title: Nephrogenic gadolinium biodistribution and skin cellularity following a single injection of Omniscan in the rat.
abstract: OBJECTIVE
  The development of nephrogenic systemic fibrosis (NSF) following MRI contrast examination has been associated with gadolinium (Gd) toxicity. Animal models should show the key features of NSF in man where, the only immutable epidemiological feature is renal impairment. A rat model of chronic renal insufficiency has been employed to establish whether tissue gadolinium retention and increased skin cellularity following a gadolinium based contrast agent (GBCA) can be correlated with a reduction in renal function. The GBCA chosen for investigation was Omniscan, the least stable of the commercially available agents.
  
  
  METHODS
  Wistar rats were subjected to 5/6 subtotal nephrectomy (SNx) under isoflurane anesthesia. The glomerular filtration rate (GFR) was assessed from serum creatinine and creatinine clearance. Two SNx rats groups were established, following either 75% or 80% resection of the kidney, which reduced the GFR down to 40% and down to 20%, respectively, of sham-operated controls. Three months after surgery, rats received a single intravenous injection of either saline or Omniscan (gadodiamide 2.5 mmol/kg). Four weeks later, the Gd content of serum, skin, liver, and bone was measured by inductively coupled plasma mass spectrometry and skin cellularity determined.
  
  
  RESULTS
  In sham-operated rats, Gd was detected in skin < liver < bone. SNx rats with the GFR reduced down to 20% normal, had an increased tissue Gd concentration in bone (2.5-fold), skin (3-fold), and liver (10-fold) compared with sham-operated controls. The Gd concentration in all 3 tissues showed a positive linear correlation with serum creatinine (P < 0.01). No external skin lesions were observed. The skin cellularity of rats with the GFR reduced down to 20% of normal was increased following Omniscan, together with positive immunostain for CD34 and prolyl-4-hydroxylase.
  
  
  CONCLUSIONS
  The SNx rat is a sensitive model for investigating the pathophysiology of NSF. A positive linear correlation was obtained between tissue Gd and serum creatinine, the major clinical marker of renal function. An increase in skin cellularity, a feature of human NSF, was demonstrated in rats with a level of renal impairment equivalent of stage 4 chronic kidney disease following just a single intravenous dose of Omniscan. This response was obtained in the absence of ulcerogenic skin lesions, at skin Gd concentrations as low as 50 nmol/g.
authors.affiliation: Academic Nephrology Unit, Medical School, Sheffield, UK. j.l.haylor@sheffield.ac.uk
authors.forename: John
authors.initials: J
authors.lastname: Haylor
authors.forename: Anne
authors.initials: A
authors.lastname: Dencausse
authors.forename: Melissa
authors.initials: M
authors.lastname: Vickers
authors.forename: Faith
authors.initials: F
authors.lastname: Nutter
authors.forename: Gaelle
authors.initials: G
authors.lastname: Jestin
authors.forename: David
authors.initials: D
authors.lastname: Slater
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Idee
authors.forename: Sameh
authors.initials: S
authors.lastname: Morcos
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001681:Biological Assay; D003287:Contrast Media / Q000009:adverse effects* / Q000494:pharmacology; D003404:Creatinine / Q000097:blood / Q000378:metabolism / Q000652:urine; D019786:Gadolinium DTPA / Q000009:adverse effects* / Q000494:pharmacology; D005919:Glomerular Filtration Rate; D007150:Immunohistochemistry; D007262:Infusions, Intravenous; D007668:Kidney / Q000187:drug effects* / Q000601:surgery; D016014:Linear Models; D008279:Magnetic Resonance Imaging; D008297:Male; D023421:Models, Animal; D009392:Nephrectomy; D051381:Rats; D017208:Rats, Wistar; D051436:Renal Insufficiency, Chronic / Q000139:chemically induced* / Q000209:etiology; D012867:Skin / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D013223:Statistics as Topic; D018709:Statistics, Nonparametric
chemical_list: D003287:Contrast Media; C064925:gadodiamide; D003404:Creatinine; D019786:Gadolinium DTPA