Panel recommends caution in administration ofcontrast in the wake of gadolinium-related NSFcasesJames BriceMay 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 administeredprior 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 toestablish the facts of NSF and to render recommendations on how radiologists can best minimize therisk of NSF for their patients.

The session was moderated by past ISMRM president Dr. Walter Kucharczyk and scientific programchair Dr. Georg Bongartz. Panelists were:

Dr. Shawn Cowper, the Yale University dermatopathologist who has compiled the largest registryof NSF case experience;

Dr. Henrik S. Thomsen of Copenhagen University. He also established an early directory and hasinfluenced European Union policy concern contrast use and NSF;

Peter Dawson, Ph.D., of the University of London, who has profiled the chemical properties ofchelated 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.

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A BIG PROBLEM

Chelated gadolinium-related NSF is a big problem, Bongartz said. Radiologists are just beginning tocome to grips with its scope, its effect on patients who contract the disease, and the practicemodifications needed to assure that what are now clusters of gadolinium-related NSF do not become anepidemic.

Cowper has analyzed and confirmed 239 cases. The first was diagnosed in 1999 at Sharp MemorialHospital in San Diego, California. Cases have been reported from around the world, though clustershave 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 patientswith renal dysfunction, he said.

According to Thomsen, 59% of patients with gadolinium-related NSF were not on dialysis when theydeveloped NSF. Thomsen also maintains an NSF registry. No new cases have appeared in Denmarksince 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 themedical literature, he estimated that 1000 people have developed gadolinium-related NSF. He calculatesthat 200 have died.

Thomsen said that 3% to 7% of patients with renal failure will develop the symptoms of NSF afterOmniscan administration.

The U.S. Centers for Disease Control was called in after the first 25 cases were reported, Cowper said. Itinvestigated 19 early cases at Sharp Memorial. CDC investigators used a case-control study, with threematched controls per case, to identify that no medication, toxin, infectious agent, or therapy was a clearcause of the disease.

"They felt that NSF patients were more likely to reflect poor renal function post-transplant, but theyreally 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 useof Omniscan in patients with severe renal failure and ordered a warning for all gadolinium products. Theban 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 withmoderate renal failure. It noted that hemodialysis removes gadolinium from the body, but that there isno evidence that it prevents development of NSF.

The EMEA is pursuing an ongoing review. It is attempting to clarify the evidence and risk potential forthe gadolinium classes and to implement additional measures to minimize risk, according to PanoTsintis, the agency's head of the sector for pharmacovigilance and postauthorization safety and efficacy.

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European physicians and government officials agree there's a link between chelated gadolinium contrastand NSF cases. Most cases have allegedly occurred after the patient underwent an MRI procedureenhanced with Omniscan (gadodiamide). A small proportion arose after Magnevist (Gd-DTPA)administration. Anecdotal evidence suggests that other agents are involved as well. Symptoms usuallyappear within two months of the procedure, Thomsen said.

WEAK CHEMICAL BONDS

Pharmacologists say that chemical release of the gadolinium element from its protective array ofchelator compounds most likely led to the cases of NSF. Gadolinium is an element and falls into theclass 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 EUwere produced from a chemical core of gadolinium encapsulated in chelator compounds that insulatepatients from the element's otherwise toxic effects. The chelators are toxic themselves, however, leadingsome chemists to wonder whether the NSF stems from gadolinium or chelators, which would tend toabsorb metals, such as iron, when released. The bond holding chelators to gadolinium weakens when itencounters a low-pH environment, according to Dawson.

"Gadolinium chelates do possess nephrotoxic potential, and may be the cause of NSF," he said. "Thecase is very strong."

The chemical composition of Omniscan (gadodiamide) involves the weakest conditional stability in thiscontrast class, Dawson said. Magnevist (Gd-DPTA) has the third weakest conditional stabilitycharacteristic. Dotarem (Gd-DOTA), an agent that is not authorized for sale in the U.S., features thestrongest 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 agentresearchers have known about a potential problem since the 1980s. Animal studies showed that a fewmice retained gadolinium and exhibited NSF-like symptoms. Such results were reported but neverpublished. The firm that sponsored the research no longer exists, and its scientists have dispersed, hesaid.

The tide of opinion in the 1980s among radiologists also discouraged anyone from taking the findingsseriously. MR gadolinium contrast was considered extremely safe, especially compared to the ionic CTcontrast media that at the time were infamous for inducing nephrotoxic reactions. Weinmann was acodeveloper of Magnevist, the first MRI contrast medium applied in clinical practice. It was patented in1981 and became the first agent to secure FDA clearance.

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Among the well-documented NSF cases in Cowper's registry, gadodiamide (Omniscan) was involved in85%. Magnevist, which accounts for about half of all clinical MR contrast sales, is involved in about10% of the documented NSF incidents. Other agents have been implicated, but most of those cases areanecdotal, Cowper said.

Still, it can be argued that chelated gadolinium is not a mechanism for NSF, Dawson said. Some NSFpatients have no proven history of gadolinium chelate exposure. Some have undergonegadolinium-contrast enhanced MRI in the past without ill-effects. Gadolinium has not been shown to bepresent in the skin biopsies of all cases, and gadolinium in the skin may be a so-called passenger and nota cause, he said.

The panelists generally agreed that an accurate estimation of morbidity and mortality are impossible atthis point. It is known that 20% of patients with end-stage renal disease will die within two yearsbecause of their underlying condition. It is not known to what extent the additional physiological effectsof 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. Handand finger mobility is lost. Ankle contractures are seen in 35% of patients, often leaving themwheelchair-bound. Elbow contractures appear in 29%. Thin dermal plaques often appear on the skin ofthe lower extremities, sometimes evolving into red-brown shiny papules or reticulating into amoeboidplaques. Deep cobblestoning of the thighs may appear or subcutaneous banding of the arms. Lowerextremity edema is frequently evident. A few NSF patients have asked to halt dialysis, opting to dierather than live with the NSF symptoms.

Documenting the problem is difficult, Cowper said. Physicians have been slow to come forward withcases to add to the registries. Medical records are incomplete, especially concerning the preciseformulation 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 fordiabetes or hypertension should include information on whether they are taking nephrotoxic drugs andwhether 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 useDotarem instead of Omniscan or Magnevist. When gadolinium is necessary for patients with a history ofrenal failure, he suggests radiologists should administer the lowest possible dose. They should correctfor 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 recommendationsconcerning MR contrast dosage. Opinions concerning the value of hemodialysis were also mixed. Some

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panelists supported using it soon after contrast-enhanced imaging for patients with renal failure, andothers 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 wouldnot 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 systemicfibrosis

New ACR guidelines warn against Omniscan MR contrast use in patients with any kidney disease

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