link.springer.com

Non-transferrin bound iron, cytokine activation and intracellular reactive oxygen species generation in hemodialysis patients receiving intravenous iron dextran or iron sucrose - BioMetals

  • ️Hicks, Paul
  • ️Thu Jan 13 2011

Abstract

Intravenous (IV) iron supplementation is widely used to support erythropoeisis in hemodialysis patients. IV iron products are associated with oxidative stress that has been measured principally by circulating biomarkers such as products of lipid peroxidation. The pro-oxidant effects of IV iron are presumed to be due at least in part, by free or non-transferrin bound iron (NTBI). However, the effects of IV iron on intracellular redox status and downstream effectors is not known. This prospective, crossover study compared cytokine activation, reactive oxygen species generation and oxidative stress after single IV doses of iron sucrose and iron dextran. This was a prospective, open-label, crossover study. Ten patients with end-stage renal disease (ESRD) on hemodialysis and four age and sex-matched healthy were assigned to receive 100 mg of each IV iron product over 5 min in random sequence with a 2 week washout between products. Subjects were fasted and fed a low iron diet in the General Clinical Research Center at the University of New Mexico. Serum and plasma samples for IL-1, IL-6, TNF-α and IL-10 and NTBI were obtained at baseline, 60 and 240 min after iron infusion. Peripheral blood mononuclear cells (PBMC) were isolated at the same time points and stained with fluorescent probes to identify intracellular reactive oxygen species and mitochondrial membrane potential (Δψm) by flow cytometry. Lipid peroxidation was assessed by plasma F2 isoprostane concentration. Mean ± SEM maximum serum NTBI values were significantly higher among patients receiving IS compared to ID (2.59 ± 0.31 and 1.0 ± 0.36 µM, respectively, P = 0.005 IS vs. ID) Mean ± SEM NTBI area under the serum concentration–time curve (AUC) was 3-fold higher after IS versus ID (202 ± 53 vs. 74 ± 23 µM*min/l, P = 0.04) in ESRD patients, indicating increased exposure to NTBI. IV iron administration was associated with increased pro-inflammatory cytokines. Serum IL-6 concentrations increased most profoundly, with a 2.6 and 2.1 fold increase from baseline in ESRD patients given IS and ID, respectively (P < 0.05 compared to baseline). In healthy controls, serum IL-6 was undetectable at baseline and after IV iron administration. Most ESRD patients had increased intracellular ROS generation, however, there was no difference between ID and IS. Only one healthy control had increased ROS generation post IV iron. All healthy controls experienced a loss of Δψm (100% with IS and 50% with ID). ESRD patients also had loss of Δψm with a nadir at 240 min. IS administration was associated with higher maximum serum NTBI concentrations compared to ID, however, the both compounds produced similar ROS generation and cytokine activation that was more pronounced among ESRD patients. The effect of IV iron-induced ROS production on pivotal signaling pathways needs to be explored.

Access this article

Log in via an institution

Subscribe and save

  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  • Adibhatla RM, Hatcher JF (2010) Lipid oxidation and peroxidation in CNS health and disease: from molecular mechanisms to therapeutic opportunities. Antioxid Redox Signal 12(1):125–169

    Article  PubMed  CAS  Google Scholar 

  • Balakrishnan VS et al (2009) Physiochemical properties of ferumoxytol, a new intravenous iron preparation. Eur J Clin Invest 39:1–8

    Article  Google Scholar 

  • Besarab A, Bolton WK, Browne JK et al (1998) The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. N Engl J Med 339:584–590

    Article  PubMed  CAS  Google Scholar 

  • Breuer W, Cabantchik ZI (2001) A fluorescence-based one-step assay for serum non-transferrin bound iron. Anal Biochem 299:194–202

    Article  PubMed  CAS  Google Scholar 

  • Centers for Medicare and Medicaid Services, Conditions for Coverage, ESRD Conditions Final Rule, April 15, 2008. http://www.cms.gov/CFCsAndCoPs/13_ESRD.asp. Cited 9 Aug 2010

  • Danielson BG (2004) Structure, chemistry, and pharmacokinetics of intravenous iron agents. J Am Soc Nephrol 15(Suppl 2):S93–S98

    PubMed  Google Scholar 

  • den Elzen WP, van Manen JG, Boeschoten EW et al (2006) The effect of single and repeatedly high concentrations of C-reactive protein on cardiovascular and non-cardiovascular mortality in patients starting with dialysis. Nephrol Dial Transplant 21(6):1588–1595

    Article  Google Scholar 

  • Drüeke TB, Locatelli F, Clyne N et al (2006) Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med 355(20):2071–2084

    Article  PubMed  Google Scholar 

  • Feldman HI, Joffe M, Robinson B et al (2004) Administration of parenteral iron and mortality among hemodialysis patients. J Am Soc Nephrol 15(6):1623–1632

    Article  PubMed  CAS  Google Scholar 

  • Fleming MD (2008) The regulation of hepcidin and its effects on systemic and cellular iron metabolism. Hematology Am Soc Hematol Educ Program 151–158

  • Garcia-Fernandez N, Echeverria A, Sanchez-Ibarrola A et al (2010) Randomized clinical trial on acute effects of i.v. iron sucrose during haemodialysis. Nephrology (Carlton) 15(2):178–183

    Article  CAS  Google Scholar 

  • Granata S, Zaza G, Simone S et al (2009) Mitochondrial dysregulation and oxidative stress in patients with chronic kidney disease. BMC Genomics 10:388

    Article  PubMed  Google Scholar 

  • Henderson PA, Hillman RS (1969) Characteristics of iron dextran utilization in man. Blood 34(3):357–375

    PubMed  CAS  Google Scholar 

  • Himmelfarb J, Stenvinkel P, Ikizler TA et al (2002) The elephant in uremia: oxidant stress as a unifying concept of cardiovascular disease in uremia. Kidney Int 62(5):1524–1538

    Article  PubMed  CAS  Google Scholar 

  • Johnson AC, Becker K, Zager RA (2010) Parenteral iron formulations differentially affect MCP-1, HO-1, and NGAL gene expression and renal responses to injury. Am J Physiol Renal Physiol 299(2):F426–F435

    Article  PubMed  CAS  Google Scholar 

  • Kalantar-Zadeh K, Regidor DL, McAllister CJ et al (2005) Time-dependent associations between iron and mortality in hemodialysis patients. J Am Soc Nephrol 16(10):3070–3080

    Article  PubMed  CAS  Google Scholar 

  • KDOQI (2006) Clinical practice guidelines, clinical practice recommendations for anemia in chronic kidney disease. Am J Kidney Dis 47:S11–S145

    Article  Google Scholar 

  • Kuo KL, Hung SC, Wei YH et al (2008) Intravenous iron exacerbates oxidative DNA damage in peripheral blood lymphocytes in chronic hemodialysis patients. J Am Soc Nephrol 19(9):1817–1826

    Article  PubMed  CAS  Google Scholar 

  • Lim PS, Wei YH, Yu YL et al (1999) Enhanced oxidative stress in haemodialysis patients receiving intravenous iron therapy. Nephrol Dial Transplant 14:268–2680

    Article  Google Scholar 

  • Manley HJ, Grabe DW (2004) Determination of iron sucrose (Venofer) or iron dextran (DexFerrum) removal by hemodialysis: an in vitro study. BMC Nephrol 5(1):1–7

    Article  PubMed  Google Scholar 

  • Morrow JD, Hill KE, Burk RF et al (1990) A series of prostaglandin F2-like compounds are produced in vivo in humans by a non-cyclooxygenase, free radical-catalyzed mechanism. Proc Natl Acad Sci USA 87(23):938

    Article  Google Scholar 

  • Pai AB, Harford A, Boyd AV et al (2007) Comparison of oxidative stress markers in hemodialysis patients following administration of iron dextran, sodium ferric gluconate and iron sucrose. Pharmacotherapy 27:343–350

    Article  PubMed  CAS  Google Scholar 

  • Pai AB, Nielson JC, Kausz A et al (2010) Plasma pharmacokinetics of two consecutive doses of ferumoxytol in healthy subjects. Clin Pharmacol Ther 88(2):237–242

    Article  PubMed  CAS  Google Scholar 

  • Panichi V, Maggiore U, Taccola D (2004) Interleukin-6 is a stronger predictor of total and cardiovascular mortality than C-reactive protein in haemodialysis patients. Nephrol Dial Transplant 19(5):1154–1160

    Article  PubMed  CAS  Google Scholar 

  • Pfeffer MA, Burdmann EA, Chen CY et al (2009) A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med 361(21):2019–2032

    Article  PubMed  Google Scholar 

  • Product Information InFeD® (2009) Watson Pharma, Inc. Morristown, NJ, September 2009

  • Raj DS, Boivin MA, Dominic EA et al (2007) Haemodialysis induces mitochondrial dysfunction and apoptosis. Eur J Clin Invest 37(12):971–977

    Article  PubMed  CAS  Google Scholar 

  • Seligman PA, Dahl NV, Strobos J et al (2004) Single-dose pharmacokinetics of sodium ferric gluconate complex in iron-deficient subjects. Pharmacotherapy 24(5):574–583

    Article  PubMed  CAS  Google Scholar 

  • Shvartsman M, Kikkeri R, Shanzer A et al (2007) Non-transferrin-bound iron reaches mitochondria by a chelator-inaccessible mechanism: biological and clinical implications. Am J Physiol Cell Physiol 293(4):C1383–C1394

    Article  PubMed  CAS  Google Scholar 

  • Singh AK, Szczech L, Tang KL et al (2006) Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med 355(20):2085–2098

    Article  PubMed  CAS  Google Scholar 

  • Toblli JE, Cao G, Olivieri L et al (2010) Comparison of the renal, cardiovascular and hepatic toxicity data of original intravenous iron compounds. Nephrol Dial Transplant 25(11):3631–3640

    Article  PubMed  CAS  Google Scholar 

  • Van Campenhout A, Van Campenhout C, Lagrou A et al (2008) Iron-induced oxidative stress in hemodialysis patients: a pilot study on the impact of diabetes. Biometals 21:159–170

    Article  PubMed  CAS  Google Scholar 

  • Van Wyck D, Anderson J, Johnson K (2004) Labile iron in parenteral iron formulations: a quantitative and comparative study. Nephrol Dial Transplant 19(3):561–565

    Article  PubMed  Google Scholar 

  • Zager RA (2006) Parenteral iron compounds: potent oxidants but mainstays of anemia management in chronic renal disease. Clin J Am Soc Nephrol 1(Suppl 1):S24–S31

    Article  PubMed  CAS  Google Scholar 

  • Zager RA, Johnson ACM, Hanson SY et al (2002) Parenteral iron formulations: a comparative toxicologic analysis and mechanisms of cell injury. Am J Kidney Dis 40(1):90–103

    Article  PubMed  CAS  Google Scholar 

  • Zaritsky J, Young B, Wang HJ et al (2009) Hepcidin—a potential novel biomarker for iron status in chronic kidney disease. Clin J Am Soc Nephrol 4(6):1051–1056

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This project was supported in part by the American College of Clinical Pharmacy Watson Laboratories Anemia Research Award and by the University of New Mexico General Clinical Research Center DHHS/NIH/NCRR/GCRC 5M01RR00997.

Author information

Authors and Affiliations

  1. Department of Pharmacy Practice, ANephRx-Albany Nephrology Pharmacy Group, Albany College of Pharmacy and Health Sciences, 106 New Scotland Avenue, Albany, NY, 12208, USA

    Amy Barton Pai

  2. VA Cooperative Studies Program, Albuquerque Veteran Affairs Medical Center, 1501 San Pedro NE, Albuquerque, NM, 87108, USA

    Todd Conner

  3. College of Pharmacy, University of New Mexico, 2502 Marble NE, Albuquerque, NM, 87106, USA

    Charles R. McQuade, Jonathan Olp & Paul Hicks

Authors

  1. Amy Barton Pai

    You can also search for this author in PubMed Google Scholar

  2. Todd Conner

    You can also search for this author in PubMed Google Scholar

  3. Charles R. McQuade

    You can also search for this author in PubMed Google Scholar

  4. Jonathan Olp

    You can also search for this author in PubMed Google Scholar

  5. Paul Hicks

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Amy Barton Pai.

About this article

Cite this article

Pai, A.B., Conner, T., McQuade, C.R. et al. Non-transferrin bound iron, cytokine activation and intracellular reactive oxygen species generation in hemodialysis patients receiving intravenous iron dextran or iron sucrose. Biometals 24, 603–613 (2011). https://doi.org/10.1007/s10534-011-9409-6

Download citation

  • Received: 11 August 2010

  • Accepted: 05 January 2011

  • Published: 13 January 2011

  • Issue Date: August 2011

  • DOI: https://doi.org/10.1007/s10534-011-9409-6

Keywords