Abstract
Gadolinium based contrast agents (GBCA) are used to image patients using magnetic resonance (MR) imaging. In recent years, there has been controversy around gadolinium retention after GBCA administration. We sought to evaluate the potential toxicity of gadolinium in the rat brain up to 1-year after repeated gadodiamide dosing and tissue retention kinetics after a single administration. Histopathological and ultrastructural transmission electron microscopy (TEM) analysis revealed no findings in rats administered a cumulative dose of 12 mmol/kg. TEM-energy dispersive X-ray spectroscopy (TEM-EDS) localization of gadolinium in the deep cerebellar nuclei showed ~ 100 nm electron-dense foci in the basal lamina of the vasculature. Laser ablation-ICP-MS (LA-ICP-MS) showed diffuse gadolinium throughout the brain but concentrated in perivascular foci of the DCN and globus pallidus with no observable tissue injury or ultrastructural changes. A single dose of gadodiamide (0.6 mmol/kg) resulted in rapid cerebrospinal fluid (CSF) and blood clearance. Twenty-weeks post administration gadolinium concentrations in brain regions was reduced by 16–72-fold and in the kidney (210-fold), testes (194-fold) skin (44-fold), liver (42-fold), femur (6-fold) and lung (64-fold). Our findings suggest that gadolinium does not lead to histopathological or ultrastructural changes in the brain and demonstrate in detail the kinetics of a human equivalent dose over time in a pre-clinical model.
Highlights
Gadolinium based contrast agents (GBCA) are used to image patients using magnetic resonance (MR) imaging
In recent years hyperintensity on unenhanced T1-weighted MR images in specific brain regions such as the dentate nucleus have been identified in patients with a history of GBCA administration[1,2,3]
Trace levels of gadolinium persisted for a year post‐injection without apparent tissue injury after repeated gadodiamide administration
Summary
Gadolinium based contrast agents (GBCA) are used to image patients using magnetic resonance (MR) imaging. We sought to evaluate the potential toxicity of gadolinium in the rat brain up to 1-year after repeated gadodiamide dosing and tissue retention kinetics after a single administration. As gadolinium must be in solution to relax water protons, insoluble gadolinium is unlikely to contribute to hyperintensity and MR hyperintensity may underestimate the actual gadolinium presence in the brain Whilst these repeat dose animal studies are informative, they do not represent a likely clinical scenario. A recent s tudy[18] which assessed gadolinium levels in a limited number of tissues after high, repeated GBCA administration to rats, does not provide retention kinetics after a single human equivalent dose, which is more suitable a comparison to the clinical setting. Given that there is concern over the longer-term retention of gadolinium, discreet regions of the brain and other important organs were assessed to more fully characterize the pharmacokinetics of a single GBCA administration and histopathology was performed on the brains of the high dose animals
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