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Impact of hepcidin, interleukin 6, and other inflammatory markers with respect to erythropoietin on anemia in chronic hemodialysis patients

The Egyptian Journal of Internal Medicine volume 26, pages 6–14 (2014)Cite this article

Abstract

Background/objective

Hepcidin is a peptide hormone produced by the liver and appears to be the master regulator of iron homeostasis. This peptide is upregulated in inflammatory conditions, including uremia. Hepcidin functions to regulate (inhibit) iron transport across the gut mucosa, thereby preventing excess iron absorption and maintaining normal iron levels within the body. In this study, we aimed to investigate hepcidin levels and their relationship with the parameters of iron status, inflammation, anemia therapy, and parameters of dialysis efficiency in hemodialysis patients.

Patients and methods

Plasma hepcidin-25, inflammatory markers (high-sensitivity C-reactive protein and interleukin 6), and peripheral iron indices (serum iron, total iron-binding capacity, transferrin saturation and serum ferritin) were measured before hemodialysis in 40 end-stage renal disease (ESRD) patients treated with regular hemodialysis in a single dialysis unit as well as in 20 healthy individuals matched for age and sex serving as the control group.

Results

Plasma levels of hepcidin-25 were significantly higher in hemodialysis patients compared with controls. In a simple correlation analysis, plasma hepcidin levels were positively correlated with ferritin, transferrin saturation, CRP, and interleukin 6; however, it was negatively correlated with hemoglobin, dose of epoitin-α, and dose of iron.

Conclusion

Serum hepcidin levels were associated with iron status and inflammation in maintenance hemodialysis patients, and the high hepcidin serum levels, found in hemodialysis (HD) patients, are dependent on the magnitude of the inflammatory process and on recombinant human erythropoietin doses. Hepcidin and its regulatory pathways are potential therapeutic targets, which could lead to effective treatment of anemia in chronic hemodialysis.

References

  1. Eleftheriadis T, Liakopoulos V, Antoniadi G, Kartsios C, Stefanidis I. The role of hepcidin in iron homeostasis and anemia in hemodialysis patients. Semin Dial 2009; 22: 70–77.

    PubMed  Google Scholar 

  2. KDOQI, National Kidney Foundation. KDOQI clinical practice guidelines and clinical practice recommendations for anaemia in chronic kidney disease. Am J Kidney Dis 2006; 47: S11–S145.

    Google Scholar 

  3. Weiss G, Theurl I, Eder S, et al. Serum hepcidin concentration in chronic haemodialysis patients: associations and effects of dialysis, iron and erythropoietin therapy. Eur J Clin Invest 2009; 39: 883–890.

    CAS  PubMed  Google Scholar 

  4. Verga Falzacappa MV, Muckenthaler MU. Hepcidin: iron hormone and anti-microbial peptide. Gene 2005; 364: 37–44.

    Google Scholar 

  5. Park CH, Valore EU, Waring AJ, et al. Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J Biol Chem 2001; 276: 7806–7810.

    CAS  PubMed  Google Scholar 

  6. Nicolas G, Chauvet C, Viatte L, et al. The gene encoding the iron regulatory peptide hepcidin is regulated by anaemia, hypoxia, and inflammation. J Clin Invest 2002; 110: 1037–1044.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Nemeth E, Ganz T. Regulation of iron metabolism by hepcidin. Annu Rev Nutr 2006; 26: 323–342.

    CAS  PubMed  Google Scholar 

  8. Babitt JL, Lin HY. Molecular mechanisms of hepcidin regulation: implications for the anaemia of CKD. Am J Kidney Dis 2010; 55: 726–741.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Nemeth E, Tuttle MS, Powelson J, et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 2004; 306: 2090–2093.

    CAS  PubMed  Google Scholar 

  10. Ganz T. Hepcidin and its role in regulating systemic iron metabolism. Hematology Am Soc Hematol Educ Program 2006; 507: 29–35.

    Google Scholar 

  11. Cui YJ, Wu QY, Zhou YQ. Iron-refractory iron deficiency anemia: new molecular mechanisms. Kidney Int 2009; 76: 1137–1141.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Daugirdas JT. Second generation logarithmic estimates of single-pool variable volume Kt/V: an analysis of error. J Am Soc Nephrol 1993; 4: 1205–1213.

    CAS  PubMed  Google Scholar 

  13. Rodkey FL. Binding of bromocresol green by human serum albumin. Arch Biochem Biophys 1964; 108: 510–513.

    CAS  PubMed  Google Scholar 

  14. Kessler G, Wolfman M. An automated procedure for the simultaneous determination of calcium and phosphorus. Clin Chem 1965; 45: 290–296.

    Google Scholar 

  15. Goodwin JF. Quantification of serum inorganic phosphorus, phosphatase, and urinary phosphate without preliminary treatment. Clin Chem 1970; 16: 776–780.

    CAS  PubMed  Google Scholar 

  16. Wahlefeld AW. Triglyceride determination after enzymatic hydrolys. In: HU Berger, editor. Methods of enzymatic analysis. 2nd English ed. (translated from 3rd German ed.). NY and London: Verlag Chemie Weinheim and Academic Press Inc.; 1974. 4: 1813–1835.

    Google Scholar 

  17. Flegg HM. An investigation for the determination of serum cholesterol by an enzymatic method. Ann Clin Biochem 1973; 10: 79–84.

    CAS  Google Scholar 

  18. Friedwald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifugation. Clin Chem 1972; 18: 499–502.

    Google Scholar 

  19. Trinder L. Determination of blood glucose using an oxidase–peroxidase system with a non-carcinogenic chromagen. Ann Clin Biochem 1969; 22: 158–161

    CAS  Google Scholar 

  20. Xu Y, Ding XQ, Zou JZ, et al. Serum hepcidin in haemodialysis patients: associations with iron status and microinflammation. J Int Med Res 2011; 39: 19611967.

    Google Scholar 

  21. Tessitore N, Girelli D, Campostrini N, et al. Hepcidin is not useful as a biomarker for iron needs in haemodialysis patients on maintenance erythropoiesis-stimulating agents. Nephrol Dial Transplant 2010; 25: 3996–4002.

    CAS  PubMed  Google Scholar 

  22. Nemeth E, Valore EV, Territo M, et al. Hepcidin, a putative mediator of anemia of inflammation, is a type II acute-phase protein. Blood 2003; 101: 2461–2463.

    CAS  PubMed  Google Scholar 

  23. Kato A, Tsuji T, Luo J, et al. Association of prohepcidin and hepcidin-25 with erythropoietin response and ferritin in hemodialysis patients. Am J Nephrol 2008; 28: 115–121.

    CAS  PubMed  Google Scholar 

  24. Tomosugi N, Kawabata H, Wakatabe R, et al. Detection of serum hepcidin in renal failure and inflammation by using ProteinChip system. Blood 2006; 108: 1381–1387.

    CAS  PubMed  Google Scholar 

  25. Ashby DR, Gale DP, Busbridge M, et al. Plasma hepcidin levels are elevated but responsive to erythropoietin therapy in renal disease. Kidney Int 2009; 75: 976–981.

    CAS  PubMed  Google Scholar 

  26. Fujita N, Sugimoto R, Takeo M, Urawa N, Mifuji R, Tanaka H, et al.; Hepcidin expression in the liver : relatively low level in patients with chronic hepatitis C. Mol Med. 2007 Jan-Feb; 13: 97–104.

  27. Kumar S, Raftery M, Yaqoob M, et al. Anti-inflammatory effects of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors (statins) in peritoneal dialysis patients. Perit Dial Int 2007; 27: 283287.

    Google Scholar 

  28. Liu XB, Nguyen NB, Marquess KD, et al. Regulation of hepcidin and ferroportin expression by lipopolysaccharide in splenic macrophage. Blood Cells Mol Dis 2005; 35: 47–56.

    CAS  PubMed  Google Scholar 

  29. Kearney SL, E Nemeth, EJ Neufeld, et al. Urinary hepcidin in congenital chronic anemias. Pediatr Blood Cancer 2007; 48: 57–63.

    PubMed  Google Scholar 

  30. Stenvinkel P, Ketteler M, Johnson RJ, et al. IL-10, IL-6, and TNF-alpha: central factors in the altered cytokine network of uremia — the good, the bad, and the ugly. Kidney Int 2005; 67: 1216–1233.

    CAS  PubMed  Google Scholar 

  31. Wrighting DM, Andrews NC. Interleukin-6 induces hepcidin expression through STAT3. Blood 2006; 108: 3204–3209.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Costa E, Pereira BJG, Rocha-Pereira P, et al. Role of prohepcidin, inflammatory markers and iron status in resistance to rhEPO therapy in hemodialysis patients. Am J Nephrol 2008; 28: 677–683.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Van der Weerd NC, Grooteman MPC, Bots ML, et al. Hepcidin-25 in chronic hemodialysis patients is related to residual kidney function and not to treatment with erythropoiesis stimulating agents. PLoS One 2012; 7: e39783.

    PubMed  PubMed Central  Google Scholar 

  35. Macdougall IC, Malyszko J, Hider RC, Bansal SS. Current status of the measurement of blood hepcidin levels in chronic kidney disease. Clin J Am Soc Nephrol. 2010; 5: 1681–1689.

    CAS  PubMed  Google Scholar 

  36. Kemna EH, Tjalsma H, Willems HL, Swinkels DW. Hepcidin: from discovery to differential diagnosis. Haematologica 2008; 93: 90–97.

    CAS  PubMed  Google Scholar 

  37. Sasu BJ, Cooke KS, Arvedson TL, et al. Antihepcidin antibody treatment modulates iron metabolism and is effective in a mouse model of inflammation-induced anemia. Blood 2010; 115: 3616–3624.

    CAS  PubMed  Google Scholar 

  38. Noxxon Pharma AG. 2011. Pipeline. NOX-H94, 44-nucleotide l-RNA oligonucleotide linked to 40 kDa PEG. Available at: http://www.noxxon.com/index.php?option_com_content&view_article&id_88&Itemid_100. [Accessed 29 May 2011]

  39. Macdougall IC. New anemia therapies: translating novel strategies from bench to bedside. Am J Kidney Dis 2012; 59: 444–451.

    PubMed  Google Scholar 

  40. Pinto JP, Ribeiro S, Pontes H, et al. Erythropoietin mediates hepcidin expression in hepatocytes through EPOR signaling and regulation of C/EBPalpha. Blood 2008; 111: 5727–5733.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Tanno T, Bhanu NV, Oneal PA, et al. High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin. Nat Med 2007; 13: 1096–1101.

    CAS  PubMed  Google Scholar 

  42. Tanno T, Porayette P, Sripichai O, et al. Identification of TWSG1 as a second novel erythroid regulator of hepcidin expression in murine and human cells. Blood 2009; 114: 181–186.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Zaritsky J, Young B, Gales B, et al. Reduction of serum hepcidin by haemodialysis in pediatric and adult patients. Clin J Am Soc Nephrol 2010; 5: 1010–1014.

    PubMed  PubMed Central  Google Scholar 

  44. Swinkels DW, Wetzels JFM. Hepcidin: a new tool in the management of anaemia in patients with chronic kidney disease? Nephrol Dial Transplant 2008; 23: 2450–2453.

    CAS  PubMed  Google Scholar 

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Author information

Authors and Affiliations

  1. Departments of Internal Medicine, Division of Nephrology, Faculty of Medicine, Cairo University, 12918, Cairo, Egypt

    Ihab Abdelrahman Ibrahim BSc, MD, Usama M. Mohamad & Hatem A. Darweesh

  2. Department of Biochemistry; Faculty of Medicine, Cairo University, Cairo, Egypt

    Amal M. Rashad

Authors
  1. Ihab Abdelrahman Ibrahim BSc, MD
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  2. Usama M. Mohamad
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  3. Hatem A. Darweesh
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  4. Amal M. Rashad
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Correspondence to Ihab Abdelrahman Ibrahim BSc, MD.

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Ibrahim, I.A., Mohamad, U.M., Darweesh, H.A. et al. Impact of hepcidin, interleukin 6, and other inflammatory markers with respect to erythropoietin on anemia in chronic hemodialysis patients. Egypt J Intern Med 26, 6–14 (2014). https://doi.org/10.4103/1110-7782.132882

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