title: Gadolinium contrast agent-induced CD163+ ferroportin+ osteogenic cells in nephrogenic systemic fibrosis.
abstract: Gadolinium-based contrast agents are linked to nephrogenic systemic fibrosis in patients with renal insufficiency. The pathology of nephrogenic systemic fibrosis is characterized by abnormal tissue repair: fibrosis and ectopic ossification. The mechanisms by which gadolinium could induce fibrosis and ossification are not known. We examined in vitro the effect of a gadolinium-based contrast agent on human peripheral blood mononuclear cells for phenotype and function relevant to the pathology of nephrogenic systemic fibrosis using immunofluorescence, flow cytometry, real-time PCR, and osteogenic assays. We also examined tissues from patients with nephrogenic systemic fibrosis, using IHC to identify the presence of cells with phenotype induced by gadolinium. Gadolinium contrast induced differentiation of human peripheral blood mononuclear cells into a unique cellular phenotype--CD163(+) cells expressing proteins involved in fibrosis and bone formation. These cells express fibroblast growth factor (FGF)23, osteoblast transcription factors Runt-related transcription factor 2, and osterix, and show an osteogenic phenotype in in vitro assays. We show in vivo the presence of CD163(+)/procollagen-1(+)/osteocalcin(+) cells in the fibrotic and calcified tissues of nephrogenic systemic fibrosis patients. Gadolinium contrast-induced CD163(+)/ferroportin(+)/FGF23(+) cells with osteogenic potential may play a role in systemic fibrosis and ectopic ossification in nephrogenic systemic fibrosis.
authors.affiliation: Division of Nephrology, Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA. SS4SA@hscmail.mcc.virginia.edu
authors.forename: Sundararaman
authors.initials: S
authors.lastname: Swaminathan
authors.forename: Chhanda
authors.initials: C
authors.lastname: Bose
authors.forename: Sudhir V
authors.initials: SV
authors.lastname: Shah
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Hall
authors.forename: Kim M
authors.initials: KM
authors.lastname: Hiatt
mesh_terms: D015703:Antigens, CD / Q000378:metabolism*; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism*; D002113:Calcification, Physiologic / Q000187:drug effects; D027682:Cation Transport Proteins / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D003287:Contrast Media / Q000009:adverse effects*; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000378:metabolism; D005682:Gadolinium / Q000009:adverse effects*; D019786:Gadolinium DTPA / Q000009:adverse effects; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D054989:Nephrogenic Fibrosing Dermopathy / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology*; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015675:Osteocalcin / Q000378:metabolism; D010012:Osteogenesis; D010641:Phenotype; D011956:Receptors, Cell Surface / Q000378:metabolism*; D012867:Skin / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000378:metabolism; D000098902:CD163 Antigen; D000098742:Ferroportin
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D000098902:CD163 Antigen; D027682:Cation Transport Proteins; D003287:Contrast Media; C000717427:FGF23 protein, human; D011956:Receptors, Cell Surface; D014157:Transcription Factors; D000098742:Ferroportin; D015675:Osteocalcin; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; C064925:gadodiamide; D003094:Collagen; D005682:Gadolinium; D019786:Gadolinium DTPA