Oxidative stress and vascular injury — relevant for atherogenesis in uraemic patients ?

Cisplatin (cis-dichlorodiammine-platinum (II ), CP) is an effective antineoplastic agent in the treatment of Primary effects of platinum compounds various solid tumours, whose full clinical utility is limited because of its renal toxicity. Since even vigorous Inhibition of protein synthesis hydration may not eliminate toxicity, discontinuation of CP remains the only option in cases of progressive Cell culture as well as animal studies indicate that renal failure. Novel measures to protect kidneys from inhibition of protein synthesis is the earliest biochemCP toxicity are currently being investigated. These ical manifestation of CP toxicity in proximal tubular studies, preferentially using animal or cell culture cells. The detailed mechanisms are unclear. One models, are based upon the increasing knowledge of possibility is disruption of the nucleolus as the site of subcellular mechanisms of CP toxicity. ribosome biosynthesis. Leibbrandt et al. [2] demonstrated nucleolar condensation and fragmentation in tubular cells treated for as little as 2 h with 100 mM Proximal tubular uptake and accumulation CP, a concentration that is readily reached in patients. The major site of renal injury is the S3 segment of the These authors argue that interference of CP with proximal tubule, located in the outer stripe of the outer nucleolar structure or function might decrease ribomedulla of the kidney. Cisplatin concentrations in some number and ultimately protein synthesis. In proximal tubular epithelial cells exceed plasma concenaddition, they report on the inhibition of lysosomal trations by a factor of five. This is at least in part due protein degradation following CP treatment. to active uptake via energy-dependent processes, such Another possible explanation for inhibition of proas the probenecid inhibitable organic base transport tein synthesis is CP’s ability to decrease ribosome protein [1]. Intracellularly, the highest concentrations assembly in vitro by interference with the joining of of CP are found in the cytosol, mitochondria, nuclei, the 48S and 60S subunits [3], indicating that in nonand microsomes. Low intracellular chloride concentraproliferating cells, for instance renal tubular epithelial tions favour the replacement of the two chloride ligands cells, inhibition of protein synthesis seems to be a postof the cisplatin molecule by hydroxyl groups, resulting transcriptional event. This contrasts with the major in even more toxic aquated platinum derivates. Cisplatin toxicity in proximal tubular epithelial cells is morphologically characterized by tubular necrosis, Table 1. Potential subcellular mechanisms of cisplatin toxicity in renal proximal tubular cells loss of microvilli, alterations in number and size of lysosomes, and mitochondrial vacuolization. These structural alterations are accompanied by functional Primary effects Secondary effects disturbance of various cell organelles. Meanwhile, two distinct pathophysiological mechanisms have been Inhibition of protein Inactivation of transport proteins synthesis recognized as primary promoters of cellular damage, Nucleolar damage i.e. inhibition of protein synthesis and glutathione Disturbance of ribosome Lipid peroxidation depletion; in contrast, mitochondrial damage, inhibiassembly tion of membraneous transport proteins and lipid GSH and protein-SH Mitochondrial damage depletion Inhibition of Na+, K+-ATPase Cytoplasm Reduced Ca2+-uptake Correspondence and offprint requests to: Martin K. Kuhlmann MD, Mitochondria ATP-depletion Universitätskliniken des Saarlandes, Innere Medizin IV, D-66421 Loss of membrane potential Homburg/Saar, Germany.