What is the mechanism for aminoglycoside (antibiotic)-induced nephrotoxicity (Impaired renal function)?

From the Guidelines

Aminoglycoside nephrotoxicity occurs through several key mechanisms that damage kidney cells, including accumulation in proximal tubular epithelial cells, disruption of mitochondrial function, activation of inflammatory pathways, and interference with protein synthesis, as noted in studies such as 1. The mechanisms of aminoglycoside nephrotoxicity are complex and multifaceted. These antibiotics accumulate in the proximal tubular epithelial cells of the kidney through megalin-mediated endocytosis, reaching concentrations much higher than in plasma. Once inside these cells, aminoglycosides disrupt mitochondrial function by inhibiting phospholipid metabolism and generating reactive oxygen species, leading to cellular energy depletion. They also activate inflammatory pathways, trigger apoptosis (programmed cell death), and interfere with protein synthesis in tubular cells. Additionally, aminoglycosides can cause vasoconstriction of renal blood vessels, reducing kidney perfusion and glomerular filtration rate. Some key points to consider when evaluating the nephrotoxicity of aminoglycosides include:

• Risk factors that increase nephrotoxicity, such as pre-existing kidney disease, advanced age, dehydration, concurrent nephrotoxic medications, and prolonged treatment courses, as discussed in 1 and 1.
• The specific aminoglycosides associated with nephrotoxicity, including gentamicin, tobramycin, and amikacin, with risk increasing at higher doses and longer durations, as noted in 1.
• The importance of monitoring kidney function through serum creatinine and drug levels, maintaining hydration, and using the lowest effective dose for the shortest necessary duration to minimize aminoglycoside-induced kidney damage, as recommended in 1 and 1. It is essential to weigh the benefits of aminoglycoside use against the potential risks of nephrotoxicity, particularly in patients with pre-existing kidney disease or other risk factors, and to consider alternative treatments when possible, as suggested in 1 and 1.

From the FDA Drug Label

As with other aminoglycosides, gentamicin injection is potentially nephrotoxic. The risk of nephrotoxicity is greater in patients with impaired renal function and in those who receive high dosage of prolonged therapy Excessive peak and/or trough serum concentrations of aminoglycosides may increase the risk of renal and eighth cranial nerve toxicity.

The mechanism for aminoglycoside nephrotoxicity is not explicitly stated in the provided drug labels. However, it is mentioned that nephrotoxicity is a potential risk associated with the use of aminoglycosides, including gentamicin and tobramycin.

• Key factors that increase the risk of nephrotoxicity include:
  • Impaired renal function
  • High dosage
  • Prolonged therapy
  • Excessive peak and/or trough serum concentrations 2 2 3

From the Research

Mechanism of Aminoglycoside Nephrotoxicity

• The toxic mechanism of aminoglycoside antibiotics includes uptake of the drug by proximal tubular cells, where it is first sequestered within lysosomes 4.
• Development of a lysosomal phospholipidosis is rapidly associated with cell necrosis and various alterations to subcellular structure and function 4.
• Aminoglycosides cause tubular necrosis, epithelial oedema of proximal tubules, cellular desquamation, tubular fibrosis, glomerular congestion, perivascular edema, and inflammation, ultimately leading to renal dysfunction 5.

Pathogenesis of Nephrotoxicity

• The mechanism of renal toxicity is unclear, but aminoglycosides affect several nephron functions, including glomerular filtration, proximal tubular reabsorption, and urinary concentration 6.
• The degree of toxicity appears to correlate with the level of renal tissue concentration of aminoglycoside 6.
• Clinical nephrotoxicity is most likely to occur in the presence of volume depletion, advancing age, preexisting renal dysfunction, and exposure to other nephrotoxins 6.

Risk Factors for Nephrotoxicity

• Risk factors for nephrotoxicity in patients treated with aminoglycosides include higher initial calculated creatinine clearances, female sex, liver disease, initial 1-hour post-dose aminoglycoside level, patient age, and shock 7.
• Factors that do not add significantly to the risk of nephrotoxicity include diabetes, dehydration, serum bicarbonate, bacteremia, urinary tract infection, gentamicin or tobramycin use, duration of therapy, total aminoglycoside dose, or the use of clindamycin, furosemide, or cephalothin 7.

Prevention of Nephrotoxicity

• Correction of volume depletion and diminished renal perfusion, as well as dose adjustment for level of renal function, have been identified as critical measures for prevention of renal damage by aminoglycosides 8.
• Administration of daily doses of aminoglycosides as one or two injections, rather than as multiple injections or by continuous infusion, may also decrease the risk for toxicity 4.