How do aminoglycosides (e.g. gentamicin, tobramycin, amikacin) cause renal damage?

Mechanism of Aminoglycoside-Induced Renal Damage

Aminoglycosides cause renal damage primarily through accumulation in proximal tubular epithelial cells, where they bind to ribosomes and disrupt normal phospholipid trafficking, leading to cell necrosis and acute tubular necrosis. 1, 2, 3, 4

Cellular Uptake and Accumulation

Aminoglycosides enter the kidney through the following process:

• They are filtered through the glomerulus
• A significant fraction is reabsorbed by proximal tubular cells
• As polycationic molecules, they bind to anionic phospholipid components in the brush-border membranes
• They are then transported intracellularly and sequestered within lysosomes 5, 6

The accumulation of aminoglycosides in renal tissue is substantial:

• Renal cortical tissue concentrations can be 5-10 times higher than serum levels
• Cortical concentrations are approximately five times greater than medullary concentrations 6
• This accumulation is progressive and dose-dependent

Cellular Damage Mechanisms

Once inside proximal tubular cells, aminoglycosides cause damage through several mechanisms:

1. Lysosomal phospholipidosis:

   • Disruption of normal phospholipid trafficking
   • Formation of myeloid bodies (electron-dense concretions of phospholipid material)
   • Impaired cytoplasmic degradation of sequestered organelle membranes 7, 6

2. Ribosomal binding:

   • Aminoglycosides bind to ribosomes within the cells
   • This disrupts protein synthesis and cellular function 1, 2

3. Cell necrosis:

   • Progressive damage leads to proximal tubular epithelial cell death
   • Necrosis primarily affects the pars convoluta of the proximal tubule 6

Clinical Manifestations of Renal Toxicity

The nephrotoxicity manifests as:

• Acute tubular necrosis
• Rising blood urea nitrogen (BUN) and creatinine
• Decreased urinary output
• Electrolyte disturbances (sodium, potassium, bicarbonate, magnesium, phosphate, and calcium losses)
• Proteinuria and enzymuria (early indicators)
• Decreased specific gravity of urine
• Presence of cells or casts in urine 2, 3, 4, 8

Risk Factors for Aminoglycoside Nephrotoxicity

Several factors increase the risk of aminoglycoside-induced nephrotoxicity:

• Drug-related factors:

  • High trough levels (above 2 mcg/mL)
  • Excessive peak concentrations (above 12 mcg/mL)
  • Total cumulative dose
  • Duration of therapy
  • Choice of aminoglycoside (gentamicin appears more nephrotoxic than tobramycin) 1, 2

• Patient-related factors:

  • Pre-existing renal impairment
  • Advanced age
  • Volume depletion/dehydration
  • Diabetes
  • Concurrent use of other nephrotoxic drugs 2, 3, 4, 8

Prevention Strategies

To minimize aminoglycoside nephrotoxicity:

1. Dosing strategies:

   • Once-daily dosing rather than multiple daily doses (provides high peak levels for efficacy while minimizing prolonged trough levels)
   • Adjust dosing based on renal function
   • Monitor serum drug concentrations 1, 9

2. Monitoring:

   • Measure peak and trough serum levels
   • Monitor renal function (serum creatinine, BUN)
   • Examine urine for decreased specific gravity, protein, cells, or casts 2, 3

3. Hydration and supportive care:

   • Ensure adequate hydration
   • Consider alkalization therapy with bicarbonate 9

4. Avoid concurrent nephrotoxic agents:

   • Other aminoglycosides
   • Vancomycin
   • Amphotericin B
   • Potent diuretics (ethacrynic acid, furosemide)
   • NSAIDs
   • Cisplatin 10, 3, 4

Important Clinical Considerations

• Aminoglycoside-induced nephrotoxicity is usually reversible after discontinuation of therapy
• Subclinical nephrotoxic effects likely occur in all patients treated with aminoglycosides
• Nephrotoxicity may only become apparent after completion of the antibiotic course
• The incidence of clinically significant nephrotoxicity ranges from 5-35% of treated patients 9, 8

By understanding the mechanism of aminoglycoside nephrotoxicity and implementing appropriate prevention strategies, clinicians can minimize the risk of renal damage while maintaining the efficacy of these important antibiotics in treating severe gram-negative infections.