Triggering nephrogenic systemic fibrosis: Research looks at role of gadolinium

June 1, 2008

Results from accumulating research suggest that gadolinium is a trigger for nephrogenic systemic fibrosis (NSF). Gadolinium exposure occurs through use of gadolinium-containing contrast agent (GCCA), and the type of GCCA may influence NSF risk. Further evidence is needed to verify these theories.

Key Points

New Haven, Conn. - Accumulating research findings suggest exposure to gadolinium through the use of a gadolinium-containing contrast agent (GCCA) may be a trigger in the development of nephrogenic systemic fibrosis (NSF), and there is also some evidence indicating the type of GCCA may influence the risk.

Definitive cause-and-effect relationships have yet to be established, according to Shawn Cowper, M.D.

NSF was first described in the literature in 2001, and was originally referred to as nephrogenic fibrosing dermopathy, because it was not initially appreciated to be a systemic disorder. While the pathogenesis of NSF is still being investigated, in January 2006, a paper by Grobner suggested gadolinium was a specific trigger.

"More than 90 percent of NSF patients have a known exposure to a GCCA, and for a variety of reasons relating to the inaccuracy of medical record documentation and patient self-reports, there is reason to believe the remaining affected patients may have a similar history," says Dr. Cowper, assistant professor of dermatology and pathology, Yale University, New Haven, Conn.

Epidemiologic data show NSF has affected patients from eight to 86 years of age, but most of the reported cases were in middle-aged persons and have occurred in the United States.

Patient histories reveal a possible association between NSF and various conditions, including coagulation abnormalities, deep venous thrombosis and recent vascular surgery, but the presence of renal disease, either chronic or acute, is a common finding in all patients with NSF.

Renal disease, as well as any of the other conditions that have been associated with NSF, might warrant diagnostic evaluation with magnetic resonance imaging (MRI) or magnetic resonance angiography (MRA) using a GCCA.

"A GCCA has been favored over iodinated contrast agents when performing MRA in renal patients because of a perceived lower risk of contrast-induced nephropathy.

"However, MRA uses two to three times the dose of contrast agent injected in a conventional MRI contrast study, and no GCCA is Food and Drug Administration (FDA) approved for use in MRA," Dr. Cowper tells Dermatology Times.

Renal risks

NSF risk in patients with renal disease has been related to the level of kidney function - susceptible patients have an estimated glomerular filtration rate <30 ml/min/1.73 m2 of body surface area. Mode of dialysis is also important, with patients on peritoneal dialysis having a 7.5-fold greater risk than patients on hemodialysis given the same presumed exposure to gadolinium.

These risk factors are associated with reduced elimination of GCCA. For example, in the case of gadodiamide (Omniscan, General Electric), which has been one of the most widely used GCCAs in the United States and also the GCCA associated with the vast majority of reported cases of NSF, the mean elimination half-life is increased from about 1.3 hours in normal individuals to 32 hours in patients with end-stage renal disease.

Whereas 99 percent of an administered dose of gadodiamide is eliminated from the body after three hemodialysis sessions, only 69 percent is eliminated after 22 days of continuous ambulatory peritoneal dialysis, Dr. Cowper says.

Additional evidence that may implicate gadolinium in NSF pathogenesis derives from a variety of retrospective studies from around the world that strikingly show a similar absolute incidence of NSF development among patients exposed to GCCA. There is also evidence of a temporal association. In a matched case-control study from the Centers for Disease Control (CDC), only exposure to GCCA in the preceding months emerged as a significant risk factor for histologically confirmed NSF.

Research from Dr. Cowper and colleagues revealed the presence of gadolinium within NSF tissue specimens and in macrophages, and also identified a relationship between the tissue concentration of gadolinium and the severity of the histopathological findings.

Studies showing gadolinium can affect the activation or trafficking of fibrocytes, a circulating collagen-producing cell that has been implicated in the pathogenesis of NSF, also suggest an etiologic role for gadolinium.