Aminoglycoside nephrotoxicity predominantly affects which renal tubular segment, and what is the intracellular mechanism of tubular cell damage?

• A Distal tubule; aminoglycosides block Na-K-2Cl cotransporter causing tubular dysfunction
• B Proximal tubular S1 segment; aminoglycosides bind megalin (a multi-ligand receptor) for endocytosis into proximal tubular cells, accumulate in lysosomes, cause lysosomal membrane permeabilization and release of reactive oxygen species causing mitochondrial dysfunction ✓
• C Collecting duct; aminoglycosides directly inhibit aquaporin-2, causing nephrogenic diabetes insipidus
• D Glomerulus; aminoglycosides deposit in mesangial cells causing glomerulonephritis

Explanation

Aminoglycosides enter proximal tubular S1 and S2 segment cells via endocytosis mediated by megalin (LRP2), a multi-ligand endocytic receptor on the brush border membrane. Once internalized, they accumulate in lysosomes, inhibit lysosomal phospholipases (phospholipidosis), cause lysosomal membrane permeabilization, and release cathepsins and reactive oxygen species. Mitochondrial dysfunction ensues with ATP depletion and ultimately necrosis of proximal tubular cells. Once-daily dosing allows renal tissue drug levels to partially recover and reduces nephrotoxicity compared to multiple daily dosing.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.