Aminoglycoside nephrotoxicity preferentially damages the proximal tubular cells. The sub-cellular mechanism responsible is:

• A Aminoglycosides bind to megalin (LRP2) receptors on proximal tubular brush border, undergo receptor-mediated endocytosis, accumulate in lysosomes, and cause lysosomal membrane disruption with release of phospholipases ✓
• B Aminoglycosides inhibit mitochondrial 12S rRNA in proximal tubular cells, disrupting oxidative phosphorylation
• C Aminoglycosides bind to tubular organic anion transporters (OAT1/OAT3), depleting transporter activity and causing tubular necrosis
• D Aminoglycosides cause direct ischaemia of proximal tubules by constricting the afferent arteriole through thromboxane release

Explanation

Aminoglycosides (polycationic molecules) bind to anionic phospholipids on the proximal tubular brush border and to megalin (LRP2, a multiligand endocytic receptor highly expressed in PT). This triggers receptor-mediated endocytosis into endosomes that fuse with lysosomes. Within lysosomes, aminoglycosides inhibit phospholipase A2 and sphingomyelinase, causing lysosomal phospholipidosis; eventually lysosomal membranes rupture, releasing cathepsins and other hydrolases into the cytoplasm — triggering tubular cell necrosis. This explains why once-daily dosing (producing a Cmax-driven antibiotic effect with a drug-free trough) is less nephrotoxic than continuous infusion (which maintains sustained tubular accumulation).

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.