ANTIBIOTIC-RELATED NEPHROTOXICITY

The toxicity of aminoglycosides is related to their concentrative upta ke by proximal tubular cells and their capacity to interact with criti cal intracellular targets. Concentrative uptake is mediated by adsorpt ive endocytosis across the apical membrane followed by sequestration w ithin lysosomes. The fundamental mechanism underlying the toxicity of these organic polycations is their capacity to interact electrostatica lly with and disrupt the metabolism of anionic phospholipids, especial ly the phosphoinositides. Polyaspartic acid, a polyanionic peptide, pr otects against aminoglycoside nephrotoxicity by forming electrostatic complexes with these drugs and inhibiting their interaction with criti cal intracellular targets. The selective toxicity of beta-lactams towa rds renal proximal tubular cells is related to their concentrative upt ake via the organic anion transport system. Lipid peroxidation appears to play a major role in the toxicity of cephaloridine. Depressed mito chondrial respiration secondary to acylation of the mitochondrial tran sporter for succinate has been implicated in the pathogenesis of toxic ity caused by other cephalosporins and carbapenems. The predilection o f the kidney for amphotericin B toxicity is unclear as little drug is excreted by the kidneys. Toxicity is manifestaed by increased renal va scular resistance, depression of RBF and GFR, and altered tubular func tion that reflects the capacity of this drug to interact with choleste rol-containing membranes and increase membrane permeability to ions in cluding potassium, hydrogen, calcium, and magnesium.