Gadolinium-based MR Contrast Agents and Nephrogenic Systemic Fibrosis

Abstract

Phillip H. Kuo, MD, PhD Emanuel Kanal, MD Ali K. Abu-Alfa, MD Shawn E. Cowper, MD Nephrogenic systemic fibrosis (NSF), described in 2000 (1), is an emerging systemic disorder characterized by widespread tissue fibrosis. Originally known as nephrogenic fibrosing dermopathy because of its dominant cutaneous findings, the nomenclature was revised in recent years to reflect an increased understanding of its systemic effects (1,2). While the precise cause of NSF remains a mystery, it is known to occur only in patients with renal disease– generally in those requiring dialysis. NSF may develop rapidly and can sometimes result in patients becoming confined to a wheelchair within a few weeks. More commonly, the skin thickening is insidious and can be confused clinically with peripheral edema. Pathophysiologically, NSF results in increased tissue deposition of collagen, commonly resulting in thickening and hardening of the skin of the extremities and often culminating in immobility and contractures of the joints. In some patients, there is clinical involvement of other tissues (lung, skeletal muscle, heart, diaphragm, esophagus, etc), although the patient may not be clinically symptomatic (3). While NSF sometimes stabilizes, it rarely spontaneously remits. No consistently effective therapy exists, although rapid correction in renal function (by medical or surgical means) generally results in a cessation of progression and often in a reversal of symptoms (4). With renal dysfunction at the core of this condition, the possibility that renally excreted endogenous or exogenous substances may be triggering NSF has been of great interest. Since NSF appears not to have existed prior to 1997, suspicion that a recently introduced agent might be the culprit has been rampant, but investigation by several authors and by the Centers for Disease Control and Prevention has so far failed to identify a single causative medication (3). Of great interest, the author of a recent article (5) has suggested that administration of intravenous contrast material for magnetic resonance (MR) imaging (ie, gadolinium chelates) has been associated with a small cluster of patients with NSF in Austria (five of nine imaged patients). A Web-based medical advisory originating in Denmark claims that, since January 2002, approximately 400 patients with severely impaired renal function were administered gadolinium-based MR contrast material; 20 patients (5%) subsequently were diagnosed with NSF (6). Other unpublished U.S. experience (S.E.C., October 2006) suggests an approximate incidence of 3% for the development of NSF in the setting of severe renal failure and administration of intravenous contrast material for MR imaging. An international NSF registry at Yale University (New Haven, Conn) maintains records on over 215 patients with NSF worldwide. A survey now underway has revealed that more than 95% of all NSF patients surveyed (currently approximately 100) have been exposed to a gadolinium chelate within 2–3 months prior to disease onset. The majority of the patients were being maintained with dialysis. However, a number of patients with impaired renal function have been reported to the registry, the severity of whose disease has been difficult to determine retrospectively. To the best of our knowledge, the overwhelming majority of known NSF cases at this point ( 90%) represent patients who had previously received gadodiamide (Omniscan; GE Healthcare, Princeton, NJ) (7). Nevertheless, there have been reports of NSF cases associated with other agents. As of October 26, 2006, there have been a total of 57 cases of NSF associated with prior gadolinium-based MR contrast agent administration reported to the U.S. Food and Drug Administration (FDA) Published online before print 10.1148/radiol.2423061640