Gadolinium‐based contrast agents and their potential role in the pathogenesis of nephrogenic systemic fibrosis: The role of excess ligand

Abstract

Purpose:To investigate the role of excess ligand present in gadolinium (Gd) -based contrast agents in the development of nephrogenic systemic fibrosis (NSF). Using a dosing regimen to simulate the exposure seen in patients with severe renal impairment, we investigated the effect of excess ligand on Gd-deposition and the depletion of endogenous ions. Materials and Methods:Gadodiamide and gadoversetamide were formulated with 0%, 5%, and 10% excess ligand. Forty-two, healthy, male Hannover Wistar rats received daily intravenous injections of each formulation over a period of 20 days. At the end of the study, histopathological analysis of the skin was performed and the concentrations of Gd, Zn, and Cu were measured in several tissues. The levels of Zn in the urine were also measured. Results:The most severe skin lesions were observed after injection of formulations containing 0% free ligand and in those animals with the highest Gd concentrations in the skin. There were no significant reductions in the levels of Zn or Cu observed in the skin; however, the levels of Zn in the urine were elevated following administration of formulations with the highest amount of excess ligand. Conclusion:Our findings suggest that there is an inverse correlation between the amount of excess ligand present in Gd-containing contrast agents and the amount of Gd in the tissue, and further underline the importance of the inherent stability of these agents in the development of NSF.

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

“…Therefore, the most severe skin lesions were observed following the administration of gadoversetamide and gadodiamide without excess ligand. By contrast, no lesions were reported after the administration of gadoversetamide and gadodiamide with 10% excess ligand (12). The animal findings suggest that the presence of excess ligand does not increase the likelihood of the induction of NSF-like skin lesions.…”

“…In a different rat study, skin lesions seen after Omniscan and gadodiamide (Omniscan without excess ligand) treatment were attributed to excessive scratching rather than an NSF-like disease process (23). This hypothesis seems unlikely since, in several studies, the increased cellularity but also the infiltration of CD34-positive was also observed after GBCAs injection in animals without ulcerations (11)(12)(13)24). The infiltration of CD34-positive fibroblast is also one of the most obvious histopathological similarities between human NSF and rat pathology.…”

“…Indeed, increased urinary excretion of Zn after the administration of linear GBCAs has been described in several experiments with species including humans (12,33,36). In contrast, even after the administration of high doses of GBCAs no Zn or Cu depletion could be detected in the serum or any other investigated organ (skin, liver, and bone) (11,13,16).…”

“…In summary, the study suggests that excess ligand bears no positive relationship to the development of skin fibroses. 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).…”

“…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.…”