Expression and move of heat shock proteins from nucleus to lysosomes ( 69)įig. Suppression of gene expression for the Na +and Ca 2+ exchanger, Na +-dependent d-glucose transporter, and alpha, subunit of Na +/K + ATPase ( 23, 47) Inhibition of protein synthesis (see reference 35 for a review) and dilatation of endoplasmic reticulum
Impairment of the activities of key mitochondrial enzymes in gluconeogenesis, ammoniogenesis, and tricarboxylic acid oxidation pathways ( 107 see reference 131 for a review)Ģ.4. Impairment of respiration and cation transport swelling (see reference 35 for a review) Reduction of the electrogenic Na + transport ( 126)
Inhibition of Na +/K + ATPase ( 34, 131) Impairment of organic acid and bases transport (see reference 131 for a review) Decrease of carrier-mediated dipeptide transport ( 113) Inhibition of phosphatidylinositol phospholipase C (see reference 131 for a review) Decreased of Na + and P i cotransport and Na +and H + exchange ( 79) Decreased reabsorption of water, HCO 3 −, glucose ( 64) Interstitial proliferation (fibroblastic cells) and focal infiltration by inflammatory cells (see reference 130 for a review) Tubular dilatation (see reference 130 for a review) Tubular cell proliferation and dedifferentiation ( 127) Decreased glomerular filtration and increase in blood urea nitrogen and creatinine, without immediate signs of glomerular damage, in humans only (see reference 130 for a review) Proteinuria, hypoosmotic polyuria, in humans only (see reference 35 for a review) Increased phospholipid excretion and cast in urine f (see reference 130 for a review) Coarse granulation of epithelial cells d (see reference 130 for a review) Shedding of brush-border enzymes (e.g., alanylaminopeptidase) and release of lysosomal enzymes (e.g., N -acetyl-beta-glucosaminidase) c (see reference 130 for a review) Decreased reabsorption and/or intracellular lysosomal sequestration and digestion of filtrated, low-molecular-weight proteins (e.g., lysozyme, alpha-2-macroglobulin, beta-2-microglobulin c(see references 35 and 130 for reviews) Inhibition of the activities of lysosomal phospholipases and sphingomyelinase ( 75) Accumulation of phospholipids in lysosomes and enlargement of these organelles ( 71, 138) b GENERAL FEATURES OF AMINOGLYCOSIDE NEPHROTOXICITY A companion minireview ( 83) examines and discusses the recent research dealing with the activities of aminoglycosides and bacterial resistance. Ototoxicity, which is the second main adverse effect of aminoglycosides and which, in contrast to nephrotoxicity, is irreversible, will not be considered here since it has already been reviewed in this journal ( 52) and elsewhere ( 10). The present minireview tries to present in a prospective way the status of both the basic and the clinical research on aminoglycoside nephrotoxicity in order to clarify the main issues and to pinpoint strategies that may eventually lead to their safer use. Yet, because aminoglycosides are very effective antibiotics well suited to the treatment of severe infections ( 35), it seems important to maintain and even develop efforts to improve their therapeutic indices. Chemical research aimed at obtaining intrinsically less toxic compounds has met with only modest success, and few of the other approaches proposed to reduce the toxicities of the available agents have reached practical clinical applications. Although a clear recognition of the patient- and treatment-related risk factors ( 91), combined with the once-a-day schedule and effective monitoring procedures ( 98), have definitely improved the situation over what prevailed in the early 1980s ( 115), we are still short of having brought the safety of aminoglycosides to that of the main other wide-spectrum antibiotics. Aminoglycosides have long been one of the commonest causes of drug-induced nephrotoxicity ( 137).
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