Mohamed M Abdo PHD, Heba M ZAKİ, Mohamed MSC

Erythropoietin hyporesponsiveness among egyptian hemodialysis patients

Almost all ESRD patients on HD receive iron and EPO to treat anemia, however some patients do not respond sufficiently to the therapy. Response to EPO influenced by various factors, such as malnutrition, vitamin deficiencies, chronic blood loss, secondary hyperparathyroidism, chronic inflammation and decrease hepcidin excretion. This study included 80 anemic patients who had been on regular HD for more than 3 months. Patients received adequate doses of ESA and iron for 3 months, after that they were classified into two groups ESA responders and ESA hyporesponders. Laboratory investigations were done to assess some of risk factors which may lead to ESA hyporesponsiveness as Iron profile, IL-6, CRP, anti-EPO antibody, hepcidin level and PTH. Sixty percent of the patients were EPO hypo-responsive; ferritin has higher level in hypo-responders. Hepcidin and IL-6 markedly elevated among ESRD patients also were markedly elevated among hypo-responders. Hepcidin did not show any correlations with IL-6 or CRP but has strong correlation with ferritin. Prevalence of anti-EPO antibody was 7.5 % of total population. Parathyroid hormone had no statistically significant association with HB or reticulocytes. Hepcidin was higher among EPO-hyporesponders and had strong correlation with ferritin, so we can consider hepcidin as an important biomarker for iron stores utilization in anemic patients and to predict patient response to EPO therapy. Hepcidin did not show any correlations with IL-6 or CRP, so inflammatory mediators did not influence its high level, but mostly due to its retention in ESRD patients

PDF

___

1. Hsu CY, McCulloch CE, Curhan GC. Epidemiology of anemia associated with chronic renal insufficiency among adults in the United States: results from the third national health and nutrition examination survey. J Am Soc Nephrol. 2002;13(2):504-10.

2. Astor BC, Muntner P, Levin A, Eustace JA, Coresh J.Association of kidney function with anemia: the third national health and nutrition examination survey (1988-1994). Arch Intern Med. 2002;162(12):1401-8.

3. Kamath S, Prabhu RA, Patil A. Prevalence of anemia in patients undergoing maintenance hemodialysis. Manipal University, India. Int J Clin Surg Adv. 2013;1(2):16-21.

4. El-Shahed AM, Sharf SA, El-Sebaee HA. Hemoglobin level, associated co-morbidities and quality of life among patients undergoing hemodialysis at one of the university hospitals in cairo governorate. Wasj. 2013;23(1):29-36.

5. Foley RN, Curtis BM, Parfrey PS. Erythropoietin therapy, hemoglobin targets and quality of life in healthy hemodialysis patients: a randomized trial. Clin J Am Soc Nephrol. 2009;4(4):726- 33.

6. Hodges VM, Rainey S, Lappin TR, Maxwell AP. Pathophysiology of anemia and erythrocytosis. Crit Rev Oncol Hematol. 2007;64(2):139- 58.

7. Anees MF, Hameed A, Mumtaz M Ibrahim M, Saeed Khan MN. Dialysis-related a factors affecting quality of life in patients on. hemodialysis. Iran J Kidney Dis. 2011;5(1): 9-14.

8. National Kidney Foundation. KDOQI clinical practice guidelines and clinical practice recommendations for anemia in chronic kidney disease .2012; 2: 288-310.

9. Priyadarshi A, Shapiro JI. Erythropoietin resistance in the treatment of the anemia of chronic renal failure. Semin Dial. 2006;19(4):273-8.

10. De Lurdes Agostinho Cabrita de Lurdes Agostinho Cabrita A, Pinho A, Malho A, Morgado E, Faísca M, Carrasqueira H, Silva AP, Neves PL. Risk factors for high erythropoiesis stimulating agent resistance index in pre-dialysis chronic kidney disease patients, stages 4 and 5. Int Urol Nephrol. 2011;43(3):835-40.

11. Costa E, Lima M, Alves JM, Rocha S, Rocha‐Pereira P, Castro E, Miranda V, do SF, Loureiro A, Quintanilha A, Belo L, Santos‐Silva A. Inflammation, T-cell phenotype, and inflammatory cytokines in chronic kidney disease patients under hemodialysis and its rela‐ tionship to resistance to recombinant human erythropoietin therapy. J Clin Immunol. 2008;28(3):268-75.

12. Babitt JL, Lin HY. Molecular mechanisms of hepcidin regulation: Implications for the anemia of CKD. Am J Kidney Dis. 2010;55(4):726-41.

13. Park CH, Valore EV, Waring AJ, Ganz T. Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J Biol Chem. 2001;276(11):7806-10.

14. Nemeth E, Rivera S, Gabayan V, Keller C, Taudorf S, Pedersen BK, Ganz T. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J Clin Invest. 2004;113(9):1271-6.

15. Zaritsky J, Young B, Gales B, Wang HJ, Rastogi A, Westerman M, Nemeth E, Ganz T, Salusky IB. Reduction of serum hepcidin by hemodialysis in pediatric and adult patients. Clin J Am Soc Nephrol. 2010;5(6):1010-4.

16. Stefansson BV, Abramson M, Nilsson U, Haraldsson B. Hemodiafiltration improves plasma 25-hepcidin levels: a prospective, randomized, blinded, cross-over study comparing hemodialysis and hemodiafiltration. Nephron Extra. 2012;2(1):55-65.

17. Nemeth E, Valore EV, Territo M, Schiller G, Lichtenstein A, Ganz T.Hepcidin, a putative mediator of anemia of inflammation, is a type II acute-phase protein. Blood. 2003;101(7):2461-3.

18. Song SN, Tomosugi N, Kawabata H, Ishikawa T, Nishikawa T, Yoshizaki. Down-regulation of hepcidin resulting from long-term treatment with an anti-IL-6 receptor antibody (tocilizumab) improves anemia of inflammation in multicentric Castleman disease. Blood. 2010;116(18):3627-34.

19. Duranton F, Cohen G, De Smet R, Rodriguez M, Jankowski J, Vanholder R, Argiles A; European Uremic Toxin Work Group. Normal and Pathologic Concentrations of Uremic Toxins. J Am Soc Nephrol. 2012;23(7):1258-70.

20. Brancaccio D, Cozzolino M, Gallieni M. Hyperparathyroidism and anemia in uremic subjects: a combined therapeutic approach. J Am Soc Nephrol. 2004;1:21-4.

21. Bohrer D, Bertagnolli DC, De Oliveira SM do Nascimento PC, de Carvalho LM, Garcia SC, Arantes LC, Barros EJ. Role of medication in the level of aluminium in the blood of chronic haemodialysis patients. Nephrol Dial Transplant. 2009;24(4):1277-81.

22. Yaqoob M, Ahmad R, Mcclelland P, Shivakumar KA, Sallomi DF, Fahal IH, Roberts NB, Helliwell T. Resistance to recombinant human erythropoietin due to aluminium overload and its reversal by low dose desferrioxamine therapy. Postgrad Med J. 1993;69(808):124-8.

23. Bowry SK, Gatti E. Impact of hemodialysis therapy on anemia of chronic kidney disease: the potential mechanisms. Blood Purif. 2011;32(3):210-9.

24. Locatelli F, Altieri P, Andrulli S, Sau G, Bolasco P, Pedrini LA, Basile C, David S, Feriani M, Nebiolo PE, Ferrara R, Casu D, Logias F, Tarchini R, Cadinu F, Passaghe M, Fundoni G, Villa G, Di Iorio BR, Zoccali C. Predictors of haemoglobin levels and resistance to erythropoiesis-stimulating agents in patients treated with low-flux haemo dialysis, haemofiltration and haemodiafiltration: results of a multicentre randomized and controlled trial. Nephrol Dial Transplant. 2012;27(9):3594-600

25. Johnson DW, Pollock CA, Macdougall IC. Erythropoiesisstimulating agent hyporesponsiveness. Nephrology (Carlton). 2007;12(4):321-30.

26. Yen TH, Lin JL, Lintan DT, Hsu CW. Association between body mass and mortality in maintenance hemodialysis patients. Ther Apher Dial. 2010;14(4):400-8.

27. Fishbane S, Shapiro W, Dutka P, Valenzuela OF, Faubert J. A randomized trial of iron deficiency testing strategies in hemodialysis patients. Kidney Int. 2001;60(6):2406-11.

28. Okazaki M, Komatsu M, Kawaguchi H, Tsuchiya K, Nitta K. Erythropoietin resistance index and the all-cause mortality of chronic hemodialysis patients. Blood Purif. 2014;37(2):106-12.

29. Cooper A C, Breen C P, Vyas B, Ochola J, Kemeny DM, Macdougall IC. Poor response to recombinant erythropoietin is associated with loss of T-lymphocyte CD28 expression and altered interleukin-10 production. Nephrol Dial Transplant. 2003;18(1):133–40.

30. Ahmed MH, Khalil H BE, Adam KM. Study of erythrocyte and reticulocyte indices among patients with chronic kidney disease. Journal of Science. 2015;5:1387-90.

31. Arogundade F A, Bappa A, Sanusi A A et al. Haematologic indices and the response to erytheropoeitin in Chronic Renal Failure. Trop. J. Nephrol. 2009; 1:13-20.

32. Miri-Dashe T, Osawe S, Tokdung M, Daniel N, Choji RP, Mamman I, Deme K, Damulak D. Comprehensive reference ranges for hematology and clinical chemistry laboratory parameters derived from normal Nigerian adults. PLOS One. 2014;9(5):e93919.

33. Tekce H, Tekce B K, Aktas G, Tanrisev M, Sit M. The Evaluation of Red Cell Distribution Width in Chronic Hemodialysis Patients. Int J Nephrol. 2014;2014:754370

34. Emans ME, van der Putten K, van Rooijen KL, Kraaijenhagen RJ, Swinkels D, van Solinge WW, Cramer MJ, Doevendans PA, Braam B, Gaillard CA. Determinants of Red Cell Distribution Width (RDW) in Cardiorenal Patients: RDW is Not Related to Erythropoietin Resistance. J Cardi Fail. 2011;17(8).626-33.

35. Rubab Z, Amin H, Abbas K, Hussain S, Ullah MI, Mohsin S. Serum hepcidin levels in patients with end-stage renal disease on hemodialysis. Saudi J Kidney Dis Transpl. 2015;26(1):19-25.

36. Wish JB. Assessing iron status: Beyond serum ferritin and transferrin saturation. Clin J Am Soc Nephrol. 2006;1:S4-8.

37. Jalalzadeh M, Shekari E, Mirzamohammadi F, Ghadiani MH. Effect of short-term intravenous ascorbic acid on reducing ferritin in hemodialysis patients. Indian J Nephrol. 2012;22(3):168–73.

38. Kudoh Y, Aoyama S, Torii T, Chen Q, Nagahara D, Sakata H, Nozawa A. Long-term effects of oral L-carnitine supplementation on anemia in chronic hemodialysis. Cardiorenal Med. 2014;4(1):53– 9.

39. Kim JK, Park BS, Park MJ, Choi W, Ma SK, Nah MY, Yeum CH, Jung K, Lee SC, Kim SW, Kim NH, Kang YJ, Choi KC. The predictive parameters of erythropoietin hyporesponsiveness in patients on continuous ambulatory peritoneal dialysis. Korean J Intern Med. 2001;16(2):110-7.

40. Heidari B, Taheri H, Hajian-Tilaki K, Yolmeh M1 , Akbari R. Low baseline serum albumin a predictor of anemia in patients on chronic hemodialysis. Caspian J Intern Med. 2015;6(3):161-4.

41. Zaritsky J, Young B, Wang HJ, Westerman M, Olbina G, Nemeth E, Ganz T, Rivera S, Nissenson AR, Salusky IB. Hepcidin a potential novel biomarker for iron status in chronic kidney disease. Clin J Am Soc Nephrol. 2009;4(6):1051-6.

42. Peters HPE, Laarakkers CMM, Swinkels DW, Wetzels JF. Serum hepcidin-25 levels in patients with chronic kidney disease are independent of glomerular filtration rate. Nephrol Dial Transplant. 2010;25(3):848-53.

43. Mercadel L, Metzger M, Haymann JP, Thervet E4 , Boffa JJ5 , Flamant M6 , Vrtovsnik F7 , Houillier P8 , Froissart M9 , Stengel B2 ; NephroTest Study Group. The relation of hepcidin to iron disorders, inflammation and hemoglobin in chronic kidney disease. PLOS One. 2014;9(6):e99781.

44. Badawy A, El-Masry E, Hussein A. Role of hepcidin in recombinant human erythropoietin therapy resistance among chronic hemodialysis patients. IOSR-JDMS. 2014;86-92.

45. Sasu BJ, Cooke KS, Arvedson TL, Plewa C, Ellison AR, Sheng J, Winters A, Juan T, Li H, Begley CG, Molineux G. Antihepcidin antibody treatment modulates iron metabolism and is effective in a mouse model of inflammation-induced anemia. Blood. 2010;115(17):3616-24.

46. Ibrahim IA, Mohamad UM, Darweesh HA. Impact of hepcidin, interleukin 6, and other inflammatory markers with respect to erythropoietin on anemia in chronic hemodialysis patients. Egypt J Intern Med. 2014;26:6-14.

47. Yamaya K, Tsuboi S, Tsutaya C. Plasma hepcidin and trace elements in chronic renal failure. NMCC ANNUAL REPORT. 2011.

48. Sedlackova T, Racek J, Eiselt J. Hepcidin and ferritin in hemodialyzed patients. Klin Biochem Metab. 2011;19(40):234–6.

49. Ashby DR, Gale DP, Busbridge M, Murphy KG, Duncan ND, Cairns TD, Taube DH, Bloom SR, Tam FW, Chapman RS, Maxwell PH, Choi P. Plasma hepcidin levels are elevated but responsive to erythropoietin therapy in renal disease. Kidney Int. 2009;75(9):976- 81.

50. Cheung WW, Paik KH, Mak RH. Inflammation and cachexia in chronic kidney disease. Pediatric Nephrol. 2010;25(4):711-24.

51. Stenvinkel P, Ketteler M, Johnson RJ, Lindholm B, Pecoits-Filho R, Riella M, Heimbürger O, Cederholm T, Girndt M. Interleukin-10, IL6 and TNF-a: important factors in the altered cytokine network of end-stage renal disease - the good, the bad and the ugly. Kidney Int. 2005;67(4):1216-33.

52. Alwahaibi NY, Alissaei HK, Alshihi SA. Serum levels of TNF-α, IL6 and IL-10 in haemodialysis and renal transplant patients and in healthy subjects. Port J Nephrol Hypert. 2016.

53. Jeong JY, Silver M, Parnes A, Nikiforow S, Berliner N, Vanasse GJ. Resveratrol ameliorates TNF alpha-mediated suppression of erythropoiesis in human CD34 (+) cells via modulation of NFkappaB signalling. Br J Haematol. 2011;155(1):93-101.

54. Khalil SK, Amer HA, El Behairy AM, Warda M. Oxidative stress during erythropoietin hyporesponsiveness anemia at end stage renal disease: Molecular and biochemical studies. J Adv Res. 2016;7(3):348-58.

55. Nakagawa H, Tamura T, Mitsuda Y, Goto Y, Kamiya Y, Kondo T, Wakai K, Hamajima N. Inverse correlation between serum interleukin-6 and iron levels among Japanese adults: a cross-sectional study. BMC Hematol. 2014;14(1):6.

56. Casadevall N, Nataf J, Viron B, Kolta A, Kiladjian JJ, Martin-Dupont P, Michaud P, Papo T, Ugo V, Teyssandier I, Varet B, Mayeux P. Pure red-cell aplasia and anti-erythropoietin antibodies in patients treated with recombinant erythropoietin. N Engl J Med. 2002;346(7):469-75.

57. Eckardt KU, Casadevall N. Pure red-cell aplasia due to antierythropoietin antibodies. Nephrol Dial Transplant. 2003;18(5):865- 9.

58. Alqahwaji DB, Shubair ME, Sirdah M. Detection of antierythropoietin antibodies among hemodialyzed patients treated with recombinant human-erythropoietin. Sky Journal of Medicine and Medical Sciences. 2014;2(4):16–20.

59. El-Ghamry F, Nassar Y, El Sayed MA. The relation between the levels of C-reactive protein and the response to erythropoietin in anemic patients on haemodialysis. Al-Azhar Assiut Medical Journal (AAMJ). 2014.

60. Adhikary LP, Pokhrel A, Yadava SK, Khadka D, Thakur R. Relation between Serum Intact Parathyroid Hormone Level and Hematocrit in Chronic Kidney Disease Patients. Kathmandu Univ Med J. 2015;13(51):220-3.

61. Sabry A, El-Dahshan K, Mahmoud K. Effect of hepatitis c virus infection on haematocrit and haemoglobin levels in Egyptian hemodialysis patients. European Journal of General Medicine. 2007;4:9-15.

62. Afzal N, Abbas S, Ahmed A, Arif M, Javeed K. Effect of Hepatitis C Virus on C - reactive protein and Interleukin-6 in Hemodialysis Patients. Iran J Kidney Dis. 2011;5(3):182-6.