Mechanism of NSF: New evidence challenging the prevailing theory

Abstract

Nephrogenic systemic fibrosis (NSF) has been associated with the administration of gadolinium‐based contrast agents in patients with severely impaired renal function (SIRF), endstage renal disease (ESRD), or acute renal failure (ARF). Since the vast majority of these patients do not get NSF, it is highly likely that patient factors play a role in its development. Although “free” or dechelated gadolinium is thought by some to be the only trigger of NSF, recent evidence suggests that chelated gadolinium may be important. Chelated gadolinium such as Omniscan (gadodiamide) and Magnevist (gadopentetate) can directly stimulate macrophages and monocytes in vitro to release profibrotic cytokines and growth factors capable of initiating and supporting the tissue fibrosis that is characteristic of NSF. In addition, an effect of chelated gadolinium on fibroblasts has also been demonstrated. Chelated gadolinium in the form of Omniscan, Magnevist, MultiHance, and ProHance increased proliferation of human dermal fibroblasts. Indeed, increased numbers of macrophages, together with activated fibroblasts and fibrocytes, are essential cells in the fibrotic process and are present in NSF skin. Accordingly, it is important that chelated gadolinium, in combination with patient cofactors, is considered in the etiology of NSF associated with enhanced scans. J. Magn. Reson. Imaging 2009;30:1277–1283. © 2009 Wiley‐Liss, Inc.

Induction of a type I interferon signature in normal human monocytes by gadolinium-based contrast agents: comparison of linear and macrocyclic agents

“…Multiple, non-mutually exclusive hypotheses to explain the roles of a variety of molecular pathways and possible co-factors in NSF pathogenesis have been proposed [12][13][14][15][16]26,27]. One area of debate concerns the form of the active Gd molecule.…”

“…Two models have been proposed that differ in the nature of the bioactive form of Gd associated with NSF occurrence in CKD individuals [12][13][14][15][16]. The transmetallation model posits that GdBCA accumulate in the extravascular space and tissues where endogenous free cations such as Zn 2+ , Ca 2+ , Cu 2+ or Fe 2+ displace Gd 3+ from the chelate complex [12][13][14][15].…”

“…According to this model, linear GdBCA that are less thermodynamically stable than macrocyclic GdBCA are more prone to undergo transmetallation, thereby initiating the fibrotic process leading to NSF. The second model, the chelate model, proposes that intact Gd chelate complexes, rather than transmetallated Gd 3+ , are the bioactive agent triggering the NSF fibrotic process [16]. This model suggests that certain intrinsic property(s) of the intact Gd chelate complex is(are) responsible for the disproportionately greater association of linear GdBCA with NSF development compared to macrocyclic GdBCA based on exposure rates to these classes of agents.…”

Gadolinium and nephrogenic systemic fibrosis: an update

“…Free Gd has indeed been shown to stimulate human fibroblast proliferation in vitro, with hyaluronan and collagen synthesis, as seen in biopsies from patients with NSF [48]. Although the majority of the in vitro studies relate to nonchelated Gd as a trigger for NSF, human macrophages and monocytes also express pro-fibrotic cytokines and growth factors capable of stimulating NSF-like fibrosis in response to chelated gadodiamide and gadopentetate dimeglumine [49]. Several NSF-patients in whom no Gd exposure could be ascertained have been reported [33,50].…”

Special issue: Nephrogenic systemic fibrosis

“…The issue begins with a summary of Dr. Jeff Weinreb's excellent keynote lecture as given at the 17th annual meeting of the ISMRM in May of this year (10). Subsequent articles cover a wide variety of related topics, ranging from a basic primer on gadolinium chemistry (11), the role of thermodynamic and kinetic parameters in gadolinium chelate stability (12), the biodistribution of GBCA, including gadolinium deposition (13), and biological effector mechanisms (14)(15)(16), to the clinical spectrum of NSF (17), to practical insights on measurement of renal function (18) as well as a review on how to remove gadolinium by dialysis (19). We present current guidelines for injection of GBCA as used in the United States, Canada, Europe (20) and Japan (21).…”