An elderly patient on gentamicin for Gram-negative bacteremia develops rising creatinine after 7 days of therapy. The nephrotoxicity of aminoglycosides is primarily due to:

• A Accumulation in proximal tubular cells via megalin-mediated endocytosis, causing lysosomal disruption and mitochondrial damage ✓
• B Precipitation of drug in acidic urine causing obstructive nephropathy
• C Allergic interstitial nephritis mediated by IgE on mast cells in renal interstitium
• D Decreased GFR from systemic vasoconstriction as a pharmacodynamic side effect

Explanation

Aminoglycosides are filtered by glomeruli (they are not protein-bound), and in the proximal tubule they bind megalin (a multiligand endocytic receptor on the brush border) and are taken up into tubular cells by receptor-mediated endocytosis. Once inside lysosomes, they inhibit phospholipases, causing phospholipid accumulation (myeloid bodies). They also enter mitochondria, where they impair oxidative phosphorylation and generate reactive oxygen species, ultimately leading to proximal tubular cell necrosis. This is typically non-oliguric and reversible if the drug is stopped early. Risk factors include total cumulative dose, duration, once-daily dosing (less nephrotoxic than multiple-daily), and pre-existing renal disease.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.