Gadolinium and You: Why Imaging Centers Should Be Concerned
The connection between gadolinium and the disease known as nephrogenic fibrosis syndrome (NFS) presents an urgent and immediate reason for imaging centers to amend MR policies, procedures, and protocols. A flurry of advisories from the FDA, the ACR’s Document for Safe MR Practices: 2007, reports in the peer-review literature, and aggressive activities on the part of the legal community, have put this troubling development front and center for all parties associated with medical imaging. “To the best of my knowledge yes, imaging center cases have been reported,” says Emanual Kanal, MD, Director, MR Services, University of Pittsburgh Medical Center “I don’t think all of these patients are inpatients at all.” NSF/NFD, first observed in 1997, causes thickening and hardening of the skin, usually in the extremities, and occurs in patients with underlying renal disease. It is a progressive, irreversible, and potentially fatal disease. Nearly all known cases of the disease have occurred in patients with at least one known exposure to gadolinium within a few days to months prior to developing the disease. But experts still do not know why some patients develop NSF, or how to prevent NSF from occurring. Nonetheless, the first lawsuit pertaining to NSF and gadolinium was filed in Cleveland by law firm Spagenberg, Shibley & Liber [http://www.spanglaw.com/] on behalf of a retired Cleveland restaurant supplier who claims he contracted NSF from an MRI contrast agent. Other law firms are actively soliciting NSF patients. At-Risk Patients Most experts agree that there is a link, but it is not known whether the causative agent is released free gadolinium, prolonged exposure to abnormally high doses of gadolinium-plus-chelate, the chelate itself or some combination of the above with additional factors related to the biochemistry of patients with severe renal failure, according to the ACR’s Document for Safe MR Practices: 2007. The same document notes that some data suggest that elevated levels of phosphate, iron, zinc, or copper, or the presence of Fosrenol might serve as competitors for the chelate molecule and increase the concentration of free gadolinium in the patient. Compounding the problem is the fact that a history of multiple prior administrations of gadolinium also appears to be associated with an increased incidence of the development of NSF. And the patients most likely to require high dose administration of gadolinium are the very patients most at risk for developing NSF, namely those with underlying renal disease. “We are predominantly seeing this in high-dose, such as double- or triple-dose applications” reports Kanal. “It seems that the number one clinical situation for which high dose gadolinium based MR contrast agents are given is an MR angiographic study.” Because contrast is not typically used in MRA of the brain and a standard dose is typically used in MRA of the carotid arteries, Kanal explains, the patients getting high-dose gadolinium are primarily those who need a non-neurological, body application MR angiogram, such as a peripheral run-off or a cardiac MR examination or MR angiographic evaluation of renal artery stenosis. “So when you stop and think about it, who are the patients that are getting double dose contrast?” asks Kanal. “It’s people who have peripheral artery disease, and patients with renal artery stenosis, and diabetics, and hypertensive patients; in general, frequently it is patients who are likely to have problems with their kidneys. I believe that this is why we are seeing such a predominance of these cases in instances of MR angiography in renal disease patients.” Kanal adds that known renal disease is a predominant indication to send patients for an MR angiogram rather than to CT, as clinicians and radiologists believe that this might protect these patients from developing contrast-induced nephropathy related to iodinated contrast agents. “And it seems that the worse the renal disease and the higher the dose, the better the chance of developing NSF,” he notes. Are All Agents Dangerous? Cases of NFS have been associated with three of the five agents currently approved by the FDA: OmniscanTM, Optimark®, and, Magnevist®. “To go by pure numbers in the peer review literature, to date there have been roughly 55 cases reported to have been associated with a prior Omniscan administration, two reported with a prior Magnevist administration, and none that reported a prior administration of Optimark® or Prohance® or MultiHance®,” notes Kanal. “By the FDA MedWatch database, we found as of April 17 that there were 160 cases reported to the FDA associated with prior Omniscan administration, there were 73 associated with a prior Magnevist administration, and there that were three associated with a prior Optimark administration.” Known confounded cases in which more than one agent had been administered in the days and weeks preceding the establishment of the diagnosis of NSF were intentionally omitted from these data. Further, Henrik Thomsen, MD, reported a review of approximately 150 cases of NSF in which he found that roughly 90% had been preceded by an Omniscan administration. Kanal cautions against drawing hasty conclusions based solely on the number of reported cases associated with each agent, without taking into consideration the agent’s market share. “Those are the five agents available in the U.S. today, but the market shares of these agents are quite different,” explains Kanal. “The precise market shares are hard to come by, but from the best we can tell, it seems quite reliable to say that Magnevist enjoys a double digit percentage of the market share in the States today, with Omniscan running in second place or even a close second place and also possessing a double-digit percentage share of the market today. All of the other agents seem to maintain single digit percentages of the market share.” When viewed in conjunction with market share, the data cast a definite shadow over Omniscan. “Omniscan’s reported NSF-development rate is so significantly higher than that of Magnevist or the other agents, the data are compelling that there may be something uniquely concerning about that agent,” Kanal says. “Because of the uncertainties of the exact relative market shares of Magnevist and Optimark, it is difficult to state with certainty at this time if the incidence rate of NSF development following administration of these agents is higher or lower than the other. The only one that we know seems out of place relative to broadly reliable market share data is Omniscan relative to Magnevist. We have only three agents so far for which cases are reported, but I am not personally convinced at this time that the incidence rate for the others that right now is at ‘zero’ is going to remain at zero.” Patient Selection: Proceed with Caution Numbers aside, most experts are recommending new protocols for patient selection prior to administering any contrast agent containing gadolinium. “I would want to stay away from any agent that may specifically seem to be more associated with NSF than others,” Kanal advises. “The fact is, I would stay away from all of them if I didn’t have to give it. Now, I’m careful about giving any of these agents to anyone with any level of renal disease. If I have a patient with more severe renal disease, I am even more concerned.” The following recommendations were abridged from the ACR’s Guidance Document for Safe MR Practices: 2007: No special treatment is recommended for kidney disease patients with stage 1 or 2 renal disease defined as the presence of kidney damage with GFR > 90 mL/min/1.73 m2, or GFR between 60 and 89 mL/min/1.73 m2, respectively. However, it was advised that as a safety factor alone, it might be prudent to avoid administering particularly Omniscan to any patient with any level of kidney disease in case their renal function might have deteriorated since it was last checked, in the event that acute kidney injury might have developed in the interim. At this time prospectively checking patient renal function, serum creatinine levels, or glomular filtration rates (GFR) prior to MR imaging is not required, nearly all or all NSF patients seem to be stage 4 or 5. This recommendation may well change in the near future as more information is gathered about this issue. Especially for patients with stage 3 renal disease, the potential risk of withholding an MR imaging or angiographic exam could outweigh the potential risk of developing NSF, given the few (if any) NSF patients in this category. Further data are needed to clarify this. Patients with a GFR threshold of roughly 30 mL/min/1.73 m2 or already on dialysis (stages 4 or 5) should be given special consideration (including possible hemodialysis following the procedure especially for patients already on hemodialysis). For patients on hemodialysis, it is recommended that the patient that has undergone contrast-enhanced MRI be immediately transported to the dialysis center and begin a hemodialysis session immediately upon completion of the MR examination for which the gadolinium based MR contrast agent had been administered. An additional hemodialysis should be considered within 24 hours of administration of contrast. For all patients with stage 3, 4, or 5 kidney disease or acute kidney injury (AKI), it is recommended that one refrain from administering any gadolinium agent, unless a risk/benefit assessment for that patient indicates that the benefit of that examination outweighs the risks. Similar reasoning applies to patients with a protected area into which the gadolinium chelates might enter but from which they might not readily clear, such as amniotic fluid. Therefore, caution should be exercised with especially mid- and third-trimester pregnant patients. When risk/benefit assessments warrant administration of gadolinium to patients with stage 3-5 renal disease or AKI, consideration should be given to administering the lowest possible dose that would provide the diagnostic benefit, with half-dose being considered the default standard dose with such patients if clinically acceptable. Studies in those patients should be monitored during the exam and prior to contrast delivery to ensure that the administration of gadolinium is still considered necessary. For patients on chronic peritoneal dialysis or continuous cycler-assisted peritoneal dialysis, there is strong reason to hesitate in delivering these agents. Present data seems to suggest that peritoneal dialysis is essentially entirely ineffective in removing these gadolinium chelates from the body. If gadolinium based MR contrast agents must be delivered even in small doses, it may be wise to immediately initiate hemodialysis in these patients or, alternatively, consider other imaging options in these patients. Administrative Policies and Procedures: Revise for Safe Practices In order to ensure that at-risk patients are not inadvertently administered gadolinium, it is imperative that imaging centers amend their policies and procedures with regard to all MR requests. The following suggestions and recommendations are contained in the ACR Document for Safe MR Practices: 2007. Screen all requests for MR with an additional question inquiring about the presence of kidney disease or dialysis. Patients with stages 3-5 renal disease must have a written order from the radiologist in order to undergo contrast-enhanced MRI or MRA. The name of the patient, the name and specific brand of the contrast, the dose, route and rate of administration should all be explicitly specified on the order, along with the date and signature of the ordering radiologist. Prospective documentation of a risk-benefit assessment for each patient with stage 3-5 renal disease is recommended. All patients with stages 3-5 renal disease should provide informed consent when practical, including a review of known risks and benefits as well as the availability of alternative imaging methods, if any. All gadolinium should be administered only by a radiologist. If a request is made by a non-radiologist to administer gadolinium for off-label use such as intra-arterial administration for vascular assessment in renal failure patients, the request should be made in a written order and prospectively reviewed or approved by a radiologist or a knowledgeable pharmacist. For patients in which NFS has been established, consider avoiding administration of any further gadolinium-based MR contrast agents for any indication. If a new diagnosis of NFS is made, the FDA should be notified through their MedWatch program or by phone (1800 FDA-1088) and that the international NFS registry at Yale University be notified.