Case Cluster Reinforces MR Contrast Agent Alert

ATLANTA, Feb. 23 -- Radiologists should avoid the use of contrast agents that contain gadolinium in patients with advanced renal disease if at all possible, according to the CDC.

The recommendation was part of a preliminary report on the largest cluster of nephrogenic systemic fibrosis (also known as nephrogenic fibrosing dermopathy), a rare condition characterized by thickening and hardening of the skin, often in the extremities, in St. Louis patients with underlying renal disease.

The CDC report comes days after the European regulatory agency concluded that two of the agents -- gadodiamide (Omniscan) and gadoversetamide (OptiMark) -- are contraindicated in patients with advanced renal disease.

And it comes only weeks after the FDA warned of the possible link.

• FDA Issues Alert on Gadolinium-Based Contrast Agent for Kidney Patients

The mechanism for possible gadolinium-associated nephrogenic fibrosing dermopathy is unknown. However, one hypothesis is that the gadolinium ions might dissociate from the chelate and result in a fibrotic reaction.

Thirty-three patients with the condition were identified in St. Louis, and a matched case-control study showed that only gadolinium contrast agents were independently associated with the condition, according to Steven Cheng, M.D., of Washington University School of Medicine, and colleagues, reporting in the Feb. 23 issue of Morbidity and Mortality Weekly Report.

In the study, exposure to the agents increased the risk of the condition nearly nine-fold, the researchers found. In a multivariate analysis, the odds ratio was 8.97 with a 95% confidence interval from 1.28 to 63.01.

The research was prompted by a cluster of nephrogenic fibrosing dermopathy among dialysis patients in a St. Louis hospital (which was not named). Investigation found a total of 33 confirmed or suspected cases between 2002 and 2006, of whom 28 had been treated at the hospital.

A case was considered confirmed if both clinical findings, such as skin thickening or hardening, and skin biopsy findings were consistent with the condition. A suspected case was one in which either clinical or biopsy findings but not both were consistent with the condition.

The subsequent case-control study included 19 of the confirmed cases from the hospital, each matched with three unaffected patients who were treated in the same dialysis clinic or treatment center on the same day that a case was diagnosed.

Analysis found significant differences in:

• Age. The median age of cases was 50 years, compared to 58 for controls, which was significant at P=0.04.
• History of deep venous thrombosis. Thirty-seven per cent of the cases had had DVT, compared to 12% of controls, which was significant at P=0.02.
• History of hypothyroidism. Thirty-two per cent of the cases had such a history, but only 9% of controls, which was significant at P=0.01.
• Presence of dependent edema. Among cases, 78% had swelling below the knees, compared to 31% of controls, which was significant at P=.001.

But in the multivariate analysis, only the use of contrast agents containing gadolinium within the previous year remained significant, Dr. Cheng and colleagues found.

Interestingly, five of the cases had not been exposed to such contrast agents within a year of diagnosis, but four of the five had been exposed from 16 to 68 months before. The remaining patient had no known exposure.

The issue is controversial, because American and European authorities have significant disagreements, according to Emanuel Kanal, M.D., of the University of Pittsburgh.

Although the Europeans rule out the use of gadodiamide and gadoversetamide entirely and suggest caution in the use of others, American regulators have been less restrictive, but urge immediate hemodialysis if the agents are used.

"You should go immediately, directly from the MR suite to hemodialysis," Dr. Kanal said in an interview. The Europeans, on the other hand, say there is no evidence that hemodialysis is protective.

According to the CDC, excretion of gadolinium-containing contrast agents primarily occurs renally. The amount of contrast eliminated from the body after dialysis has not been well evaluated.

Two studies the CDC cited suggest that 65% to 78% of gadolinium-containing contrast might be cleared after one hemodialysis session and 98% after three sessions.

Dr. Kanal and colleagues, in an editorial in the journal Radiology, published online in advance of the March issue, noted that more than 95% of all cases of the illness worldwide area associated with gadolinium-containing agents.

And about 90% of the cases, they said, are associated with gadodiamide.

The condition was first identified in 1977. There is no consistently effective treatment and, while the disease stabilizes occasionally, it rarely remits entirely.

Because of its sudden appearance, "suspicion that a recently introduced agent might be the culprit has been rampant," Dr. Kanal and colleagues wrote

They noted, however, that the etiology is still unclear, but despite that "caution in the use of these agents in the setting of renal disease" is advisable.

Five agents that contain gadolinium are approved in the U.S. - gadodiamide and gadoversetamide, as well as gadopentetate dimeglumine (Magnevist), gadoteridol (ProHance), and gadobenate dimeglumine (MultiHance).

Dr. Kanal said radiologists should consider using other contrast agents or other imaging techniques. If agents containing gadolinium are used, he said, only the lowest possible dose should be given, followed immediately by hemodialysis.