BIRMINGHAM, ENGLAND A direct relationship between gadodiamidea chelate used regularly to identify renal artery stenosis in patients who are potential transplant recipientsand the activation of fibroblasts in nephrogenic systemic fibrosis has been identified, Dr. Susie Mukherjee reported at the annual meeting of the British Association of Dermatologists.
The origin of nephrogenic systemic fibrosis (NSF) has long intrigued the radiologic, renal, and dermatologic worlds because of the paucity of cases, said Dr. Mukherjee. Although NSF was initially thought to be a cutaneous condition, two recent case reports have indicated that it is in fact systemic.
Dr. Mukherjee, a dermatologist at Glasgow University, and her colleagues examined the levels of hyaluronan and collagenboth key components of the extracellular matrixof six female patients with end-stage renal failure and biopsy proven NSF. Their median duration of dialysis was 4.8 years and the mean time to developing NSF symptoms after receiving gadodiamide was 1 month.
The investigators obtained 20 mL of blood from the patients and compared the blood with that of controls. Punch biopsies were used to establish fibroblast activity.
Serum samples from the NSF patients stimulated up to a 7-fold increase in hyaluronan synthesis and a 3.3-fold increase in collagen; both increases were statistically significant when compared with control patient samples, she said. Histology samples showed thickened collagen bundles signified by strong alcian blue staining on slides, she said.
Dr. Mukherjee also found that it only takes tiny concentrations of gadolinium to stimulate hyaluronan synthesis by fibroblasts. Both 10-mmol/L and 1-mmol/L concentrations of gadolinium caused a 2.3-fold increase in hyaluronan synthesis, "which is still quite a small level compared to what patients are exposed to," she said. "So really from these simple in vitro experiments we can suggest that NSF lesional fibroblasts synthesize excess hyaluronan and collagen, which increases after prolonged exposure to gadodiamide," explained Dr. Mukherjee. "These are the first experiments to demonstrate a direct relation between gadodiamide and activation of fibroblasts."
Evidence for a link between NSF and gadolinium was first described in a case series of 13 patients, all of whom developed NSF after being exposed to gadolinium (J. Am. Soc. Nephrol. 2006;17:2359-62).
Early symptoms of NSF include swelling, pruritus, and muscle pain of the limbs. Later changes include flexion contractures and grossly thickened indurated skin.
Further work should assess the effect of gadolinium on circulating fibrocytes and their ability to migrate into skin, according to Dr. Mukherjee.