What is the mechanism by which Tenofovir (antiretroviral medication) causes nephrotoxicity?

Mechanism of Tenofovir-Induced Nephrotoxicity

Tenofovir primarily causes nephrotoxicity through direct toxic effects on proximal tubular mitochondria, leading to proximal tubular dysfunction that can manifest as Fanconi syndrome with normoglycemic glycosuria, hypophosphatemia, proteinuria, and metabolic acidosis. 1, 2

Primary Pathophysiological Mechanisms

• Tenofovir accumulates in proximal tubular cells due to active secretion, where it targets and damages mitochondria 2
• Histologically, tenofovir nephrotoxicity presents as toxic acute tubular necrosis with distinctive proximal tubular eosinophilic inclusions representing giant mitochondria 2
• Electron microscopy reveals mitochondrial enlargement, depletion, and dysmorphic changes in proximal tubular cells 2
• Altered mitochondrial COX (cytochrome c oxidase) activity in proximal tubules appears to be an early cellular alteration in tenofovir nephrotoxicity 3

Molecular Mechanisms

• Tenofovir causes decreased expression of megalin and cubilin (proximal tubular transporters) 3
• Loss of megalin/cubilin expression correlates with:
  • Lower eGFR at presentation
  • Higher urinary retinol binding protein levels
  • Poorer renal outcomes at follow-up 3
• The severity of megalin/cubilin loss is greater in patients with multifactorial toxicity 3

Clinical Manifestations of Proximal Tubular Dysfunction

• Fanconi syndrome characterized by:
  • Normoglycemic glycosuria
  • Hypophosphatemia due to phosphaturia
  • Proteinuria (particularly low molecular weight proteins)
  • Metabolic acidosis due to bicarbonate wasting 1, 4
• Acute kidney injury or progressive chronic kidney disease 5
• Decreased glomerular filtration rate (up to 10% reduction) 5

Risk Factors for Tenofovir Nephrotoxicity

• Pre-existing kidney disease 5
• Advanced age 6
• Low body mass 6
• Concurrent use of medications that increase tenofovir levels, particularly ritonavir-boosted protease inhibitors 1, 5
• Comorbid conditions:
  • Hypertension
  • Diabetes
  • HIV-associated kidney disease
  • Hepatitis B or C co-infection 5

Monitoring and Early Detection

• Regular assessment of renal function using creatinine-based estimated GFR:
  • At initiation of tenofovir
  • 1-3 months after starting therapy
  • Every 6-12 months if stable 5
• More frequent monitoring for high-risk patients 5
• Monitoring for proximal tubular dysfunction:
  • Spot protein or albumin:creatinine ratio (preferred)
  • Urine dipstick in resource-limited settings 5

Management of Tenofovir Nephrotoxicity

• Discontinue tenofovir immediately upon diagnosis of Fanconi syndrome or significant renal dysfunction 7
• Consider alternative antiretrovirals:
  • Tenofovir alafenamide (TAF) if creatinine clearance >30 mL/min
  • Abacavir (preferred option for renal impairment)
  • Dose-adjusted tenofovir if concomitant hepatitis B 7, 5
• Monitor electrolytes closely, particularly phosphate, potassium, and bicarbonate levels 7
• Assess for recovery of renal function after discontinuation 2

Prognosis

• Significant improvement of renal function occurs in many patients after discontinuation of tenofovir 2
• However, renal function may not always return completely to baseline 6
• Patients with concomitant exposure to other nephrotoxic conditions generally have worse renal outcomes 3

Prevention Strategies

• Avoid tenofovir in patients with pre-existing kidney disease when alternatives exist 8
• Reduce tenofovir dose based on estimated creatinine clearance in patients with renal impairment 8
• Avoid concurrent use of other potentially nephrotoxic drugs, especially ritonavir-boosted protease inhibitors 8
• Consider tenofovir alafenamide as an alternative with less renal toxicity 5