title: Low urine osmolarity as a determinant of cisplatin-induced nephrotoxicity.
abstract: Cisplatin is widely used in the treatment of human tumors, but it is a nephrotoxic drug. Early pragmatic clinical trials have shown that cisplatin-induced renal toxicity is greatly reduced through the use of high hydration, a large NaCl supply and mannitol infusion, but the precise mechanisms of these nephroprotective measures are not fully understood. We show here an increase in the cisplatin uptake and cytotoxicity on 56/10 A1 human glomerular and HK-2 human tubular cells when the drug incubation was performed in a hypotonic phosphate-buffered saline solution or in human urine ("drag in" transport hypothesis). When 4 mg/kg cisplatin was intraperitoneally injected in rats in 20 ml of a hypotonic 4 g/l NaCl solution, the platinum accumulation increased in both the cortex and papilla but not in the subcutaneously grafted colon tumors when compared to rats injected with cisplatin in normal or hyperosmotic solutions (9 and 14 g/l NaCl, respectively). The urea and creatinine blood levels were significantly increased, and more apoptotic cells were detected by the caspase-3 cleavage and TUNEL assays in the tubular cells of rats treated with cisplatin in a hypotonic solution compared to animals that received normal or hypertonic solutions. Osmolarity was sometimes low in urine from patients receiving an intravenous hydration for a cisplatin treatment or from healthy volunteers who were given an oral hydration with a 50 g/l glucose solution. Our results show that low urine osmolarity could be a major determinant in the increase of cisplatin-induced nephrotoxicity and justify the widely used concurrent infusion of osmotically active substances during intravenous hydration.
authors.affiliation: INSERM 517, Faculty of Medicine, Dijon, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Polycarpe
authors.forename: Laurent
authors.initials: L
authors.lastname: Arnould
authors.forename: Elise
authors.initials: E
authors.lastname: Schmitt
authors.forename: Laurence
authors.initials: L
authors.lastname: Duvillard
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Ferrant
authors.forename: Nicolas
authors.initials: N
authors.lastname: Isambert
authors.forename: Christian
authors.initials: C
authors.lastname: Duvillard
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Beltramo
authors.forename: Dominique
authors.initials: D
authors.lastname: Chevet
authors.forename: Bruno
authors.initials: B
authors.lastname: Chauffert
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D017209:Apoptosis; D002945:Cisplatin / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000662:veterinary; D003404:Creatinine / Q000097:blood; D020287:In Situ Nick-End Labeling; D007274:Injections, Intraperitoneal; D007678:Kidney Glomerulus / Q000187:drug effects* / Q000473:pathology* / Q000502:physiology; D007684:Kidney Tubules / Q000187:drug effects* / Q000473:pathology* / Q000502:physiology; D008297:Male; D009374:Neoplasms, Experimental; D009994:Osmolar Concentration; D051381:Rats; D012965:Sodium Chloride / Q000493:pharmacokinetics; D014508:Urea / Q000097:blood; D014556:Urine
chemical_list: D000970:Antineoplastic Agents; D012965:Sodium Chloride; D014508:Urea; D003404:Creatinine; D002945:Cisplatin