Effect of Different Classes of Gadolinium-based Contrast Agents on Control and Nephrogenic Systemic Fibrosis-derived Fibroblast Proliferation

Purpose: To determine the ability of different types of gadolinium-based contrast agents (GBCAs) to stimulate fibroblast proliferation in monolayer cell culture. Materials and Methods: The National Health Service West Glasgow Ethics Committee granted approval for this study. Fibroblasts established from healthy volunteers (control subjects) and from lesional skin of patients with nephrogenic systemic fibrosis were exposed to a range of concentrations of ionic and nonionic linear and macrocyclic contrast agents over 4 days, and the effect on growth was determined. The lowest concentration of contrast agent that stimulated the maximum effect on fibroblast growth was selected for determination of its effect on fibroblast growth over 8 days. The effect of contrast agents on hyaluronan and collagen synthesis was determined with an enzyme-linked immunosorbent assay. Responses were assessed with analysis of variance (general linear model). Results: The linear gadolinium contrast agents (gadodiamide, gadoversetamide, gadopentetate dimeglumine, and gadobenate dimeglumine) produced a maximum stimulation of fibroblast proliferation at a concentration of 0.1 mmol/L, with cell numbers increasing up to 2.3-fold. The macrocyclic contrast agents (gadoteric acid and gadoteridol) produced a maximum stimulation of fibroblast proliferation at a concentration of 5 mmol/L. The reference gadolinium agents (N-methylglucamine gadolinium ethylenediaminetetraacetic acid and gadolinium trichloride) stimulated fibroblast proliferation at a concentration of 0.01 mmol/L and were toxic at a concentration greater than 1 mmol/L. Growth curves supported the dose-response observations. Hyaluronan synthesis was stimulated by gadoversetamide, gadobenate dimeglumine, gadodiamide, and gadopentetate dimeglumine at a concentration of 0.1 mmol/L and by gadolinium trichloride at a concentration of 0.01 mmol/L, whereas collagen synthesis was unaffected. Conclusion: This study provides evidence that different classes of gadolinium chelates stimulate human fibroblast proliferation.