Numerous studies showing evidence of gadolinium retention in the brains of MRI contrast patients are building momentum for an industry-wide reassessment of the current usage of gadolinium-based contrast agents. A new editorial published in Radiology authored by Emanuel Kanal, MD, of the University of Pittsburgh Medical Center; and Michael Tweedle, PhD, of The Ohio State College of Medicine, advocates for increased accountability and oversight by radiologists regarding the administration of these agents. Kanal, a nationally recognized leader in the area of MRI safety, spoke with Health Imaging for an exclusive interview regarding this new evidence of gadolinium retention and its potential impact on diagnostic imaging and patient safety.
HI: When did this issue of gadolinium retention in contrast MRI patients with normal kidney function first begin to come to light?
EK: We first heard from Kanda in 2014 (Radiology 2014;270:834–841) that there was T1-shortening in the brain. At that point we didn't know the cause of it: Is it gadolinium, or is it something else? If it is gadolinium, in what form? Is it gadolinium that has dissociated, which has its own adverse event potential, or is it gadolinium in its initial form just like you had injected it that somehow is accumulating in these tissues? When Kanda first published in 2014 we didn't know if it was the contrast agent Omniscan or Magnevist, or how much his patients had received of each one.
HI: And those patients began to show signs of gadolinium retention.
EK: Yes, and remember, as far as we knew, for patients with normal kidneys, you give the contrast, it does its thing, and then it gets excreted: There was either nothing left in the body after a while, or anything left in the body was of such trivial amount that it should be of no clinical consequence. Now we're hearing that, even in patients with normal kidneys, the magnetic behavior of these locations in the brain, as evidenced by non-enhanced MRI, is changing—it’s different from what it's supposed to be. So that's a surprise, but we don't know if there's any clinical consequence to that, we just know that it's not expected.
HI: Is there any indication that specific agents may be more prone to leaving behind residual contrast than others?
EK: Well in 2015, Kanda published another study showing that there was no such T1-shortening seen in patients who had received Prohance, a macrocyclic agent, but that we did see this T1- shortening in patients who had received Magnevist, a linear agent. So now, this is very much shades of Nephrogenic Systemic Fibrosis (NSF). Once again, we're seeing differentiation among the agents, in a way that seems to stratify in a manner similar to how they had differentiated along NSF concerns.
HI: So it could be possible that linear agents, and not necessarily macrocyclics, are causing all the problems?
EK: Well that may be one possibility, but we don’t yet have the science or knowledge to support such a generalization, and I am hesitant to try and automatically glibly apply it that way.
HI: What does all of this mean for the future of contrast-enhanced MRI?
EK: Well that's the interesting part: One of the co-authors of the recently published Mayo Clinic study has said something to the effect of ‘Well, no one has ever shown that this is harmful.’ That's true. But at the same time, no one has ever studied it to date, so how could they show whether it's harmful or not? Let's look at this the way a patient would: Gadolinium is a known toxin to humans. We would never put a heavy metal, a lanthanide, into a human. The only reasons we do is because number one, we chelate it, and thereby make it safer; number two, we expect to have substantial benefit to this patient by doing so; and number three, we expect that the body will get rid of it. Under those assumptions, it had been approved. Now, it is confirmed that a very small amount of this material is dissociating. It is also confirmed that a very small amount of it is remaining in the body for years and years and years after it was last injected.
HI: What do you think the response should be from the medical industry in light of these findings?
EK: Right now it seems as if we're being defensive. It's as if we're saying ‘don't take away my drugs, these are such very valuable, useful drugs.’ Of course they're valuable—they're exquisitely powerful, they have immensely aided our ability for diagnostic sensitivity and specificity. No one is going to take them away. But the time has come to start asking ourselves about the agents that show retained gadolinium at a higher rate than other agents. If there's no significant competitive advantage to using them, should we still be administering them? The real question is not ‘are we going to lose our agents?’ The real question is which agents should we be using? And what are you going to do if the ones that seem to stay in the body—the same contrast agents that are also most associated with NSF—drop their prices dramatically. What do you do now? Can you defend making decisions today as to which agents to use based on cost alone?
HI: So you disagree with the idea that because no harm has been shown to result from this retained gadolinium, these findings shouldn’t be cause for alarm?
EK: I maintain that the burden of proof is upon the individual who's selecting that agent. You want to use it? Don't tell me that it's never been shown to be unsafe, you show me that have a reason to suggest that it is safe to use that agent. If you want to use a gadolinium-based contrast agent today, we need to consider such factors as when we use it, on whom we use it, how much we use, and which one we use each and every time. Our patients would demand that of us.
HI: Speaking of patients, what do you think they would say about how these decisions are being made regarding gadolinium-based contrast agents?
EK: What do you think the patient is going to want you to inject them with? The agent that you found is least expensive for your hospital, even though it may have a higher rate of residual or retained gadolinium, even though they don't know whether it is or isn’t harmful, even though it's a heavy metal and it's not something we want in humans? If patients were free to choose, they would almost certainly select an agent which would leave the smallest amounts in the human, even if today we do not yet know if these levels of residual/retained gadolinium is in any way clinically significant or toxic to humans. This would be especially the case for those populations who are most likely to be exposed to repeated doses and/or multiple repeat contrast enhanced MR examinations, such as certain pediatric patients, patients with metastatic disease to the CNS, patients with multiple sclerosis, etc.
HI: In your estimation, how many of the patients who receive one or more of the roughly 10 million contrast injections in the U.S. each year could have retained gadolinium in their bodies?
EK: There is the potential for some level of gadolinium retention for essentially 100 percent of those patients who receive contrast for an MR examination.
HI: How can we prevent overuse of contrast agents in MRI patients?
EK: For every single contrast patient, you have to by asking yourself the question, ‘Am I going to give contrast and why? Which one will I give, how much will I administer?’ At the University of Pittsburgh Medical Center, I do emergency neuroradiology. In the last few months, I have been keeping records and reviewing, and I've been cancelling roughly 20-25 percent of contrast requested MRs with the blessing of the referring physician after I contact them and ask them ‘tell me what you're looking for,' and then I say ‘I hear what you are saying: we don't need contrast for that diagnostic evaluation, we can do that without it.' Then they say, ‘Great, fantastic, go ahead.’ Now that's an extreme exception. Radiologists—at least today—do not typically do that. But it's time for radiologists to step up to the plate and take care of their patients, and before every contrast agent is administered, a radiologist should review the indications to make sure it's appropriate, and then decide what's being used, how much is being used and if it should be used at all, just like all physicians have to do with any other prescription drug. In my institution, I have initiated that no patient gets contrast on my watch without my first prospectively approving it on every one of my patients. And we advised that approach in the 2007 ACR Guidance Document for MR Safe Practices—that radiologists have to approve the administration of gadolinium-based contrast agents on all of their patients.
HI: If gadolinium deposits in contrast patients are confirmed to be harmful from a clinically significant standpoint, then what happens next?
EK: Well the next step after that is to see if it's seen with all the GBCAs or are there agents that are not going to show that problem. And we start to stratify the risks based on which agents you get. Remember, we diagnostically desperately need these drugs, and want to be sure that we don’t discard all of them for a finding that may be seen in, or predominantly seen in, only a few.
HI: What’s the best way to balance these potential risks with the benefits of contrast-enhanced imaging?
EK: The public has assigned that responsibility of the risk-benefit assessment to their physician. In this case, the physician who would be expected to have the education, training, background, and expertise to make such an assessment is certainly not the referring physician—it is the diagnostic radiologist. They expect that you appropriately calculate the potential benefit to [the patient] by undergoing a test or a procedure of some sort, versus the potential risk of undergoing that same procedure, and recommend that a potential benefit outweighs the potential risk, and that you've done everything you possibly could to reasonably decrease the risk. For example: We have multiple agents to choose from. If they appear to be essentially interchangeable in some areas, and they appear to be not interchangeable in this area, then the question would be brought to the forefront: Why would you use this agent? Why don't you use one of the others that doesn't seem to suggest that this finding is there, even if we don't know for sure today whether it is or is not harmful? The best way to approach this, ironically, is from the point of view of the patient. Because if anything ever happens, I guarantee you it will be solved in the courtroom, and the courtroom has only one concern: What was the patient's reasonable expectation? Because it is the patient's expectation that defines what we need to consider in the practice of medicine.
HI: With everything that we know right now about these gadolinium contrast agents, what would you advise medical professionals ordering and administering these tests?
EK: Reassess for every single patient that has an order for an MR examination with contrast. Every one of them needs to be prospectively reviewed by a radiologist. The decisions have to be made about, number one, is it an appropriate indication for contrast? If it is, which agents should you be using, and how much of that agent should you be using? That needs to be considered in 100 percent of cases in which patients are receiving contrast. The data at this point do not permit us to ignore that consideration. We cannot leave the decision as to whether or not it is appropriate to administer contrast to a given patient only to the referring physician when the diagnostic radiologist is the one far better suited to assess the true risks and benefits of such an administration. Further, we cannot leave the decision as to which agents to be used to several people sitting in a room with pocket protectors. To relegate that to a financial decision only based on best price alone is something that at this stage I believe cannot be any longer condoned.
(Comments edited for length and clarity.)