title: Comparative evaluation of nephrotoxicity and management by macrophages of intravenous pharmaceutical iron formulations.
abstract: BACKGROUND
  There is a significant clinical need for effective treatment of iron deficiency. A number of compounds that can be administered intravenously have been developed. This study examines how the compounds are handled by macrophages and their relative potential to provoke oxidative stress.
  
  
  METHODS
  Human kidney (HK-2) cells, rat peritoneal macrophages and renal cortical homogenates were exposed to pharmaceutical iron preparations. Analyses were performed for indices of oxidative stress and cell integrity. In addition, in macrophages, iron uptake and release and cytokine secretion was monitored.
  
  
  RESULTS
  HK-2 cell viability was decreased by iron isomaltoside and ferumoxytol and all compounds induced lipid peroxidation. In the renal cortical homogenates, lipid peroxidation occurred at lowest concentrations with ferric carboxymaltose, iron dextran, iron sucrose and sodium ferric gluconate. In the macrophages, iron sucrose caused loss of cell viability. Iron uptake was highest for ferumoxytol and iron isomaltoside and lowest for iron sucrose and sodium ferric gluconate. Iron was released as secretion of ferritin or as ferrous iron via ferroportin. The latter was blocked by hepcidin. Exposure to ferric carboxymaltose and iron dextran resulted in release of tumor necrosis factor α.
  
  
  CONCLUSIONS
  Exposure to iron compounds increased cell stress but was tissue and dose dependent. There was a clear difference in the handling of iron from the different compounds by macrophages that suggests in vivo responses may differ.
authors.affiliation: Department of Neurosurgery, M.S. Hershey Penn State University College of Medicine, M.S. Hershey Medical Center, Hershey, Pennsylvania, United States of America.
authors.forename: James R
authors.initials: JR
authors.lastname: Connor
authors.affiliation: Department of Neurosurgery, M.S. Hershey Penn State University College of Medicine, M.S. Hershey Medical Center, Hershey, Pennsylvania, United States of America.
authors.forename: Xuesheng
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery, M.S. Hershey Penn State University College of Medicine, M.S. Hershey Medical Center, Hershey, Pennsylvania, United States of America.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Nixon
authors.affiliation: Department of Neurosurgery, M.S. Hershey Penn State University College of Medicine, M.S. Hershey Medical Center, Hershey, Pennsylvania, United States of America.
authors.forename: Becky
authors.initials: B
authors.lastname: Webb
authors.affiliation: Luitpold Pharmaceuticals, Inc., Norristown, Pennsylvania, United States of America.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Perno
mesh_terms: D000818:Animals; D027682:Cation Transport Proteins / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004187:Disaccharides / Q000494:pharmacology*; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005290:Ferric Compounds / Q000494:pharmacology*; D000077605:Ferric Oxide, Saccharated; D005293:Ferritins / Q000378:metabolism; D052203:Ferrosoferric Oxide / Q000494:pharmacology*; D005937:Glucaric Acid / Q000494:pharmacology; D064451:Hepcidins / Q000378:metabolism; D006801:Humans; D007501:Iron / Q000378:metabolism*; D007505:Iron-Dextran Complex / Q000494:pharmacology; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015227:Lipid Peroxidation; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008320:Maltose / Q000031:analogs & derivatives / Q000494:pharmacology; D018384:Oxidative Stress; D061251:Primary Cell Culture; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000098742:Ferroportin
chemical_list: D027682:Cation Transport Proteins; D004187:Disaccharides; D005290:Ferric Compounds; D064451:Hepcidins; D014409:Tumor Necrosis Factor-alpha; D000098742:Ferroportin; C557707:iron isomaltoside 1000; C522335:ferric carboxymaltose; D008320:Maltose; D007505:Iron-Dextran Complex; D005293:Ferritins; D007501:Iron; D000077605:Ferric Oxide, Saccharated; D005937:Glucaric Acid; C035552:ferric gluconate; D052203:Ferrosoferric Oxide