Which molecular mechanism of aminoglycoside-induced nephrotoxicity distinguishes it from most other antibiotic nephrotoxins?

• A Aminoglycosides directly block mitochondrial ribosomal RNA in renal tubular cells causing energy depletion and apoptosis
• B Aminoglycosides are cationic and bind phosphatidylinositol-4,5-bisphosphate in the proximal tubular cell brush border, accumulating in lysosomes where they inhibit phospholipases, causing phospholipidosis and tubular cell death ✓
• C Aminoglycosides inhibit NF-κB in proximal tubular cells, reducing protective heat-shock protein expression
• D Aminoglycosides bind megalin receptor on basolateral membranes of proximal tubules, causing receptor-mediated endocytosis

Explanation

Aminoglycoside nephrotoxicity has a unique subcellular mechanism. The highly cationic aminoglycosides bind with high affinity to negatively charged phosphatidylinositol-4,5-bisphosphate (PIP2) in the brush border membrane of proximal tubular (S1/S2 segment) cells. They are internalized via pinocytosis (with contribution from megalin/cubilin receptor-mediated endocytosis at the brush border) and accumulate in lysosomes, where they inhibit lysosomal phospholipases A and C, causing lysosomal phospholipidosis. Lysosomal rupture releases hydrolytic enzymes and reactive oxygen species, leading to mitochondrial dysfunction, loss of tubular cell polarity, and cell death. This explains why aminoglycoside nephrotoxicity causes non-oliguric renal failure with cast-free urine, is amplified by repeated dosing, and why once-daily dosing (allowing drug-free intervals for cellular recovery) is less nephrotoxic than multiple daily dosing.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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