Evaluation of imatinib mesylate as a possible treatment for nephrogenic systemic fibrosis in a rat model.
BACKGROUND
The purpose of the study was to evaluate the efficacy of imatinib mesylate in the treatment of nephrogenic systemic fibrosis (NSF) in a rat model administered high-dose gadodiamide, erythropoietin (Epo) and intravenous iron (IV iron).


METHODS
The local committee for animal research approved this study. Four groups of six Hannover-Wistar rats were studied. Group A received normal saline; Group B, IV iron and Epo; Group C, gadodiamide, IV iron and Epo; and Group D, gadodiamide, IV iron, Epo and imatinib. Gadodiamide was administered at 10 mmol/kg of body weight for 5 consecutive days. Imatinib was administered at 50 mg/kg starting 3 days before gadodiamide injections and was continued for 50 days afterwards. Biopsies were taken 3 and 7 weeks after gadodiamide injection, and dermal histology was analyzed as well as gadolinium deposition as measured by inductively coupled plasma mass spectrometry. Additionally, rats treated with gadodiamide were observed for a total of 16 weeks. For comparison of cellularity, a linear mixed-effects model was used, and for metal deposition, an analysis of variance was used, which was corrected with a Tamhane correction for unequal variances.


RESULTS
Rats treated with gadodiamide in addition to IV iron and Epo (group C) had worse skin lesions on histology (P<.001) compared to control animals (groups A and B). Treatment with imatinib resulted in decreased cellularity (group D vs C, P<.001), although there was no difference in the amount of deposited gadolinium (P>.5). Histology at 16 weeks demonstrated increased fibrosis and dermal calcifications, consistent with the clinical presentation of NSF.


CONCLUSIONS
The administration of imatinib to rats treated with high-dose gadodiamide resulted in decreased lesion severity.
Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA 94143, USA. tom.hope@radiology.ucsf.edu
Thomas A
TA
Hope
Philip E
PE
Leboit
Whitney A
WA
High
Yanjun
Y
Fu
Robert C
RC
Brasch
D000818:Animals; D001549:Benzamides / Q000627:therapeutic use*; D003287:Contrast Media / Q000009:adverse effects; D019786:Gadolinium DTPA / Q000009:adverse effects*; D000068877:Imatinib Mesylate; D008297:Male; D054989:Nephrogenic Fibrosing Dermopathy / Q000188:drug therapy* / Q000473:pathology*; D010879:Piperazines / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011743:Pyrimidines / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D016896:Treatment Outcome
D001549:Benzamides; D003287:Contrast Media; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C064925:gadodiamide; D000068877:Imatinib Mesylate; D019786:Gadolinium DTPA