Sevoflurane undergoes degradation in soda lime to produce Compound A (fluoromethyl-2,2-difluoro-1-(trifluoromethyl) vinyl ether). Compound A is nephrotoxic predominantly through which mechanism?

• A Direct tubular necrosis via reactive fluoride ions at the brush border
• B Beta-lyase pathway metabolism in renal tubular cells generating reactive intermediates ✓
• C Inhibition of mitochondrial electron transport chain in collecting duct cells
• D Competitive inhibition of aquaporin-2 channels causing nephrogenic diabetes insipidus

Explanation

Compound A nephrotoxicity in rats occurs via the cysteine beta-lyase pathway: Compound A is conjugated with glutathione, cleaved to cysteine conjugates in the kidney, and the beta-lyase enzyme converts these to reactive thiol intermediates that alkylate macromolecules in proximal tubular cells. Inorganic fluoride ions themselves (option A) cause distal nephrotoxicity as with methoxyflurane, not proximal. Compound A exposure in clinical doses does not reach nephrotoxic thresholds in humans due to lower renal beta-lyase activity compared to rats.

Reference: Morgan & Mikhail's Clinical Anesthesiology, 6th ed.

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