Tenofovir disoproxil fumarate (TDF) causes nephrotoxicity through which specific tubular mechanism, and which newer formulation reduces this risk?

• A TDF causes proximal tubular mitochondrial toxicity by inhibiting DNA polymerase-gamma; tenofovir alafenamide (TAF) achieves high intracellular concentrations at much lower plasma levels, reducing systemic and renal exposure ✓
• B TDF causes interstitial nephritis via immune complex deposition; TAF does not trigger the same immune response
• C TDF is directly toxic to glomerular podocytes; TAF selectively distributes to hepatocytes, bypassing the kidney
• D TDF chelates calcium in tubular cells causing nephrocalcinosis; TAF has no calcium-chelating activity

Explanation

Tenofovir is a nucleotide reverse transcriptase inhibitor that accumulates in proximal tubular cells (via organic anion transporters OAT1/3) and inhibits mitochondrial DNA polymerase-gamma, impairing mitochondrial biogenesis. This causes proximal tubular dysfunction (Fanconi syndrome: phosphaturia, normoglycaemic glycosuria, aminoaciduria, hypouricaemia) and, in severe cases, renal failure and osteomalacia (via phosphate wasting). Tenofovir alafenamide (TAF) is a prodrug that is more efficiently activated intracellularly; 90% lower plasma tenofovir exposure is achieved compared to TDF for equivalent intracellular activity, dramatically reducing renal tubular and bone toxicity. TAF is now preferred over TDF in most HIV regimens.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.