Table 1.

Main alterations elicited by aminoglycosides in kidney cortex

1. At low dosesa
1.1. Early alterations
- Accumulation of phospholipids in lysosomes and enlargement of these organelles (71,138)b
- Inhibition of the activities of lysosomal phospholipases and sphingomyelinase (75)
- Decreased reabsorption and/or intracellular lysosomal sequestration and digestion of filtrated, low-molecular-weight proteins (e.g., lysozyme, alpha-2-macroglobulin, beta-2-microglobulinc(see references 35 and 130 for reviews)
- 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)
1.2. Later alterations
1.2.1. Degenerative alterations
- Coarse granulation of epithelial cellsd (see reference130 for a review)
- Focal necroses,e apoptoses (77)
- Increased phospholipid excretion and cast in urinef (see reference 130 for a review)
- Proteinuria, hypoosmotic polyuria, in humans only (see reference 35 for a review)
- 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)
1.2.2. Regenerative lesions
- Tubular cell proliferation and dedifferentiation (127)
- Tubular dilatation (see reference 130 for a review)
- Interstitial proliferation (fibroblastic cells) and focal infiltration by inflammatory cells (see reference 130 for a review)
2. At high doses
2.1. Brush-border and apical membranes
- Wasting of K+, Mg2+, and Ca2+(35, 116)
- Decreased reabsorption of water, HCO3 , glucose (64)
- Decreased of Na+ and Pi cotransport and Na+and H+ exchange (79)
- Inhibition of phosphatidylinositol phospholipase C (see reference131 for a review)
- Decrease of carrier-mediated dipeptide transport (113)
2.2. Basolateral membrane
- Impairment of organic acid and bases transport (see reference131 for a review)
- Inhibition of Na+/K+ ATPase (34, 131)
- Reduction of the electrogenic Na+ transport (126)
2.3. Mitochondria
- Impairment of respiration and cation transport; swelling (see reference 35 for a review)
- Impairment of the activities of key mitochondrial enzymes in gluconeogenesis, ammoniogenesis, and tricarboxylic acid oxidation pathways (107; see reference131 for a review)
2.4. Protein synthesis and related phenomena
- Inhibition of protein synthesis (see reference35 for a review) and dilatation of endoplasmic reticulum
- Suppression of gene expression for the Na+and Ca2+ exchanger, Na+-dependentd-glucose transporter, and alpha, subunit of Na+/K+ ATPase (23, 47)
- Expression and move of heat shock proteins from nucleus to lysosomes (69)
  • a Low doses refer to either clinical dosages for humans or of dosages less than 20 mg/kg per day for animals.

  • b References are given as a source for illustration of the typical effect that is described or refer to review papers; see text for more comprehensive citations.

  • c These alterations have often been used for the early detection of aminoglycoside insult; however, their measurement is of limited practical value in diseased patients.

  • d These cells show markedly enlarged lysosomes, with a decreased buoyant density and prominent myeloid bodies.

  • e Electron microscopy shows widespread alteration of the cell ultrastructure and subcellular organelles, including mitochondria, endoplasmic reticulum, and nuclei.

  • f Myeloid bodies are abundant in lumen and urine.