The involvement of pro-inflammatory cytokines in nephrogenic systemic fibrosis – A mechanistic hypothesis based on preclinical results from a rat model treated with gadodiamide

Abstract The evidence for the potential involvement of gadolinium-based contrast agents (GBCAs) in the pathomechanism of nephrogenic systemic fibrosis (NSF), a rare but serious disease occurring in patients with severe or end-stage renal failure, has grown due to recent epidemiological and preclinical research. Nevertheless there is still uncertainty with regard to the prevailing patho-physiological processes that may lead to NSF. To examine the potential mechanism of the fibrotic skin changes we applied a recently published rat model of NSF for investigations into serum markers for inflammation. For this purpose male Wistar rats were treated either once, three, or eight times with a daily intravenous injection of 2.5 mmol/kg gadodiamide, the drug substance of the magnetic resonance imaging (MRI) agent Omniscan ® . Clinical observations, hematology, clinical pathology, histopathology including electron microscopy and gadolinium (Gd) determination in serum, skin, femur and liver tissue, and a multiplexed analysis of 70 protein serum markers were performed. Gd was detectable in the skin, femur, and liver of the gadodiamide-treated rats 6 h after the first administration. Macroscopic skin changes, appearing as reddening and early scab formation, were observed in one animal after the third daily administration and affected all animals after 8 daily administrations. Microscopy revealed dermal infiltrations after three administrations, progressing towards inflammatory lesions, ulcerations and crusts. Among the investigated serum marker panel 13 cytokines were significantly ( p Reflecting the physiological role of osteopontin, we hypothesize that Gd release from the GBCA-complex leads to the formation of insoluble Gd-deposits subsequently eliciting a physiological response similar to that seen during dystrophic calcification, i.e. an up-regulation of osteopontin and chemoattractant cytokines. Concomitant increase in vascular permeability caused by MIP-1, TNF-α and VEGF may lead to extravasation of chelated Gd or Gd-deposits. The inherent persistence of the Gd-deposits may subsequently result in an overactivation of pro-inflammatory pathways progressing towards overt skin effects.