Nephrotoxicity of recent anti-cancer agents

Abstract

Cancer patients may develop a variety of kidney lesions that impair not only their immediate survival but also limit the adequate treatment of the underlying malignant process. This review summarizes the nephrotoxic potential of some of the most recently developed anti-cancer drugs, focusing on those interfering with the vascular endothelial growth factor and epidermal growth factor receptor pathways and mammalian target of rapamycin inhibitors. Thrombotic microangiopathy (haemolytic-uraemic syndrome), proteinuria, hypertension and magnesium depletion are the most common side effects. Also the risk for developing acute kidney injury in patients with advanced prostate cancer undergoing androgen deprivation therapy is discussed.

Keywords: androgen deprivation therapy and AKI; anti-angiogenesis drugs and cancer; anti-cancer drugs and nephrotoxicity.

Fig. 1.

Microscopic appearance of kidney biopsy showing diffuse segmental thickening of glomerular basement membranes and increased extracellular matrix within the glomeruli. The findings are consistent with thrombotic microangiopathy/antineoplastic drug-induced atypical haemolytic-uraemic syndrome. For more clinical details see text. Figure taken from ref. [52] with permission.

Fig. 2.

(a) Model of VEGF signalling in the glomerulus. VEGF is released by podocytes and acts on VEGF receptors on endothelial cells (EC), causing receptor phosphorylation and signal transduction that is required to maintain endothelial cell integrity and the glomerular filtration barrier. TMA, thrombotic microangiopathy. (b) Targeting the VEGF pathway at a number of levels. Anti-VEGF antibodies and VEGF-trap bind VEGF ligand; anti-VEGF-receptor antibodies block at the level of the receptors, whereas TKIs inhibit intracellular pathways activated by VEGF. TKI, tyrosine kinase inhibitors. Both figures are taken from [69] with permission.

Fig. 3.

Different types of agents used to target EGFR with their mechanism of action. Figure taken from ref. [81] with permission.

Fig. 4.

Cetuximab (C), a chimeric s against EGF receptor (EGFR), competitively inhibits EGF binding to its receptor, thereby blunting the placement of transient receptor potential M6 (TRPM6) into the apical membrane. Normally, EGF binds its receptor (EGFR) and stimulates magnesium reabsorption in the distal convoluted cell. An EGFR antibody causes renal magnesium wasting by competing with EGF for its receptor. NCC, sodium chloride cotransporter. Figure taken from ref. [18] with permission.