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

Abstract

Introduction: 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". Objectives: 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. Methods: Electronic databases (PUBMED, Ovid MEDLINE and EMBASE) were searched up to 1 st 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. Does "gadolinium deposition disease" exist as a novel condition? 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 gadoliniumbased 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. Role of chelation therapy in patients exposed to gadolinium-based contrast agent: 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. Conclusion: 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. Clinic...

Iron(III)‐tCDTA derivatives as MRI contrast agents: Increased T1 relaxivities at higher magnetic field strength and pH sensing

“…2.2 | Synthesis of trans-1,2diaminocyclohexane-N,N,N′,N′-tetraacetic acid monoanhydride (tCDTA-MA) 6.53 g (17.9 mmol) of trans-1,2-diaminocyclohexane-N,N,N′,N′-tetraacetic acid (tCDTA) (Carl Roth GmbH, Karlsruhe, Germany) was added to a solution of 12.87 mL (136.2 mmol) acetic anhydride and 2.75 mL pyridine (34.0 mmol). After stirring for 24 h at room temperature under an argon atmosphere, the reaction mixture was filtered and washed with acetic anhydride followed by excess ethyl acetate.…”

“…Furthermore, there is an ongoing controversy about what has been termed gadolinium deposition disease. 6 Although apart from the bones the brain appears to accumulate substantial Gd, it appears not to be the most severely affected organ because even a patient who died of nephrogenic systemic fibrosis had no obvious brain tissue alterations. 4 Thus, other organs and cells, especially of the immune system, should be investigated for evidence of potential gadolinium side effects in the future.…”

“…The occurrence of nephrogenic systemic fibrosis in patients with disturbed kidney function 1 but especially the deposition of gadolinium originating from linear and macrocyclic gadolinium‐based contrast agents (GBCA) in several organs, including, skin, bones, and brain, 2‐5 in patients with normal kidney function resulted in the suspension of less stable linear GBCA, with the exception of 2 liver‐targeted GBCA (gadoxetic acid and gadobenic acid), by the European Medicines Agency in 2017. Furthermore, there is an ongoing controversy about what has been termed gadolinium deposition disease 6 . Although apart from the bones the brain appears to accumulate substantial Gd, it appears not to be the most severely affected organ because even a patient who died of nephrogenic systemic fibrosis had no obvious brain tissue alterations 4 .…”

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“…In this study we introduced MR-labelling onto ultrasound responsive liposomes to better control the timing of the thermally-triggered drug release. For this we synthesised a novel MR-lipid and took special attention to use a macrocyclic Gd 3+ chelator that is considered to be substantially safe and it is widely used in clinical imaging 58 . We assessed the gadolinium retention under challenging conditions, and we evidence for the first time that these iTSL do not suffer significant Gd 3+ leakage under in vivo relevant conditions and time frames.…”

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

“…Als mögliche Therapie der GDD wurde eine Therapie mit intravenös verabreichtem Kalzium oder Zink-Trisodiumpentetat vorgeschlagen, wobei von einer erhöhten Gadolinium-Konzentration im Urin berichtet wurde im Sinne eines Einfangens von retiniertem Gadolinium. Da bislang kein eindeutiger wissenschaftlicher Nachweis der Existenz einer GDD vorliegt, wird vor dem unkritischen Einsatz der Chelator-Therapie gewarnt, da mögliche unerwünschte Wirkungen dieses Vorgehens auftreten könnten [59]. Dieser Meinung schließt sich das BfArM an, welches die GDD nicht als Krankheitsentität anerkennt und somit auch keine therapeutische Intervention empfiehlt (https://www.bfarm.de/SharedDocs/Risikoinformationen/ Pharmakovigilanz/DE/RV_STP/g-l/gadolinium-kernspin-neu.…”