Does Age Interfere With Gadolinium Toxicity and Presence in Brain and Bone Tissues?

Fretellier, Nathalie; Granottier, Agnès; Rasschaert, Marlène; Grindel, Anne-Laure; Baudimont, Fannie; Robert, Philippe; Idée, Jean‐Marc; Corot, Claire

doi:10.1097/rli.0000000000000517

Cited by 34 publications

(36 citation statements)

References 98 publications

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“…Previously unknown site of Gd accumulation was identified by Delfino et al, who observed Gd deposition in the periodontal tissues in murine model with induced renal disease, using SR-XRF and LA-ICP-MS 47 . Interesting results showing differential accumulation of Gd by different bone tissues -cortical, trabecular bone and bone marrow in juvenile and adult rats by ICP-MS were published by Fretellier et al 48 . An interesting line of research -usage of GBCAs in pregnancy and potential effect of Gd on foetus, were investigated by Prola-Netto et al in rhesus macaques, and although only extremely low levels of Gd were found in juvenile tissues after in utero exposure, femur was identified as a site of consistent Gd retention in all the animals 49 .…”

Section: Analysis Ex Vivo Localization Within Bonementioning

confidence: 99%

Detection and imaging of gadolinium accumulation in human bone tissue by micro- and submicro-XRF

Turyanskaya

Rauwolf

Pichler

et al. 2020

Sci Rep

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Gadolinium-based contrast agents (GBcAs) are frequently used in patients undergoing magnetic resonance imaging. in GBcAs gadolinium (Gd) is present in a bound chelated form. Gadolinium is a rareearth element, which is normally not present in human body. though the blood elimination half-life of contrast agents is about 90 minutes, recent studies demonstrated that some tissues retain gadolinium, which might further pose a health threat due to toxic effects of free gadolinium. It is known that the bone tissue can serve as a gadolinium depot, but so far only bulk measurements were performed. Here we present a summary of experiments in which for the first time we mapped gadolinium in bone biopsy from a male patient with idiopathic osteoporosis (without indication of renal impairment), who received MRI 8 months prior to biopsy. In our studies performed by means of synchrotron radiation induced micro-and submicro-X-ray fluorescence spectroscopy (SR-XRF), gadolinium was detected in human cortical bone tissue. The distribution of gadolinium displays a specific accumulation pattern. Correlation of elemental maps obtained at AnKA synchrotron with qBei images (quantitative backscattered electron imaging) allowed assignment of Gd structures to the histological bone structures. follow-up beamtimes at eSRf and Diamond Light Source using submicro-SR-XRf allowed resolving thin Gd structures in cortical bone, as well as correlating them with calcium and zinc. The method of contrast-enhanced MRI (CE-MRI) dates to 1988, when the first gadolinium (Gd)-based contrast agent (GBCA), gadopentetate dimeglumine (Magnevist, Bayer), was approved for clinical use. CE-MRI is a useful imaging tool nowadays, with approximately 30 million procedures done each year worldwide, and more than 300 million procedures already performed to date 1. Estimates show that the GBCAs are administered in 25-35% of all MRI examinations 1,2. According to the data available, most of the administered dose of GBCAs (regardless of an agent used), should be cleared in less than 2 and >95% by 24 hours 3. Recent findings, however, demonstrate that the GBCAs are not fully excreted and the accumulation of Gd in, e.g. neuronal tissues and organs such as brain takes place 4. The GBCAs are considered to be rather safe, yet there is a number of papers reporting nephrotoxic, hematotoxic, hepatotoxic and neurotoxic effects observed in animals and humans 5. One of the most serious adverse reactions associated with the use of GBCAs is nephrogenic systemic fibrosis (NSF), which had been observed in patients with renal insufficiency 6. NSF is a rare, but serious disease characterized by widespread tissue hardening (primarily skin is affected) with fibrotic nodules and plaques. First described in 1997, it was finally linked to the use of GBCAs in patients with kidney dysfunction in 2006 6,7. The pathophysiological mechanism involved

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Section: Analysis Ex Vivo Localization Within Bonementioning

confidence: 99%

Detection and imaging of gadolinium accumulation in human bone tissue by micro- and submicro-XRF

Turyanskaya

Rauwolf

Pichler

et al. 2020

Sci Rep

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“…Whilst there was an initial washout between 1 h and 1 day (81.69 ± 67.46 nmol Gd/g tissue and 18.46 ± 1.96 nmol Gd/g tissue, respectively), levels of gadolinium detected remained consistent up to 20 weeks (14.00 ± 0.06 nmol Gd/g tissue) post-dosing (Davies et al 2021 ). Age has been shown to have an impact on bone gadolinium retention, with a higher concentration of gadolinium in the bone marrow of gadodiamide-treated juvenile rats compared with adults, but not noted in any other tissues analysed (Fretellier et al 2019 ). Among animal models used to mimic BBB disruption that is seen in human CNS disease, one such model uses lipopolysaccharide (LPS) to stimulate sepsis in rats, and this results in an increase in bone retention with gadobenate (0.2 mmol/kg) administration compared to control animals (394.22 ng/g ± 62.6 and 292.52 ng/g ± 43.9, respectively).…”

Section: Gadolinium Distribution In Humans and Animalsmentioning

confidence: 99%

“…Gadolinium retention in the skin of rodents has been demonstrated in multiple studies and can persist for up to 1 year post-dosing (Pietsch et al 2009 ; Murata et al 2016a ; Lohrke et al 2017 ; Bussi et al 2018a , b ; Fretellier et al 2019 ). In a comprehensive study, rats were given a cumulative dose of 12.5 mmol/kg (20 times the human equivalent dose) of either a linear GBCA (gadodiamide, gadopentetate, gadobenate or gadoversetamide) or a macrocyclic GBCA (gadoteridol, gadoterate or gadobutrol) and skin biopsies were taken at various time points up to 364 days post-dosing (Pietsch et al 2009 ).…”

Section: Gadolinium Distribution In Humans and Animalsmentioning

confidence: 99%

“…The same authors have also shown that repeated macrocyclic GBCA administration (12 mmol/kg; gadoterate, gadobutrol and gadoteridol) result in no skin gadolinium 28 days post-dosing; however, the techniques employed here were not as sensitive and the limit of quantification for these studies was 1 nmol Gd/g (Bussi et al 2018b ). Finally, sex and age of rats has been shown to have no impact on gadolinium retention or lesion formation (Fretellier et al 2019 ).…”

Section: Gadolinium Distribution In Humans and Animalsmentioning

confidence: 99%

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Gadolinium: pharmacokinetics and toxicity in humans and laboratory animals following contrast agent administration

Davies¹,

Siebenhandl-Wolff²,

Tranquart³

et al. 2022

Arch Toxicol

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Gadolinium-based contrast agents (GBCAs) have transformed magnetic resonance imaging (MRI) by facilitating the use of contrast-enhanced MRI to allow vital clinical diagnosis in a plethora of disease that would otherwise remain undetected. Although over 500 million doses have been administered worldwide, scientific research has documented the retention of gadolinium in tissues, long after exposure, and the discovery of a GBCA-associated disease termed nephrogenic systemic fibrosis, found in patients with impaired renal function. An understanding of the pharmacokinetics in humans and animals alike are pivotal to the understanding of the distribution and excretion of gadolinium and GBCAs, and ultimately their potential retention. This has been well studied in humans and more so in animals, and recently there has been a particular focus on potential toxicities associated with multiple GBCA administration. The purpose of this review is to highlight what is currently known in the literature regarding the pharmacokinetics of gadolinium in humans and animals, and any toxicity associated with GBCA use.

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“…B. in der Haut durch die Pathogenese der NSF, aber auch im Knochen [46,47]. Die absoluten Konzentrationen von Gadolinium waren dabei in Haut und Knochen deutlich höher als im Gehirn [48]. Auch in peripheren Nerven und dem Rückenmark waren nach Verabreichung von linearen GBCAs im Tierversuch höhere Gadolinium-Konzentrationen als im Gehirn bestimmt worden, wobei das gemessene Gadolinium nach Injektion von Makrozyklen in diesen Lokalisationen insgesamt geringer nachgewiesen wurde [49].…”

Section: Gadolinium-retention Im Gehirnunclassified

Gadolinium-based contrast agents: What we learned from acute adverse events, nephrogenic systemic fibrosis and brain retention

Bäuerle¹,

Saake²,

Uder³

2020

Rofo

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Background Radiologists have been administering gadolinium-based contrast agents (GBCA) in magnetic resonance imaging for several decades, so that there is abundant experience with these agents regarding allergic-like reactions, nephrogenic systemic fibrosis (NSF) and gadolinium retention in the brain. Methods This review is based on a selective literature search and reflects the current state of research on acute adverse effects of GBCA, NSF and brain retention of gadolinium. Results Due to the frequent use of GBCA, data on adverse effects of these compounds are available in large collectives. Allergic-like reactions occurred rarely, whereas severe acute reactions were very rarely observed. Systemic changes in NSF also occur very rarely, although measures to avoid NSF resulted in a significantly reduced incidence of NSF. Due to gadolinium retention in the body after administration of linear MR contrast agents, only macrocyclic preparations are currently used with few exceptions. Clear clinical correlates of gadolinium retention in the brain could not be identified so far. Although the clinical added value of GBCA is undisputed, individual risks associated with the injection of GBCA should be identified and the use of non-contrast enhanced MR techniques should be considered. Alternative contrast agents such as iron oxide nanoparticles are not clinically approved, but are currently undergoing clinical trials. Conclusion GBCA have a very good risk profile with a low rate of adverse effects or systemic manifestations such as NSF. Gadolinium retention in the brain can be minimized by the use of macrocyclic GBCA, although clear clinical correlates due to gadolinium retention in the brain following administration of linear GBCA could not be identified yet. Key Points: Citation Format

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Does Age Interfere With Gadolinium Toxicity and Presence in Brain and Bone Tissues?

Abstract: Supplemental digital content is available in the text.

Cited by 34 publications

References 98 publications

Detection and imaging of gadolinium accumulation in human bone tissue by micro- and submicro-XRF

Detection and imaging of gadolinium accumulation in human bone tissue by micro- and submicro-XRF

Gadolinium: pharmacokinetics and toxicity in humans and laboratory animals following contrast agent administration

Gadolinium-based contrast agents: What we learned from acute adverse events, nephrogenic systemic fibrosis and brain retention

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