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The Role of Residual Gadolinium in the Induction of Nephrogenic Systemic Fibrosis-Like Skin Lesions in Rats

Pietsch, Hubertus PhD*; Raschke, Marian PhD; Ellinger-Ziegelbauer, Heidrun PhD; Jost, Gregor PhD*; Walter, Jakob PhD; Frenzel, Thomas PhD*; Lenhard, Diana PhD*; Hütter, Joachim MD*; Sieber, Martin A. PhD*

doi: 10.1097/RLI.0b013e3181efd49a
Original Article

Objective: Nephrogenic systemic fibrosis (NSF) is an acquired, idiopathic disorder. Most of the cases are observed in patients with end stage renal disease (ESRD). The objective of this nonclinical animal study was to test the hypothesis that gadolinium (Gd) deposits play a role in the induction of NSF lesions. In addition, we evaluated whether an acute response to Gd exposure can initiate a process that results in fibrosis of the skin.

Materials and Methods: Han-Wistar rats were administered 3 intravenous injections of Gd-DTPA-BMA formulated without Gd-free excess ligand (Gadodiamide without Caldiamide) at a dose of 2.5 mmol/kg of body weight (b.w.) per injection given at 24-hour or 14-, 28-, or 56-day intervals. The occurrence and development of NSF-like fibrosing dermopathy lesions were followed. The Gd concentration was determined by Inductively Coupled Plasma Mass Spectrometry in skin biopsies taken during the study and organ samples taken at the end of the study.

In a separate study, after injection of a single intravenous dose of 2.5 mmol/kg b.w. Gd-DTPA-BMA administered to Han-Wistar rats, the expression of cytokines and signaling molecules in serum and skin tissue was determined by quantitative RT-PCR and Luminex technology 6 hours or 14, 28, or 56 days.

Results: The occurrence of NSF-like macroscopic skin lesions differed between the injection groups. Shorter injection intervals resulted in more severe skin reactions. In contrast, the injection interval did not influence the long-term presence and level of accumulation of Gd concentration in tissue. The single injection of Gd-DTPA-BMA was followed by a rapid and transient induction of signaling molecules in the serum (MCP1, MCP3, IL1, IP-10, Osteopontine SCF and Timp1) as well as in the skin (MCP1 and TGFb).

Conclusion: The presence of NSF-like fibrosing dermopathy in rats was found to be dependent on the injection interval and not on the amount of Gd in tissue. Our findings suggest the possibility of a more acute intrinsic reaction on administration of Gd-DTPA-BMA that triggers events leading to the development of skin lesions. The finding that single injections of Gd-DTPA-BMA were accompanied by a fast and transient induction of signaling molecules that are known to be involved in several fibrotic events provides additional support for this hypothesis. The study findings, however, do not support the theory that the long-term presence of Gd plays a relevant role in the development of NSF.

From the *Contrast Media Research, Bayer Schering Pharma AG, Berlin, Germany; and †Nonclinical Drug Safety, Bayer Schering Pharma AG, Berlin, Germany.

Received March 29, 2010; accepted for publication (after revision) June 27, 2010.

Supported by Bayer Schering Pharma AG, Berlin, Germany.

Reprints: Martin A. Sieber, PhD, Intendis GmbH, Max-Dohrn-Strasse 10, 10589 Berlin, Germany.

© 2011 Lippincott Williams & Wilkins, Inc.