All patients who developed NSF had abnormal renal function at some time before the onset of skin changes, although this was not required by the case definition.1 About half had undergone renal transplantation, which suggested that this condition was not caused by a specific type of renal replacement therapy and that it did not require renal failure to be present at onset. This observation raised the possibility that an environmental exposure might trigger the onset of NSF in patients with chronic kidney disease. A subsequent report by Swaminathan and colleagues suggested that patients with NSF had been exposed to higher doses of erythropoietin than control subjects.14 However, this observation was superseded by a key observation made by a very astute clinician in Austria.
Between 2003 and 2005, Thomas Grobner, MD, a nephrologist at the General Hospital of Wiener Neustadt, Austria, observed that five of nine patients receiving hemodialysis under his care developed skin changes of NSF within two to four weeks after undergoing magnetic resonance (MR) angiography with gadodiamide contrast.8 In contrast to the four patients who did not develop NSF after MR angiography, the five who developed skin changes had metabolic acidosis when the gadolinium-containing contrast agent was administered. Also, the five patients who developed NSF underwent hemodialysis for a longer time then those who did not, but Dr. Grobner found no other significant demographic differences between the two groups.
Shortly thereafter, Peter Marckmann, MD, of the department of nephrology, and colleagues from Copenhagen University Hospital at Herlev, Denmark, reported on 13 patients who also developed NSF following exposure to gadodiamide contrast during MR imaging.15 These patients developed skin changes between two and 75 days after exposure to a gadolinium-containing contrast agent. These reports and the report of seven additional patients prompted the Danish Medicines Agency to post an alert on its Web site on May 29, 2006, suggesting the possibility of a relationship between gadolinium exposure and the development of NSF.16
Guidelines for Using Gadolinium Contrast Agents in Chronic Kidney Disease Patients
- Do not administer intravenous gadodiamide to dialysis patients or to other patients with stage 5 chronic kidney disease;
- Avoid double-dose (0.2 mmol/kg) or triple-dose (0.3 mmol/kg) studies;
- Exercise caution in administering gadodiamide to patients with acute renal failure;
- Screen patients scheduled for contrast-enhanced MRI examinations by obtaining a recent serum creatinine level and calculated creatinine clearance if they have a history of kidney disease or diabetes mellitus; and
- Check serum creatinine and calculated creatinine clearance in patients older than 60 years before gadodiamide administration.
Cases Mount and Understanding Grows
By 2006, more than 200 cases of NSF had been identified around the world.17 At Massachusetts General Hospital in Boston, I had seen more than 25 patients with NSF confirmed by skin biopsy. To assess the prevalence of NSF among patients with stage 5 chronic kidney disease, my colleagues and I screened 186 patients receiving hemodialysis in five outpatient dialysis units in the Boston area for skin changes characteristic of NSF: hyperpigmentation, thickening, and tethering.18 We found that 25 (13%) of the 186 patients had cutaneous changes of NSF. Most strikingly, when we followed this cohort of patients for 24 months, we determined that the presence of cutaneous changes of NSF was associated with a three-fold increased risk of dying among patients receiving hemodialysis. Although the number of patients studied was too small to determine a specific cause of death, cardiovascular causes of mortality predominated. Thus, NSF is not only a condition that causes devastating symptoms, but it is also a disease associated with shortened lifespan.
