A painful and debilitating condition that affects patients with kidney failure may be more common than previously believed and appears to be strongly associated with prior exposure to certain contrast agents used in imaging studies. In addition, individuals with this syndrome -- called nephrogenic systemic fibrosis (NSF) -- appear to have a significantly increased risk of dying. The findings are published in the journal Arthritis & Rheumatism.
"Our analysis found that hemodialysis patients who had undergone imaging studies using a gadolinium-containing contrast agent have more than 10 times the risk of developing NSF as do patients with no prior exposure to gadolinium," says Jonathan Kay, MD, director of the Rheumatology Clinical Research Unit at Massachusetts General Hospital (MGH)), the report's senior author. "Among those with NSF, the risk of dying within two years was three to five times greater than for patients without the condition from the same dialysis centers."
The primary symptoms of NSF are rapid and progressive thickening, hardening and darkening of the skin, primarily on the arms and legs. Originally believed to affect only the skin, the condition now is known to involve internal organs. NSF can be extremely painful, causing the skin to contract to the point where movement is difficult or impossible. The condition has been reported only during the past 10 years and only among patients with abnormal kidney function, primarily those with advanced kidney disease. In 2006, an Austrian physician noted that NSF developed in several of his dialysis patients who had undergone MR imaging studies using gadolinium-containing contrast.
Reports of NSF in the medical literature have discussed only small numbers of cases and have not included comparative information from patients shown to not have the disorder. To better assess the prevalence of NSF among patients with advanced kidney disease and to examine a potential association with gadolinium-containing contrast agents, the team led by Derrick J. Todd, MD, PhD, now a rheumatology fellow at the Brigham & Women's Hospital, enrolled hemodialysis patients treated at six outpatient centers in the Boston area.
The investigators devised a simple examination to check for the three skin features of NSF -- tightening, thickening and darkening -- and also collected demographic information. Available electronic medical records for participants were analyzed for any history of imaging studies, predominantly MRI examinations, using gadolinium-containing contrast.
Among 186 study participants, 25 (13 percent) were determined to have NSF based on the presence of at least two of the three skin findings. Examination of skin biopsy samples from five study participants supported the examination-based diagnosis of NSF in each. Electronic medical records were available for 90 participants; 17 of those had a skin examination consistent with NSF, all but one with documented prior exposure to gadolinium. The investigators were particularly surprised to find that 48 percent of participants with skin changes of NSF died within two years of their examination. Among participants without NSF, the death rate was 20 percent, which would be expected among patients with advanced kidney failure undergoing long-term hemodialysis treatment.
"Our study demonstrates a definite and very strong association between exposure to gadolinium-containing contrast and the subsequent development of NSF," says Kay, an associate clinical professor of Medicine at Harvard Medical School. "We need to address the mechanism by which this devastating disease occurs and develop effective treatment and preventive strategies, so that gadolinium-containing contrast agents -- which provide important clinical information -- can be used safely in patients with kidney failure."
At this time, Kay notes, patients scheduled to undergo such imaging studies should first have their kidney function checked, and gadolinium-containing contrast should not be used in those with significant underlying kidney disease. More information is needed to determine the risk for those with milder forms of kidney disease. The study was conducted by Todd and co-author Anna Kagan, MD, PhD, while they were medical residents at MGH. Lori B. Chibnik of Brigham and Women's Hospital was the study's biostatician.
In an accompanying editorial in the same issue of Arthritis & Rheumatism , Shawn E. Cowper, Phillip H. Kuo and Richard Bucala of Yale University School of Medicine in New Haven, CT, point out that reported cases of NSF have led to a Public Health Advisory urging caution in the use of MRI scans for patients with kidney disease and prompt dialysis in those who have undergone scans involving gadolinium.
They note that the study by Todd and colleagues contributes to this evolving story, and that the evidence of early skin changes seen in the study raises the possibility that such changes are more common than was previously thought and may point to an early or less severe form of NSF.
Many questions remain about the origins of NSF (including why some patients exposed to gadolinium develop the disease and others do not) and they suggest that studying how cells respond to gadolinium exposure will shed light on this disease. They conclude: "Such information also could facilitate the development of MR contrast agents that have a less toxic response profile, and preserve the high clinical utility of contrast-enhanced MR as an imaging modality in patients with renal insufficiency."
"Cutaneous Changes of Nephrogenic Systemic Fibrosis: Predictor of Early Mortality and Association With Gadolinium Exposure," Derrick J. Todd, Anna Kagan, Lori B. Chibnik, Jonathan Kay, Arthritis & Rheumatism, October 2007; (10.1002/art.22925).
"Nephrogenic Systemic Fibrosis and Gadolinium Exposure: Association and Lessons for Idiopathic Fibrosing Disorders," Shawn E. Cowper, Phillip H. Kuo, Richard Bucala, Arthritis & Rheumatism, October 2007; (10.1002/art.22926).
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