Aminoglycoside nephrotoxicity

Abstract

Aminoglycoside nephrotoxicity is manifested functionally by decreased urine concentrating capacity, tubular proteinuria, lysosomal enzymuria, mild glucosuria, decreased ammonium excretion, and depression of GFR. Histopathologic lesions are confined primarily to the proximal tubule and consist of an increase in the number and size of secondary lysosomes and cytosegresomes containing myeloid bodies, disruption of brush border membranes, mitochondrial swelling, and frank tubular cell necrosis. The first step in the pathogenesis of aminoglycoside toxicity involves the accumulation of these drugs within renal proximal tubular epithelium. The renal handling of aminoglycosides includes glomerular filtration and absorption of a variable fraction of filtered drug along the pars convoluta and pars recta mediated in part by pinocytosis, which results in the segregation of aminoglycoside within lysosomes. Basolateral membrane transport of aminoglycosides has been inferred from in vitro studies of drug accumulation by renal cortical slices. The latter mechanism is independent of the organic acid or base transport systems. Unequivocal evidence of basolateral membrane transport and transtubular secretion, however, is lacking. Transport of aminoglycosides across the apical membrane of distal tubular epithelium has not been demonstrated. All aminoglycosides are concentrated in renal cortex, but there is no correlation between cortical concentration of drug and nephrotoxic potential. The second step in the pathogenesis of aminoglycoside nephrotoxicity involves the propensity of these drugs to interact with one or more intracellular metabolic pathways. Recent studies have shown that aminoglycosides induce a phospholipidosis in cells grown in tissue culture. These findings, together with the observation that aminoglycosides accumulate within lysosomes and induce myeloid body formation, suggest that aminoglycoside nephrotoxicity may be a manifestation of drug-induced lysosomal dysfunction involving phospholipid metabolism.