Antiviral Drug Nephrotoxicity

Antiviral Drug Nephrotoxicity

Shane M. Meehan, MBBCh

H&E shows acute tubular injury with severe attenuation of the epithelium, luminal widening, and necrotic debris image in an HIV-positive patient exposed to tenofovir. There is also diffuse interstitial fibrosis.

Tubular karyomegaly image and acute tubular injury are evident in this biopsy specimen from a patient with tenofovir toxicity. The interstitium has extensive fibrosis.



  • Antiviral nephrotoxicity


  • Kidney dysfunction due to exposure to antiviral agents


Environmental Exposure

  • Antiviral agents with known nephrotoxicity

    • Nucleoside analogs (reverse transcriptase inhibitors): Acyclovir, valacyclovir, ganciclovir, abacavir, lamivudine, didanosine

    • Nucleotide analogs (reverse transcriptase inhibitors): Tenofovir, adefovir, cidofovir

    • Peptide analogs (protease inhibitors): Indinavir, ritonavir, atazanavir

    • Pyrophosphate analogs: Foscarnet (trisodium phosphonoformate)

    • Fusion or entry inhibitors: Enfurtivide

    • Other agents: Intravenous immunoglobulin, interferon-α

  • Risk factors for nephrotoxicity

    • Kidney

      • Drugs are concentrated in specific nephron segments; proximal tubules are at greatest risk of injury

      • Organic anion transporter system concentrates tenofovir and cidofovir in proximal tubules

    • Patient

      • Infection, e.g., HIV

      • Underlying chronic kidney disease and dehydration

      • Pharmacogenetics and immune response genes

    • Drug

      • Dose dependent: High dose increases risk of renal injury

      • Solubility: Concentration and pH dependent

      • Immune stimulatory potential

  • Pathogenesis

    • Direct tubular toxicity: Tenofovir, adefovir, acyclovir, cidofovir

      • Mitochondrial toxicity: Antiviral nucleoside and nucleotide analogs (ANA) act as competitive alternative substrate for mitochondrial thymidine kinase

      • ANA triphosphate inhibits mitochondrial DNA polymerase-γ, resulting in altered mitochondrial DNA

      • Mitochondrial depletion and mitochondrial DNA depletion are associated with tenofovir, adefovir, and cidofovir

    • Tubulointerstitial nephritis (TIN): Indinavir, atazanavir, abacavir, efavirenz, foscarnet

      • Dysfunction associated with inflammatory injury

      • Injury may be precipitated by tubular injury or idiosyncratic immunologic reactions ± effects of HIV infection

    • Crystal nephropathy: Acyclovir, indinavir

      • Crystals may be toxic to epithelium and may obstruct tubules

      • Crystal precipitation often associated with tubulointerstitial nephritis

    • Glomerulopathy: Foscarnet, valacyclovir, acyclovir, enfuvirtide

      • Glomerular crystal deposition



  • Proximal tubulopathy and Fanconi syndrome: Cidofovir, tenofovir, adefovir, foscarnet, stavudine, lamivudine

    • Frequency: Tenofovir (0.3-2%), adefovir (up to 50% at high dose)

  • Distal tubular acidosis: Foscarnet

  • Nephrogenic diabetes insipidus: Foscarnet, didanosine, abacavir

  • Acute renal failure/kidney injury: Acyclovir, ganciclovir, cidofovir, indinavir, tenofovir, adefovir, foscarnet

    • Frequency: Tenofovir (0.5-1.5%), acyclovir (10%)

  • Crystalluria, lithiasis: Acyclovir, indinavir

    • Frequency: Indinavir (10-20%), acyclovir (12-48% with intravenous infusions), atazanavir (0.01%)

    • Crystalluria may be associated with acute kidney injury

  • Proteinuria: Cidofovir, foscarnet, interferon-α

  • Chronic renal failure: Cidofovir, indinavir, tenofovir


  • Drug withdrawal or substitution

  • Hydration and restoration of high urinary output


  • Most acute dysfunction due to antiviral agents is reversible

    • Most acute kidney injuries and acute crystal nephropathies are reversible

    • TIN ± crystal deposits are reversible if interstitial fibrosis is limited

    • Lesions have limited reversibility if there is extensive scarring on biopsy

  • Anecdotal reports of end-stage renal failure due to cidofovir and foscarnet toxicity


Histologic Features

  • Acute tubular injury or necrosis

    • Tubular injury can be associated with most antiviral agents

      • Proximal tubules are most severely affected with loss of apical cytoplasm, brush border, irregular tubular luminal boundary

      • Karyomegaly with nuclear enlargement, irregular nuclear membrane, hyperchromatism, coarse nucleoli

      • Proximal tubular megamitochondria are rounded eosinophilic cytoplasmic inclusions; fuchsinophilic on trichrome stain; PAS negative

      • Megamitochondria are characteristic of tenofovir, but also described in cidofovir, adefovir, lamivudine, and stavudine toxicity

      • Distal tubular segments and collecting ducts also have evidence of injury with regeneration

      • Interstitial fibrosis may be prominent

    • Myoglobinuric acute tubular necrosis has been described with use of didanosine and zidovudine in patients with HIV infection

    • Intravenous immunoglobulin may be associated with osmotic tubulopathy

  • Crystal nephropathy: Intrarenal precipitation of crystallized salts of antiviral agent

Jul 7, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Antiviral Drug Nephrotoxicity

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