Impact of serum hepcidin and inflammatory markers on resistance to erythropoiesis-stimulating therapy in haemodialysis patients

  • D. A. El Sewefy
  • B. A. FarweezEmail author
  • M. A. Behairy
  • N. R. Yassin
Nephrology - Original Paper



Anaemia and resistance to erythropoiesis-stimulating agents (ESAs) are common complications in haemodialysis (HD) patients. We investigated the role of hepcidin in the development of anaemia and ESA resistance/hyporesponsiveness and its relation to the plasma levels of the inflammatory markers interleukin 6 (IL-6) and high-sensitivity C-reactive protein (hsCRP).


This study included 60 maintenance HD patients attending Ain Shams University Hospital and 30 age- and sex-matched healthy subjects as a control group. Serum hepcidin, IL-6, hsCRP and haemoglobin (Hb) levels were measured in all subjects. The erythropoietin resistance index (ERI) was calculated in the patient group only.


There was a significant difference between the patients and controls; the patients had higher hepcidin, IL-6, and hsCRP levels and a lower Hb level. Patients were classified according to their response to ESAs into responder and non-responder groups. Those in the non-responder group had higher hepcidin, IL-6, and hsCRP levels, a higher ERI, and a lower Hb level. Hepcidin showed a positive correlation with IL-6 and hsCRP but a negative correlation with Hb. Upon performing a ROC curve analysis, a cut-off of ≥ 280 ng/ml for hepcidin and ≥ 7.5 for ERI was able to discriminate the responder and non-responder groups with a prognostic accuracy of 83% and 77.3%, respectively. In addition, upon classifying the patients into tertiles according to the ERI, hepcidin significantly increased with increasing ERI.


Our findings demonstrate an association between the hepcidin level, anaemia and ESA resistance/hyporesponsiveness in HD patients, suggesting its possible role as a candidate marker for ESA resistance.


Hepcidin Anaemia Haemodialysis IL-6 HsCRP Erythropoietin resistance index 


Compliance with ethical standards

Conflict of interest

The authors state that they have no conflicts of interest.


  1. 1.
    Rubab Z, Amin H, Abbas K, Hussain S, Ullah I, Mohsin S (2015) Serum hepcidin levels in patients with end-stage renal disease on hemodialysis. Saudi J Kidney Dis Transplant 26(1):19–25CrossRefGoogle Scholar
  2. 2.
    KDOQI; National Kidney Foundation (2006) KDOQI clinical practice guidelines and clinical practice recommendations for anemia in chronic kidney disease. Am J Kidney Dis 47(5 Suppl 3):S11–S145Google Scholar
  3. 3.
    Sibbel S, Koro C, Brunelli S, Cobitz R (2015) Characterization of chronic and acute ESA hyporesponse: a retrospective cohort study of hemodialysis patients. BMC Nephrol 16:144–154CrossRefGoogle Scholar
  4. 4.
    Ogawa T, Nitta K (2015) Erythropoiesis-stimulating agent hyporesponsiveness in end-stage renal disease patients. Contrib Nephrol 185:76–86PubMedGoogle Scholar
  5. 5.
    Weiss G, Theurl I, Eder S, Koppelstaetter C, Kurz K, Sonnweber T et al (2009) Serum hepcidin concentration in chronic haemodialysis patients: associations and effects of dialysis, iron and erythropoietin therapy. Eur J Clin Investig 39(10):883–890CrossRefGoogle Scholar
  6. 6.
    Xu Y, Ding X, Zou J, Liu Z, Jiang S, Chen Y (2011) Serum hepcidin in haemodialysis patients: associations with iron status and microinflammation. J Int Med Res 39(5):1961–1967CrossRefGoogle Scholar
  7. 7.
    Hamada Y, Fukagawa M (2009) Is hepcidin the star player in iron metabolism in chronic kidney disease and quest. Kidney Int 75(9):873–874CrossRefGoogle Scholar
  8. 8.
    Eleftheriadis T, Pissas G, Remoundou M, Fillipidis G, Antoniadi G, Oustampasidou N et al (2014) Ferroportin in monocytes of hemodialysis patients and its associations with hepcidin, inflammation, markers of iron status and resistance to erythropoietin. Int Urol Nephrol 46:161–167CrossRefGoogle Scholar
  9. 9.
    Locatelli F, Aljama PA, Barany P, Canaud B, Carrera F, Eckardt KU et al (2004) Revised European best practice guidelines for the management of anaemia in patients with chronic renal failure. Nephrol Dial Transplant 19(Suppl. 2):1–47Google Scholar
  10. 10.
    Singh A, Szczech L, Tang K, Barnhart H, Sapp S, Wolfson M et al (2006) Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med 355:2085– 2098CrossRefGoogle Scholar
  11. 11.
    Okazaki M, Komatsu M, Kawaguchi H, Tsuchiya K, Nitta K (2014) Erythropoietin resistance index and the all-cause mortality of chronic hemodialysis patients. Blood Purif 37:106–112CrossRefGoogle Scholar
  12. 12.
    Gaweda A, Goldsmith L, Brier M, Aronoff G (2010) Iron, inflammation, dialysis adequacy, nutritional status, and hyperparathyroidism modify erythropoietic response. Clin J Am Soc Nephrol 5:576–581CrossRefGoogle Scholar
  13. 13.
    Inrig J, Sapp S, Barnhart H, Patel U, Reddan D, Singh A et al (2012) Impact of higher hemoglobin targets on blood pressure and clinical outcomes: a secondary analysis of choir. Nephrol Dial Transplant 27:3606–3614CrossRefGoogle Scholar
  14. 14.
    Renal Data System US (2013) USRDS 2013 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MDGoogle Scholar
  15. 15.
    Barany P (2001) Inflammation, serum C-reactive protein, and erythropoietin resistance. Nephrol Dial Transplant 16(2):224–227CrossRefGoogle Scholar
  16. 16.
    Nemeth E, Ganz T (2006) Regulation of iron metabolism by hepcidin. Annu Rev Nutr 26:323–342CrossRefGoogle Scholar
  17. 17.
    Nelson G, Tuttle R (2007) The new KDOQI clinical practice guidelines and clinical practice recommendations for diabetes and CKD. Blood Purif 25(1):112–114CrossRefGoogle Scholar
  18. 18.
    Ganz T, Olbina G, Girelli D, Nemeth E, Westerman M (2008) Immunoassay for human serum hepcidin. Blood 112(10):4292–4297CrossRefGoogle Scholar
  19. 19.
    Costa E, Pereira J, Rocha-Pereira P, Rocha S, Reis F, Castro E et al (2008) Role of prohepcidin, inflammatory markers and iron status in resistance to rhEPO therapy in hemodialysis patients. Am J Nephrol 28(4):677–683CrossRefGoogle Scholar
  20. 20.
    Putten K, Jie E, Broek D, Kraaijenhagen J, Laarakkers C, Swinkels W et al (2010) Hepcidin-25 is a marker of the response rather than resistance to exogenous erythropoietin in chronic kidney disease/chronic heart failure patients. Eur J Heart Fail 12(9):943–950CrossRefGoogle Scholar
  21. 21.
    Tessitore N, Girelli D, Campostrini N, Bedogna V, Pietro Solero G, Castagna A (2010) Hepcidin is not useful as a biomarker for iron needs in haemodialysis patients on maintenance erythropoiesis-stimulating agents. Nephrol Dial Transplant 25:3996–4002CrossRefGoogle Scholar
  22. 22.
    Caliskan Y, Yelken B, Ozkok A, Gorgulu N, Yazici H, Telci A et al (2012) Lower serum prohepcidin levels associated with lower iron and erythropoietin requirements in hemodialysis patients with chronic hepatitis C. BMC Nephrol 13(1):56–62CrossRefGoogle Scholar
  23. 23.
    Yılmaz I, Ozkok A, Kostek O, Kolukısa A, Duran I, Odabaş R et al (2016) C-reactive protein but not hepcidin, NGAL and transferrin determines the ESA resistance in hemodialysis patients. Renal Fail 38(1):89–95CrossRefGoogle Scholar
  24. 24.
    Zaritsky J, Young B, Wang J, Westerman M, Olbina G, Nemeth E et al (2009) Hepcidin—a potential novel biomarker for iron status in chronic kidney disease. Clin J Am Soc Nephrol 4(6):1051–1056CrossRefGoogle Scholar
  25. 25.
    Nemeth E, Valore E, Territo M, Schiller G, Lichtenstein A, Ganz T (2003) Hepcidin, a putative mediator of anemia of inflammation, is a type II acute-phase protein. Blood 101:2461–2463CrossRefGoogle Scholar
  26. 26.
    Weiss G, Goodnough T (2005) Anemia of chronic disease. N Engl J Med 352(10):1011–1023CrossRefGoogle Scholar
  27. 27.
    Ganz T, Nemeth E (2009) Iron sequestration and anemia of inflammation. Semin Hematol 46(4):387–393CrossRefGoogle Scholar
  28. 28.
    Cheng P, Jiao Y, Lin H, Wang X, Cai Y (2011) Hepcidin expression in anemia of chronic disease and concomitant iron-deficiency anemia. Clin Exp Med 11(1):33–42CrossRefGoogle Scholar
  29. 29.
    Ashby R, Gale P, Busbridge M, Murphy G, Duncan D, Cairns D et al (2010) Erythropoietin administration in humans causes a marked and prolonged reduction in circulating hepcidin. Haematologica 95(3):505–508CrossRefGoogle Scholar
  30. 30.
    Ganz T (2007) Molecular control of iron transport. J Am Soc Nephrol 18(2):394–400CrossRefGoogle Scholar
  31. 31.
    Brătescu O, Bârsan L, Munteanu D, Stancu S, Mircescu G (2010) Is hepcidin-25 a clinically relevant parameter for the iron status in hemodialysis patients? J Renal Nutr 20(5):S77–S83CrossRefGoogle Scholar
  32. 32.
    Nicolas G, Bennoun M, Devaux I, Beaumont C, Grandchamp B, Kahn A (2001) Lack of hepcidin gene expression and severe tissue iron overload in upstream stimulatory factor 2 (USF2) knockout mice. Proc Natl Acad Sci 98:8780–8785CrossRefGoogle Scholar
  33. 33.
    Pigeon C, Ilyin G, Courselaud B, Leroyer P, Turlin B, Brissot P et al (2001) A new mouse liver-specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload. J Biol Chem 276(11):7811–7819CrossRefGoogle Scholar
  34. 34.
    Bovy C, Gothot A, Delanaye P, Warling X, Krzesinski JM, Beguin Y (2007) Mature erythrocyte parameters as new markers of functional iron deficiency in hemodialysis: sensitivity and specificity. Nephrol Dial Transplant 22:1156–1162CrossRefGoogle Scholar
  35. 35.
    Malyszko J, Malyszko S, Pawlak K, Mysliwiec M (2006) Hepcidin, an acute-phase protein and a marker of inflammation in kidney transplant recipients with and without coronary artery disease. Transplant Proc 38(9):2895–2898CrossRefGoogle Scholar
  36. 36.
    Nemeth E, Rivera S, Gabayan V, Keller C, Taudorf S. Pedersen K (2004) IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J Clin Investig 113(9):1271–1276CrossRefGoogle Scholar
  37. 37.
    Wrighting D, Andrews C (2008) Iron homeostasis and erythropoiesis. Curr Top Dev Biol 82:141–167CrossRefGoogle Scholar
  38. 38.
    Rodriguez R, Jung C, Gabayan V, Deng Jane C, Ganz T, Nemeth E et al (2014) Hepcidin induction by pathogens and pathogen-derived molecules is strongly dependent on interleukin-6. Infect Immun 82(2):745–752CrossRefGoogle Scholar
  39. 39.
    Malyszko J, Malyszko J, Pawlak K, Mysliwiec M (2006) Hepcidin, iron status and renal function in chronic renal failure, kidney transplantation and hemodialysis. Am J Hematol 81:832–837CrossRefGoogle Scholar
  40. 40.
    Ashby D, Gale D, Busbridge M, Murphy K, Duncan N, Cairns T et al (2009) Plasma hepcidin levels are elevated but responsive to erythropoietin therapy in renal disease. Kidney Int 75(9):976–981CrossRefGoogle Scholar
  41. 41.
    Aydin Z, Gursu M, Karadag S, Uzun S, Sumnu A, Doventas Y et al (2014) The relationship of Prohepcidin levels with anemia and inflammatory markers in non-diabetic uremic patients: a controlled study. Renal Fail 36(8):1253–1257CrossRefGoogle Scholar
  42. 42.
    Kato A, Tsuji T, Luo J, Sakao Y, Yasuda H, Hishida A (2008) Association of prohepcidin and hepcidin-25 with erythropoietin response and ferritin in hemodialysis patients. Am J Nephrol 28(1):115–121CrossRefGoogle Scholar
  43. 43.
    Detivaud L, Nemeth E, Boudjema K, Turlin B, Troadec M, Leroyer P et al (2005) Hepcidin levels in humans are correlated with hepatic iron stores, hemoglobin levels and hepatic function. Blood 106:746–748CrossRefGoogle Scholar
  44. 44.
    Eleftheriadis T, Liakopoulos V, Antoniadi G, Kartsios C, Stefanidis I (2009) The role of hepcidin in iron homeostasis and anemia in hemodialysis patients. Semin Dial 22(1):70–77CrossRefGoogle Scholar
  45. 45.
    Macdougall I, Cooper A (2002) Erythropoietin resistance: the role of inflammation and pro-inflammatory cytokines. Nephrol Dial Transplant 17(Suppl 11):39–43CrossRefGoogle Scholar
  46. 46.
    Panichi V, Rosati A, Bigazzi R, Paoletti S, Mantuano E, Beati S et al (2011) Anaemia and resistance to erythropoiesis-stimulating agents as prognostic factors in haemodialysis patients: results from the RISCAVID study. Nephrol Dial Transplant 26(8):2641–2648CrossRefGoogle Scholar
  47. 47.
    Icardi A, Paoletti E, De Nicola L, Mazzaferro S, Russo R, Cozzolino M (2013) Renal anaemia and EPO hyporesponsiveness associated with vitamin D deficiency: the potential role of inflammation. Nephrol Dial Transplant 28(7):1672–1679CrossRefGoogle Scholar
  48. 48.
    Petrulienė k, Žiginskienė E, Kuzminskis V, Nedzelskienė I, Bumblytė I (2017) Hepcidin serum levels and resistance to recombinant human erythropoietin therapy in hemodialysis patients. Medicina (Kaunas) 53(2):90–100CrossRefGoogle Scholar
  49. 49.
    Lee S, Kim J, Lim H, Hwang Y, Kim S, Chung W et al (2017) Serum hepcidin may be a novel uremic toxin, which might be related to erythropoietin resistance. Sci Rep 7:4260. CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Ward D, Kaplan J (2012) Ferroportin-mediated iron transport: expression and regulation. Biochim Biophys Acta 9:1426–1433CrossRefGoogle Scholar
  51. 51.
    Ford A, Eby S, Scott G, Coyne W (2010) Intra-individual variability in serum hepcidin precludes its use as a marker of iron status in hemodialysis patients. Kidney Int 78(8):769–773CrossRefGoogle Scholar
  52. 52.
    van der Weerd N, Grooteman M, Bots M, van den Dorpel M, den Hoedt C, Mazairac A 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(7):e39783. CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Kanbay M, Perazella M, Kasapoglu B, Koroglu M, Covic A (2010) Erythropoiesis stimulatory agent- resistant anemia in dialysis patients: review of causes and management. Blood Purif 29(1):1–12CrossRefGoogle Scholar
  54. 54.
    Santos E, Hortegal E, Serra H, Lages J, Salgado-Filho N, Dos Santos A (2018) Epoetin alfa resistance in hemodialysis patients with chronic kidney disease: a longitudinal study. Braz J Med Biol Res 51(7):e7288. CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Schneider A, Schneider M, Scharnagl H, Jardine A, Wanner C, Drechsler C (2013) Predicting erythropoietin resistance in hemodialysis patients with type 2 diabetes. BMC Nephrol 14:67–73CrossRefGoogle Scholar
  56. 56.
    Lopez-Gomez J, Portoles J, Aljama P (2008) Factors that condition the response to erythropoietin in patients on hemodialysis and their relation to mortality. Kidney Int 74(Suppl 111):S75–S81CrossRefGoogle Scholar

Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  1. 1.Hematology Unit, Department of Clinical Pathology, Faculty of MedicineAin Shams UniversityCairoEgypt
  2. 2.Nephrology Unit, Internal Medicine Department, Faculty of MedicineAin Shams UniversityCairoEgypt

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