Tubular cell apoptosis and cidofovir-induced acute renal failure.
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.
Ortiz
Alberto
A
Unidad de Diálisis, Fundación Jiménez Diaz, Universidad Autónoma, Madrid, Spain. aortiz@fjd.es
Justo
Pilar
P
Sanz
Ana
A
Melero
Rosa
R
Caramelo
Carlos
C
Guerrero
Manuel Fernández
MF
Strutz
Frank
F
Müller
Gerhard
G
Barat
Antonio
A
Egido
Jesus
J
D058186:Acute Kidney Injury / Q000139:chemically induced* / Q000150:complications / Q000378:metabolism / Q000473:pathology; D000328:Adult; D017304:Annexin A5 / Q000378:metabolism; D000998:Antiviral Agents / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D000077404:Cidofovir; D017726:Cytomegalovirus Retinitis / Q000150:complications / Q000188:drug therapy; D003596:Cytosine / Q000009:adverse effects* / Q000031:analogs & derivatives*; D015658:HIV Infections / Q000150:complications; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D063065:Organophosphonates / Q000009:adverse effects*
D017304:Annexin A5; D000998:Antiviral Agents; D063065:Organophosphonates; D003596:Cytosine; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D000077404:Cidofovir