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. 2024 Aug 12:6:1376587.
doi: 10.3389/ftox.2024.1376587. eCollection 2024.

The safety of magnetic resonance imaging contrast agents

Amy Cunningham  1 , Martin Kirk  2 , Emily Hong  1 , Jing Yang  2 , Tamara Howard  3 , Adrian Brearley  4 , Angelica Sáenz-Trevizo  4 , Jacob Krawchuck  5 , John Watt  6 , Ian Henderson  7 , Karol Dokladny  8 , Joshua DeAguero  8 , G Patricia Escobar  8 , Brent Wagner  8   9
Affiliations

The safety of magnetic resonance imaging contrast agents

Amy Cunningham et al. Front Toxicol. .

Abstract

Gadolinium-based contrast agents are increasingly used in clinical practice. While these pharmaceuticals are verified causal agents in nephrogenic systemic fibrosis, there is a growing body of literature supporting their role as causal agents in symptoms associated with gadolinium exposure after intravenous use and encephalopathy following intrathecal administration. Gadolinium-based contrast agents are multidentate organic ligands that strongly bind the metal ion to reduce the toxicity of the metal. The notion that cationic gadolinium dissociates from these chelates and causes the disease is prevalent among patients and providers. We hypothesize that non-ligand-bound (soluble) gadolinium will be exceedingly low in patients. Soluble, ionic gadolinium is not likely to be the initial step in mediating any disease. The Kidney Institute of New Mexico was the first to identify gadolinium-rich nanoparticles in skin and kidney tissues from magnetic resonance imaging contrast agents in rodents. In 2023, they found similar nanoparticles in the kidney cells of humans with normal renal function, likely from contrast agents. We suspect these nanoparticles are the mediators of chronic toxicity from magnetic resonance imaging contrast agents. This article explores associations between gadolinium contrast and adverse health outcomes supported by clinical reports and rodent models.

Keywords: X-ray spectra; electron microscopy; gadodiamide; gadolinium; magnetic resonance imaging contrast; metals; mitochondriopathy; renal tubular epithelium.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Magnetic resonance imaging contrast agent chemical structures, formulae, United States approval years, thermodynamic (log(K therm )) and conditional [log(K cond )] stability constants.
FIGURE 2
FIGURE 2
Reactions reported to the United States Food & Drug Administration Adverse Event Reporting System. We queried the FAERS Public Dashboard for magnetic resonance imaging contrast agents (generic and brand names).
FIGURE 3
FIGURE 3
Unique cases were reported to the Food & Drug Administration Adverse Event Reporting System by the American College of Radiology Magnetic Resonance Imaging Contrast Agent Class. After discovering that gadolinium was the cause of nephrogenic systemic fibrosis, the American College of Radiology categorized magnetic resonance imaging contrast agents according to the number of cases associated with the complication at the time. Group I agents (Omniscan, OptiMark, and Magnevist) are presumed to have the highest association with nephrogenic systemic fibrosis, Group II agents (Dotarem, Gadavist, MultiHance, ProHance, and Vueway) are presumed to have less tendency to elicit nephrogenic systemic fibrosis. Group III agents (Ablavar, Eovist) have an unknown propensity to cause systemic fibrosis. Most Group II agents were approved after the association between gadolinium and systemic fibrosis was known. Because the market share of the only Group II agent, ProHance, was less than 5% before 2006, the propensity of this category and systemic fibrosis was likely in a window where there was more caution with their use (Leyba and Wagner, 2019).
FIGURE 4
FIGURE 4
Systemic treatment with magnetic resonance imaging contrast agents induces the formation of gadolinium-rich nanoparticles. (A). Renal cortex from magnetic resonance imaging contrast agent-treated mice may demonstrate subtle vacuolization by light microscopy. We obtain tissues 5 days or more after the last magnet resonance imaging contrast agent exposure. (B) Transmission scanning electron microscopy (darkfield mode) reveals unilamellar bodies rimmed with electron-dense material and mitochondrial swelling. FEI Tecnai G (2) S-Twin (300 kV) transmission electron microscope. (C) Transmission electron microscopy of a renal proximal tubular cell from a magnetic resonance imaging contrast-treated mouse. The shrunken, ballooned mitochondria are no longer oriented perpendicularly to the basolateral plane. The enlarged image demonstrates mitochondrial stress. (D) Cryo-transmission electron microscopy of nanoparticles from renal cortices from magnetic resonance imaging contrast agent-treated mice that were purified by ultracentrifugation through a sucrose gradient. The image shows a nanoparticle with an organic corona.
FIGURE 5
FIGURE 5
Causal diagram depicting the multiple avenues of metal-ligand complex-induced disease.
FIGURE 6
FIGURE 6
Mechanistic framework linking gadolinium retention to disease.
See this image and copyright information in PMC

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