Effects of gadolinium contrast agents in naïve and nephrectomized rats: Relevance to nephrogenic systemic fibrosis

Abstract

Human nephrogenic systemic fibrosis (NSF) is a rare condition reported in patients with severe renal insufficiency exposed to a gadolinium (Gd)-based contrast agent. An animal model of NSF could help to investigate its mechanisms and lead to prevention and treatment. To evaluate a possible animal model of NSF using naive and partially nephrectomized rats to induce conditions similar to those in patients at risk of NSF. Naive rats received intravenous doses of 5 or 10 mmol/kg Omniscan; 5 mmol/kg Magnevist; 1 mmol/kg caldiamide; 1, 2.5, or 5 mmol/kg gadodiamide; 25 micromol/kg GdCl(3); or 25 micromol/kg Gd citrate. Partially nephrectomized rats received 5 mmol/kg Omniscan; 5 mmol/kg Magnevist; 1 mmol/kg caldiamide; 1 mmol/kg gadodiamide; 25 micromol/kg GdCl(3); or 25 micromol/kg Gd citrate. There were three or four animals per group. Clinical signs were recorded during treatment. At termination, clinical biochemistry, histopathology, and tissue Gd and Zn concentrations were investigated. Similar responses to treatment were seen in naive and nephrectomized rats. High doses of gadodiamide were toxic, necessitating early termination of the affected animals. Skin lesions appeared in naive and nephrectomized groups treated with gadodiamide or Omniscan, coinciding with the onset of signs of pruritus, i.e., intensive scratching. The histomorphological features of the skin lesions were also consistent with superficial physical trauma. Dermal fibrosis was not a feature of these skin lesions in any of the groups, i.e., no increased collagen density, CD34+ cells, or increased fibroblasts. This was supported by skinfold measurements that demonstrated no increased skin thickness. Treatment with the gadolinium-based contrast agents and Gd salts resulted in increased Gd content of several tissues. The Gd salts were mainly taken up by the liver and spleen, possibly reflecting formation of insoluble particles and macrophage uptake. Zn tissue concentrations were normal or increased. Other major treatment-related changes included increased serum rat C-reactive protein and histamine; mineralization affecting the dermis, stomach, and blood vessels; and renal proximal tubule vacuolation. The visible skin lesions seen in this study appeared to be caused by excessive scratching in response to pruritus. As there was no evidence of dermal fibrosis, the cardinal feature of human NSF, this did not appear to be a model of human NSF.