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Macrocyclic and Other Non–Group 1 Gadolinium Contrast Agents Deposit Low Levels of Gadolinium in Brain and Bone Tissue: Preliminary Results From 9 Patients With Normal Renal Function

Murata, Nozomu MD, PhD; Gonzalez-Cuyar, Luis F. MD; Murata, Kiyoko MD, PhD; Fligner, Corinne MD; Dills, Russell PhD; Hippe, Daniel MS; Maravilla, Kenneth R. MD

doi: 10.1097/RLI.0000000000000252
Original Articles
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Objective The purpose of this study was to determine whether gadolinium (Gd) is deposited in brain and bone tissues in patients receiving only non–Group 1 agents, either macrocyclic or linear protein interacting Gd-based contrast agents, with normal renal function. Group 1 agents are linear agents most associated with nephrogenic systemic fibrosis that the US Federal Drug Administration has defined as contraindicated in patients at risk for this disease.

Materials and Methods This study was institutional review board approved and Health Insurance Portability and Accountability Act compliant for retrospective review of records and also had signed autopsy consent authorizing use of decedent's tissue in research studies. Tissue samples were collected from 9 decedents undergoing autopsy who had contrast-enhanced magnetic resonance imaging (MRI) with only single agent exposure to a non–Group 1 Gd-based contrast agent. Decedents with only noncontrast MRI or no MRI served as controls. Multiple brain areas, including globus pallidus and dentate nucleus, as well as bone and skin, were sampled and analyzed for Gd using inductively coupled plasma mass spectrometry. Gadolinium levels were compared between groups of decedents using the Mann-Whitney test and between brain and bone tissues of the same cases using the Wilcoxon signed-rank test.

Results Of the 9 decedents, 5 received gadoteridol (ProHance; Bracco Diagnostics, Princeton, NJ), 2 received gadobutrol (Gadovist; Bayer Healthcare, Whippany, NJ), and 1 each had gadobenate (MultiHance; Bracco Diagnostics) and gadoxetate (Eovist; Bayer Healthcare). Gadolinium was found with all agents in all brain areas sampled with highest levels in globus pallidus and dentate. Bone levels measured 23 times higher (median) than brain levels (P = 0.008 for bone vs globus pallidus) and showed a significant correlation (r = 0.81, P = 0.022). In controls, Gd levels in the brain were at or below limits of measurement and were significantly lower compared with study cases (P = 0.005 for globus pallidus).

Conclusion Gadolinium deposition in normal brain and bone tissue occurs with macrocyclic and linear protein interacting agents in patients with normal renal function. Deposition of Gd in cortical bone occurs at much higher levels compared with brain tissue and shows a notable correlation between the two. Thus, the bone may serve as a surrogate to estimate brain deposition if brain Gd were to become a useful clinical or research marker.

From the *Department of Radiology, University of Washington, Seattle; †Department of Radiology, Toho University Ohashi Medical Center, Tokyo, Japan; ‡Department of Pathology, University of Washington, Seattle; §Department of Neurology, Toho University Omori Medical Center, Tokyo, Japan; and ∥Department of Environmental Health, University of Washington, Seattle.

Received for publication October 2, 2015; and accepted for publication, after revision, December 12, 2015.

Conflicts of interest and sources of funding: none declared.

Correspondence to: Kenneth R. Maravilla, MD, University of Washington, Department of Radiology, 1959 NE Pacific St, MS-357115, Seattle, WA 98195. E-mail: kmarav@uw.edu.

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