Impact of Renal Impairment on Long-Term Retention of Gadolinium in the Rodent Skin Following the Administration of Gadolinium-Based Contrast Agents

Abstract

Several publications have suggested a possible association between Gd-based contrast agents (GBCAs) and the development of nephrogenic systemic fibrosis, a rare but serious disease. To date, nephrogenic systemic fibrosis has been observed only in patients with severe renal insufficiency.The aim of this study was to determine the impact of a prolonged circulation time of GBCAs caused by reduced renal clearance on the long-term retention of Gd in the skin of rats after administration of different GBCAs. Renally impaired Han Wistar Rats (5/6-nephrectomized rats) were injected with Omniscan, OptiMARK, Magnevist, or Gadovist. The contrast agents were administered once daily for 5 consecutive days into the tail vein at a dose of 2.5 mmol Gd/kg b.w. Skin biopsies were taken at various time points, and the gadolinium (Gd) concentration was determined by inductive coupled plasma mass spectrometry (ICP-MS) over an observation period of 168 days post injection (p.i.). Differences in the skin Gd concentrations were observed between the 4 investigated GBCAs. For the nonionic linear compounds, Omniscan and OptiMARK, high Gd concentrations were maintained in the skin over the observation period of up to 168 days p.i. For the ionic linear compound, Magnevist, comparatively lower Gd retention in the skin was observed over time. For the macrocyclic compound, Gadovist, the Gd values in the skin were even lower, and significantly lower than Gd values in the skin in Omniscan and OptiMARK treated animals. The results of this preclinical study support the use of 5/6-nephrectomized rats as a model for prolonged circulation time of GBCAs as seen in patients with severe renal impairment. Surgically induced severe renal impairment resulted in delayed clearance of the administered GBCAs in the study animals. The highest amount of Gd was observed in the skin after treatment with the nonionic linear GBCAs, whereas the lowest Gd values were observed after treatment with the macrocyclic agent. This suggests that the difference in the Gd values observed in rat skin tissue after treatment with the different GBCAs is caused of a different propensity of the different GBCAs to release Gd in vivo. However, the analytical method used does not distinguish between chelated and unchelated Gd.