Nephrogenic systemic fibrosis in rats treated with erythropoietin and intravenous iron.
OBJECTIVE
To use a rat model for nephrogenic systemic fibrosis (NSF) that was administered high-dose gadodiamide to determine whether the co-administration of erythropoietin (Epo) and intravenous iron potentiated development of skin lesions that are thought to be a marker for the development of NSF.


METHODS
The local committee for animal research approved this study. High-dose gadodiamide was administered, 2.5 mmol per kilogram of body weight for 20 days, or 500 times the U.S. Food and Drug Administration-approved dose, to four groups of Hannover-Wistar rats: group A, gadodiamide only; B, gadodiamide and Epo; C, gadodiamide and intravenous iron; and D, gadodiamide, Epo, and intravenous iron. The animals were sacrificed 7 days after final injection, and the authors examined dermal histologic findings from each animal and measured metal deposition by using inductively coupled plasma mass spectrometry. To compare the effect of metal deposition and cellularity, a linear mixed effects model was used to fit the data within PROC MIXED modeled with rat-specific random effects, and subsequently a Dunnett adjustment was performed.


RESULTS
Rats treated with gadodiamide and both Epo and intravenous iron (group D) had significantly worse skin lesions at gross and histologic analysis (P = .004) compared with the rate treated with gadodiamide only (group A). Group D also had increased levels of deposited gadolinium as measured by means of mass spectrometry (P = .012).


CONCLUSIONS
With a rat model similar to those already existing in the literature, skin changes were more marked in animals exposed to gadodiamide, Epo, and intravenous iron, as opposed to those animals exposed to gadodiamide alone; this experiment suggests that great caution may be warranted when prescribing gadolinium-based contrast agents to patients receiving Epo and intravenous iron.
Department of Radiology, University of California San Francisco, 505 Parnassus Ave, San Francisco, CA 94143, USA. tom.hope@radiology.ucsf.edu
Thomas A
TA
Hope
Whitney A
WA
High
Philip E
PE
Leboit
Bundit
B
Chaopathomkul
Victor S
VS
Rogut
Robert J
RJ
Herfkens
Robert C
RC
Brasch
D000818:Animals; D002118:Calcium / Q000378:metabolism; D003287:Contrast Media / Q000008:administration & dosage / Q000633:toxicity*; D004357:Drug Synergism; D000068817:Epoetin Alfa; D004921:Erythropoietin / Q000633:toxicity*; D019786:Gadolinium DTPA / Q000008:administration & dosage / Q000633:toxicity*; D007275:Injections, Intravenous; D007505:Iron-Dextran Complex / Q000008:administration & dosage / Q000633:toxicity*; D008297:Male; D054989:Nephrogenic Fibrosing Dermopathy / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins; D012867:Skin / Q000378:metabolism / Q000473:pathology
D003287:Contrast Media; D011994:Recombinant Proteins; D004921:Erythropoietin; D000068817:Epoetin Alfa; C064925:gadodiamide; D007505:Iron-Dextran Complex; D019786:Gadolinium DTPA; D002118:Calcium