The leitmotifs of magnetic resonance imaging (MRI) contrast agent-induced complications range from acute kidney injury, symptoms associated with gadolinium exposure (SAGE)/gadolinium deposition disease, potentially fatal gadolinium encephalopathy, and irreversible systemic fibrosis. Gadolinium is the active ingredient of these contrast agents, a non-physiologic lanthanide metal. The mechanisms of MRI contrast agent-induced diseases are unknown. Mice were treated with a MRI contrast agent. Human kidney tissues from contrast-naïve and MRI contrast agent-treated patients were obtained and analyzed. Kidneys (human and mouse) were assessed with transmission electron microscopy and scanning transmission electron microscopy with X-ray energy-dispersive spectroscopy. MRI contrast agent treatment resulted in unilamellar vesicles and mitochondriopathy in renal epithelium. Electron-dense intracellular precipitates and the outer rim of lipid droplets were rich in gadolinium and phosphorus. We conclude that MRI contrast agents are not physiologically inert. The long-term safety of these synthetic metal–ligand complexes, especially with repeated use, should be studied further.
The properties of magnetic resonance imaging (MRI) contrast agents rely on a rare earth metal, gadolinium. Because gadolinium is toxic, magnetic resonance imaging contrast agents are proprietary aminopolycarboxylic acid chelates designed to bind the metal tightly and enhance renal elimination. Complications of MRI contrast agents include (sometimes fatal) gadolinium encephalopathy, acute kidney injury, gadolinium deposition disease/symptoms associated with gadolinium exposure (SAGE)1, and ‘nephrogenic’ systemic fibrosis1,2,3,4,5. Exposure to any class of MRI contrast agent leads to the long-term retention of gadolinium6. Residual gadolinium from MRI contrast agent exposure has been found in every vital organ, including the brain, in both patients and animal models7,8,9,10,11. Urine can contain gadolinium years after exposure to MRI contrast agents12.
Our rodent models demonstrated the formation of gadolinium-rich nanoparticles in the kidney and skin following systemic MRI contrast agent treatment13,14,15,16,17,18,19. Gadolinium-rich densities have been found in neuronal cytoplasm and nuclei in the brains of individuals exposed to MRI contrast agents during the course of routine care11. The nanotoxicologic mechanisms of gadolinium-induced disease are poorly understood5,13,14,15,16,17,18,19,20. Our understanding of MRI contrast-induced complications is far from complete. These studies were conducted to characterize the composition of intracellular gadolinium-rich minerals that form after systemic MRI contrast agent treatment.
Magnetic resonance imaging (MRI) contrast agent treatment induced pathologic changes in the skin, liver, and kidney
Mice were treated with gadolinium-based contrast agent according to our established protocols13,14,15,16,17,18,20,21. Skin changes, including fibrosis, increased dermal cellularity, and epidermal thickening (Supplementary Fig. S1a–d), were like what we have previously reported15,16,20,21. There was vacuolation of renal cortical tubular epithelium from gadolinium-treated mice (Supplementary Fig. S1e). These findings are similar to what we have previously reported in rodent models of gadolinium-induced renal damage14,15,16,17,20,21.
MRI contrast agent treatment induced renal pathologic changes in the male and the female mouse groups
At the ultrastructural level, renal glomerular and tubular pathologies were evident in the treated mice (Supplementary Fig. S2). Electron-dense material was a common feature in the kidney in males and females (Fig. 1). The electron-dense precipitates were dispersed throughout kidney sections and often rimmed large unilamellar vesicles (Supplementary Fig. S2b–d, g–j, Fig. 1c–h, j–n). Mitochondrial toxicity, characterized by swelling and an increased matrix-to-cristae ratio, was a common finding in gadolinium-treated males (Supplementary Fig. S2e–f, g, i) and females (Fig. 1c, d, j, m). Renal proximal tubules from gadolinium-treated males and females demonstrated increased numbers of enlarged cytoplasmic vesicles (Fig. 1g–j), apical blebbing (Supplementary Figs. S2j, S1d, I, j), tubular damage (Supplementary Fig. S2j), reduced mitochondrial density (Supplementary Fig. S2k, l), basement membrane rupture (Supplementary Fig. S2m), and occasionally rupture of the apical membranes (Supplementary Fig. S2n). Quantified morphometry from transmission electron microscopy is provided in Table 1.
Gadolinium treatment affected renal glomeruli (Supplementary Fig. S3), distal tubules, and interstitia in mice (Supplementary Fig. S4)
Renal glomerular parietal cells of gadolinium-treated mice demonstrated vacuolization (Supplementary Fig. S3e, f), sometimes with unilamellar vesicles (Supplementary Fig. S3g–i). Occasionally, podocytes showed similar abnormalities (Supplementary Fig. S3j). Distal tubular epithelial cells occasionally contained electron-dense material within vacuoles and signs of mitochondrial stress (Supplementary Fig. S4). Distal tubular epithelia also demonstrated intracellular unilamellar vesicles, occasionally rimmed with electron-dense material (Supplementary Fig. S4d). Interstitial expansion and increased cellularity with occasional vacuolized electron-dense material were present in the gadolinium-treated groups (Supplementary Fig. S4e–h).
Concomitant with the Warburg effect in the kidney, systemic gadolinium-based contrast agent treatment induces dyslipidemia and insulin resistance14. The impact of gadolinium-based contrast agent treatment in the liver was examined (Supplementary Fig. S5). Gadolinium increased intracellular triglycerides as assessed by oil red O staining. Electron microscopy revealed that gadolinium treatment increased unilamellar vesicles and reduced mitochondrial volume. Metabolomic analysis of the livers demonstrated alterations in metabolites associated with amino acid metabolism, glycogenesis, and glycolysis (Supplementary Table S1). These findings support the hypothesis that gadolinium-based contrast agents are not biologically inert5.
Electron-dense material in kidney cells from MRI contrast agent-treated mice contained gadolinium
Gadolinium can be detected in several organs after systemic treatment with MRI contrast agents18. The electron-dense precipitates and electron-dense material rimming unilamellar vesicles/lipid droplets were localized using transmission electron microscopy (Fig. 2). These regions were then identified using a STEM equipped with XEDS (Fig. 2b–i). The spiculated, sea-urchin-like intracellular precipitates were visualized in darkfield mode from specially sectioned and mounted tissues (Fig. 2c). Electron-dense material rimming vacuolized lipid droplets (Fig. 2d–e) and spiculated nanostructures (Fig. 2f) were identifiable by Z-contrast. In addition to the pathologic electron-dense material, mitochondria and cellular nuclei could often be visualized (Fig. 2g, h). Electron-dense regions were occasionally found within the mitochondria of treated animals (Fig. 2i).
Intracellular gadolinium-rich material correlated with high phosphorus concentrations in mice
Gadolinium is not a normal trace element13 and possesses a signature signal (particularly in the L electron shell energy range) detectable by XEDS18. The chemical compositions of these electron-dense materials were assessed in many subcellular regions via XEDS (Supplementary Figs. S6, S7, S8). XEDS line scan data were obtained for gadolinium, phosphorus, calcium, chlorine, chromium, magnesium, oxygen, and silicon. Electron-dense precipitates contained gadolinium and phosphorus (Fig. 3, Supplementary Figs. S6, S7, S8). Non-precipitate regions and the centers of lipid droplets did not contain gadolinium (Supplementary Figs. S6, S7, S8), and the electron-dense material rimming lipids (Supplementary Figs. S6b, S7e, f). Mitochondria tended to have low gadolinium concentrations (Supplementary Fig. S9, Fig. 4). The XEDS line scan data of the subcellular regions (Supplementary Fig. S9, Fig. 4) revealed that gadolinium concentrations differed among electron-dense precipitates from mitochondria, lipid, and non-mitochondrial/non-lipid regions (P = 0) (Fig. 4b, Supplementary Table S2). Concomitantly, phosphorus (P < 1 × 10–5), calcium (P < 3 × 10–9), magnesium (P = 0), manganese (P = 0), and sulfur (P = 0.001) in the precipitate differed from these subcellular regions (Supplementary Figs. S9, S10). Linear regression for gadolinium and phosphorus signal intensities showed the strongest correlation between the 2 in precipitates (multiple r2 of 0.22, 0.25 for females and males, respectively; P < 0.001 by ordinary least squares).
The electron-dense precipitates' concordance of gadolinium with phosphorus in mice was confirmed with 2D XEDS (Fig. 5)
Regions rich in electron-dense nanostructures were mapped (Fig. 5a, b) using STEM and XEDS. XEDS signals from precipitates in the gadolinium L electron shell energy ranges were non-zero (Fig. 5c). Two-dimensional mapping demonstrated the colocalization of gadolinium with phosphorus (Fig. 5d). Secondary 2D XEDS mapping of the electron densities confirmed that these nanoparticles were rich in gadolinium and phosphorus (Supplementary Fig. S11). Outside of the nanoparticles, other subcellular regions contained little or no gadolinium (Fig. 4, Supplementary Fig. S6).
From the mouse tissues, multiple variable linear modeling of the XEDS line scan data was used to analyze the elemental composition of the subcellular regions (i.e., gadolinium-rich nanoparticles, unilamellar/lipid-rich droplets, and mitochondria) relating gadolinium to the other assessed elements (Table 2). The quality of the model for electron-dense precipitates was optimized by the Akaike information criterion (AIC) method. The optimal model (Akaike information criteria, AIC) for the electron-dense debris correlated gadolinium to phosphorus and oxygen (Table 3). Principal component analysis supported the correlations of phosphorus and gadolinium in precipitates (Fig. S12). These data show that gadolinium de-chelates from MRI contrast agent formulations and precipitates intracellularly. This phenomenon is concomitant with lipid vacuolization, mitochondrial damage, and subacute tubular damage.
MRI contrast agent use in humans leads to detectable gadolinium in the kidney
In humans, permanent brain gadolinium retention may occur from the routine use of MRI contrast agents22. The kidney is a reservoir for gadolinium in rodent models13,14,18,20,23. Therefore, we investigated the potential of lanthanide metallosis in humans. Human kidney samples were obtained from the University of New Mexico Human Tissue Repository. The Repository is accredited by the College of American Pathologists Guidelines for Biorepositories. There were equal numbers of MRI contrast agent-exposed and unexposed donors (n = 5 each). Gadolinium was quantitated with inductively coupled plasma mass spectroscopy (University of New Mexico Department of Earth & Planetary Sciences). Gadolinium was detectable in 100% of the samples where the donors had histories of MRI contrast agent exposure (Supplementary Fig. S13).
Nanoparticles in human kidney are also primarily gadolinium and phosphorus
These human samples were analyzed by TEM and XEDS (University of New Mexico Department of Earth & Planetary Sciences, Fig. 6). Several specimens contained intracellular electron-dense precipitates. The electron densities were roughly 100 nm in diameter. XEDS analysis revealed that these intracellular precipitates contained gadolinium (Fig. 6B). Human tissues were also analyzed by 2D XEDS (Fig. 7). Again, nanoprecipitates showed elevations in gadolinium and phosphorus. STEM XEDS line scans through multiple precipitates (from different patients) again showed a correlation between gadolinium and phosphorus levels (Fig. 8). These results demonstrate that routine MRI contrast agent use leads to lanthanide metallosis.
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 models13,14,15. 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 solutions24. (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 and13,14,15) 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 measurement25) 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 nephropathy27.
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 kidney13,14,15,20 and skin15,16,17,19. 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.
All methods were carried out in compliance with relevant guidelines and the study was approved by the University of New Mexico’s Institutional Animal Care and Use Committee (IACUC, protocol 21-201088-HSC, Animal Welfare Assurance # D16-00228, A3350-01, USDA Registration # 85-R-0014). Sex-matched wild-type C57/BL6 mice were randomized by weight into untreated (n = 10) or gadolinium-based contrast agent treatment (Omniscan, n = 10) groups13,14,15,16,17,18,20,21. Male C57/BL6 mice weighed 27 g, whereas female C57/BL6 mice weighed 20 g and were 6–8 weeks of age at the start of the experiment. The contrast agent Omniscan was injected intraperitoneally at a dose of 2.5 mmol per kilogram body weight. This dose is equivalent to twice the clinically approved human dose (human equivalent dose) after adjustment for body surface area and is in accordance with the Food and Drug Administration Guidance for Industry29. Injections were administered 5 days a week for 4 weeks. The experiments adhered to the ARRIVE guidelines.
Human pathological specimens
Were obtained from the University of New Mexico Human Tissue Repository (approved by the University of New Mexico Health Sciences Center Institutional Review Board, IRB, protocol #01-313). The experimental protocol was approved by the University of New Mexico Health Sciences Center, Human Research Protections Program/Human Tissue Oversight Committee/Scientific Review Committee (SRC #007-21, de-identified materials, Exempt Category 4 HRP-582; University of New Mexico Health Sciences Center IRB-approved protocol #19-660). All samples were obtained as unidentified in compliance with this protocol. Flash-frozen kidney tissue was obtained from 5 individuals with histories of MRI contrast agent exposure and 5 who were contrast-naïve. The frozen tissue samples with no embedding medium were transported on dry ice from the repository and stored at −80C for further analysis. Pieces (10–15 mg) of frozen tissue were digested and gadolinium concentrations were quantified using PerkinElmer NexION 3000 inductively coupled plasma mass spectrometry with a detection limit of 0.01 ppm. For electron microscopy, flash-frozen tissues were fixed in 3% formaldehyde, 2% glutaraldehyde in phosphate-buffered saline for one hour at room temperature then cut into smaller sections with fresh fixative overnight at 4ºC. Pieces were washed, stained with 1% tannic acid × 1 h, dehydrated, and embedded in epoxy resin. For transmission electron microscopy (TEM), pieces were sectioned at 60–80 nm and placed on copper grids. For darkfield scanning TEM (STEM), pieces were sectioned at 100–200 nm onto holey carbon grids.
Tissues were harvested and processed as previously described14,15,16,19. Organs are divided into fixative (10% neutral buffered formalin and electron microscopy as described herein). Kidneys are decapsulated, butterflied, and cortices divided into fixative. Flash-frozen liver tissues were embedded in optimal cutting temperature medium, and cryostat sectioned onto glass slides (70–80 μm) and subsequently stained with lipid dye, oil red O. Microscopy was performed using a Nikon Eclipse E200 microscope coupled with a DS-Fi3 digital camera (Nikon Instruments Inc., Melville, New York). The veterinary pathologist (DK) was blinded to the groups.
Quantification of hepatic steatosis
Oil red O-stained liver sections were imaged using an oil immersion objective lens (100 ×), and the images digitally analyzed. Images were digitally assessed for lipid area in untreated, and gadolinium-based contrast agent treated livers using Nikon NIS-Elements BR software (Nikon Instruments Inc., Melville, New York).
Frozen liver samples were processed by Human Metabolome Technologies (HMT, Japan), and capillary electrophoresis mass spectrometry (CE-MS) was performed. Liver metabolites from gadolinium-treated groups that differed from untreated liver using false discovery rate (FDR, Benjamini and Hochberg method), *P < 0.05, **P < 0.01, ***P < 0.001, were selected for inclusion in this study.
Renal cortices and liver were fixed in glutaraldehyde-containing fixative, post-fixed with 1% tannic acid, embedded in epoxy resin, and sectioned at 200 nm. Semithin sections, without secondary staining, were placed onto carbon holey support grids (Supplementary Fig. S15) for scanning transmission electron microscopy. Conventional transmission electron microscopy was performed on 60–80 nm-thick sections using the Hitachi HT7700 with AMT 16-megapixel digital camera operating at 80 kV. STEM implemented the use of a JEOL 2010F FEGSTEM 200 kV transmission electron microscope (TEM), with Oxford Analytical AZTec X-ray energy-dispersive spectroscopy system, equipped with an XMax 80N 80mm2 silicon drift detector (UNM), and the FEI Tecnai G(2) F30 S-Twin 300 kV transmission electron microscope equipped with Fischione Instruments HAADF STEM detectors (CINT). Human kidney sections (200 nm) were mounted on holey carbon grids and scanned with a JEOL NEOARM 200 kV Aberration Corrected scanning transmission microscope (STEM) equipped with two JEOL 100 mm2 EDS detectors controlled by Oxford Instruments AZTec software.
X-ray energy dispersive spectroscopy (XEDS)
Multiple line scan profiles (JEOL 2010F FEGSTEM) were performed on regions of interest. Data were collected for elements of interest; gadolinium (Gd), magnesium (Mg), phosphorus (P), calcium (Ca), sulfur (S), oxygen (O), potassium (K), chlorine (Cl), and silicon (Si). Counts were normalized (indexed) for visualization of XEDS line scan data; the location of the line scan was matched to regions of interest. XEDS analysis was performed using a Tecnai F30 TEM operating at 300 keV with an EDAX XEDS detector. Secondary XEDS analysis of the electron-dense material was performed using an EDAX Octane Elite T Super (70 mm2) detector on a monochromated ThermoFisher Scientific Titan transmission electron microscope (300 keV) and the JEOL NEOARM 200 kV Aberration Corrected STEM (described above).
XEDS line scan data for each element were indexed to their total area under the curve. Multiple regression analysis included the index values for elements of comparison, subcellular regions, and sex. Statistical analysis was conducted with RStudio (2022.07.1)/R (version 4.0.3).
The datasets generated and analyzed during the current study are available in the Kidney Institute of New Mexico repository, (https://digitalrepository.unm.edu/kinm/5/).
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The research was funded by a Veterans Administration Merit Award (I01 BX001958, BW), a National Institutes of Health R01 grant (DK-102085), and Dialysis Clinic, Inc. This project was supported in part by the Dedicated Health Research Funds of the University of New Mexico School of Medicine allocated to the Signature Program in Cardiovascular and Metabolic Disease (CVMD), National Center for Research Resources and the National Center for Advancing Translational Sciences of the National Institutes of Health through Grant Number UL1TR001449 (CTSC/DCI Kidney Pilot Project CTSC004-12 and CTSC/Environmental Health Signature Program Pilot Project CTSC003-13) and partial support by the University of New Mexico (UNM) Brain and Behavioral Health Institute (BBHI 2018-1008, 2020-21-002), and UNM School of Medicine Research Allocation Committee (C-2459-RAC, New Mexico Medical Trust). BW is an associate member of the Autophagy, Inflammation, and Metabolomics (AIM) Center of Biomedical Research Excellence (NIH grant P20GM121176). AIM Center Metabolomics Studies Vouchers supported some of the work herein. JD is supported by an NIH Diversity Supplement (3UL1TR001449-08S1). Data were generated in the HSC-Electron Microscopy Facility, which is supported by The University of New Mexico Health Science. Scanning transmission electron microscopy was performed, in part, at the Transmission Electron Microscopy Facility in the Department of Earth and Planetary Sciences at the University of New Mexico, a facility supported by the State of New Mexico, NSF, and NASA. The JEOL NEOARM in the Nanomaterials Characterization Facility at the University of New Mexico was supported by NSF MRI grant DMR-1828731. This work was performed, in part, at the Center for Integrated Nanotechnologies, an Office of Science User Facility operated for the U.S. Department of Energy (DOE) Office of Science (BW User Agreements 2019AU0120/#204-01_2014, 2021BC0021/#204-01_2020). Los Alamos National Laboratory, an affirmative action equal opportunity employer, is managed by Triad National Security, LLC for the U.S. Department of Energy’s NNSA, under contract 89233218CNA000001. Support for in vivo experiments in this paper was provided by the University of New Mexico Cancer Center Animal Models Shared Resource, funded by NCI 2P30 CA118100 (PI Willman, C.) “UNM Cancer Center Support Grant”. The research in this paper was supported by the Human Tissue Repository and Tissue Analysis Shared Resource, funded by the Department of Pathology, The University of New Mexico Comprehensive Cancer Center and NCI 2P30CA118100.
The authors declare no competing interests.
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DeAguero, J., Howard, T., Kusewitt, D. et al. The onset of rare earth metallosis begins with renal gadolinium-rich nanoparticles from magnetic resonance imaging contrast agent exposure. Sci Rep 13, 2025 (2023). https://doi.org/10.1038/s41598-023-28666-1