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Study Suggests "Potent" Link Between NSF, Gadolinium Contrast Dyes

Apr 3, 2009 | Parker Waichman Alonso LLP

Another study has found a strong link between the use of gadolinium contrast dyes and the development of Nephrogenic Systemic Fibrosis (NSF).   According to researchers at the University of Pennsylvania in Philadelphia, patients with advanced chronic kidney disease were 27 percent more likely to develop NSF if they were exposed to a gadolinium contrast dye than those who were not.

Gadolinium contrast dyes are approved for use in MRI procedures, and are sometimes used off-label in MRA studies.  These agents were first introduced in the 1980s, and there are currently five such dyes on the market.  These dyes include:  Omniscan by GE Healthcare; OptiMARK by Mallinckrodt/Tyco Healthcare; Magnevist by Bayer/Schering AG/Berlex; ProHance by Bracco Diagnostics and MultiHance by Bracco Diagnostics.

In September 2007, the Food & Drug Administration (FDA) asked the manufacturers of gadolinium contrast dyes to add a black box warning to the products' labels regarding their association with NSF. The FDA also warned that patients with kidney disease should avoid gadolinium contrast agents.

NSF is a debilitating disease that leads  to excessive formation of connective tissue in the skin and internal organs. It is characterized by high blood pressure, burning, itching, swelling and hardening of the skin. Other symptoms include red or dark patches on the skin; pain deep in the hip bones or ribs and muscle weakness.  NSF can progress to the point of causing severe stiffness in joints, and it can lead to death.

NSF is a relatively new disease.  In fact, the first known diagnosis of NSF  only occurred in 1997, but it wasn't until September 2000 that details of the disease were published in the medical journal Lancet.  It appears that it only develops in people with pre-existing kidney disease.

Several studies have strongly suggested a link between NSF and gadolinium contrast dyes.  This latest study, published in the journal Nephrology Dialysis Transplantation, consisted of a systemic review and meta-analysis of seven controlled studies that have examined the association between gadolinium contrast dyes  and NSF.

The meta-analysis found very strong  evidence of a causal relationship between NSF and gadolinium contrast dyes.  According to a press release detailing the University of Pennsylvania study, that evidence included: 

• consistently similar results and large magnitude of effect shown in all studies analyzed;
• a clear temporal relationship found in all but one study;
• a dose-response relationship shown in three studies. Two studies did not find this relationship and the other studies did not examine the relationship.

In addition, gadodiamide is excreted renally, so it is biologically plausible for it to cause NSF, the investigators observed. Furthermore, gadodiamide is both detectable and quantifiable in the tissues of patients with NSF.   Finally, the researchers cited a case in which a patient who had clinical resolution of NSF developed the condition again when re-exposed to a gadolinium contrast dye.

The authors of the met-analysis concluded that their findings suggest a "potent and significant"  association between gadolinium contrast dyes and NSF among patients with advanced chronic kidney disease.