Why is tenofovir (Antiretroviral medication) nephrotoxic?

Mechanisms of Tenofovir Nephrotoxicity

Tenofovir causes nephrotoxicity primarily through proximal tubular cell dysfunction due to mitochondrial injury, which can lead to Fanconi syndrome and acute tubular necrosis in severe cases. 1

Pathophysiological Mechanisms

• Tenofovir is principally eliminated by the kidney and accumulates in proximal tubular cells, which are rich in mitochondria 2, 3
• Tenofovir causes mitochondrial toxicity in proximal tubular cells, leading to:
  • Enlarged, dysmorphic mitochondria with distinctive eosinophilic inclusions visible by light microscopy 1
  • Mitochondrial depletion and structural abnormalities visible on electron microscopy 1
• The drug is structurally similar to other nephrotoxic nucleotide analogues (adefovir and cidofovir), but was initially thought to have less nephrotoxicity 4, 3

Clinical Manifestations of Tenofovir Nephrotoxicity

• Proximal tubular dysfunction manifesting as Fanconi syndrome with:
  • Normoglycemic glycosuria (sugar in urine despite normal blood glucose) 5, 6
  • Hypophosphatemia due to phosphate wasting 5, 6
  • Proteinuria (predominantly non-albumin proteins) 5
  • Metabolic acidosis due to bicarbonate wasting 7
• Acute kidney injury or progressive decline in renal function 1
• In severe cases, acute tubular necrosis requiring temporary hemodialysis 1

Risk Factors for Tenofovir-Induced Nephrotoxicity

• Pre-existing renal dysfunction significantly increases risk:
  • Patients with mild renal dysfunction (CrCl 60-89 mL/min) have 4.8 times higher risk 8
  • Patients with moderate renal dysfunction (CrCl 30-59 mL/min) have 15 times higher risk 8
• Concurrent medications that increase tenofovir levels:
  • Ritonavir-boosted protease inhibitors increase tenofovir accumulation in proximal tubules 5, 4
  • Didanosine co-administration increases risk 4, 6
• Low body weight (<60 kg) appears to be a significant risk factor 6
• Duration of therapy - toxicity can develop from 5 weeks to several years after initiation 6, 1

Monitoring and Prevention

• Before starting tenofovir:
  • Assess baseline renal function with estimated creatinine clearance 2
  • In high-risk patients, also check serum phosphorus, urine glucose, and urine protein 2
• During treatment:
  • Regular monitoring of renal function is essential, especially in high-risk patients 5, 2
  • Monitor for signs of tubulopathy: glycosuria, phosphaturia, proteinuria 4
  • Twice-yearly monitoring for patients on tenofovir plus ritonavir or cobicistat 5
• Dose adjustment is required for patients with reduced renal function:
  • CrCl 30-49 mL/min: dose every 48 hours 2
  • CrCl 10-29 mL/min: dose every 72-96 hours 2
  • Hemodialysis patients: dose every 7 days or after approximately 12 hours of dialysis 2

Management of Tenofovir Nephrotoxicity

• Discontinue tenofovir immediately upon diagnosis of Fanconi syndrome or significant renal dysfunction 7
• Monitor electrolytes closely, particularly phosphate, potassium, and bicarbonate levels 7
• Consider alternative antiretrovirals:
  • Tenofovir alafenamide (TAF) has less renal toxicity if CrCl >30 mL/min 7
  • Abacavir does not require dose adjustment in renal disease 5, 7
• Recovery of renal function typically occurs after discontinuation of tenofovir, though it may be partial 1, 3

Pathological Findings

• Renal biopsy shows toxic acute tubular necrosis 1
• Distinctive proximal tubular eosinophilic inclusions representing giant mitochondria 1
• Electron microscopy reveals mitochondrial enlargement, depletion, and dysmorphic changes 1
• Animal studies confirm bone toxicity (osteomalacia) and renal toxicity with increased serum creatinine, BUN, glycosuria, proteinuria, and phosphaturia 2

Understanding these mechanisms of nephrotoxicity is crucial for appropriate patient selection, monitoring, and early intervention to prevent permanent kidney damage in patients receiving tenofovir therapy.