Long-term retention of gadolinium in the skin of rodents following the administration of gadolinium-based contrast agents

Pietsch, Hubertus; Lengsfeld, Philipp; Jošt, Gregor; Frenzel, Thomas; Hütter, Joachim; Sieber, Martin

doi:10.1007/s00330-008-1259-4

Cited by 60 publications

(70 citation statements)

References 26 publications

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“…These small particles were shown to be located within the nonmembrane delineated areas of macrophages (15). A high concentration of phosphorus was also found in the observed deposits, suggesting that at least some Gd may have been deposited as Gd-phosphate (GdPO 4 ) (11,16). Phosphate deposits can also be detected with von Kossa staining, which stains anions (PO 3À 4 ) rather than the cations Ca 2þ or Gd 3þ (15).…”

Section: Nsf Animal Modelsmentioning

confidence: 85%

“…ligand itself without Gd 3þ did not induce skin lesions, and incubation with a ligand also did not induce fibroblast proliferation in vitro (11,16,25). These preclinical data suggest that neither skin lesions nor fibroblast proliferation are related to the presence of free ligand but are, instead, correlated with high Gd concentration in the skin.…”

Section: Potential Role Of Gbcas In Nsfmentioning

confidence: 85%

“…Due to this rapid precipitation, GdCl 3 and Gd-acetate possess different pharmacokinetic and toxicological profiles compared with GBCAs (37). For example, injection of GdCl 3 leads to a depletion of macrophages from the bloodstream (38) and the preferential accumulation of Gd in the liver and spleen (11,16). This is in contrast to the administration of GBCAs, after which a depletion of macrophages or a preferential accumulation in the liver and spleen have not been observed (13).…”

Section: Potential Role Of Gbcas In Nsfmentioning

confidence: 99%

“…Data taken from Sieber et al (12). endogenous ions as a factor in the development of NSF-like skin lesions in rats is further called into question by the fact that administering supplementary essential elements through an injection of Zn aspartate did not reduce the number of skin lesions seen in animal studies nor did the depletion of Zn in animals by a Zn-deficient diet increase the propensity of the animals to develop skin lesions after the administration of GBCAs (16). In summary, the animal data suggest that a depletion of endogenous ions like Zn is not associated with the development of NSF.…”

Section: Role Of Zincmentioning

confidence: 99%

“…The aim of this review is to summarize knowledge regarding the pathogenesis of NSF and the potential role of GBCAs in its pathology, with a focus on the animal experiments performed in our laboratory (11)(12)(13)(14)(15)(16)(17)(18). The potential role of complex stability of GCBAs will be highlighted by results from several in vitro and in vivo experiments in rodent models of NSF.…”

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confidence: 99%

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Gadolinium‐based contrast agents and NSF: Evidence from animal experience

Sieber

Steger‐Hartmann

Lengsfeld

et al. 2009

Magnetic Resonance Imaging

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Nephrogenic systemic fibrosis (NSF) is a potentially severe systemic disease typically characterized by fibrosis of the skin and connective tissues. The etiology of NSF is still unknown but is likely to be multifactorial. Specific triggers under scientific evaluation have included surgery and/or the occurrence of thrombosis or other vascular injury, proinflammatory state, the administration of high doses of erythropoietin, and more recently the use of gadolinium-based contrast agents (GBCAs). The aim of this review is to summarize knowledge regarding the pathogenesis of NSF and the potential role of GBCAs in its pathology, with a focus on animal experiments. The potential role of complex stability of GCBAs will be highlighted by results from several in vitro and in vivo experiments in rodent models of NSF.

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Section: Nsf Animal Modelsmentioning

confidence: 85%

Section: Potential Role Of Gbcas In Nsfmentioning

confidence: 85%

Section: Potential Role Of Gbcas In Nsfmentioning

confidence: 99%

Section: Role Of Zincmentioning

confidence: 99%

mentioning

confidence: 99%

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Gadolinium‐based contrast agents and NSF: Evidence from animal experience

Sieber

Steger‐Hartmann

Lengsfeld

et al. 2009

Magnetic Resonance Imaging

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[Gd(HB‐DO3A)]: Equilibrium, Dissociation Kinetic and Structural Differences in a Simple Homolog of [Gd(HP‐DO3A)] (Prohance^®)

Versolatto,

Boccalon,

Guidolin

et al. 2024

Chemistry A European J

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[Gd(HP‐DO3A)] (gadoteridol) as an active compound of ProHance® is a widely employed contrast agent in clinical MRI scans in the last 30 years. Recent concerns about the long‐term retention of gadolinium‐based contrast agents (GBCAs) led to a deeper investigation of the structural features underlying the integrity of the paramagnetic metal complex. Several human and nonclinical studies have noted marked differences among the macrocyclic GBCAs, with the least retention of Gd traces and most rapid elimination consistently being reported for [Gd(HP‐DO3A)]. It was deemed of interest to assess how minor structural/electronic changes associated to the ligand structure may affect basic properties of the metal complex with several [Gd(HP‐DO3A)] analogues synthesized and characterized in the last years. We recently reported that the closest homolog of [Gd(HP‐DO3A)], i.e.: [Gd(HB‐DO3A)], in which (±)‐2‐hydroxy‐1‐propyl pendant arm is replaced by (±)‐2‐hydroxy‐1‐butyl moiety, showed a significantly different retention behaviour in the model interaction with collagen, despite the apparently very minor structural difference. In this paper we report a comprehensive study of the structural, thermodynamic, kinetic and relaxation properties of [Gd(HB‐DO3A)], compared to the parent [Gd(HP‐DO3A)] and to other closely related macrocyclic GBCAs to assess whether very minor structural changes can modulate the physico‐chemical properties of Gd3+ complexes.

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Gadolinium‐containing magnetic resonance contrast media: investigation on the possible transchelation of Gd³⁺ to the glycosaminoglycan heparin

Taupitz

Stolzenburg

Ebert

et al. 2012

Contrast Media & Molecular

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Retention of gadolinium (Gd) in biological tissues is considered an important cofactor in the development of nephrogenic systemic fibrosis (NSF). Research on this issue has so far focused on the stability of Gd-based contrast media (GdCM) and a possible release of Gd³⁺ from the complex. No studies have investigated competing chelators that may occur in vivo. We performed proton T(1) -relaxometry in solutions of nine approved GdCM and the macromolecular chelator heparin (250 000 IU per 10 ml) without and with addition of ZnCl₂. For the three linear, nonspecific GdCM complexes, Omniscan®, OptiMARK® and Magnevist®, 2 h of incubation in heparin at 37 °C in the presence of 2.0 mm ZnCl₂ led to an increase in T₁-relaxivity by a factor of 7.7, 5.6 and 5.1, respectively. For the three macrocyclic complexes, Gadovist®, Dotarem® and Prohance®, only a minor increase in T₁-relaxivity by a factor of 1.5, 1.6 and 1.7 was found, respectively. Without addition of ZnCl₂, no difference between the two GdCM groups was observed (factors of 1.4, 1.2, 1.1, 1.3, 1.5 and 1.4, respectively). The increase in T₁-relaxivities observed for linear GdCM complexes may be attributable to partial transchelation with formation of a macromolecular Gd-heparin complex. For comparison, mixing of GdCl₃ and heparin results in a 8.7-fold higher T₁-relaxivity compared with a solution of GdCl₃ in water. Heparin is a glycosaminoglycan (GAG) and as such occurs in the human body as a component of the extracellular matrix. GAGs generally are known to be strong chelators. Gd³⁺ released from chelates of GdCM might be complexed by GAGs in vivo, which would explain their retention in biological tissues. Plasma GAG levels are elevated in end-stage renal disease; hence, our results might contribute to the elucidation of NSF.

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Long-term retention of gadolinium in the skin of rodents following the administration of gadolinium-based contrast agents

Cited by 60 publications

References 26 publications

Gadolinium‐based contrast agents and NSF: Evidence from animal experience

Gadolinium‐based contrast agents and NSF: Evidence from animal experience

[Gd(HB‐DO3A)]: Equilibrium, Dissociation Kinetic and Structural Differences in a Simple Homolog of [Gd(HP‐DO3A)] (Prohance^®)

Gadolinium‐containing magnetic resonance contrast media: investigation on the possible transchelation of Gd³⁺ to the glycosaminoglycan heparin

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Long-term retention of gadolinium in the skin of rodents following the administration of gadolinium-based contrast agents

Cited by 60 publications

References 26 publications

Gadolinium‐based contrast agents and NSF: Evidence from animal experience

Gadolinium‐based contrast agents and NSF: Evidence from animal experience

[Gd(HB‐DO3A)]: Equilibrium, Dissociation Kinetic and Structural Differences in a Simple Homolog of [Gd(HP‐DO3A)] (Prohance®)

Gadolinium‐containing magnetic resonance contrast media: investigation on the possible transchelation of Gd3+ to the glycosaminoglycan heparin

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[Gd(HB‐DO3A)]: Equilibrium, Dissociation Kinetic and Structural Differences in a Simple Homolog of [Gd(HP‐DO3A)] (Prohance^®)

Gadolinium‐containing magnetic resonance contrast media: investigation on the possible transchelation of Gd³⁺ to the glycosaminoglycan heparin