Parenteral iron nephrotoxicity: potential mechanisms and consequences.
BACKGROUND
Parenteral iron administration is a mainstay of anemia management in renal disease patients. However, concerns of potential iron toxicity persist. Thus, this study was conducted to more fully gauge iron toxicologic profiles and potential determinants thereof.


METHODS
Isolated mouse proximal tubule segments (PTS) or cultured proximal tubular [human kidney (HK-2)] cells were exposed to four representative iron preparations [iron sucrose (FeS), iron dextran (FeD), iron gluconate (FeG), or iron oligosaccharide (FeOS)] over a broad dosage range (0, 30 to 1000 microg iron/mL). Cell injury was assessed by lactate deyhdrogenase (LDH) release, adenosine triphosphate (ATP) reductions, cell cytochrome c efflux, and/or electron microscopy. In vivo toxicity (after 2 mg intravenous iron injections) was assessed by plasma/renal/cardiac lipid peroxidation [malondialdehyde (MDA)], renal ferritin (protein)/heme oxygenase-1 (HO-1) (mRNA) expression, electron microscopy, or postiron injection PTS susceptibility to attack.


RESULTS
In each test, iron evoked in vitro toxicity, but up to 30x differences in severity (e.g., ATP declines) were observed (FeS > FeG > FeD = FeOS). The in vitro differences paralleled degrees of cell (HK-2) iron uptake. In vivo correlates of iron toxicity included variable increases in renal MDA, ferritin, and HO-1 mRNA levels. Again, these changes appeared to parallel in vivo (glomerular) iron uptake (seen with FeS and FeG, but not with FeD or FeOS). Iron also effected in vivo alterations in proximal tubule cell homeostasis, as reflected by the "downstream" emergence of tubule resistance to in vitro oxidant attack.


CONCLUSIONS
Parenteral iron formulations have potent, but highly variable, cytotoxic potentials which appear to parallel degrees of cell iron uptake (FeS > FeG >> FeD or FeOS). That in vitro injury can be expressed at clinically relevant iron concentrations, and that in vivo glomerular iron deposition/injury may result, suggest caution is warranted if these agents are to be administered to patients with active renal disease.
Zager
Richard A
RA
Department of Medicine, University of Washington, Seattle, Washington, USA. dzager@fhcrc.org
Johnson
Ali C M
AC
Hanson
Sherry Y
SY
D000818:Animals; D002460:Cell Line; D045304:Cytochromes c / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005290:Ferric Compounds / Q000008:administration & dosage / Q000506:poisoning; D000077605:Ferric Oxide, Saccharated; D005937:Glucaric Acid; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics; D051547:Heme Oxygenase-1; D006801:Humans; D066298:In Vitro Techniques; D007263:Infusions, Parenteral; D007501:Iron / Q000008:administration & dosage* / Q000506:poisoning*; D007505:Iron-Dextran Complex / Q000008:administration & dosage / Q000506:poisoning; D007668:Kidney / Q000473:pathology / Q000648:ultrastructure; D007672:Kidney Cortex / Q000201:enzymology; D007674:Kidney Diseases / Q000139:chemically induced* / Q000201:enzymology / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008815:Mice, Inbred Strains; D008854:Microscopy, Electron; D012333:RNA, Messenger / Q000378:metabolism; D012720:Severity of Illness Index
D005290:Ferric Compounds; D008565:Membrane Proteins; D012333:RNA, Messenger; D007505:Iron-Dextran Complex; D045304:Cytochromes c; D007501:Iron; C496541:HMOX1 protein, human; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D000077605:Ferric Oxide, Saccharated; D005937:Glucaric Acid; C035552:ferric gluconate