title: Sub-nephrotoxic cisplatin sensitizes rats to acute renal failure and increases urinary excretion of fumarylacetoacetase.
abstract: Nephrotoxicity limits the therapeutic efficacy of the antineoplastic drug cisplatin. Due to dosage adjustment and appropriate monitoring, most therapeutic courses with cisplatin produce no or minimal kidney damage. However, we studied whether even sub-nephrotoxic dosage of cisplatin poses a potential risk for the kidneys by predisposing to acute kidney injury (AKI), specifically by lowering the toxicity threshold for a second nephrotoxin. With this purpose rats were treated with a single sub-nephrotoxic dosage of cisplatin (3mg/kg, i.p.) and after two days, with a sub-nephrotoxic regime of gentamicin (50mg/kg/day, during 6 days, i.p.). Control groups received only one of the drugs or the vehicle. Renal function and renal histology were monitored throughout the experiment. Cisplatin treatment did not cause any relevant functional or histological alterations in the kidneys. Rats treated with cisplatin and gentamicin, but not those under single treatments, developed an overt renal failure characterized by both renal dysfunction and massive tubular necrosis. In addition, the urinary excretion of fumarylacetoacetase was increased in cisplatin-treated animals at subtoxic doses, which might be exploited as a cisplatin-induced predisposition marker. In fact, the urinary level of fumarylacetoacetase prior to the second nephrotoxin correlated with the level of AKI triggered by gentamicin in predisposed animals.
authors: Unidad de Toxicología and Unidad de Fisiopatología Renal y Cardiovascular, Departamento de Fisiología y Farmacología, Universidad de Salamanca, Spain; Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain; Fundación Renal Íñigo Álvarez de Toledo, Instituto Reina Sofía de Investigación Nefrológica, Madrid, Spain.
authors: Laura
authors: L
authors: Vicente-Vicente
authors: Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain; Unidad de Investigación, Hospital Universitario de Salamanca, Salamanca, Spain.
authors: Fernando
authors: F
authors: Sánchez-Juanes
authors: Unidad de Toxicología and Unidad de Fisiopatología Renal y Cardiovascular, Departamento de Fisiología y Farmacología, Universidad de Salamanca, Spain.
authors: Omar
authors: O
authors: García-Sánchez
authors: Bio-inRen SL, Salamanca, Spain.
authors: Víctor
authors: V
authors: Blanco-Gozalo
authors: Unidad de Toxicología and Unidad de Fisiopatología Renal y Cardiovascular, Departamento de Fisiología y Farmacología, Universidad de Salamanca, Spain.
authors: Moisés
authors: M
authors: Pescador
authors: Unidad de Toxicología and Unidad de Fisiopatología Renal y Cardiovascular, Departamento de Fisiología y Farmacología, Universidad de Salamanca, Spain.
authors: María A
authors: MA
authors: Sevilla
authors: Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain; Unidad de Investigación, Hospital Universitario de Salamanca, Salamanca, Spain; Departamento de Bioquímica y Biología Molecular, Universidad de Salamanca, Salamanca, Spain.
authors: José Manuel
authors: JM
authors: González-Buitrago
authors: Unidad de Toxicología and Unidad de Fisiopatología Renal y Cardiovascular, Departamento de Fisiología y Farmacología, Universidad de Salamanca, Spain; Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain; Fundación Renal Íñigo Álvarez de Toledo, Instituto Reina Sofía de Investigación Nefrológica, Madrid, Spain; Unidad de Investigación, Hospital Universitario de Salamanca, Salamanca, Spain; Instituto de Estudios de Ciencias de la Salud de Castilla y León (IECSCYL), Soria, Spain.
authors: Francisco J
authors: FJ
authors: López-Hernández
authors: Unidad de Toxicología and Unidad de Fisiopatología Renal y Cardiovascular, Departamento de Fisiología y Farmacología, Universidad de Salamanca, Spain; Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain; Fundación Renal Íñigo Álvarez de Toledo, Instituto Reina Sofía de Investigación Nefrológica, Madrid, Spain.
authors: José Miguel
authors: JM
authors: López-Novoa
authors: Unidad de Toxicología and Unidad de Fisiopatología Renal y Cardiovascular, Departamento de Fisiología y Farmacología, Universidad de Salamanca, Spain; Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain; Fundación Renal Íñigo Álvarez de Toledo, Instituto Reina Sofía de Investigación Nefrológica, Madrid, Spain. Electronic address: amorales@usal.es.
authors: Ana Isabel
authors: AI
authors: Morales
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology / Q000652:urine; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D015415:Biomarkers / Q000652:urine; D002945:Cisplatin / Q000633:toxicity*; D004195:Disease Models, Animal; D005839:Gentamicins; D006801:Humans; D006867:Hydrolases / Q000652:urine*; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D007683:Kidney Tubular Necrosis, Acute / Q000139:chemically induced / Q000201:enzymology / Q000652:urine; D008297:Male; D017208:Rats, Wistar; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D005839:Gentamicins; D006867:Hydrolases; C020156:fumarylacetoacetase; D002945:Cisplatin
keywords: Acquired predisposition; Acute kidney injury; Cisplatin; Fumarylacetoacetase; Urinary biomarkers