Vol. No.

May 24, 2007

Panel recommends caution in administration of contrast in the wake of gadolinium-related NSF cases
James Brice May 24, 2007

Nephrogenic systemic fibrosis is the train radiologists never saw coming. NSF is a painful, debilitating, possibly fatal skin disorder that has been linked to chelated gadolinium contrast media administered prior to MRI for patients with renal disorder. More than 200 cases have been confirmed worldwide. The ISMRM and ESMRMB convened a special symposium Tuesday at their joint annual meeting to establish the facts of NSF and to render recommendations on how radiologists can best minimize the risk of NSF for their patients. The session was moderated by past ISMRM president Dr. Walter Kucharczyk and scientific program chair Dr. Georg Bongartz. Panelists were: Dr. Shawn Cowper, the Yale University dermatopathologist who has compiled the largest registry of NSF case experience; Dr. Henrik S. Thomsen of Copenhagen University. He also established an early directory and has influenced European Union policy concern contrast use and NSF; Peter Dawson, Ph.D., of the University of London, who has profiled the chemical properties of chelated gadolinium agents; Members of the European Medicines Agency (EMEA), who participated via conference call; and Dr. Harm Peters, a nephrologist from Charité School of Medicine in Berlin.

The FDA turned down an invitation from the ISMRM and ESMRMB to send a representative.



Vol. No. May 24, 2007 A BIG PROBLEM

Chelated gadolinium-related NSF is a big problem, Bongartz said. Radiologists are just beginning to come to grips with its scope, its effect on patients who contract the disease, and the practice modifications needed to assure that what are now clusters of gadolinium-related NSF do not become an epidemic. Cowper has analyzed and confirmed 239 cases. The first was diagnosed in 1999 at Sharp Memorial Hospital in San Diego, California. Cases have been reported from around the world, though clusters have come to Cowper's attention. They account for 199 cases. These clusters arose in Detroit, Michigan; San Francisco and Los Angeles, California; and Jackson, Mississippi. All cases have involved patients with renal dysfunction, he said. According to Thomsen, 59% of patients with gadolinium-related NSF were not on dialysis when they developed NSF. Thomsen also maintains an NSF registry. No new cases have appeared in Denmark since the EMEA directive against gadodiamide use in renal failure patients, he said. Thomsen has documented 25 European cases. Based on personal experience and his reading of the medical literature, he estimated that 1000 people have developed gadolinium-related NSF. He calculates that 200 have died. Thomsen said that 3% to 7% of patients with renal failure will develop the symptoms of NSF after Omniscan administration. The U.S. Centers for Disease Control was called in after the first 25 cases were reported, Cowper said. It investigated 19 early cases at Sharp Memorial. CDC investigators used a case-control study, with three matched controls per case, to identify that no medication, toxin, infectious agent, or therapy was a clear cause of the disease. "They felt that NSF patients were more likely to reflect poor renal function post-transplant, but they really had nothing else to say," Cowper said. EUROPEAN AGENCY ENACTS RESTRICTION

The EMEA, a unit of the EU, intervened Feb. 7 when it introduced a strict contraindication for the use of Omniscan in patients with severe renal failure and ordered a warning for all gadolinium products. The ban applies to the 27 states of the EU plus Norway and Iceland. The revised labeling for Omniscan added a warning that NSF has been observed in patients with moderate renal failure. It noted that hemodialysis removes gadolinium from the body, but that there is no evidence that it prevents development of NSF. The EMEA is pursuing an ongoing review. It is attempting to clarify the evidence and risk potential for the gadolinium classes and to implement additional measures to minimize risk, according to Pano Tsintis, the agency's head of the sector for pharmacovigilance and postauthorization safety and efficacy.


Vol. No. May 24, 2007 European physicians and government officials agree there's a link between chelated gadolinium contrast and NSF cases. Most cases have allegedly occurred after the patient underwent an MRI procedure enhanced with Omniscan (gadodiamide). A small proportion arose after Magnevist (Gd-DTPA) administration. Anecdotal evidence suggests that other agents are involved as well. Symptoms usually appear within two months of the procedure, Thomsen said. WEAK CHEMICAL BONDS

Pharmacologists say that chemical release of the gadolinium element from its protective array of chelator compounds most likely led to the cases of NSF. Gadolinium is an element and falls into the class of highly toxic heavy metals called lanthanides, Dawson said. Raw gadolinium is highly toxic when ingested. MR contrast agents approved by the FDA and the EU were produced from a chemical core of gadolinium encapsulated in chelator compounds that insulate patients from the element's otherwise toxic effects. The chelators are toxic themselves, however, leading some chemists to wonder whether the NSF stems from gadolinium or chelators, which would tend to absorb metals, such as iron, when released. The bond holding chelators to gadolinium weakens when it encounters a low-pH environment, according to Dawson. "Gadolinium chelates do possess nephrotoxic potential, and may be the cause of NSF," he said. "The case is very strong." The chemical composition of Omniscan (gadodiamide) involves the weakest conditional stability in this contrast class, Dawson said. Magnevist (Gd-DPTA) has the third weakest conditional stability characteristic. Dotarem (Gd-DOTA), an agent that is not authorized for sale in the U.S., features the strongest chelator bonds in this pharmaceutical class. EARLY EVIDENCE OF A PROBLEM

Hanns-Joachim Weinmann, Ph.D., the director of contrast media research at Bayer Schering Pharma, admitted at a microphone during the question and answer session that he and fellow contrast agent researchers have known about a potential problem since the 1980s. Animal studies showed that a few mice retained gadolinium and exhibited NSF-like symptoms. Such results were reported but never published. The firm that sponsored the research no longer exists, and its scientists have dispersed, he said. The tide of opinion in the 1980s among radiologists also discouraged anyone from taking the findings seriously. MR gadolinium contrast was considered extremely safe, especially compared to the ionic CT contrast media that at the time were infamous for inducing nephrotoxic reactions. Weinmann was a codeveloper of Magnevist, the first MRI contrast medium applied in clinical practice. It was patented in 1981 and became the first agent to secure FDA clearance.



Vol. No. May 24, 2007

Among the well-documented NSF cases in Cowper's registry, gadodiamide (Omniscan) was involved in 85%. Magnevist, which accounts for about half of all clinical MR contrast sales, is involved in about 10% of the documented NSF incidents. Other agents have been implicated, but most of those cases are anecdotal, Cowper said. Still, it can be argued that chelated gadolinium is not a mechanism for NSF, Dawson said. Some NSF patients have no proven history of gadolinium chelate exposure. Some have undergone gadolinium-contrast enhanced MRI in the past without ill-effects. Gadolinium has not been shown to be present in the skin biopsies of all cases, and gadolinium in the skin may be a so-called passenger and not a cause, he said. The panelists generally agreed that an accurate estimation of morbidity and mortality are impossible at this point. It is known that 20% of patients with end-stage renal disease will die within two years because of their underlying condition. It is not known to what extent the additional physiological effects of the NSF will contribute to that death rate. A HORRIBLE DISEASE

It is known that NSF is a horrific form of sclerosis. The victim's skin hardens and loses flexibility. Hand and finger mobility is lost. Ankle contractures are seen in 35% of patients, often leaving them wheelchair-bound. Elbow contractures appear in 29%. Thin dermal plaques often appear on the skin of the lower extremities, sometimes evolving into red-brown shiny papules or reticulating into amoeboid plaques. Deep cobblestoning of the thighs may appear or subcutaneous banding of the arms. Lower extremity edema is frequently evident. A few NSF patients have asked to halt dialysis, opting to die rather than live with the NSF symptoms. Documenting the problem is difficult, Cowper said. Physicians have been slow to come forward with cases to add to the registries. Medical records are incomplete, especially concerning the precise formulation administered to these patients. Records often note only that "gadolinium" was administered. ADVICE FOR RADIOLOGISTS

So, what can practicing radiologists do? According to Dawson, a screen before patients are imaged for diabetes or hypertension should include information on whether they are taking nephrotoxic drugs and whether they have a history of gout, proteinuria, or renal surgery, Dawson said. For such patients, noncontrast MRI or MSCT should be considered as an alternative. Peters recommended strong, narrow indications for gadolinium contrast. European radiologists can use Dotarem instead of Omniscan or Magnevist. When gadolinium is necessary for patients with a history of renal failure, he suggests radiologists should administer the lowest possible dose. They should correct for acidosis and perform dialysis in three sessions over three days following MRI. Most panelists agreed that more data are needed before they were willing to frame recommendations concerning MR contrast dosage. Opinions concerning the value of hemodialysis were also mixed. Some


Vol. No. May 24, 2007 panelists supported using it soon after contrast-enhanced imaging for patients with renal failure, and others said it is too soon to venture an opinion. Cowper cautioned radiologists not to overreact. "As far as we know, gadolinium administration in patients with normal renal function is OK. I would not change it at this point," he said. For more information, examine these stories from the Diagnostic Imaging archives: Europeans urge caution with all gadolinium agents Skin disease linked to gadolinium prompts warning Report from ECR: Scottish researchers probe link between gadolinium and nephrogenic systemic fibrosis New ACR guidelines warn against Omniscan MR contrast use in patients with any kidney disease



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