Parenteral iron therapy exacerbates experimental sepsis

Kidney Int. 2004 Jun;65(6):2108-12. doi: 10.1111/j.1523-1755.2004.00742.x.


Background: Catalytic iron can potentiate systemic inflammation via its pro-oxidant effects. This raises the possibility that parenteral iron administration might exacerbate a concomitant septic state. This study sought to experimentally test this hypothesis.

Methods: Male CD-1 mice were subjected to experimental sepsis via intraperitoneal injection of heat-killed Escherichia coli +/- concomitant intravenous iron sucrose (Venofer; 2 mg). Nonseptic mice +/- iron therapy served as controls. Plasma tumor necrosis factor-alpha (TNF-alpha) levels were assessed 2 hours postinjections (serving as an inflammatory marker). Oxidative stress was gauged in heart or kidney tissue (at either 4 or 24 hours) by heme oxygenase-1 (HO-1) mRNA or protein levels. Overall sepsis severity was assessed by morbidity/mortality rates (at 24 hours).

Results: Iron alone or sepsis alone each induced oxidant stress in heart and kidney (HO-1 mRNA/protein increases). When iron and E. coli were coadministered, additive or synergistic HO-1 mRNA/protein increments resulted. Iron injection alone only slightly raised TNF-alpha levels (from 0 to 2.3 pg/mL; P= 0.01). However, iron approximately doubled the TNF-alpha increments which arose from the septic state (1400 --> 2600 pg/mL). Neither sepsis alone, nor iron alone, induced any mortality and no mice became moribund (0/24 mice). However, when iron + sepsis were combined, approximately 60% of mice either died (5/12) or developed a moribund (2/12) state (P= 0.005).

Conclusion: Parenteral iron administration can induce systemic oxidative stress and modest TNF-alpha release. However, when iron is given during experimental sepsis, profound increases in both processes, and approximately 60% mortality, result. Given that renal failure patients have decreased antioxidant defenses and intermittently develop bacteremia, the potential for parenteral iron therapy to exacerbate clinical sepsis needs to be addressed.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Endotoxins / toxicity
  • Heme Oxygenase (Decyclizing) / genetics
  • Heme Oxygenase (Decyclizing) / metabolism
  • Heme Oxygenase-1
  • Inflammation / etiology
  • Inflammation / genetics
  • Inflammation / metabolism
  • Injections, Intravenous
  • Iron / administration & dosage
  • Iron / toxicity*
  • Kidney / metabolism
  • Male
  • Membrane Proteins
  • Mice
  • Myocardium / metabolism
  • Oxidative Stress / drug effects
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Sepsis / etiology*
  • Sepsis / genetics
  • Sepsis / metabolism
  • Tumor Necrosis Factor-alpha / metabolism


  • Endotoxins
  • Membrane Proteins
  • RNA, Messenger
  • Tumor Necrosis Factor-alpha
  • endotoxin, Escherichia coli
  • Iron
  • Heme Oxygenase (Decyclizing)
  • Heme Oxygenase-1
  • Hmox1 protein, mouse