Meryam Maazouz, Abstract Co-Author: Researcher, Guerbet SA

Nathalie Fretellier PhD, Presenter: Employee, Guerbet SA

Patrick Bruneval, Abstract Co-Author: Nothing to Disclose

Gaelle Jestin-Mayer, Abstract Co-Author: Employee, Guerbet SA

Cecile Factor, Abstract Co-Author: Employee, Guerbet SA

Alexandrine Luseau, Abstract Co-Author: Employee, Atlantic Bone Screen

Fannie Baudimont, Abstract Co-Author: Employee, Atlantic Bone Screen

Jean-Marc Idee PHARM D, Abstract Co-Author: Employee, Guerbet SA

Claire Corot PhD, Abstract Co-Author: Employee, Guerbet SA

The need for contrast-enhanced MRI is widely recognized in neonates and infants with immature renal function. The aim of this study was to compare the tolerance of two marketed gadolinium-based contrast agents (GBCAs) of different thermodynamic stabilities in rats with immature renal function.

Firstly, changes in renal function (plasma creatinine and cystatin C levels) and kidney histopathology were identified in juvenile rats (from post-natal day [PND] 4 to PND 30). Subsequently, juvenile rats received 5 intravenous injections (between PND 4 and 18) of gadoteric acid (macrocyclic and ionic GBCA, Dotarem®), gadodiamide (linear and non-ionic GBCA, Omniscan®) or saline. Daily clinical examinations were performed. At sacrifice (PND 25), the Gd concentration was measured in the tissues (plasma, skin, liver, bone, heart). Histopathologic and relaxometry studies were also performed. The study was blinded.

Biochemical characterization showed maturation of renal function from PND 21. The histopathology evidenced maturation of the renal structure from PND 11. In the comparative study, gadodiamide induced mortality (4 out of 14 rats from PND 10), heterogeneous hair growth (from PND 8), alopecia (from PND 18) and hyperpigmentation of the dorsal skin. Two gadodiamide-treated rats had severe epidermal and dermal lesions (from PND 21). No abnormal sign was detected following the administration of gadoteric acid or saline. Higher tissue Gd concentrations were found in gadodiamide-treated rats compared to those found in gadoteric acid-treated rats. Relaxometry studies showed dissociation of gadodiamide in the skin and liver, with the presence of dissociated and soluble Gd3+. The dissociated Gd3+ concentration in plasma was < limit of detection for gadoteric acid and 0.12 ± 0.06 µmol/L in the gadodiamide group, corresponding to 61 ± 32% of the total Gd concentration.

Repeated administration of gadoteric acid was well tolerated in juvenile rats with immature renal function. Conversely, gadodiamide induced significant morbi-mortality, skin abnormalities, and more Gd retention (at least in part, in the dissociated and soluble form) in the skin and liver of juvenile rats.

Neonates and infants with immature renal function could be at greater risk from the higher systemic toxicity induced by the linear GBCA gadodiamide vs. the macrocyclic GBCA gadoteric acid.

Maazouz, M, Fretellier, N, Bruneval, P, Jestin-Mayer, G, Factor, C, Luseau, A, Baudimont, F, Idee, J, Corot, C, Safety Profiles of Gadolinium-based Contrast Agents in Pre-Weaning Juvenile Rats Differ according to the Risk of Gadolinium Release.  Radiological Society of North America 2014 Scientific Assembly and Annual Meeting, - ,Chicago IL. http://archive.rsna.org/2014/14004368.html