title: Gadolinium-based contrast agents and their potential role in the pathogenesis of nephrogenic systemic fibrosis: the role of excess ligand.
abstract: OBJECTIVE
  To investigate the role of excess ligand present in gadolinium (Gd) -based contrast agents in the development of nephrogenic systemic fibrosis (NSF). Using a dosing regimen to simulate the exposure seen in patients with severe renal impairment, we investigated the effect of excess ligand on Gd-deposition and the depletion of endogenous ions.
  
  
  METHODS
  Gadodiamide and gadoversetamide were formulated with 0%, 5%, and 10% excess ligand. Forty-two, healthy, male Hannover Wistar rats received daily intravenous injections of each formulation over a period of 20 days. At the end of the study, histopathological analysis of the skin was performed and the concentrations of Gd, Zn, and Cu were measured in several tissues. The levels of Zn in the urine were also measured.
  
  
  RESULTS
  The most severe skin lesions were observed after injection of formulations containing 0% free ligand and in those animals with the highest Gd concentrations in the skin. There were no significant reductions in the levels of Zn or Cu observed in the skin; however, the levels of Zn in the urine were elevated following administration of formulations with the highest amount of excess ligand.
  
  
  CONCLUSIONS
  Our findings suggest that there is an inverse correlation between the amount of excess ligand present in Gd-containing contrast agents and the amount of Gd in the tissue, and further underline the importance of the inherent stability of these agents in the development of NSF.
authors.affiliation: Research Diagnostic Imaging Bayer Schering Pharma AG, Berlin, Germany. martin.sieber@bayerhealthcare.com
authors.forename: Martin A
authors.initials: MA
authors.lastname: Sieber
authors.forename: Philipp
authors.initials: P
authors.lastname: Lengsfeld
authors.forename: Jakob
authors.initials: J
authors.lastname: Walter
authors.forename: Heiko
authors.initials: H
authors.lastname: Schirmer
authors.forename: Thomas
authors.initials: T
authors.lastname: Frenzel
authors.forename: Fred
authors.initials: F
authors.lastname: Siegmund
authors.forename: Hanns-Joachim
authors.initials: HJ
authors.lastname: Weinmann
authors.forename: Hubertus
authors.initials: H
authors.lastname: Pietsch
mesh_terms: D000818:Animals; D003287:Contrast Media / Q000633:toxicity*; D003300:Copper / Q000378:metabolism; D005355:Fibrosis / Q000139:chemically induced / Q000378:metabolism; D005682:Gadolinium / Q000378:metabolism; D019786:Gadolinium DTPA / Q000633:toxicity*; D007674:Kidney Diseases / Q000139:chemically induced* / Q000378:metabolism; D008024:Ligands; D008297:Male; D009942:Organometallic Compounds / Q000633:toxicity*; D051381:Rats; D012871:Skin Diseases / Q000139:chemically induced* / Q000378:metabolism; D018709:Statistics, Nonparametric; D014018:Tissue Distribution; D015032:Zinc / Q000378:metabolism
chemical_list: D003287:Contrast Media; D008024:Ligands; D009942:Organometallic Compounds; D003300:Copper; C064925:gadodiamide; D005682:Gadolinium; D015032:Zinc; D019786:Gadolinium DTPA; C112666:gadoversetamide