How safe are gadolinium agents?,

Stability of gadolinium-based contrast agents depends on structure. Low stability is linked to nephrogenic systemic fibrosis and gadolinium presence.

Since the 1980’s gadolinium-based contrast agents (GBCAs) have been used in MRI to aid diagnosis. Meanwhile around 300 million patients worldwide have received GBCA. The strong paramagnetic properties of gadolinium make it an excellent contrast agent. However, the free gadolinium ion (Gd+3), a heavy metal ion, is toxic for the body. To prevent toxicity, gadolinium is chelated with a ligand. The dissociation of gadolinium from the chelate depends on the kinetic and thermodynamic stability as well as the stability against competing ions. Macrocyclic agents have a higher stability than linear agents.

Nephrogenic systemic fibrosis

In 2006 first reports of the association between nephrogenic systemic fibrosis (NSF) and GBCAs appeared. NSF can progress to a debilitating disease and is potentially fatal. Grobner et al. reported that GBCAs can trigger NSF in patients suffering end stage renal failure. Castillo noted that “at the time it was common to give triple doses.” Patient related risk factors for the development of NSF include severe renal insufficiency. Hence, administration of GBCAs to patients with impaired renal function in clinical departments became restricted. In 2010 an EMA report addressed the issue of NSF risk and GBCA. Linear GBCAs were considered to pose a high risk for NSF. Castillo added, that “macrocyclic GBCAs on the other hand were considered to be quite safe”.

Gadolinium presence

In 2014, Kanda et al. reported on the occurrence of T1 hypersensitivities in the brain tissue of patients with normal renal function who had received multiple doses of GBCAs. The T1 hypersensitivities were linked to the presence of gadolinium in the brain. However, any clinical significance of this finding has not been demonstrated to date. Currently it is thought that the degree of gadolinium presence depends on the GBCA class. In particular, linear GBCAs are associated with T1 hypersensitivities and gadolinium presence in the brain. The current literature suggests that macrocyclic GBCAs do not cause T1 hypersensitivities. This is reflected in the current EMA recommendations (2017) on GBCAs: The whole body marketing authorizations of linear GBCAs gadodiamide (Omniscan™), gadopentetic acid (Magnevist®), gadobenate (MultiHance®) and gadoversetamide (OptiMark®) should be suspended in the EU. In contrast, no such restrictions were imposed on macrocyclic GBCAs.

Clinical significance

T1 hypersensitivities and gadolinium presence in the brain has been observed in the brain area of dentate nucleus, which is responsible for planning, initiation and control of voluntary movement. Recently, results of a study investigating the occurrence of cerebellar symptoms after serial administration of a macrocyclic GBCA were published. No sign of cerebellar toxicity was found. “Further prospective research is required to confirm these results”, Castillo added.

Castillo recommended that radiologists should observe the following basic rules: avoid GBCAs when not necessary, review protocols regularly and move away from double dose. Above all “the guidelines should be followed and applied as necessary”, Castillo concluded.

Conclusion

Stability is a key parameter of GBCAs. NSF and gadolinium presence in the brain are predominantly associated with the less stable linear GBCAs. The mechanism of gadolinium presence is unclear, and any potential clinical significance of this finding has not been demonstrated, and should continue to be researched.

Questions

Castillo was asked where he would see the GFR for which Gadovist® is safe. According to the ESUR guidelines Gadovist® can be used in patients with GFR ≥30, Castillo replied.