Gadolinium Tissue Distribution in a Large-Animal Model after a Single                     Dose of Gadolinium-based Contrast Agents

Richter, Henning; Bücker, Patrick; Martin, Louise F.; Dunker, Calvin; Fingerhut, Stefanie; Xia, Anna; Karol, Agnieszka; Sperling, Michael; Kärst, Uwe; Radbruch, Alexander; Jeibmann, Astrid

doi:10.1148/radiol.2021210553

Cited by 17 publications

(24 citation statements)

References 29 publications

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“…32 Moreover, there is a significant linear relationship between Gd content of the dentate nucleus (at least partially detectable on conventional MRI) and the skin (not detectable on conventional MRI). 33 Recently, in a sheep model with normal renal function and intravenous exposure to only 1 single injection of various GBCAs, Richter et al 34 found retained Gd into all investigated tissues (kidney>liver>skin>dentate nucleus) with higher concentrations after the use of linear compounds. No histologic alterations were found in tissues.…”

Section: Discussionmentioning

confidence: 99%

Skin Thickening of the Scalp and High Signal Intensity of Dentate Nucleus in Multiple Sclerosis

et al. 2022

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The aim of this study was to assess the presence of detectable changes of skin thickness on clinical brain magnetic resonance imaging (MRI) scans in patients with MS, history of multiple gadolinium-based contrast agents (GBCAs) administrations, and evidence of gadolinium deposition in the brain. Materials and Methods: In this observational cross-sectional study, 71 patients with MS who underwent conventional brain MRI with an imaging protocol including enhanced 3D volumetric interpolated breath-hold examination (VIBE) T1-weighted with fat saturation were assessed. Patients with bilateral isointense dentate nucleus on unenhanced T1-weighted images were assigned to group A (controls without MRI evidence of gadolinium deposition), and patients with visually hyperintense dentate nuclei were assigned to group B. Qualitative and quantitative assessment of the skin thickness were performed. Results: Group A included 27 patients (median age, 33 years [IQR,[27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46]; 20 women), and group B included 44 patients (median age, 42 years [IQR,[35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53]; 29 women). Qualitative and quantitative assessment of the skin revealed significant differences between group A and group B. The average skin-to-scalp thickness ratios was significantly higher in group B than in group A (mean ± standard deviation = 0.52 ± 0.02 in group B vs 0.41 ± 0.02 in group A, P < 0.0001) and showed a positive correlation with the total number of enhanced MRI scans (r = 0.39; 95% confidence interval, 0.17-0.57, P < 0.01). Conclusions: Brain MRI detects increased skin thickness of the scalp in patients with MS and dentate nucleus high signal intensity on unenhanced T1-weighted images and shows positive association with previous exposures to linear GBCAs rather than macrocyclic GBCAs.

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Section: Discussionmentioning

confidence: 99%

Skin Thickening of the Scalp and High Signal Intensity of Dentate Nucleus in Multiple Sclerosis

et al. 2022

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“…Gadoteridol is eliminated more rapidly from the skin compared with gadoterate and gadobutrol in the first 5 weeks after administration. Richter et al 40 Sheep Gadobutrol, gadoteridol, gadoterate meglumine, gadodiamide, and gadobenate dimeglumine At 10 weeks after injection, linear GBCAs resulted in the highest mean gadolinium concentration, without evidence of histopathologic alterations, but no IENFD was performed.…”

Section: Preclinical Animal Studiesmentioning

confidence: 99%

Skin Toxicity After Exposure to Gadolinium-Based Contrast Agents in Normal Renal Function, Using Clinical Approved Doses

et al. 2023

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Objectives The aim of this study was to summarize the current preclinical and clinical evidence on the association between exposure to gadolinium (Gd) compounds and skin toxicity in a setting similar to clinical practice. Materials and Methods A search of MEDLINE and PubMed references from January 2000 to December 2022 was performed using keywords related to gadolinium deposition and its effects on the skin, such as “gadolinium,” “gadolinium-based contrast agents,” “skin,” “deposition,” and “toxicity.” In addition, cross-referencing was added when appropriate. For preclinical in vitro studies, we included all the studies that analyzed the response of human dermal fibroblasts to exposure to various gadolinium compounds. For preclinical animal studies and clinical studies, we included only those that analyzed animals or patients with preserved renal function (estimated glomerular filtration rate >30 mL/min/1.73 m2), using a dosage of gadolinium-based contrast agents (GBCAs) similar to that commonly applied (0.1 mmol/kg). Results Forty studies were selected. Preclinical findings suggest that Gd compounds can produce profibrotic responses in the skin in vitro, through the activation and proliferation of dermal fibroblasts and promoting their myofibroblast differentiation. Gadolinium influences the process of collagen production and the collagen content of skin, by increasing the levels of matrix metalloproteinase-1 and tissue inhibitor of metalloproteinase-1. Preclinical animal studies show that Gd can deposit in the skin with higher concentrations when linear GBCAs are applied. However, these deposits decrease over time and are not associated with obvious macroscopic or histological modifications. The clinical relevance of GBCAs in inducing small fiber neuropathy remains to be determined. Clinical studies show that Gd is detectable in the skin and hair of subjects with normal renal function in higher concentrations after intravenous administration of linear compared with macrocyclic GBCA. However, these deposits decrease over time and are not associated with cutaneous or histological modifications. Also, subclinical dermal involvement related to linear GBCA exposure may be detectable on brain MRI. There is no conclusive evidence to support a causal relationship between GBCA administration at the clinical dose and cutaneous manifestations in patients with normal renal function. Conclusions Gadolinium can produce profibrotic responses in the skin, especially acting on fibroblasts, as shown by preclinical in vitro studies. Gadolinium deposits are detectable in the skin even in subjects with normal renal function with higher concentrations when linear GBCAs are used, as confirmed by both preclinical animal and human studies. There is no proof to date of a cause-effect relationship between GBCA administration at clinical doses and cutaneous consequences in patients with normal renal function. Multiple factors, yet to be determined, should be considered for sporadic patients with normal renal function who develop clinical skin manifestations temporally related to GBCA administration.

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“…Since Gd complexes are very stable, they pass unmetabolized through the human body and are excreted via the urine. Only a small part of the injected Gd can accumulate in animal tissues [ 5 , 6 ]. However, Gd complexes are also recalcitrant in municipal wastewater treatment and are thus emitted into rivers, which has resulted in the accumulation of the tracer in aquatic environments.…”

Section: Introductionmentioning

confidence: 99%

Analytical strategies to measure gadolinium as a wastewater marker in surface and groundwater systems

2023

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Gadolinium Tissue Distribution in a Large-Animal Model after a Single Dose of Gadolinium-based Contrast Agents

Cited by 17 publications

References 29 publications

Skin Thickening of the Scalp and High Signal Intensity of Dentate Nucleus in Multiple Sclerosis

Skin Thickening of the Scalp and High Signal Intensity of Dentate Nucleus in Multiple Sclerosis

Skin Toxicity After Exposure to Gadolinium-Based Contrast Agents in Normal Renal Function, Using Clinical Approved Doses

Analytical strategies to measure gadolinium as a wastewater marker in surface and groundwater systems

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