Jump to ContentJump to Main Navigation
Show Summary Details

Open Medicine

formerly Central European Journal of Medicine

Editor-in-Chief: Darzynkiewicz, Zbigniew

1 Issue per year

IMPACT FACTOR increased in 2015: 0.190
5-year IMPACT FACTOR: 0.221

SCImago Journal Rank (SJR) 2015: 0.140
Source Normalized Impact per Paper (SNIP) 2015: 0.154
Impact per Publication (IPP) 2015: 0.197

Open Access
See all formats and pricing
Volume 2, Issue 4 (Dec 2007)


New alternatives for erythropoietin therapy in chronic renal failure

Irina Stoian
  • Department of Biochemistry, Faculty of Medicine, University of Medicine and Pharmacy “Carol Davila”, 050473, Bucharest, Romania
  • Email:
/ Bogdan Manolescu
  • Department of Biochemistry, Faculty of Medicine, University of Medicine and Pharmacy “Carol Davila”, 050473, Bucharest, Romania
  • Email:
/ Valeriu Atanasiu
  • Department of Biochemistry, Faculty of Medicine, University of Medicine and Pharmacy “Carol Davila”, 050473, Bucharest, Romania
  • Email:
/ Olivera Lupescu
  • Department of Thrauma and Ortopaedics, Faculty of Medicine, University of Medicine and Pharmacy “Carol Davila”, 050473, Bucharest, Romania
  • Email:
Published Online: 2007-12-01 | DOI: https://doi.org/10.2478/s11536-007-0038-y


Erythropoietin (EPO) is one of the main cytokines involved in the regulation of erythropoiesis. The main site of EPO production are the kidneys. An altered EPO production leads to pathological conditions such as anemia and polycythaemia. Due to the progressive loss of renal peritubular cells, patients with chronic kidney disease (CKD) have low EPO plasma levels. This decreases erythron stimulation with the direct consequence of developing anemia. Before the introduction in the clinical practice of rHuEpo, in the late 1980s, the only solution for treating this type of anemia were blood transfusions and anabolic steroids. Even rHuEpo has proven to be safe and effective for treatment of anemias, there are some concerns about its cost, the need for frequent parenteral administration, and development of anti-EPO antibodies. These inconveniences prompted the search for novel erythropoiesis stimulating agents. Different strategies lead to isolation or chemical synthesis of such agents as darbepoetin alfa and EPO mimetics. In this review, we present some general aspects of EPO biology, with emphasis on chronic renal failure, and expose some of the alternatives to EPO used for anemia correction.

Keywords: Erythropoietin; darbepoetin; hematide; synthetic erythropoiesis protein; chronic kidney disease; hepcidin

  • [1] P. Carnot and C. Deflandre: “Sur l’activite hemopoietique du serum au cours de la regeneration du sang”, C R Acad Sci (Paris), Vol. 143, (1906), pp. 384–386.

  • [2] E. Bondsdorff and E. Jalavisto: “A humoral mechanism in anoxic erythrocytosis”, Acta Physiol. Scand., Vol. 16, (1948), pp. 150–170. http://dx.doi.org/10.1111/j.1748-1716.1948.tb00535.x [Crossref]

  • [3] L.O. Jacobson, E. Goldwasser, W. Fried and L. Ptzak: “Role of the kidney in erythropoiesis”, Nature, Vol. 179, (1957), pp. 633–634. http://dx.doi.org/10.1038/179633a0 [Crossref]

  • [4] W. Fried: “The liver as a source of extrarenal erythropoietin production”, Blood, Vol. 40, (1972), pp. 671–677.

  • [5] T. Miyake, C.K.H. Kung and E. Goldwasser: “Purification of human erythropoietin”, J. Biol. Chem., Vol. 252, (1977), pp. 5558–5564.

  • [6] F-K. Lin, S. Suggs, C-H. Lin, J.K. Browne, R. Smalling, J.C. Egrie, K.K. Chen, G.M. Fox, F. Martin, Z. Stabinsky, S.M. Badrawi, P-H. Lai and E. Goldwasser: “Cloning and expression of the human erythropoietin gene”, Proc. Natl. Acad. Sci. U.S.A., Vol. 82, (1985), pp. 7580–7584. http://dx.doi.org/10.1073/pnas.82.22.7580 [Crossref]

  • [7] K. Jacobs, C. Shoemaker and R. Rundersforf: “Isolation and characterization of genomic and cDNA clones of human erythropoietin”, Nature, Vol. 313, (1985), pp. 806–810. http://dx.doi.org/10.1038/313806a0 [Crossref]

  • [8] J.W. Eschbach, J.C. Egrie, M.R. Downing, J.K. Browne and J.W. Adamson: “Correction of the anemia of end-stage renal disease with recombinant human erythropoietin”, N. Engl. J. Med., Vol. 316, (1987), pp. 73–78. http://dx.doi.org/10.1056/NEJM198701083160203 [Crossref]

  • [9] G.L. Semenza, M.K. Nejfelt, S.M. Chi and S.E. Antonarakis: “Hypoxia-inducuble nuclear factors bind to an enhancer element located 3’ to the human erythropoietin gene”, Proc. Natl. Acad. Sci. U.S.A., Vol. 88, (1991), pp. 5680–5684. http://dx.doi.org/10.1073/pnas.88.13.5680 [Crossref]

  • [10] C. Brahimi-Horn and J. Pouyssegur: “The role of the hypoxia-inducible factor in tumor metabolism growth and invasion”, Bull. Cancer, Vol. 93(8), (2006), pp. E73–E80.

  • [11] G.L. Wang, B.H. Jiang, E.A. Rue and G.L. Semenza: “Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension”, Proc. Natl. Acad. Sci. U.S.A., Vol. 92, (1995), pp. 5510–5514. http://dx.doi.org/10.1073/pnas.92.12.5510

  • [12] P.J. Kallio, I. Pongratz, K. Gradin, J. McGuire and L. Poellinger: “Activation of hypoxia-inducible factor 1 alpha: posttranscriptional regulation and conformational change by recruitment of the Arnt transcription factor”, Proc. Natl. Acad. Sci. U.S.A., Vol. 94, (1997), pp. 5667–5672. http://dx.doi.org/10.1073/pnas.94.11.5667 [Crossref]

  • [13] N. Masson, C. Willam, P.H. Maxwell, C.W. Pugh and P.J. Ratcliffe: “Independent function of two destruction domains in hypoxia-inducible factor-α chains activated by prolyl hydroxylation”, EMBO J., Vol. 20, (2001), pp. 5197–5206. http://dx.doi.org/10.1093/emboj/20.18.5197 [Crossref]

  • [14] L.E. Huang, J. Gu, M. Schau and H.F. Bunn: “Regulation of hypoxia-inducible factor 1 is mediated by an O2-dependent degradation domain via the ubiquitin-proteasome pathway”, Proc. Natl. Acad. Sci. U.S.A., Vol. 95, (1998), pp. 7987–7992. http://dx.doi.org/10.1073/pnas.95.14.7987

  • [15] C.W. Pugh, J.F. O’Rourke, M. Nagao, J.M. Gleadle and P.J. Ratcliffe: “Activation of hypoxia-inducible factor-1; definition of regulatory domains within the α subunit”, J. Biol. Chem., Vol. 272, (1997), pp. 11205–11214. http://dx.doi.org/10.1074/jbc.272.2.984

  • [16] P.H. Maxwell, M.S. Wiesener, G.W. Chang, S.C. Clifford, E.C. Vaux, M.E. Cockman, C.C. Wykoff, C.W. Pugh, E.R. Maher and P.J. Ratcliffe: “The tumor suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis”, Nature, Vol. 399, (1999), pp. 271–275. http://dx.doi.org/10.1038/20459 [Crossref]

  • [17] Q. Ke and M. Costa: “Hypoxia-inducible factor-1 (HIF-1)”, Mol. Pharmacol., Vol. 70, (2006), pp. 1469–1480. http://dx.doi.org/10.1124/mol.106.027029 [Crossref]

  • [18] P.C. Mahon, K. Hirota and G.L. Semenza: “FIH-1: a novel protein that interacts with HIF-1α and VHL to mediate repression of HIF-1 transcription activity”, Genes Dev., Vol. 15, (2001), pp. 2675–2686. http://dx.doi.org/10.1101/gad.924501 [Crossref]

  • [19] C. Warnecke, Z. Zaborowska, J. Kurreck, V.A. Erdmann, U. Frei, M. Wiesener and K.U. Eckardt: “Differentiating the functional role of hypoxia-inducible factor (HIF)-1 alpha and HIF-2 alpha (EPAS-1) by the use of RNA interference: erythropoietin is a HIF-2 alpha target gene in Hep3B and Kelly cells”, FASEB J., Vol. 18, (2004), pp. 1462–1464.

  • [20] P-H. Lai, R. Everett, F.F. Wang, T. Arakawa and E. Goldwasser: “Structural characterization of human erythropoietin”, J. Biol. Chem., Vol. 261, (1986), pp. 3116–3121.

  • [21] M.A. Recny, H.A. Scoble and Y. Kim: “Structural characterization of natural human urinary and recombinant DNA-derived erythropoietin. Identification of des-arginine 166 erythropoietin”, J.Biol. Chem., Vol. 262, (1987), pp. 17156–17163.

  • [22] E. Delorme, T. Lorenzini and J. Giffin: “Role of glycosylation on the secretion and biological activity of erythropoietin”, Biochemistry, Vol. 31, (1992), pp. 9871–9876. http://dx.doi.org/10.1021/bi00156a003 [Crossref]

  • [23] C. Wasley, G. Timony and P. Murtha: “The importance of N-and O-linked oligosaccharides for the biosynthesis and in vitro and in vivo biologic activities of erythropoietin”, Blood, Vol. 77, (1991), pp. 2624–2632.

  • [24] M.N. Fukuda, H. Sasaki, L. Lopez and M. Fukuda: “Survival of recombinant erythropoietin in the circulation: the role of carbohydrates”, Blood, Vol. 73, (1989), pp. 84–89.

  • [25] B. Witthuhn, F.W. Quelle, O. Silvennoinen, T. Yi, B. Tang, O. Miura and J.N. Ihle: “JAK2 associates with the erythropoietin receptor and is tyrosine phosphorylated and activated following Epo stimulation”, Cell, Vol. 74, (1996), pp. 227–236. http://dx.doi.org/10.1016/0092-8674(93)90414-L [Crossref]

  • [26] Y. Miura, O. Muira, J.N. Ihle and N. Aoki: “Activation of the mitogen activated protein kinase pathway by the erythropoietin receptor”, J. Biol. Chem., Vol. 269, (1994), pp. 29962–29969.

  • [27] J.E. Damen, A.L.F. Mui, L. Puil, T. Pawson and G. Krystal: “Phosphatidylinositol 3-kinase associates, via its Src homology 2 domains, with the activated erythropoietin receptor”, Blood, Vol. 81, (1996), pp. 3204–3210.

  • [28] J. Damen, R.L. Cutler, H. Jiao, T. Yi and G. Krystal: “Phosphorylation of tyrosine 503 in the erythropoietin receptor (EpR) is essential for binding the p85 subunit of phosphatidylinositol (PI) 3-kinase and for EpR-associated PI 3-kinase activity”, J. Biol. Chem., Vol. 270, (1995), pp. 23402–23406. http://dx.doi.org/10.1074/jbc.270.40.23402 [Crossref]

  • [29] J.N. Ihle: “Cytokine receptor signaling”, Nature, Vol. 377, (1995), pp. 591–594. http://dx.doi.org/10.1038/377591a0 [Crossref]

  • [30] R.J. Darling, U. Kuchibhotla, W. Glaesner, R. Micanovic, D.R. Witcher and J.M. Beals: “Glycosylation of erythropoietin affects receptor binding kinetics: role of electrostatic interactions”, Biochemistry, Vol. 41, (2002), pp. 14524–14531. http://dx.doi.org/10.1021/bi0265022 [Crossref]

  • [31] K. Sawda, S.B. Krantz, C-H. Dai, S.T. Koury, S.T. Horn, A.D. Glick and C.I. Civin: “Purification of human blood burst-forming units-erythroid and demonstration of the evolution oferytrooietin recetor”, J. Cel. Physiol., Vol. 142, (1990), pp. 142219–142220.

  • [32] A. Wickrema, S.B. Krantz, J.C. Winkelmann and M.C. Bondurant: “Differentiation and erythropoietin receptor gene expression in human erythroid progenitor cells”, Blood, Vol. 80, (1992), pp. 1940–1949.

  • [33] W. Jelkmann: “Erythropoietin: Structure, control of production, and function”, Physiol. Rev., Vol. 72, (1992), pp. 449–489.

  • [34] P. Stenvinkel: “The role of inflammation in the anaemia end-stage renal disease”, Nephrol. Dial. Transplant., Vol. 16, (2001), pp. 36–40. [Crossref]

  • [35] I.C. Macdougall: “Present and future strategies in the treatment of renal anaemia”, Nephrol. Dial. Trasplant., Vol. 16, (2001), pp. 50–55. [Crossref]

  • [36] A. Levin, C.R. Thompson and J. Ethier: “Left ventricular mass index increase in early renal disease impact of decline in hemoglobin”, Am. J. Kidney. Dis., Vol. 34, (1999), pp. 125–134. [Crossref]

  • [37] J.D. Harnett, R.N. Foley, G.M. Kent, P.E. Barre, D. Murray and P.S. Parfrey: “Congestive heart failure in dialysis patients: prevalence, incidence, prognosis and risk factors”, Kidney Int., Vol. 47, (1995), pp. 884–890. http://dx.doi.org/10.1038/ki.1995.132 [Crossref]

  • [38] D.L. Wolcott, J.T. Marsh, A. La Rue, C. Carr and A.R. Nissenson: “Recombinant human erythropoietin treatment may improve quality of life and cognitive function in chronic hemodialysis patients”, Am. J. Kidney Dis., Vol. 14, (1989), pp. 478–485. [Crossref]

  • [39] R.W. Evans, B. Rader and D.L. Manninem: “Cooperative Multicenter EPO Clinical Trial Group. The quality of life of hemodialysis recepients treated with recombinant human erythropoietin”, JAMA, Vol. 263, (1990), pp. 825–830. http://dx.doi.org/10.1001/jama.263.6.825 [Crossref]

  • [40] M. Abdelrahman, E.J. Sharples and M.C. McDonald: “Erythropoietin attenuates the tissue injury associated with hemorrhagic shock and myocardial ischemia”, Shock, Vol. 22, (2004), pp. 63–69. http://dx.doi.org/10.1097/01.shk.00001276869.21260.9d [Crossref]

  • [41] T. Nemoto, N. Yokota, W.F. Keane and H. Rabb: “Recombinant erythropoietin rapidly treats anemia in ischemic acute renal failure”, Kidney Int., Vol. 59, (2001), pp. 246–251. http://dx.doi.org/10.1046/j.1523-1755.2001.00485.x [Crossref]

  • [42] N.S.A. Patel, E.J. Sharples, S. Cuzzocrea, P.K. Chatterjee, D. Britti, M.M. Yaqoob and C. Thiemermann: “Pretreatment with reduces the injury and dysfunction caused by ischemia/reperfusion in the mouse kidney in vivo”, Kidney Int., Vol. 66, (2004), pp. 983–989. http://dx.doi.org/10.1111/j.1523-1755.2004.00847.x [Crossref]

  • [43] A. Vesey, C. Cheung, B. Pat, Z. Endre, G. Gobe and D.W. Johnson: “Erythropoietin protects against ischaemic acute renal injury”, Nephrol. Dial. Transplant., Vol 19, (2004), pp. 348–355. http://dx.doi.org/10.1093/ndt/gfg547 [Crossref]

  • [44] E.J. Sharples, N. Patl, P. Brown, K. Stewart, H. Mota-Philipe, M. Sheaff, J. Kieswich, D. Allen, S. Harwood, M. Raftery, C. Thiemermann and M.M. Yagoob: “Erythropoietin protects the kidney against the injury and dysfunction caused by ischemia-reperfusion”, J. Am. Soc. Nephrol., Vol. 15, (2004), pp. 2115–2124. http://dx.doi.org/10.1097/01.ASN.0000135059.67385.5D [Crossref]

  • [45] C. Westenfelder, D.L. Biddle and R.L. Baranowski: “Human, rat, and mouse kidney cells express functional erythropoietin receptors”, Kidney Int., Vol. 55, (1999), pp. 808–820. http://dx.doi.org/10.1046/j.1523-1755.1999.055003808.x [Crossref]

  • [46] C.G. Winearls, D.O Oliver and M.J. Pippard: “Effects of human erythropoietin derived from recombinant DNA on the anaemia of patients maintained by chronic haemodialysis”, Lancet, Vol. ii, (1986), pp. 1175–1178. http://dx.doi.org/10.1016/S0140-6736(86)92192-6 [Crossref]

  • [47] J.W. Eschbach, J.C. Egrie and M.R. Downing: “Correction of the anaemia of end-stage renal disease with recombinant human erythropoietin: results of a combined phase I and II clinical trial”, N. Engl. J. Med., Vol. 316, (1987), pp. 73–78. http://dx.doi.org/10.1056/NEJM198701083160203 [Crossref]

  • [48] J.W. Eschbach, M.H. Abdulhadi and J.K. Browne: “Recombinant human erythropoietin in anemic patient with end-stage renal disease. Results of a phase III multicenter clinical trial”, Ann. Intern. Med., Vol. 111, (1989), pp. 992–1000.

  • [49] R. Deicher, W.H. Horl: “Differentiating factors between erythropoiesis-stimulating agents: a guide to selection for anaemia of chronic kidney disease”, Drugs, Vol. 64, (2004), pp. 499–509. http://dx.doi.org/10.2165/00003495-200464050-00004 [Crossref]

  • [50] I.C. Macdougall: “Meeting the challenges of a new millenium: optimising the use of recombinant human erythropoietin”, Nephrol. Dial. Transplant., Vol. 13, (1998), pp. 23–27. http://dx.doi.org/10.1093/ndt/13.suppl_2.23 [Crossref]

  • [51] Deputy Chief Medical Officer. Eprex® (epoetin alfa) and pure red cell aplasia-contraindication of sucutaneous administration to patients with chronic renal disease, Medical Control Agency, December 2002.

  • [52] I.C. Macdougall, S.J. Gray, O. Elston, C. Breen, B. Jenkins, J. Browne and J. Egrie: “Pharmacokinetics of novel erythropoiesis stimulating protein compared with epoetin alfa in dialysis patients”, J. Am. Soc. Nephrol., Vol. 10, (1999), pp. 2392–2395.

  • [53] Y. Vanrenterghem, P. Barany and J.F.E. Mann: “Randomized trial of darbepoetin alfa for treatment of renal anemia at a reduced dose frequency compared with epoetin in dialysis patients”, Kidney Int., Vol. 62, (2002), pp. 2167–2175. http://dx.doi.org/10.1046/j.1523-1755.2002.00657.x [Crossref]

  • [54] M. Jadoul, Y. Vanrenterghem, M. Foret, R. Walker and S.J. Gray: “Darbepoetin alfa administered once monthly maintains haemoglobin levels in stable dialysis patients”, Nephrol. Dial. Transplant., Vol. 19, (2004), pp. 898–903. http://dx.doi.org/10.1093/ndt/gfh021 [Crossref]

  • [55] NKF-DOQI: “Clinical Practice Guidelines for the Treatment of Anemia of Chronic Renal Failure”, Am. J. Kidney Dis., Vol. 30[Suppl 3], (1997), pp. S192–S240.

  • [56] T. Drueke: “Hyporesponsiveness to recombinant human erythropoietin”, Nephrol. Dial. Transplant., Vol. 16[Suppl 7], (2001), pp. 25–28. [Crossref]

  • [57] I.C. Macdougall and A.C. Cooper: “Hyporesponsiveness to erythropoietic therapy due to chronic inflammation”, Europ. J. Clin. Invest., Vol. 35[Suppl 3], (2005), pp. 32–35. http://dx.doi.org/10.1111/j.1365-2362.2005.01528.x [Crossref]

  • [58] T. Sitter. A. Berner and H. Schiffl: “Dialysate related cytokine induction and response to recombinant human erythropoietin in haemodialysis patients”, Nephrol. Dial. Transplant., Vol. 15, (2000), pp. 1207–1211. http://dx.doi.org/10.1093/ndt/15.8.1207 [Crossref]

  • [59] D.A. Allen, C. Breen, M.M. Yaqoob and I.C. Macdougall: “Inhibition of CFU-E colony formation in uremic patients with inflammatory disease: role of IFN-gamma and TNF-alpha”, J. Invest. Med., Vol. 47, (1999), pp. 204–211.

  • [60] R.T. Means and S.B. Krantz Jr.: “Inhibition of human erythroid colony-forming units by tumor necrosis factor requires beta interferon”, J. Clin. Invest., Vol. 91, (1993), pp. 416–419. [Crossref]

  • [61] W. Jelkmann, H. Pagel, M. Wolff and J. Fandrey: “Monokines inhibiting erythropoietin production in human hepatoma cultures and isolated perfused rat kidneys”, Life Sci., Vol. 50, (1992), pp. 301–308. http://dx.doi.org/10.1016/0024-3205(92)90338-P [Crossref]

  • [62] NKF-K/DOQI: “Clinical Practice Guidelines for Anemia of Chronic Kidney Disease: update 2000. III. Iron support”, Am. J. Kidney Dis., Vol. 37, (2001), pp. S194–S206.

  • [63] T. Ganz: “Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation”, Blood, Vol. 102, (2003), pp. 783–788. http://dx.doi.org/10.1182/blood-2003-03-0672 [Crossref]

  • [64] D.M. Wrighting and N.C. Andrews: “Interleukin-6 induces hepcidin expression through STAT3”, Blood, Vol. 108, (2006), pp. 3204–3209. http://dx.doi.org/10.1182/blood-2006-06-027631 [Crossref]

  • [65] A. Pietrangelo, U. Dierssen and L. Valli: “STAT3 is required for IL-6-gp130-dependent activation of hepcidin in vivo”, Gastroenterol., Vol. 132, (2007), pp. 294–300. http://dx.doi.org/10.1053/j.gastro.2006.10.018 [Crossref]

  • [66] M.V. Verga Falzacappa, M.V. Spasic, R. Kessler, J. Stolte, M.W. Hentze and M.U. Muckenthaler: “STAT-3 mediates hepatic hepcidin expression and its inflammatory stimulation”, Blood, Vol. 109, (2007), pp. 353–358. http://dx.doi.org/10.1182/blood-2006-07-033969 [Crossref]

  • [67] E. Nemeth, M.S. Tuttle and J. Powelson: “Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization”, Science, Vol. 306, (2004), pp. 2090–2093. http://dx.doi.org/10.1126/science.1104742 [Crossref]

  • [68] I.C. Macdougall: “CERA (Continuous Erythropoietin Receptor Activator): a new erythropoiesis-stimulating agent for the treatment of anemia”, Curr. Hematol. Rep., Vol. 4, (2005), pp. 436–440.

  • [69] R.B. Stead, J. Lambert, D. Wessels, J.S. Iwashita, K.K. Leuther, K.W. Woodburn, P.J. Schatz, D.M. Okamoto, R. Naso and A-M. Duliege: “Evaluation of the safety and pharmacodynamics of Hematide, a novel erythropoietic agent, in a phase 1, double-blind, placebo-controlled, dose-escalation study in healthy volunteers”, Blood, Vol. 108, (2006), pp. 1830–1834. http://dx.doi.org/10.1182/blood-2006-04-015818 [Crossref]

  • [70] Q. Fan, K.K. Leuther, C.P. Holmes, K.L. Fong, J. Zhang, S. Yelkovska, M.J. Chen, R.B. Mortensen, K. Leu, J.M. Green, P.J. Schatz and K.W. Woodburn: “Preclinical evaluation of Hematide, a novel erythropoiesis stimulating agent, for the treatment of anemia”, Exp. Hematol., Vol. 34, (2006), pp. 1303–1311. http://dx.doi.org/10.1016/j.exphem.2006.05.012 [Crossref]

  • [71] G.G. Kochendoerfer, S-Y. Chen, F. Mao, S. Cressman and S. Traviglia: “Design and chemical synthesis of a homogeneous polymer-modified erythropoiesis protein”, Science, Vol. 299, (2003), pp. 884–887. http://dx.doi.org/10.1126/science.1079085 [Crossref]

  • [72] M.N. Fukuda, H. Sasaki, L. Lopez and M. Fukuda: “Survival of recombinant erythropoietin in the circulation: the role of carbohydrates”, Blood, Vol. 73, (1989), pp. 84–89.

  • [73] J.L. Spivak and B.B. Hogans: “The in vivo metabolism of recombinant human erythropoietin in the rat”, Blood, Vol. 73, (1989), pp. 90–99. [PubMed]

  • [74] M.M. Hsieh, N.S. Linde, A. Wyter and M. Metzger: “HIF-prolyl hydroxylase inhibition results in endogenous erythropoietin induction, erythrocytosis, and modest fetal hemoglobin expression in rhesus macaques”, Blood, (2007). [Crossref]

  • [75] C. Peyssonnaux, A.S. Zinkernagel, R.A. Schuepbach, E. Rankin, S. Vaulont, V.H. Haase, V. Nizet and R.S. Johnson: “Regulation of iron homeostasis by the hypoxiainducible transcription factors (HIFs)”, J. Clin. Invest., Vol. 117, (2007), pp. 1926–1932. http://dx.doi.org/10.1172/JCI31370 [Crossref]

  • [76] H. Kasiganesan, V. Sridharan and G. Wright: “Prolyl hydroxylase inhibitor treatment confers whole-animal hypoxia tolerance”, Acta Physiol., Vol. 190, (2007), pp. 163–169. http://dx.doi.org/10.1111/j.1748-1716.2007.01676.x [Crossref]

  • [77] C. Rinsch, E. Regulier, N. Deglon, B. Dalle, Y. Beuzard and P. Aebischer: “A gene therapy approach to regulated delivery of erythropoietin as a function of oxygen tension”, Human. Gene Ther., Vol. 8, (1997), pp. 1881–1889. http://dx.doi.org/10.1089/hum.1997.8.16-1881 [Crossref]

  • [78] Y. Lippin, M. Dranitzki-Elhalel, E. Brill-Almon, C. Mei-Zahav, S. Mizrachi, Y. Liberman, A. Iaina, E. Kaplan, E. Podjarny, E. Zeira, M. Harati, N. Casadevall, N. Shani and E. Galun: “Human erythropoietin gene therapy for patients with chronic renal failure”, Blood, Vol. 106, (2005), pp. 2280–2286. http://dx.doi.org/10.1182/blood-2004-11-4174 [Crossref]

  • [79] G. Gao, C. Lebherz, D.J. Weiner, R. Grant, R. Calcedo, B. McCullough, A. Bagg, Y. Zhang and J.M. Wilson: “Erythropoietin gene therapy leads to autoimmune anemia in macaques”, Blood, Vol. 103, (2004), pp. 3300–3302. http://dx.doi.org/10.1182/blood-2003-11-3852 [Crossref]

  • [80] N. Eliopoulos, R.F. Gagnon, M. Francois and J. Galipeau: “Erythropoietin delivery by genetically engineered bone marrow stromal cells for correction of anemia in mice with chronic renal failure”, J. Am. Soc. Nephrol., Vol. 17, (2006), pp. 1576–1584. http://dx.doi.org/10.1681/ASN.2005101035 [Crossref]

  • [81] KDOQI, National Kidney Foundation: “KDOQI clinical practice guidelines and clinical practice recommendations for anemia in chronic kidney disease”, Am. J. Kidney Dis., Vol 47[Suppl 3] (2006), pp. S11–S145.

  • [82] E. Paoletti and G. Cannella: “Update on erythropoietin treatment: should hemoglobin be normalized in patients with chronic kidney disease?”, J. Am. Soc. Nephrol., Vol. 17 (2006), pp. S74–S77. http://dx.doi.org/10.1681/ASN.2005121325 [Crossref]

  • [83] A. Levin, O. Djurdjev and C. Thompson: “Canadian randomized trial of hemoglobin maintenance to prevent or delay left ventricular mass growth in patients with CKD”, Am. J. Kidney Dis., Vol. 46 (2005), pp. 799–811. http://dx.doi.org/10.1053/j.ajkd.2005.08.007 [Crossref]

  • [84] T.B. Drueke, F. Locatelli, N. Clyne, K-U. Eckardt and I.C. Macdougall: “Normalization of hemoglobin level in patients with chronic kidney disease and anemia”, N. Engl. J. Med., Vol. 355 (2006), pp. 2071–2084. http://dx.doi.org/10.1056/NEJMoa062276 [Crossref]

  • [85] A.K. Singh, L. Szczech, K.L. Tang and H. Barnhart: “Correction of anemia with Epoetin alfa in chronic kidney disease”, N. Engl. J. Med., Vol. 355 (2006), pp. 2085–2098. http://dx.doi.org/10.1056/NEJMoa065485 [Crossref]

  • [86] F. Li, Z.Z. Chong and K. Maiese: “Erythropoietin on a tightrope: balancing neuronal and vascular protection between intrinsic and extrinsic pathways”, Neurosignals, Vol. 13, (2004), pp. 265–289. http://dx.doi.org/10.1159/000081963 [Crossref]

  • [87] M. Joyeux-Faure, D. Godin-Ribout and C. Ribuot: “Erythropoietin and myocardial protection: What’s new?”, Fundam. Clin. Pharmacol., Vol. 19, (2005), pp. 439–446. http://dx.doi.org/10.1111/j.1472-8206.2005.00347.x [Crossref]

  • [88] M. Digicaylioglu and S.A. Lipton: “Erythropoietin-mediated neuroprotection involves cross-talk between Jak2 and NF-kappaB signaling cascades”, Nature, Vol. 412, (2001), pp. 641–647. http://dx.doi.org/10.1038/35088074

  • [89] A. Anagnostou, E.S. Lee, N. Kessimian, R. Levinson and M. Steiner: “Erythropoietin has a mitogenic and positive chemotactic effect on endothelial cells”, Proc. Natl. Acad. Sci. U.S.A., Vol. 87, (1990), pp. 5978–5982. http://dx.doi.org/10.1073/pnas.87.15.5978 [Crossref]

  • [90] A. Anagnostou, Z. Liu, M. Steiner, K. Chin, E.S. Lee, N. Kessimian and C.T. Noguchi: “Erythropoietin receptor mRNA expression in human endothelial cells”, Proc. Natl. Acad. Sci. U.S.A., Vol. 91, (1994), pp. 3974–3978. http://dx.doi.org/10.1073/pnas.91.9.3974 [Crossref]

  • [91] P. Chowdhury: “Functional significance of erythropoietin receptor on tumor cells”, World J. Gastroenterol., Vol. 12, (2006), pp. 7460–7462.

  • [92] P.L. Storring, R.J. Tiplady and R.E. Gaines Das: “Epoetin alfa and beta differ in their erythropoietin isoform composition and biological properties”, Br. J. Haematol., Vol. 100, (1998), pp. 79–89. http://dx.doi.org/10.1046/j.1365-2141.1998.00521.x [Crossref]

  • [93] I.C. Macdougall: “Pure red cell aplasia with anti-erythropoietin antibodies occurs more commonly with one formulation of epoetin alfa than another”, Curr. Med. Res. Opin., Vol. 20, (2004), pp. 83–86. http://dx.doi.org/10.1185/030079903125002702 [Crossref]

  • [94] S.K. Gershon, H. Luksenburg, T.R. Cote and M.M. Braun: “Pure red-cell aplasia and recombinant erythropoietin”, N. Engl. J. Med., Vol. 346, (2002), pp. 1584–1586. http://dx.doi.org/10.1056/NEJM200205163462015 [Crossref]

  • [95] H. Schellekens and D.J. Crommelin: “Equivocal role of micelles in Eprex adverse events”, Nat. Biotechnol., Vol. 21, (2003), pp. 1265–1270. http://dx.doi.org/10.1038/nbt1103-1265b [Crossref]

About the article

Published Online: 2007-12-01

Published in Print: 2007-12-01

Citation Information: Open Medicine, ISSN (Online) 2391-5463, DOI: https://doi.org/10.2478/s11536-007-0038-y. Export Citation

© 2007 Versita Warsaw. This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License. (CC BY-NC-ND 3.0)

Citing Articles

Here you can find all Crossref-listed publications in which this article is cited. If you would like to receive automatic email messages as soon as this article is cited in other publications, simply activate the “Citation Alert” on the top of this page.

Yoanna María Álvarez-Ginarte, Luis Alberto Montero-Cabrera, José Manuel García de la Vega, Pedro Noheda-Marín, Yovani Marrero-Ponce, and José Alberto Ruíz-García
The Journal of Steroid Biochemistry and Molecular Biology, 2011, Volume 126, Number 1-2, Page 35

Comments (0)

Please log in or register to comment.
Log in