Nanoparticles of gadolinium rare earth metal used in MRI contrast agents can infiltrate kidney tissue

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Physicians routinely prescribe an infusion containing gadolinium to enhance MRI scans, but there is evidence that nanoparticles of the toxic rare earth metal infiltrate kidney cells, sometimes triggering severe side effects, University of New Mexico researchers have found.

More information: Joshua DeAguero et al, The onset of rare earth metallosis begins with renal gadolinium-rich nanoparticles from magnetic resonance imaging contrast agent exposure, Scientific Reports (2023). DOI: 10.1038/s41598-023-28666-1

The affinities of the proprietary chemical formulations of MRI contrast agents for gadolinium do not correlate with the incidences of ‘nephrogenic’/gadolinium-induced systemic fibrosis or gadolinium deposition disease (Supplementary Fig. S14).

The amount of time a brand of gadolinium-based contrast agent has been on the market does correlate with cases of gadolinium-induced systemic fibrosis and gadolinium deposition disease.

Systemic treatment with MRI contrast agents results in the formation of gadolinium-rich nanoparticles in our rodent models 13,14,15.

Gadolinium-based contrast agent treatment induced various pathological changes in multiple organs of both male and female mice. Herein we provide a detailed atlas of electron microscopic analyses of renal damage from MRI contrast agents with the characterization of gadolinium-rich nanoparticles that form from dechelation and complexation with physiologic elements.

Our findings demonstrate that systemic treatment with MRI contrast agents leads to electron-dense intracellular precipitation within the renal tubular epithelium and interstitial cells in males and females.

The formation of spiculated nanoparticles is similar to what has been reported to form from gadolinium oxide (Gd2O3) in phagolysosomal simulated solutions 24. (There were no differences in pathology between the sexes.)

Our results also demonstrate gadolinium precipitation in human kidneys as a result of routine MRI contrast agent use. Gadolinium precipitation into an insoluble mineral form demonstrates Le Chatelier’s Principle25 in vivo (herein and 13,14,15) and in humans. The principle of A. L. Le Chatelier and F. Braun is that a chemical equilibrium subject to perturbation (e.g., precipitation of gadolinium) will shift to partially oppose the stress.

Because gadolinium precipitates into an insoluble metal-salt form, then the relative affinities of the proprietary pharmaceutical chelates (log(Ktherm)—an in vitro measurement 25) will be perturbed. If gadolinium precipitates out of solution (with phosphate, for example), the equilibrium of this rare earth metal (Gd3+) and the ligand (L3-) will proceed in the following direction,

The formation of lanthanide-laden nanoparticles in vivo and the sequellae may be the initial step for the rare earth element metalloses nephrogenic systemic fibrosis and multisymptomatic illnesses such as SAGE. This phenomenon raises important questions regarding the safety of MRI contrast agents.

Phosphorus in these gadolinium-rich nanoparticles implies these are a type of gadolinium phosphate (GdPO4). Although gadolinium phosphate is not found in nature, it has been detected intracellularly in gadolinium chloride-treated rats26.

Delicate biologic specimens are subject to decimation from the high energies of scanning transmission electron microscopes purposed for materials science applications. Herein, we report a method for assessing lanthanide-rich nanostructures in biologic specimens that preserves enough contrast to localize subcellular structures.

Our model is similar to that reported in patients with the characteristic renal proximal tubule vacuolization of gadolinium-induced nephropathy 27.

Rare earth elements, including gadolinium, have unique physical and chemical properties that render them indispensable for critical technologies28. Gadolinium usage and indications are rising despite prescribing information boxed warnings of permanent brain retention and sometimes fatal ‘nephrogenic’ systemic fibrosis.

The data presented here demonstrate that gadolinium-based contrast agents are not entirely benign. Gadolinium-based contrast agents induce significant pathologic changes in the kidney 13,14,15,20 and skin 15,16,17,19. Dechelation and precipitation are likely related to the multi-symptom illness reported in patients with gadolinium-induced diseases.

Localization, identification, and speciation of retained gadolinium are critical to understanding the mechanisms of toxicity. Our findings are a foundation for understanding the mechanisms of gadolinium-induced disorders and the development of therapies. Rather than dismiss patients who may have suffered from complications due to enhanced MRI procedures, pathologic specimens should be examined for evidence of gadolinium-rich deposits.

Our results suggest that gadolinium is dechelated from MRI contrast agent formulations in vivo and is metabolized into mineralized intracellular nanoparticles. The high concentrations of phosphorus (and oxygen) suggest that the nanoparticles contain insoluble GdPO4 (and perhaps Gd2O3/Gd(OH)3) or a more complex/heterogenous mineral.

The phosphorus reservoir is unknown. The abundance of phosphorus in lipids and systemic response to gadolinium suggest that leaching from intracellular membranes may be a mechanism.

Gadolinium is not a physiologic element. It is reasonable to assume that iatrogenic kidney injury, systemic fibrosis, dermal plaques, and SAGE are all part of a spectrum of disorders resulting from the retention of a toxic lanthanide metal.

Nanotoxicity is undoubtedly a mediator of MRI contrast agent complications. Differential decomposition of MRI contrast agents may explain susceptibility to complications.

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