title: Nephrogenic systemic fibrosis-like effects of magnetic resonance imaging contrast agents in rats with adenine-induced renal failure.
abstract: Nephrogenic systemic fibrosis (NSF) is a scleroderma-like disease associated with prior administration of certain gadolinium chelates (GCs). NSF occurs in patients with severe renal failure. The purpose of this study was to set up a rat model of GC-associated NSF to elucidate the mechanism of this devastating disease. Firstly, after characterization of the model, male Wistar rats received a 0.75% adenine-enriched diet for 8, 14, or 16 days to obtain various degrees of renal failure. Rats received five consecutive daily iv injections of saline or gadodiamide (2.5 mmol/kg/day). Secondly, the safety profile and in vivo propensity to dissociate of all categories of marketed GCs (gadoterate, gadobutrol, gadobenate, gadopentetate, and gadodiamide) were compared in rats receiving adenine-enriched diet for 16 days. Serial skin biopsies were performed for blinded histopathological study. Total Gd concentration in tissues was measured by Inductively Coupled Plasma Mass Spectrometry. Relaxometry was used to evaluate the presence of dissociated Gd in skin and bone. Gadodiamide-induced high mortality and skin lesions (dermal fibrosis, calcification, and inflammation) were related to adenine diet duration. No skin lesions were observed with other molecules. Unlike macrocyclic GCs, gadodiamide, gadopentetate, and gadobenate gradually increased the r(1) relaxivity value, consistent with in vivo dissociation and release of soluble Gd (or, in the case of gadobenate, the consequence of protein binding). Gadodiamide-induced cutaneous and systemic toxicity depended on baseline renal function. We demonstrate in vivo dissociation of linear GCs, gadodiamide, and gadopentetate, whereas macrocyclic agents remained stable over the study period.
authors.affiliation: Research Division, Guerbet, Roissy Charles de Gaulle Cedex, France. nathalie.fretellier@guerbet-group.com
authors.forename: Nathalie
authors.initials: N
authors.lastname: Fretellier
authors.forename: Nejma
authors.initials: N
authors.lastname: Bouzian
authors.forename: Nadège
authors.initials: N
authors.lastname: Parmentier
authors.forename: Patrick
authors.initials: P
authors.lastname: Bruneval
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Jestin
authors.forename: Cécile
authors.initials: C
authors.lastname: Factor
authors.forename: Chantal
authors.initials: C
authors.lastname: Mandet
authors.forename: Florence
authors.initials: F
authors.lastname: Daubiné
authors.forename: France
authors.initials: F
authors.lastname: Massicot
authors.forename: Olivier
authors.initials: O
authors.lastname: Laprévote
authors.forename: Claire
authors.initials: C
authors.lastname: Hollenbeck
authors.forename: Marc
authors.initials: M
authors.lastname: Port
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Idée
authors.forename: Claire
authors.initials: C
authors.lastname: Corot
mesh_terms: D000225:Adenine / Q000008:administration & dosage*; D000818:Animals; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003287:Contrast Media / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity*; D004032:Diet; D004195:Disease Models, Animal; D005682:Gadolinium / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007677:Kidney Function Tests; D008297:Male; D054989:Nephrogenic Fibrosing Dermopathy / Q000139:chemically induced* / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D009942:Organometallic Compounds / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D051437:Renal Insufficiency / Q000139:chemically induced / Q000150:complications* / Q000378:metabolism; D012867:Skin / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013054:Spectrophotometry, Atomic; D014018:Tissue Distribution
chemical_list: D003287:Contrast Media; D009942:Organometallic Compounds; D005682:Gadolinium; D000225:Adenine