Editorial: Gadolinium retention should spur reevaluation of contrast use

As more research suggests gadolinium-based contrast agents (GBCAs) may remain in the brain for years after a contrast MRI, an editorial in Radiology has called for radiologists to rethink the appropriate use and indications of these agents while more studies are conducted to assess the long-term clinical effect, if any, of lingering gadolinium retention.

“At this stage, we now have clear evidence that the administration of various GBCAs results in notably var­ied levels of accumulation of residual gadolinium in the brain and bones of patients, even those with normal renal function,” wrote Emanuel Kanal, MD, director of magnetic resonance services and professor of radiology and neuroradiology at the University of Pittsburgh Medical Center; and Michael F. Tweedle, PhD, the Stefanie Spielman Professor of Cancer Imaging at The Ohio State University. “What we still do not know is the clinical significance, if any, of this observation. The present data now con­firm that long-term multi-year residual gadolinium at these observed levels is a reality for some, but not all, of the GBCAs.”

GBCAs have been used in diagnosis and treatment guidance for more than 100 million patients worldwide in the past 25 years. While gadolinium on its own is toxic, GBCAs bond the heavy metal with chelating agents to control distribution.

While GBCAs are generally considered safe and the early assumption was that all gadolinium was cleared from the body after an exam, research over the last decade has revealed patients with severe kidney disease could develop nephrogenic systemic fibrosis (NSF) from elevated levels of gadolinium. The latest research showing gadolinium in the brain in patients with no history of kidney disease represents a new cause for concern.

Evidence of gadolinium in the brain

Kanal and Tweedle highlighted a few recent studies that have raised questions about residual gadolinium concentrations in the brains of patients following contrast MRI. Japanese researchers led by Tomonori Kanda, MD, PhD, of Hyogo Cancer Center, first showed a connection between abnormal T1 shortening in the brains of patients and repeated prior administration of GBCAs gadopentetate dimeglumine and/or gadodiamide in a study published last year. A greater number of previous contrast administrations resulted in a higher degree of observed intracranial T1 shortening.

Earlier this year, a separate study from the Mayo Clinic in Rochester, Minn., showed gadolinium deposits in postmortem tissue samples from the brains of 13 patients who had undergone four or more MRIs using a GBCA.

Results from a third study, conducted by researchers at the University of Heidelberg Medical Center in Germany, suggested abnormal T1 shortening and thus gadolinium retention was related to the specific class of GBCA used. GBCAs come in either a linear or macrocyclic molecular structure. Gadolinium is bound more tightly to the chelating agent in macrocyclic GBCAs compared to linear GBCAs, suggesting there is less of a chance of free gadolinium being released using a macrocyclic agent. The Heidelberg study featured two groups of 50 patients who had undergone scans exclusively with linear or macrocyclic agents, and an increased MRI signal intensity was indeed found in specific brain regions in the linear group, but not the macrocyclic group.

Changing course

“These provocative findings cause us to reconsider what we know and what we need to learn to better care for our patients,” wrote Kanal and Tweedle. They likened the current moment to the realization in 2006 that there was a relationship between NSF and GBCAs in patients with significant kidney disease. Research then led to permanent changes in product labeling and prescribing information of GBCAs, as well as screening of patient renal function before use.

A new approach may once again be in order given the developments with regard to gadolinium retention in the brain. “We must first and foremost confirm that the requested contrast material–enhanced MR examination is truly indicated,” wrote Kanal and Tweedle. “We must now also consider the unknown risks of previously unanticipated residual gadolinium in our decisions as to which agent to administer, how much to administer, and whether to administer it at all.”

While it will be a challenge, they called for more research to determine whether any toxic effects accompany residual gadolinium in the brain or other organs, including studies of cognitive impact. While GBCAs are extremely valuable, their safety must be confirmed, they wrote.

“Our use of these and other exogenous agents has always been guided by risks and benefits, and new knowledge will inevitably affect both the numerator and the denominator of the equation. Of all of the possible endings to this story, one of the worst would be for us to unnecessarily deprive our patients of crucial, even life-saving, medical data from GBCA-enhanced MR imaging. Another would be for us to ignore these new findings and continue prescribing them as we have until now, without change.”