The aminoglycosides are amongst the most well-known nephrotoxic drugs. Yet due to their efficacy against many organisms, they are amongst the most common antibiotics used. The next time your nephrology service goes toe-to-toe with the infectious disease service in the ongoing battle as to whether or not a patient with CKD should get gentamicin, you can arm yourself with these factoids regarding the mechanism of aminoglycoside toxicity:
Aminoglycosides are a potent tubular toxin; the reduction in GFR which results is therefore thought to be an indirect effect on the glomerulus. The predominant sites of aminoglycoside toxicity are the S1 & S2 segments of the proximal tubule. Aminoglycosides are filtered by the glomerulus, and once concentrated in the urine in these segments occurs, they are known to bind to phospholipids, followed by internalization within the cell via megalin. Once inside the proximal tubular cell, they they are concentrated within lysosomes and cause a stereotypical disorganization of the lysosomes termed “myeloid bodies.”
The myeloid bodies are a sign that the tubular cells are functioning poorly, and as a result there is decreased tubular function often manifesting as K, Mg, Ca, PO4, and glucose wasting–almost like a “Fanconi’s Syndrome” picture. Overt necrosis of the tubular epithelial cells can also occur, resulting in ATN. Stereotypically, aminoglycoside toxicity results in non-oliguric renal failure which more often than not recovers (after a few weeks) once the drug is withdrawn.
From a pharmacokinetics standpoint, the toxicity of aminoglycosides correlates best with the peak concentration of the drug. Interestingly, in common clinical practice the drug is dosed based on following aminoglycoside trough levels…