Nephrogenic Systemic Fibrosis Predicts Early Mortality in Patients Receiving Hemodialysis

September 27, 2007 — In patients receiving hemodialysis, nephrogenic systemic fibrosis (NSF) is a predictor of early mortality, and exposure to gadolinium-containing contrast material is a significant risk factor for development of NSF, according to the results of a study published in the October issue of Arthritis & Rheumatism.

"NSF is a rapidly progressive, debilitating condition that causes cutaneous and visceral fibrosis in patients with renal failure," write Derrick J. Todd, MD, PhD, from the Massachusetts General Hospital in Boston, and colleagues. "Little is known about its prevalence or etiology."

At 6 outpatient centers in the Boston area, 186 patients treated with dialysis underwent a simple 3-part skin examination to detect the 3 skin changes associated with NSF: hyperpigmentation, hardening, and tethering of the skin on the extremities. Positive examination for NSF was defined as having at least 2 of these 3 findings. Mortality was followed for 2 years after the skin examination. Using electronic medical records, the investigators identified patients who had undergone scans with gadolinium-containing contrast agents, as well as the dates of exposure to these agents.

Of 186 patients, 25 (13%) had cutaneous changes consistent with NSF. Within 2 years of the skin examination, 45 (24%) patients died. Mortality rate was 48% for those with NSF vs 20% for those with a negative cutaneous examination (adjusted hazard ratio [HR], 2.9; 95% confidence interval [CI], 1.4 - 5.9). Increased risk for death in patients with skin changes of NSF occurred primarily within the first 6 months after the skin examination, suggesting an increased risk for early mortality.

In the subgroup of 90 patients for whom electronic records were available, 54 had been exposed to gadopentetate dimeglumine contrast during imaging studies, and 16 (30%) of these developed cutaneous changes of NSF. In contrast, only 1% of the 36 patients who had not been exposed to gadolinium developed NSF. Compared with patients who had not been exposed to gadolinium, those with such exposure were almost 15 times as likely to develop cutaneous changes of NSF (odds ratio [OR], 14.7; 95% CI, 1.9 - 117.0).

Because NSF is a recently reported condition, only 5 patients had skin biopsies. For each of these patients, the results of the biopsies confirmed the diagnosis of NSF.

"The paucity of available skin biopsy specimens highlights that NSF is likely underrecognized by many practicing physicians," the study authors write. "The identification of larger numbers of patients with NSF will allow further investigations into the pathogenesis, treatment, and prevention of this recently described debilitating, and potentially fatal, condition."

In an accompanying editorial, Shawn E. Cowper, MD, from Yale University School of Medicine in New Haven, Connecticut, and colleagues note that reported cases of NSF have prompted a Public Health Advisory urging caution when using magnetic resonance imaging scans for patients with renal disease, as well as prompt dialysis in those who have undergone gadolinium-enhanced imaging procedures.

The early cutaneous changes reported in this study suggest that such changes may occur more frequently than was previously believed. These changes may reflect an early or less severe form of NSF. Unanswered questions about the cause and pathogenesis of NSF include why some patients exposed to gadolinium develop the disease, whereas others do not. Studying the response of cells to gadolinium exposure may help resolve these issues.

"Such information also could facilitate the development of MR [magnetic resonance] 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," Dr. Cowper and colleagues write.

Arthritis Rheum. 2007;56:3173-3175, 3433-3441.