Gadolinium-based contrast poses lethal threat to CKD patients

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Evidence is mounting that gadolinium-based MR agents can cause nephrogenic systemic fibrosis (NSF) in patients with chronic kidney disease (CKD)—something radiologists need to put on their radar screen. Such was the message of the panel discussion on Monday at the 93rd annual meeting of the Radiological Society of North America (RSNA) this week in Chicago. The panel discussion, “Gadolinium Toxicity: Nephrogenic Systemic Fibrosis/Nephrogenic Fibrosing Dermopathy—A Lethal Threat to Patients with Renal Insufficiency,” was moderated by Emanuel Kanal, MD, FACR, FISMRM, director, magnetic resonance services and professor of radiology and neuroradiology, department of radiology, University of Pittsburgh Medical Center.

“We have been relatively confident all along that increasing the administered dose of a gadolinium-based MR contrast agent (GBMCA) for patients with severe or end-stage chronic kidney disease (CKD) increases the likelihood of a patient developing NSF. However, relatively new data from several more recent articles in the peer-reviewed literature now strongly suggest that cumulative doses of administered GBMCA (over an as yet undefined time period, possibly even a lifetime) seems to play a role in determining not only the likelihood of developing NSF, but also the severity of the clinical case of NSF that will be developed/experienced,” Kanal said. “This suggests that radiologists may likely imminently have to start grappling with the concept of identifying total, possibly lifetime, prior-administered GBMCA dosages to patients with significant renal disease prior to deciding on whether or not to administer any GBMCA in the future and, if so, which one and how much to administer.”
 
Providing the nephrology input at the special session was Georges Saab, MD, assistant professor of clinical medicine, University of Missouri, Columbia, while Leonard Lucey, JD, legal counsel for the American College of Radiology, addressed the key legal considerations. Lucey was not the only attorney present; Kanal said he recognized at least three other attorneys in the audience representing both sides of the issue.

“With the tremendous interest I have seen from attorneys representing both sides of the NSF cases and with the active advertising for NSF clients by plaintiff attorneys, I thought it would be interesting for the course attendees to get a legal analysis of where we stand today,” said Kanal. Currently, there are lawsuits in progress with more likely to follow with more information coming available.

The potential product liability issue with the possibility of a medical malpractice issue is sure to get the attention of radiologists. Kanal pointed to the Sept. 12 joint letter from pharmaceutical companies distributing FDA-approved MR contrast agents that advised providers of a potential association with the administration of any GBMCAs to patients with severe or end stage chronic renal disease and the subsequent development of NSF. In Lucey’s presentation, he explained that this seemed to shift much of the legal liability from the pharmaceutical firms to the physicians administering these agents. Kanal noted that in subsequent discussions with many who attended this session, this observation “seems to have proven quite eye-opening to most radiologists in attendance.”

As of last week, more than 450 NSF cases had been reported to the FDA MedWatch reporting system. 

The greatest risk is to patients with significant renal disease, most especially those with stage 5 CKD, and perhaps some with stage 4 CKD. Additionally at risk are patients with acute renal failure/acute kidney injury who receive any GBMCA, but especially those who receive a linear GBMCA and, it seems, especially those who receive Omniscan. Approximately 3 to 7 percent of stage 5 CKD patients who receive a higher dose of Omniscan have been diagnosed with NSF. Other cases have been reported with the administration of Magnevist or Optimark, though not as many as those who reportedly received Omniscan. Only one report may be tied to repeated high dose Prohance and there are no cases related to having received only Multihance. 

“Gadolinium has been observed in NSF patient tissue biopsies as long as at least 3 years subsequent to that patient's most recently recorded administration of a GBMCA,” said Kanal. The likely mechanism setting off NSF in renal disease patients is the theory of transmetallation—the separation over time of the gadolinium ion from its ligand in the administered chelated complex while still in the human.

Currently, 30 to 40 percent of MR exams involve the use of contrast. Since more than 25 percent of Americans over age 70 have GFR values less than 59, and they make up a large portion of the MR population, there is potential risk especially in that demographic group. 

Kanal said the message of risk needs to get out to the radiologists. The May 23 public health advisory from the FDA requesting a black box warning fell short because didn’t differentiate between contrasts. “We believe that considering the risk to be the same among all the GBMCAs is ill-advised and not supported by the data available today,” he said. “Although much of the data available today is circumstantial at best, considering the significant amount of such circumstantial data available today and the overwhelming majority of Omniscan-associated cases reported today worldwide, together with a plausible theory to explain this association, with the lack of other solid data to demonstrate otherwise, prudence dictates that we avoid the administration of Omniscan to renal disease patients at this time.”

The FDA remains the only international regulatory body or agency that does not clearly differentiate apparent relative risks among the various GBMCAs available today for NSF development in renal disease patients he added. Both the European and Japanese societies have specifically contraindicated Omniscan and Magnevist in stage 4 or 5 CKD patients.  The agency did issue a black box warning that stated that NSF may result from administration of any of these GBMCAs, but does not differentiate among relative risks from these agents.”

Noting the seriousness of the issue, recently the department of radiology at the University of Pittsburgh Medical Center proactively drafted a letter to all its physicians explaining new screening guidelines for their patients to help educate them and reduce the incidence of contrast induced nephropathy (for iodinated contrast administrations) and NSF (for GMBCA administrations). The healthcare facility is now applying screening guidelines similar to the ACR MR safety committee's renal disease screening guidelines to all patients who were to undergo a contrast enhanced CT or MR examination to determine who might require a GFR assessment prior to administering a contrast agent to them. In the ACR Document for Safe MR Practices: 2007, the organization recommends starting to administer GBMCAs with caution to stage 3, 4, or 5 CKD patients, (while the FDA recommends caution in stages 4 and 5).

 “Since there are essentially no environmental exposures to gadolinium for humanity today, if we find gadolinium in an NSF patient tissue biopsy, that means that we, as radiologists, are responsible for having placed it in this patient,” said Kanal. “If it can ever be shown that there is a truly causative relationship between GBMCAs and NSF in these patients, radiologists will play the critical pivotal role in preventing any future cases from ever developing.”

Kanal will be speaking on this hot topic during the plenary session, “Intravenous Contrast Agents for CT and MR Imaging: Predicting and Preventing Adverse Effects” on Friday. The session begins at 12:45 p.m. in the Arie Crown Theater.