Tubular cell apoptosis and cidofovir-induced acute renal failure

Antivir Ther. 2005;10(1):185-90.


Cidofovir is an antiviral drug with activity against a wide array of DNA viruses including poxvirus. The therapeutic use of cidofovir is marred by a dose-limiting side effect, nephrotoxicity, leading to proximal tubular cell injury and acute renal failure. Treatment with cidofovir requires the routine use of prophylactic measures. A correct knowledge of the cellular and molecular mechanisms of cidofovir toxicity may lead to the development of alternative prophylactic strategies. We recently cared for a patient with irreversible acute renal failure due to cidofovir. Renal biopsy showed tubular cell apoptosis. Cidofovir induced apoptosis in primary cultures of human proximal tubular cells in a temporal (peak apoptosis at 7 days) and concentration (10-40 microg/ml) pattern consistent with that of clinical toxicity. Apoptosis was identified by the presence of hypodiploid cells, by the exposure of annexin V binding sites and by morphological features and was associated with the appearance of active caspase-3 fragments. Cell death was specific as it was also present in a human proximal tubular epithelial cell line (HK-2), but not in a human kidney fibroblast cell line, and was prevented by probenecid. An inhibitor of caspase-3 (DEVD) prevented cidofovir apoptosis. The survival factors present in serum, insulin-like growth factor-1 and hepatocyte growth factor, were also protective. The present data suggest that apoptosis induction is a mechanism contributing to cidofovir nephrotoxicity. The prophylactic administration of factors with survival activity for tubular epithelium should be further explored in cidofovir renal injury.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Kidney Injury / chemically induced*
  • Acute Kidney Injury / complications
  • Acute Kidney Injury / metabolism
  • Acute Kidney Injury / pathology
  • Adult
  • Annexin A5 / metabolism
  • Antiviral Agents / administration & dosage*
  • Apoptosis / drug effects
  • Caspase 3
  • Caspases / metabolism
  • Cells, Cultured
  • Cidofovir
  • Cytomegalovirus Retinitis / complications
  • Cytomegalovirus Retinitis / drug therapy
  • Cytosine / adverse effects*
  • Cytosine / analogs & derivatives*
  • HIV Infections / complications
  • Humans
  • Kidney Tubules, Proximal / drug effects*
  • Kidney Tubules, Proximal / metabolism
  • Kidney Tubules, Proximal / pathology
  • Male
  • Organophosphonates / adverse effects*


  • Annexin A5
  • Antiviral Agents
  • Organophosphonates
  • Cytosine
  • CASP3 protein, human
  • Caspase 3
  • Caspases
  • Cidofovir