Intravenous ferric chloride hexahydrate supplementation induced endothelial dysfunction and increased cardiovascular risk among hemodialysis patients

PLoS One. 2012;7(12):e50295. doi: 10.1371/journal.pone.0050295. Epub 2012 Dec 5.

Abstract

Background: The association between intravenous (IV) iron administration and outcomes in hemodialysis (HD) patients is still debated. Therefore, this study was aimed to assess the relationship between the IV administration of ferric chloride hexahydrate (Atofen®) and cardiovascular (CV) outcome and the interaction between iron-induced oxidative stress and endothelial dysfunction in chronic HD patients.

Methodology/principal findings: A cohort of 1239 chronic HD patients was recruited. In a follow-up of 12 months, Kaplan-Meier survival curves showed that higher doses of IV Atofen associated with higher risks for CV events and deaths in HD patients. In multivariate Cox models, compared to no iron supplementation, IV Atofen administration was an independent predictor for CV events and overall mortality. However, the nature of the observational cohort study possibly bears selection bias. We further found that IV Atofen enhanced the superoxide production of mononuclear cells (MNCs), the levels of circulating soluble adhesion molecules, and the adhesion of MNCs to human aortic endothelial cells (HAECs). In vitro experiments showed that Atofen increased the expression of intracellular cell adhesion molecule-1 and vascular cell adhesion molecule-1 in HAECs and aggravated the endothelial adhesiveness in a dose-dependent manner. These iron-induced changes were significantly attenuated by the co-treatment of HAECs with N-acetylcysteine and inhibitors of NADPH oxidase, nuclear factor κB, and activator protein-1.

Conclusion: A cumulative dose of IV Atofen >800 mg within 6 months was associated with an adverse CV outcome and a higher mortality among chronic HD patients. The detrimental effects of IV iron supplementation were partly due to the increased oxidative stress and induction of MNC adhesion to endothelial cells, a pivotal index of early atherogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Cardiovascular Diseases / epidemiology*
  • Cell Adhesion Molecules / metabolism
  • Cells, Cultured
  • Chlorides / administration & dosage*
  • Endothelium, Vascular / physiopathology*
  • Female
  • Ferric Compounds / administration & dosage*
  • Humans
  • Male
  • Middle Aged
  • Prospective Studies
  • Renal Dialysis*
  • Superoxides / metabolism

Substances

  • Cell Adhesion Molecules
  • Chlorides
  • Ferric Compounds
  • Superoxides
  • ferric chloride

Grant support

This work was supported by grants from the National Science Council (NSC 96-2628-B-010-001-MY3 and NSC 99-2314-B-303-002-MY3), Taipei Veterans General Hospital (V100C-143 and V100E4-003), Ministry of Education’s Aim for the Top University Plan, and Taipei Tzu Chi General Hospital (TCRD-TPE-97-15). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.