments) and mesangial and parietal epithelial cells. EGF is involved in maintaining tubular integrity and is a potent mitogen for cultured mesangial cells. Few cases of acute renal failure have been reported related to EGFR inhibitors. VEGF and VEGF receptors are still highly expressed in the kidney. VEGF is expressed in podocytes in the glomerulus, and VEGF receptors are present on endothelial, mesangial, and peritubular capillary cells. Signaling between endothelial cells and podocytes is essential for the proper development and maintenance of the filtration function of the kidney glomerulus. The most common renal class effects of VEGF antagonists are both manageable; hypertension and proteinuria commonly regressive on drug withdrawal. There was a dose-dependent increase in risk of proteinuria and hypertension in patients with cancer who received targeted therapies. Furthermore, few patients with glomerulonephritis or thrombotic microangiopathy secondary to treatment were reported. Hypertension is believed to be nitric oxide dependent, whereas proteinuria seems to be related to downregulation of podocyte tight junction protein. This article reviews data relating to hypertension and proteinuria associated with the use of these drugs.