An August 1, 2015 article by Richard Dargan, Radiology Society of North America (RSNA), reviewed recent studies that reported finding evidence of gadolinium retention in the brains of patients with normal renal function.  The article, “Radiology Should Take Lead in MRI Contrast Media Use, Research”, also included comments from Emanuel Kanal, M.D., regarding the role radiologists should play in MRI contrast agent research and usage.  Dr. Kanal, a Professor of Radiology at the University of Pittsburgh Medical Center (UPMC), chairman of the American College of Radiology MR Safety Committee from 2002-2012, and chairman of the new American Board of Magnetic Resonance Safety (ABMRS), made his comments in an interview with RSNA News.

Recent research has shown that gadolinium-based-contrast agents (GBCAs) are leaving residual gadolinium in the brains of patients, including patients with normal renal function.  Two regions in particular have been affected: the dentate nucleus and the globus pallidus.  A 2013 study by Kanda et al, first reported finding high signal intensity in those two brain regions on unenhanced T1-weighted magnetic resonance (MR) images that appeared to be related to the increasing cumulative dose of a gadolinium-based contrast agent.  Since then, additional studies have been published which confirmed the increased signal intensity is the result of gadolinium accumulation within the brain. 

Besides hyperintense signals on unenhanced MR images, gadolinium has been detected in brain tissues obtained at autopsy from patients that did not have severe renal disease.  In studies published in Radiology, Kanda et al and McDonald et al reported that gadolinium was detected in all of the postmortem brain tissue specimens of patients that had received multiple doses of a GBCA.  The findings of McDonald, and his colleagues from Mayo Clinic in Rochester, Minnesota, indicate that either the GBCA itself or the free gadolinium ion is somehow able to cross the blood-brain barrier.

Concerns about GBCA safety were first raised in 2006, when it was determined that the disease known as Nephrogenic Systemic Fibrosis (NSF) was caused by gadolinium retained from the GBCAs administered for contrast-enhanced MRIs.  NSF occurred in patients with severely impaired renal function.  Because the GBCA is eliminated primarily via the kidneys, the delayed excretion in those patients caused the GBCA to remain in the patient longer, which resulted in the separation of the GBCA complex.  In other words, the toxic gadolinium ion was left in the patients’ bodies where it triggered a systemic disease process that affected the skin and internal organs.  (See Background on NSF for more details.)

It wasn’t until the first study by Dr. Tomonori Kanda and his colleagues, of the Teiko University School of Medicine in Tokyo, Japan, that the radiology community really started to take notice of what might prove to be a serious safety problem with at least some of the gadolinium-based contrast agents currently being administered for MRIs and MRAs with contrast.

Dr. Kanal was quoted as saying, “NSF is a severe condition, but it applies to only a very small section of the population.  Now we’re talking about patients with normal kidneys.  There are tens of million of patients in the United States alone who are receiving these contrast agents and we don’t at this point know what the significance may be, it any.”

What role should radiologists play going forward?

According to Dr. Kanal, rather than being defensive about the findings, radiologists should take the lead in studying their clinical implications.  He noted that one potentially important area of study is cognitive function in people who received multiple GBCA administrations.

“The question of clinical consequence has to be front and center until we can answer it,” Dr. Kanal said.

Research will seek to determine which of the nine different GBCAs approved by the FDA leave residual gadolinium in the brains of patients.  Recently published studies seem to indicate that it is a problem with the linear GBCAs, but not with the macrocyclic agents.  If so, that would be similar to the findings with NSF.

According to the article, Dr. Kanal said, “The recent findings of gadolinium deposition in the brain have the potential to change the practice of radiology, which would ideally involve a higher profile for radiologists in the selection of MRI contrast.”

Patients might be surprised to hear that, at the institution level, radiologists are not generally involved with decisions about which GBCAs are kept in stock.  Those decisions are made by non-physicians, and are often cost-driven.  With the higher profile envisioned by Dr. Kanal, radiologists could be involved in decisions about which GBCA is used.  They could also have an active role in ensuring that GBCAs are used for MRI only when absolutely necessary.

According to the article, Dr. Kanal believes that the best-case scenario for patients involves a more central role for the radiologist.  “Patients need to know that someone is watching their back and safeguarding their best interests, and the radiologist is in the best position to do that.”

My thoughts   

I applaud Dr. Kanal’s efforts and those of other leaders within the radiology community to investigate the problem of gadolinium retention from GBCAs in all populations of patients, including those with normal renal function.

I hope that new research related to gadolinium-based contrast agent safety will not be limited to findings in the brain.  While retention of gadolinium in the brain is cause for serious concern, it might also be deposited in other areas of patients’ bodies, such as the liver, bones, heart, lungs, and elsewhere.  That is what happened to NSF patients when they retained gadolinium, and it would seem that the same might occur in other patients that retain gadolinium.

I believe all patients will appreciate having someone watching their back as the FDA and radiology community investigate gadolinium-based contrast agents further.  In the meantime, we are still left with the many millions of people who have already received multiple doses of one or more GBCAs.  Patients that have tried to have their symptoms of Gadolinium Toxicity recognized by their doctors are still waiting to be properly diagnosed and treated.  Hopefully someone will step forward soon to help those patients that have already been adversely affected by retained gadolinium from GBCAs.

Sharon Williams

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Dargan, R. S. (2015). Radiology Should Take Lead in MRI Contrast Media Use, Research. Retrieved August 21, 2015, from http://www.rsna.org/News.aspx?id=17022

Kanal, E., & Tweedle, M. F. (2015). Residual or Retained Gadolinium: Practical Implications for Radiologists and Our Patients. Radiology, 150805. http://doi.org/10.1148/radiol.2015150805

Kanda, T., Ishii, K., Kawaguchi, H., Kitajima, K., & Takenaka, D. (2013). High Signal Intensity in the Dentate Nucleus and Globus Pallidus on Unenhanced T1-weighted MR Images: Relationship with Increasing Cumulative Dose of a Gadolinium-based Contrast Material. Radiology, 131669. http://doi.org/10.1148/radiol.13131669

Radbruch, A., Weberling, L. D., Kieslich, P. J., Eidel, O., Burth, S., Kickingereder, P., … Bendszus, M. (2015). Gadolinium Retention in the Dentate Nucleus and Globus Pallidus Is Dependent on the Class of Contrast Agent. Radiology, 150337. http://doi.org/10.1148/radiol.2015150337

Kanda, T., Fukusato, T., Matsuda, M., Toyoda, K., Oba, H., Kotoku, J., … Furui, S. (2015). Gadolinium-based Contrast Agent Accumulates in the Brain Even in Subjects without Severe Renal Dysfunction: Evaluation of Autopsy Brain Specimens with Inductively Coupled Plasma Mass Spectroscopy. Radiology, 142690. http://doi.org/10.1148/radiol.2015142690

McDonald, R. J., McDonald, J. S., Kallmes, D. F., Jentoft, M. E., Murray, D. L., Thielen, K. R., … Eckel, L. J. (2015). Intracranial Gadolinium Deposition after Contrast-enhanced MR Imaging. Radiology, 150025. http://doi.org/10.1148/radiol.15150025