Antiviral Drug Nephrotoxicity



Antiviral Drug Nephrotoxicity


Shane M. Meehan, MBBCh





Key Facts


Terminology



  • Kidney dysfunction due to exposure to antiviral agents


Etiology/Pathogenesis



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


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


  • Crystal nephropathy: Acyclovir, indinavir


  • Glomerulopathy: Foscarnet, valacyclovir, acyclovir, enfuvirtide


Microscopic Pathology



  • Acute tubular injury or necrosis ± TIN



    • Karyomegaly + megamitochondria


    • Proximal tubules are most severely affected


  • Interstitial fibrosis may be prominent


  • Crystal nephropathy: Intrarenal precipitation of crystallized salts of antiviral agent (indinavir and foscarnet)


  • TIN: Acute and chronic


  • Glomerular crystals (foscarnet), thrombotic microangiopathy (acyclovir)


Ancillary Tests



  • Mitochondrial enlargement, dysmorphism, distortion of cristae; mitochondrial depletion on electron microscopy


  • Infrared spectroscopy allows definitive identification of crystal composition







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.


TERMINOLOGY


Synonyms



  • Antiviral nephrotoxicity


Definitions



  • Kidney dysfunction due to exposure to antiviral agents


ETIOLOGY/PATHOGENESIS


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


CLINICAL ISSUES


Presentation



  • 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


Treatment



  • Drug withdrawal or substitution


  • Hydration and restoration of high urinary output


Prognosis



  • 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


MICROSCOPIC PATHOLOGY


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

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

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