Neither gender, race, nor age appeared relevant. However, all patients had renal disease—acute, chronic, or transient—and more than 90% of patients were dialysis dependent. Factors since recognized to confirm a diagnosis of NSF are severe renal impairment (ie, glomerular filtration rate [GFR] < 30 mL/min/1.73 m2),3 CD34+ dendritic cells found on deep biopsy,4 and the following clinical manifestations:
• Skin. Burning or itching, reddened or darkened patches; possible skin swelling, hardening, and/or tightening.
• Eyes. Yellow raised spots in the whites of the eyes.
• Bones, joints, muscles. Joint stiffness; limited range of motion in the arms, hands, legs, or feet; pain deep in the hip bone or ribs; and/or muscle weakness.3
Theories abounded on the cause of NSF. While the presence of renal disease is a requirement, dialysis did not seem to be.5 Ten percent of NSF cases are patients who have never been dialyzed, and thousands of dialysis patients never develop NSF. Neither was any temporal correlation to dialysis found: While some patients developed NSF soon after starting dialysis, many had been on dialysis for years before NSF occurred. No association was found between NSF and the type of dialysis (inpatient, outpatient, hemodialysis, or peritoneal dialysis), the filter, manufacturer, dialysate, technique, or dialysis unit.2
Authors of a retrospective study involving two large tissue repositories looked for cases of NSF before 1997, but none were found.6 If dialysis was not causing NSF, and the disease did not appear to have existed before 1997, what renal toxin had been introduced in the 1990s to explain it?
One early suspicion involved erythropoietin (EPO), used to treat anemia in patients with kidney disease. Skin changes had been reported in some patients after initiation of treatment with EPO, and the NSF patients received a significantly higher mean dose of EPO than controls received.7
Ninety percent of patients with NSF had fistula reconstruction or dialysis catheter placement, but these are common in renal disease patients.8 Forty-eight percent of patients had had liver or kidney transplants, and 12% had hypercoagulable states. Most patients with NSF had never received ACE inhibitors. Were the protective antifibrogenic properties of these agents missing?
Mystery Solved
In a triumph for the Internet and its capacity to disseminate information around the world, a breakthrough came in 2006 from a small town in Austria. Grobner9 described nine patients who had received gadodiamide (Omniscan™)–enhanced MRA, five of whom developed NSF. Upon release of this report, researchers reexamined the original cases and detected a clear correlation between gadolinium and NSF. Because the contrast dose given for MRA can be as much as three times that required for routine MRI, the absence of NSF cases before 1997 suddenly made sense.
In May 2006, researchers for the Danish Medicines Agency reported 13 cases of NSF in patients injected with gadodiamide.10 Within months, 28 biopsy-proven cases were reported in St. Louis, six in Texas, and 13 at the University of Wisconsin—all involving patients exposed to gadolinium.11-13 It was apparent that NSF was iatrogenic and could be controlled.
What We Have Learned Since
In subsequent research, it has been found that more than 90% of reported cases of NSF occurred following exposure to gadodiamide—although gadodiamide accounts for only 15% of all gadolinium injections worldwide,14 and this number is decreasing as more cases are reported. The correlation between gadodiamide and NSF is so strong that its manufacturer, GE Healthcare, sent practitioners a letter in June 2006 warning of NSF as an adverse effect of gadolinium exposure.15 Two days later, the FDA issued an advisory on gadolinium-enhanced imaging procedures, recommending prompt hemodialysis after gadolinium exposure and reminding radiologists and nephrologists that gadolinium is not FDA approved for MRA.1
Although the 44% incidence rate of NSF reported by Grobner9 has never been replicated, a retrospective review of all known NSF cases affirmed that more than 90% of patients had been exposed to gadolinium.14 Two 2007 reports published in the Journal of the American Academy of Dermatology demonstrated that gadolinium was detectable in the tissues of patients with NSF.16,17
In Europe, in response to the May 2006 report from the Danish Medicines Agency,10 the European Society of Urogenital Radiology revised its guidelines with a directive that gadodiamide not be administered in any patients who had reduced kidney function or were undergoing dialysis.18 Shortly thereafter, the European Committee for Medicinal Products for Human Use issued a contraindication for gadodiamide use in patients with severe renal impairment and advised that these patients not be given gadolinium unless there was no other choice.19 A contraindication was also issued for gadodiamide use in patients with previous or anticipated liver transplantation.