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

• Published in: Experimental and toxicologic pathology : official journal of the Gesellschaft für Toxikologische Pathologie 2009-11, Vol.61 (6), p.537-552
• Main Authors: Steger-Hartmann, T., Raschke, M., Riefke, B., Pietsch, H., Sieber, M.A., Walter, J.
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Blood Proteins - analysis; Capillary Permeability - drug effects; Contrast Media - toxicity; Cytokines; Cytokines - physiology; Disease Models, Animal; Gadolinium - pharmacokinetics; Gadolinium chelates; Gadolinium DTPA - pharmacokinetics; Gadolinium DTPA - toxicity; Gadolinium toxicity; Gadolinium-based contrast agents; Investigative techniques, diagnostic techniques (general aspects); Kidney - drug effects; Kidney - pathology; Male; Medical sciences; Nephrogenic Fibrosing Dermopathy - chemically induced; Nephrogenic systemic fibrosis; Nephrology. Urinary tract diseases; Nephropathies. Renovascular diseases. Renal failure; Osteopontin - physiology; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Principal Component Analysis; Rats; Rats, Wistar; Renal failure; Skin - drug effects; Skin - pathology; Skin toxicity
• ISSN: 0940-2993; 1618-1433
• DOI: 10.1016/j.etp.2008.11.004

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