Nephrotoxicity of Combined Treatment with Cisplatin and Gentamicin in the Guinea Pig: Glomerular Injury Findings

Abstract

The drugs cisplatin and gentamicin are given consecutively to various cancer patients suffering from infections. Little information exists about the ultrastructural alterations of kidney glomeruli caused by treatment with these drugs. Renal glomeruli of guinea pigs treated with cisplatin alone and in combination with gentamicin were studied by transmission electron microscopy. The findings revealed foci of damage induced by cisplatin and especially by cisplatin/gentamicin in all glomerular components: glomerular capillaries, including their endothelial cells; basement membrane, epithelial podocytes, mesangial cells, and parietal cells of Bowman's capsule. The damage was expressed by endothelial cytoplasmic extrusions into the vascular lumen, thickening and lamination of capillary basement membrane, focal foot process fusion of podocytes, vacuolization in cytoplasm of endothelial cells of epithelial podocytes and of parietal cells, and the presence of lipid bodies and myeloid bodies in all glomerular cell types. Additionally, injurious effects to cytoplasmic organelles such as mitochondria, nuclei, and endoplasmic reticulum were observed. The results indicate that cisplatin alone and in combination with gentamicin is toxic to renal glomerular tissue. Since these drugs were previously found toxic for strial capillaries in the inner ear and since the main glomerular component is the glomerular capillaries, potential vascular damage and vascular complications in different body systems have to be taken into consideration when these drugs are needed in clinical use.

Increased Macrophage Infiltration and Fractalkine Expression in Cisplatin-Induced Acute Renal Failure in Mice

“…In a rat model of cisplatin nephrotoxicity, damage to glomerular capillaries, including endothelial cells, has been described previously (Kohn et al, 2002). Caspases and calpain are independent mediators of cisplatin-induced endothelial cell necrosis in vitro (Dursun et al, 2006).…”

Cisplatin up‐regulates ICAM‐1 expression in endothelial cell via a NF‐κB dependent pathway

“…Approaches to reduce the incidence and severity of cisplatin-associated toxicity are under intensive investigation indicate that. (9,12,18,24) Cisplatininduced nephrotoxicity, ototoxicity, and neurotoxicity have been associated with potential microvascular damage, (17)(18)(19) and previous animal experiments and clinical reports have demonstrated that vascular factors (20)(21)(22) contribute to renal dysfunction following exposure to cisplatin. The mechanisms underlying these troublesome vascular-injury-associated side-effects, which are regarded as crucial in the pathogenesis of tissue damage, might involve the proliferation inhibition effect of cisplatin on endothelial cells in vitro (18,32,33) and in vivo.…”

“…Cisplatin-stimulated ICAM-1 induction in endothelial cell will promote or reinforce leukocyte/endothelium interactions as we observed in vivo, which in turn may contribute to the cisplatin-associated toxicities. First and foremost, enhanced leukocyte/endothelium interactions may directly or/ and indirectly induce vascular damage, (17)(18)(19) which may be associated with cisplatin-induced nephrotoxicity, ototoxicity and neurotoxicity. Once adhered to the endothelium, neutrophils may then release proteases, toxic oxygen metabolites and vasoactive substances.…”

“…(16) The presence of these dangerous side-effects has prompted research to achieve a better understanding of the biochemical mechanisms underlying the toxicities. Previous studies and data indicated that cisplatin-induced ototoxicity, renal, peripheral sensory and autonomic nervous system toxicity have been associated with potential microvascular damage, (17)(18)(19) in which the stria capillaries, (19) glomerular capillaries, (17) and the vasa nervorum, (18) were resulted in destruction more or less in the presence of cisplatin challenge. Animal experiments and clinical reports have also demonstrated that vascular factors, (20)(21)(22) contribute to renal dysfunction following exposure to cisplatin.…”

Effects of cisplatin on the contractile function of thoracic aorta of Sprague-Dawley rats

“…Such vascular toxicity has been manifested by increased von Willebrand factor plasma levels as well as an enhanced intima-media thickness of the carotid artery (8). In addition, cisplatin has the potential to induce ototoxicity and toxicity towards renal, peripheral sensory and autonomic nervous systems, potentially attributed to cisplatin-caused microvascular damage (9)(10)(11). Ca 2+ plays an important role in the regulation of vascular tone, which is generally relatively constant.…”