Gadolinium Contrast Agent Associated Stimulation of Human Fibroblast Collagen Production

Abstract

Nephrogenic systemic fibrosis occurs in patients with poor renal function who receive gadolinium-based contrast agents (Gd-CAs). Several reports suggest that this is more likely to occur with the less stable forms of Gd chelates, suggesting a release of cytotoxic free Gd ions from these. There is evidence that Gd can stimulate human fibroblast proliferation but the evidence is less clear concerning the production of collagen by these cells. Our aim was to assess effects of Gd chelates on human skin cell activity and collagen production. Keratinocytes and fibroblasts were cultured with 3 Gd chelates (Gd-EDTA, Omniscan [nonionic linear Gd-CA], and Dotarem [ionic macrocyclic Gd-CA]) for up to 7 days, and cell viability and collagen production were assessed using the colorimetric assays of MTT (3-(4, 5-dimethylthiazol-2-yl) 2, 5-diphenyltetrazolium bromide) and Sirius Red, respectively. The uptake of Gd by cultured fibroblasts was also undertaken using the techniques of inductively coupled plasma mass spectrometry and relaxometry. Our data show that Gd-EDTA and Omniscan significantly stimulated both fibroblast and keratinocyte viability and fibroblast (but not keratinocyte) collagen production. In contrast, Dotarem had little, if any, effect on these cultured cells. The Omniscan-induced increase in fibroblast collagen was around 40% over 7 days-a similar increase to that seen for cell viability, suggesting that collagen production was secondary to an initial stimulatory effect on fibroblast viability. Studies of the uptake of Gd by the cultured fibroblasts showed that these took up Gd when cultured with Omniscan for 7 days, and our study also suggests that some of this Gd was in a free dissociated form. We conclude that these results support a simple nephrogenic systemic fibrosis causative role of low-stability nonionic linear Gd-CA inducing dermal collagen via the release of dissociated Gd which enters fibroblasts and stimulates their activity and associated collagen production.