title: Effect of iron treatment on circulating cytokine levels in ESRD patients receiving recombinant human erythropoietin.
abstract: BACKGROUND
  Anemia in patients with end-stage renal disease (ESRD) is treated with recombinant human erythropoietin (rhEPO) often in combination with iron. However, iron catalyzes the formation of toxic radicals, which might promote vascular damage, is a nutrient for microorganisms, and negatively affects immune pathways, thus increasing the risk for severe infections.
  
  
  METHODS
  We investigated 28 patients on chronic hemodialysis who were randomized to receive either rhEPO alone (N = 15) or rhEPO in combination with intravenous iron (N = 13) for a period of 12 weeks. We analyzed iron therapy associated changes in cytokine patterns and endogenous radical formation.
  
  
  RESULTS
  Tumor necrosis factor-alpha (TNF-alpha) levels were increased in ESRD patients at study entry and then decreased significantly over time in subjects receiving additional iron, while they increased with rhEPO alone. In contrast, we found serum concentrations of the anti-inflammatory cytokine interleukin (IL)-4 to increase with iron therapy. A significant negative correlation between iron availability, as determined by transferrin saturation, and TNF-alpha levels (P = 0.008) and a positive one between transferring saturation and IL-4 (P = 0.02) pointed to the potential role of iron to induce immunologic changes. Interestingly, iron therapy resulted in a slight decrease in the amounts of endogenous peroxides, which may be referred to reduced TNF-alpha concentrations since peroxide concentrations were positively correlated to TNF-alpha levels (P = 0.046) and negatively to transferrin saturation (P = 0.02).
  
  
  CONCLUSIONS
  Iron supplementation in ESRD patients down-regulates proinflammatory immune effector pathways and stimulates the expression of the anti-inflammatory cytokine IL-4. Such a condition is detrimental for host response toward invading pathogens. However, tissue damage by radicals such as endogenous peroxides may be reduced in this condition due to impaired TNF-alpha formation.
authors.affiliation: Department of Internal Medicine and Division of Nephrology, University Hospital of Innsbruck, Innsbruck, Austria. guenter.weiss@uibk.ac.at
authors.forename: Günter
authors.initials: G
authors.lastname: Weiss
authors.forename: Edgar
authors.initials: E
authors.lastname: Meusburger
authors.forename: Gudrun
authors.initials: G
authors.lastname: Radacher
authors.forename: Katja
authors.initials: K
authors.lastname: Garimorth
authors.forename: Ulrich
authors.initials: U
authors.lastname: Neyer
authors.forename: Gert
authors.initials: G
authors.lastname: Mayer
mesh_terms: D000368:Aged; D000740:Anemia / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D004359:Drug Therapy, Combination; D004921:Erythropoietin / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D015847:Interleukin-4 / Q000378:metabolism*; D007501:Iron / Q000008:administration & dosage*; D007676:Kidney Failure, Chronic / Q000150:complications* / Q000276:immunology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress; D011994:Recombinant Proteins; D006435:Renal Dialysis; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D004921:Erythropoietin; D015847:Interleukin-4; D007501:Iron