Gadolinium-based contrast agents - what is the evidence for 'gadolinium deposition disease' and the use of chelation therapy?

Gadolinium-based contrast agents are widely used for magnetic resonance imaging and, until recently, had been generally considered to have an excellent safety profile in patients with normal renal function. Nephrogenic systemic fibrosis is a well-established disease process involving fibrosis of the skin and internal organs seen in some patients with severely impaired renal function following exposure to these agents. Following reports that individuals with normal renal function may experience gadolinium deposition within brain and bone tissue, the term "gadolinium deposition disease" has been proposed and the use of chelating agents has been recommended to treat this "disease". This review will address the clinical evidence for "gadolinium deposition disease" and discuss whether chelation therapy is appropriate for individuals who believe they have this condition. Electronic databases (PUBMED, Ovid MEDLINE and EMBASE) were searched up to 1 October 2019 for all studies evaluating clinical signs or symptoms related to potential gadolinium toxicity post-gadolinium-based contrast agent exposure in subjects with normal renal function, or papers evaluating the potential chelation of gadolinium in humans. We identified four clinical studies relating to "gadolinium deposition disease", including one that included some discussion of the use of chelation therapy. Two of the clinical studies presented data from anonymous online surveys that recruited participants from support forums for people who self-identified as having gadolinium-based contrast agent-induced toxicity, with questions focussing on their reported symptoms and signs. The published literature to date has demonstrated that gadolinium deposition within the brain primarily occurs within the dentate nucleus and globus pallidus. These patients did not complain of movement disorders, but instead reported generalised sensory symptoms, which would not be expected to occur with pathology in these areas of the brain. There was considerable selection bias and a lack of available clinical information to exclude alternative medical diagnoses for these series, thus rendering the results difficult to interpret. One study reported data from 25 patients who were diagnosed with "gadolinium deposition disease" according to unspecified criteria and were treated with intravenous calcium or zinc trisodium pentetate. The authors reported an increase in urine gadolinium concentrations following administration of the chelating agents, which they attributed to re-chelation of gadolinium from tissue deposits, however, there are insufficient data to be able to substantiate this. There is currently no published information from well-designed clinical studies that support a link between gadolinium deposition and the development of clinical sequelae in patients with normal renal function. Clinicians should exercise caution when considering whether or not gadolinium is of relevance in patients reporting symptoms after administration of gadolinium-based contrast agents. The inappropriate use of chelation therapy in patients with no clear evidence-based indication for their use potentially increases the risk of clinically significant harm to these patients from the adverse effects of chelation. Further research and well-designed clinical and epidemiological surveillance is needed to determine whether there are toxicological risks related to gadolinium exposure from the use of gadolinium-based contrast agents in patients with normal renal function.