PMID: 

Toxicol Appl Pharmacol. 2019 Jul 15 ;375:32-45. Epub 2019 May 10. PMID: 31082427

Abstract Title: 

Gadolinium-based contrast agents: Stimulators of myeloid-induced renal fibrosis and major metabolic disruptors.

Abstract: 

Evidence for gadolinium-based contrast agent- (GBCA-) induced disease continues to mount. Risk factors for gadolinium-induced systemic fibrosis are entirely unexplored. Obesity-related renal injury is characterized by activation of glomerular mesangial cells and podocyte damage with alteration of lipid metabolism/lipid accumulation in both cell types resulting in matrix accumulation and eventual progression to glomerulosclerosis. We examined the consequences of GBCA treatment in the kidneys from mice with normal kidney function and the potential interplay between obesity and gadolinium exposure. We found that administration of GBCA (4 weeks) causes significant renal fibrosis and podocyte injury that are associated with metabolic disorders as evidenced by dyslipidemia. Metabolomic analysis demonstrated that renal lipid metabolism and metabolic markers of collagen turnover are significantly altered by gadolinium. GBCA stimulatesmyeloid-derived fibrocytes to the kidney. Obesity was induced by feeding a group of mice a high fat diet (HFD) for 22 weeks. Groups were sub-randomized to GBCA treatment versus none for 4 weeks before sacrifice. HFD-induced fibrosis and podocyte injury were worsened by GBCA. Similarly, HFD-mediated hyperlipidemia and lipid metabolites were exacerbated by gadolinium. This is the first evidence that GBCA causes significant metabolic disorders and kidney injury in mice without renal insufficiency and that the injurious actions of GBCA are amplified by obesity. The understanding of the functional interplay between gadolinium and obesity will allow the development of therapeutic interventions or the establishment of effective preventive measures to reduce gadolinium- and obesity-mediated renal pathologies.

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PMID: 

JAMA Dermatol. 2015 Oct ;151(10):1117-20. PMID: 26017458

Abstract Title: 

Nephrogenic Systemic Fibrosis Manifesting a Decade After Exposure to Gadolinium.

Abstract: 

IMPORTANCE: Nephrogenic systemic fibrosis (NSF) is a fibrosing skin disorder that develops in patients with kidney failure and has been linked to exposure to gadolinium-containing contrast agents. The time between exposure to gadolinium and the initial presentation of NSF is typically weeks to months but has been documented to be as long as 3½ years. We report a case of NSF developing 10 years after exposure to gadolinium.OBSERVATIONS: A long-term hemodialysis patient was exposed to gadolinium several times between 1998 and 2004 during magnetic resonance angiography of his abdominal vessels and arteriovenous fistula. In 2014, he was seen at our clinic with new dermal papules and plaques. Biopsy of affected skin showed thickening of collagen, CD34+ spindle cells, and increased mucin in the dermis, supporting the diagnosis of NSF.CONCLUSIONS AND RELEVANCE: The clinical history and histopathological features of this case support the diagnosis of NSF 10 years after exposure to gadolinium. Although the use of gadolinium contrast agents in patients with kidney failure has markedly decreased, patients with exposure to gadolinium years to decades previously may manifest the disease.

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PMID: 

J Vasc Access. 2017 Mar 28 ;18(Suppl. 2):1-7. Epub 2017 Mar 21. PMID: 28362042

Abstract Title: 

Gadolinium contrast agents – are they really safe?

Abstract: 

Gadolinium-based contrast agents (GBCA) are used worldwide for enhanced MRI examinations, including heart and vessels. Gadolinium is a highly toxic heavy metal. If used in GBCA it must be tightly bound to ligands. The configuration of ligands influences the stability of the GBCA and two types of chelates have been used. Macrocyclic chelates offer better protection and binding of gadolinium ion than linear chelates with a flexible open chain – gadolinium could be more easily released from the latter ones. GBCAs are excreted from the body mostly by the kidneys, which is of importance in chronic kidney disease.Two states are related to gadolinium: nephrogenic systemic fibrosis (NSF) and gadolinium body storage. NSF is a severe and debilitating disease, directly connected to gadolinium toxicity, proven after the use of linear chelates. Due to strict recommendations of radiology societies, NSF was practically eradicated. Gadolinium deposition was observed especially in bones and in some brain areas: in dentate nucleus and in globus pallidus, even years after the GBCA administration. The form of the storage (chelated or free), as well as their clinical impact, are not clear, but first observations of"gadolinium deposition disease"have been reported.

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PMID: 

Radiol Technol. 2017 Jul ;88(6):583-589. PMID: 28900045

Abstract Title: 

GBCAs and Risk for Nephrogenic Systemic Fibrosis: A Literature Review.

Abstract: 

PURPOSE: To examine the risks of using of gadolinium-based contrast agents (GBCAs) in magnetic resonance (MR) imaging and explore strategies to reduce the likeliness of adverse effects in patients who might be at risk for developing nephrogenic system fibrosis (NSF).METHODS: A search of 3 scholarly databases was performed to identify articles that discuss adverse reactions to GBCAs, specifically relating to kidney function, in MR examinations. A total of 20 peer-reviewed articles were analyzed.DISCUSSION: Safety of contrast media is related to the stability of the chelate bond (ie, macrocyclic or linear). Patients who have decreased kidney function or chronic kidney disease are at higher risk for an adverse reaction to GBCAs; typically, macrocyclic contrast agents are considered safer than linear contrast agents for patients at risk for developing NSF because of their higher kinetic stability. Recommended doses of gadolinium should be adhered to carefully for all patients in conjunction with the glomerular filtration rate guidelines for contrast administration defined by the American College of Radiology.CONCLUSION: Although there are advantages to contrast use in MR examinations, technologists should work closely with referring physicians and radiologists to minimize risks for developing NSF in patients who have decreased kidney function.

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PMID: 

Magn Reson Imaging. 2016 Oct ;34(8):1078-80. Epub 2016 May 19. PMID: 27211256

Abstract Title: 

Self-reported gadolinium toxicity: A survey of patients with chronic symptoms.

Abstract: 

PURPOSE: This study aims to describe the self-reporting symptoms experienced by individuals with self-reported normal renal function after gadolinium based contrast agent (GBCA) administration.MATERIALS AND METHODS: This HIPAA-compliant, IRB-approved study consisted of an anonymous online survey of patients who believe that they suffer from gadolinium toxicity. 50 respondents completed the nine-question survey.RESULTS: Fifty (100%) of the subjects ascribed their complaints to gadolinium exposure. Thirty-three (66%) described the onset immediately following GBCA administration and 16 (32%) within 6weeks. The most common symptoms included bone/joint pain and head/neck symptoms including headache, vision change, and hearing change (77.6% each). Other symptoms occurred with lesser incidence.CONCLUSIONS: This survey represents an initial description of patients with normal renal function who self-described toxicity related to GBCA administration. Bone and joint complaints and skin changes are two of the most common complaints.

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PMID: 

Environ Toxicol Chem. 2018 06 ;37(6):1523-1534. Epub 2018 Apr 19. PMID: 29473658

Abstract Title: 

Gadolinium as a new emerging contaminant of aquatic environments.

Abstract: 

Since the 1980s, gadolinium (Gd)-based contrast agents (GBCAs) have been routinely used in magnetic resonance imaging as stable chelates of the Gdion, without toxic effects. Generally, GBCAs are considered some of the safest contrast agents. However, it has been observed that they can accumulate in patient tissue, bone, and probably brain (causing nephrogenic systemic fibrosis in patients with kidney failure or insufficiency and disturbance of calcium homeostasis in the organism). The GBCAs are predominantly removed renally without metabolization. Subsequently, they do not undergo degradation processes in wastewater-treatment plants and are emitted into the aquatic ecosystem. Their occurrence was confirmed in surface waters (up to 1100 ng/L), sediments (up to 90.5 μg/g), and living organisms. Based on a literature review, there is a need to investigate the contamination of different ecosystems and to ascertain the environmental fate of Gd. Long-term ecotoxicological data, degradation, metabolism, bioaccumulation processes, and biochemical effects of the Gd complexes should be explored. These data can be used to assess detailed environmental risks because currently only hotspots with high levels of Gd can be marked as dangerous for aquatic environments according to environmental risk assessments. Environ Toxicol Chem 2018;37:1523-1534. © 2018 SETAC.

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PMID: 

Contrast Media Mol Imaging. 2018 ;2018:3535769. Epub 2018 Dec 2. PMID: 30627059

Abstract Title: 

Exposure of Macrophages to Low-Dose Gadolinium-Based Contrast Medium: Impact on Oxidative Stress and Cytokines Production.

Abstract: 

The toxicity of gadolinium-based contrast agents (GBCAs) has drawn a lot of attention. Nephrogenic systemic fibrosis (NSF), a lethal disease related to the use of GBCAs, is still not understood. Recently, gadolinium retention is found in brain tissues after repeated use of GBCAs in magnetic resonance imaging (MRI). However, most of the works investigating the toxicity of GBCAs are focusing on its high-concentration (0.5-10 mM) part, which is not reflective of the physiological conditions in human beings. Macrophages play a regulatory role in immune responses and are responsible for the fibrosis process. Their role in gadolinium retention and the pathogenesis of NSF, however, has seldom been investigated. This studyaimed to evaluate the immune response generated by macrophages (RAW 264.7) exposing to low levels of GBCAs. The incubation concentration of GBCAs, including Omniscan®, Primovist®, Magnevist®, and Gadovist®, is proportional to the level of gadolinium uptake when detected via inductively coupledplasma mass spectrometry (ICP-MS) and imaged by MRI, whereas Primovist® treatment groups have highest gadolinium uptake among all of the tested concentrations. Low-concentration (2.5 mol/L) Gd chloride or GBCAs exposure promoted the reactive production of oxygen species (ROS), nitrate/nitrite, prostaglandin E2 (PGE2), and suppressed the potential of mitochondrial membrane. There was higher ROS, nitrate/nitrite, and PGE2 production in the Primovist®, Omniscan®, and Magnevist® groups compared to the Gadovist® group. In face of lipopolysaccharide (LPS) stimulation, Primovist®, Omniscan®, and Magnevist® groups exhibited elevated nitrite/nitrate and suppressed IL-1secretion and IL-6 and IL-10 secretion. Moreover, upon LPS stimulation, there is decreased TNF-secretion 4 hours after Primovist® or Omiscan® exposure but the TNF-secretion increased at 24 hours. Our data suggest that there is upregulated inflammation even in the presence of low levels of GBCAs, even similar to the physiological condition in murine macrophage. Further investigation of GBCAs on the human macrophage oranimal study may clarify the role of macrophage on the pathogenesis of NSF and other GBCAs-related disease.

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PMID: 

Invest Radiol. 1997 May ;32(5):249-59. PMID: 9140744

Abstract Title: 

Influence of contrast media on blood coagulation.

Abstract: 

RATIONALE AND OBJECTIVES: Contrast agents have been reported to influence the blood clotting system to an extent depending mainly on whether the compounds are ionic or nonionic. The objective of the current series of studies was to determine interspecies differences; the effect of variable incubation times; and the effect on thromboplastin times (TPT) of adding heparin to a number of x-ray and magnetic resonance imaging (MRI) contrast agents. In addition, the stability of clots formed in the presence of iopromide was studied. In a final experiment, the effect of the contrast agents on the bleeding time was studied in rats.METHODS: Nine x-ray and three MRI contrast agents were used in the study. Thromboplastin times was determined in platelet-poor plasma of humans, rats, rabbits, or dogs using calcium (Ca) thromboplastin from human placenta or rabbit brain and lung tissue and incubation times as long as 4 hours. Bleeding times were determined in rats 5 minutes, 4 hours, 24 hours, and 48 hours after intravenous injection of the contrast agents by making a small incision into the tail of the animal, immersing the tail in saline, and measuring the time period during which small blood streaks were visible.RESULTS: Nonionic contrast agents (x-ray and MRI) increased the TPT by a factor of 1.5 to 2, whereas ionic compounds prolonged TPT by a factor of>3. Thromboplastin times increased in the order of dog

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PMID: 

J Nucl Med Technol. 2017 03 ;45(1):30-33. Epub 2016 Nov 10. PMID: 27834725

Abstract Title: 

Do Gadolinium-Based Contrast Agents AffectF-FDG PET/CT Uptake in the Dentate Nucleus and the Globus Pallidus? A Pilot Study.

Abstract: 

Gadolinium is toxic and to avoid its deposition in tissues, it must be chemically bonded with nonmetal ions to facilitate its excretion by the kidneys. High signal intensity in the dentate nucleus (DN) and globus pallidus (GP) on unenhanced T1-weighted MR images has been both morphologically and pathologically linked to gadolinium-based contrast agent (GBCA) retention in the brain. The purpose of this study was to determine whether repeated administrations of GBCA would affect the uptake ofF-FDG in the DN and GP on PET/CT.Three hundred seventy-six patients who underwent both contrast-enhanced MR (CE MR) of the brain and PET/CT from January 2004 to October 2015 were identified. Patients with a history of brain irradiation or hepatic or renal disease were excluded. The SUVwas measured in the DN and GP on the PET/CT scan in patients who had 3-6 successive CE MR brain studies. The SUVof the corresponding areas in the control group of patients who had not undergone previous CE MR and who had a normal, unenhanced MR finding of the brain was also measured. A Wilcoxon 2-sample test was used for statistical analysis.Fifteen of 376 (4%) patients (mean age± SD, 54 ± 18 y; 10 men and 5 women) were included in the subject group, and 15 patients (mean age ± SD, 36 ± 9 y; 11 men and 4 women) were included in the control group. The median DN SUVwas significantly lower in the subject group than in the control group (5.4 vs. 6.4, respectively;= 0.021). Similarly, the median GP SUVwas significantly lower in the subject group than in the control group (8.8 vs. 12.1, respectively;= 0.003).The median SUVin the DN and GP was 16% and 27% lower, respectively, in patients who received GBCAs than in those who had not received GBCAs, possibly related to gadolinium deposition in these areas.

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PMID: 

PLoS One. 2017 ;12(2):e0171704. Epub 2017 Feb 10. PMID: 28187173

Abstract Title: 

The presence of the gadolinium-based contrast agent depositions in the brain and symptoms of gadolinium neurotoxicity – A systematic review.

Abstract: 

BACKGROUND AND PURPOSE: Gadolinium based contrast agents (GBCAs) are widely used in magnetic resonance imaging, but recently, high signal intensity in the cerebellum structures was reported after repeated administrations of contrast- enhanced magnetic resonance images. The aim of this systematic review was to investigate the association between increased signal intensity in the dentate nucleus and globus pallidus in the brain and repeated administrations of GBCAs. Additionally, we focused on possible short- and long-term consequences of gadolinium use in those patients.METHODS: Systematic review of retrospective investigations in PubMed and Medline was performed in July 2016. Primary outcomes included the presence of increased signal intensity within the dentate nucleus and globus pallidus on unenhanced T1-weighted MR images in patients following administrations of GBCAs. Two independent reviewers were responsible for search and data extraction.RESULTS: 25 publications satisfied inclusion criteria (19 magnetic resonance images analyses, 3 case reports; 3 autopsy studies). Magnetic resonance images of 1247 patients with increased signal intensity on unenhanced T1-weighted MR images were analyzed as well as tissue specimens from 27 patients. Signal intensity correlated positively with the exposure to GBCAs and was greater after serial administrations of linear nonionic than cyclic contrast agents. Gadolinium was detected in all tissue examinations.CONCLUSIONS: High signal intensity in the dentate nucleus and globus pallidus on unenhanced T1-weighted magnetic resonance images were associated with previous administration of GBCAs. Signal intensity correlated negatively with stability of contrast agents. Clinical significance of gadolinium deposition in the brain remains unclear. There is a strong need for further research to identify type of gadolinium deposited in the brain as well as to gather knowledge about long-term consequences.

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