Advertisement

Management of Renal Anemia in Children with Chronic Kidney Disease

  • Peter D. Yorgin
  • Joshua Zaritsky
Chapter

Abstract

Renal anemia management is on the cusp of ­dramatic changes due to development of novel erythropoiesis-stimulating agents (ESAs) and new understandings of iron metabolism. As a result of a greater understanding of hypoxia-inducible factor (HIF) regulation and erythropoietin receptor binding site kinetics, the next generation of ESAs are being developed. The adverse effects of erythropoietin, which has been the treatment standard for renal anemia, have become more apparent and concerning. The increased risk of cardiac death associated with normalizing hemoglobins in adult dialysis patients and the lack of a survival benefit for cancer patients have pharmaceutical corporations “smelling blood in the water.” The mechanism of action of hepcidin, a new iron-regulating molecule produced by the liver, provides a better understanding of why dialysis patients do not absorb oral iron well. There is also great interest in exploring how new ESAs, and particularly the prolyl hydroxylase inhibitors, impact hepcidin levels.

Keywords

renal anemia chronic kidney disease children pediatric diaylsis 

References

  1. 1.
    Rothstein G. Origin and development of the blood and blood-forming tissues. In: Cann C, editor. Wintrobe’s clinical hematology, vol. 1. Malvern: Lea & Febiger; 1993. p. 41–78.Google Scholar
  2. 2.
    Nishio M, et al. Stem cell factor prevents Fas-mediated apoptosis of human erythroid precursor cells with Src-family kinase dependency. Exp Hematol. 2001;29:19–29.PubMedGoogle Scholar
  3. 3.
    Sui X, Krantz SB, You M, Zhao Z. Synergistic activation of MAP kinase (ERK1/2) by erythropoietin and stem cell factor is essential for expanded erythropoiesis. Blood. 1998;92:1142–9.PubMedGoogle Scholar
  4. 4.
    Ottmann OG, Abboud M, Welte K, Souza LM, Pelus LM. Stimulation of human hematopoietic progenitor cell proliferation and differentiation by recombinant human interleukin 3. Comparison and interactions with recombinant human granulocyte-macrophage and granulocyte colony-stimulating factors. Exp Hematol. 1989;17:191–7.PubMedGoogle Scholar
  5. 5.
    Sawada K, et al. Transitional change of colony stimulating factor requirements for erythroid progenitors. J Cell Physiol. 1991;149:1–8.PubMedGoogle Scholar
  6. 6.
    Abboud M, Xu F, LaVia M, Laver J. Study of early hematopoietic precursors in human cord blood. Exp Hematol. 1992;20:1043–7.PubMedGoogle Scholar
  7. 7.
    Bastion Y, et al. IL-3 increases marrow and peripheral erythroid precursors in chronic pure red cell aplasia presenting in childhood. Br J Haematol. 1995;89:413–6.PubMedGoogle Scholar
  8. 8.
    Miles SA, et al. Recombinant human granulocyte colony-stimulating factor increases circulating burst forming unit-erythron and red blood cell production in patients with severe human immunodeficiency virus infection. Blood. 1990;75:2137–42.PubMedGoogle Scholar
  9. 9.
    Park K, et al. Positive effect of granulocyte-colony stimulating factor on erythropoiesis in humans. Osaka City Med J. 1991;37:123–32.PubMedGoogle Scholar
  10. 10.
    Negrin RS, et al. Treatment of the anemia of myelodysplastic syndromes using recombinant human granulocyte colony-stimulating factor in combination with erythropoietin. Blood. 1993;82:737–43.PubMedGoogle Scholar
  11. 11.
    Bessho M, et al. Treatment of the anemia of aplastic anemia patients with recombinant human erythropoietin in combination with granulocyte colony-stimulating factor: a multicenter randomized controlled study. Multicenter Study Group. Eur J Haematol. 1997;58:265–72.PubMedGoogle Scholar
  12. 12.
    Migliaccio G, Migliaccio AR, Adamson JW. In vitro differentiation of human granulocyte/macrophage and erythroid progenitors: comparative analysis of the influence of recombinant human erythropoietin, G-CSF, GM-CSF, and IL-3 in serum-supplemented and serum-deprived cultures. Blood. 1988;72: 248–56.PubMedGoogle Scholar
  13. 13.
    Claustres M, Sultan C. Stimulatory effects of androgens on normal children’s bone marrow in culture: effects on BFU-E, CFU-E, and uroporphyrinogen I synthase activity. Horm Res. 1986;23:91–8.PubMedGoogle Scholar
  14. 14.
    Moriyama Y, Fisher JW. Effects of testosterone and erythropoietin on erythroid colony formation in human bone marrow cultures. Blood. 1975;45: 665–70.PubMedGoogle Scholar
  15. 15.
    Fandrey J, Pagel H, Frede S, Wolff M, Jelkmann W. Thyroid hormones enhance hypoxia-induced erythropoietin production in vitro. Exp Hematol. 1994;22: 272–7.PubMedGoogle Scholar
  16. 16.
    Dainiak N, Hoffman R, Maffei LA, Forget BG. Potentiation of human erythropoiesis in vitro by thyroid hormone. Nature. 1978;272:260–2.PubMedGoogle Scholar
  17. 17.
    Aoki I, Taniyama M, Toyama K, Homori M, Ishikawa K. Stimulatory effect of human insulin on erythroid progenitors (CFU-E and BFU-E) in human CD34+ separated bone marrow cells and the relationship between insulin and erythropoietin. Stem Cells. 1994;12:329–38.PubMedGoogle Scholar
  18. 18.
    Okajima Y, et al. Insulin-like growth factor-I augments erythropoietin-induced proliferation through enhanced tyrosine phosphorylation of STAT5. J Biol Chem. 1998;273:22877–83.PubMedGoogle Scholar
  19. 19.
    Freudenthaler SM, Schenck T, Lucht I, Gleiter CH. Fenoterol stimulates human erythropoietin production via activation of the renin angiotensin system. Br J Clin Pharmacol. 1999;48:631–4.PubMedGoogle Scholar
  20. 20.
    Gleiter CH, Becker T, Schreeb KH, Freudenthaler S, Gundert-Remy U. Fenoterol but not dobutamine increases erythropoietin production in humans. Clin Pharmacol Ther. 1997;61:669–76.PubMedGoogle Scholar
  21. 21.
    Means Jr RT, Krantz SB. Inhibition of human erythroid colony-forming units by tumor necrosis factor requires beta interferon. J Clin Invest. 1993;91: 416–9.PubMedGoogle Scholar
  22. 22.
    Zamai L, et al. TNF-related apoptosis-inducing ligand (TRAIL) as a negative regulator of normal human erythropoiesis. Blood. 2000;95:3716–24.PubMedGoogle Scholar
  23. 23.
    Rusten LS, Jacobsen SE. Tumor necrosis factor (TNF)-alpha directly inhibits human erythropoiesis in vitro: role of p55 and p75 TNF receptors. Blood. 1995;85:989–96.PubMedGoogle Scholar
  24. 24.
    Means Jr RT, Dessypris EN, Krantz SB. Inhibition of human colony-forming-unit erythroid by tumor necrosis factor requires accessory cells. J Clin Invest. 1990;86:538–41.PubMedGoogle Scholar
  25. 25.
    Tarumi T, et al. Interferon-alpha-induced apoptosis in human erythroid progenitors. Exp Hematol. 1995;23:1310–8.PubMedGoogle Scholar
  26. 26.
    Zermati Y, et al. Transforming growth factor inhibits erythropoiesis by blocking proliferation and accelerating differentiation of erythroid progenitors. Exp Hematol. 2000;28:885–94.PubMedGoogle Scholar
  27. 27.
    Dybedal I, Jacobsen SE. Transforming growth factor beta (TGF-beta), a potent inhibitor of erythropoiesis: neutralizing TGF-beta antibodies show erythropoietin as a potent stimulator of murine burst-forming unit erythroid colony formation in the absence of a burst-promoting activity. Blood. 1995;86:949–57.PubMedGoogle Scholar
  28. 28.
    Chuncharunee S, et al. Chronic administration of transforming growth factor-beta suppresses erythropoietin-dependent erythropoiesis and induces tumour necrosis factor in vivo. Br J Haematol. 1993;84: 374–80.PubMedGoogle Scholar
  29. 29.
    Takenaka K, et al. In vitro expansion of hematopoietic progenitor cells induces functional expression of Fas antigen (CD95). Blood. 1996;88:2871–7.PubMedGoogle Scholar
  30. 30.
    Quang CT, Wessely O, Pironin M, Beug H, Ghysdael J. Cooperation of Spi-1/PU.1 with an activated erythropoietin receptor inhibits apoptosis and Epo-dependent differentiation in primary erythroblasts and induces their Kit ligand-dependent proliferation. EMBO J. 1997;16:5639–53.PubMedGoogle Scholar
  31. 31.
    Silva M, et al. Erythropoietin can promote erythroid progenitor survival by repressing apoptosis through Bcl-XL and Bcl-2. Blood. 1996;88:1576–82.PubMedGoogle Scholar
  32. 32.
    Wu H, Klingmuller U, Besmer P, Lodish HF. Interaction of the erythropoietin and stem-cell-factor receptors. Nature. 1995;377:242–6.PubMedGoogle Scholar
  33. 33.
    Muta K, Krantz SB. Apoptosis of human erythroid colony-forming cells is decreased by stem cell factor and insulin-like growth factor I as well as erythropoietin. J Cell Physiol. 1993;156:264–71.PubMedGoogle Scholar
  34. 34.
    Muta K, Krantz SB, Bondurant MC, Wickrema A. Distinct roles of erythropoietin, insulin-like growth factor I, and stem cell factor in the development of erythroid progenitor cells. J Clin Invest. 1994;94: 34–43.PubMedGoogle Scholar
  35. 35.
    Gregoli PA, Bondurant MC. The roles of Bcl-X(L) and apopain in the control of erythropoiesis by erythropoietin. Blood. 1997;90:630–40.PubMedGoogle Scholar
  36. 36.
    Sui X, Krantz SB, Zhao ZJ. Stem cell factor and erythropoietin inhibit apoptosis of human erythroid progenitor cells through different signalling pathways. Br J Haematol. 2000;110:63–70.PubMedGoogle Scholar
  37. 37.
    Shimizu R, et al. Role of c-jun in the inhibition of erythropoietin receptor-mediated apoptosis. Biochem Biophys Res Commun. 1996;222:1–6.PubMedGoogle Scholar
  38. 38.
    Tsushima H, et al. Human erythropoietin receptor increases GATA-2 and Bcl-xL by a protein kinase C-dependent pathway in human erythropoietin-dependent cell line AS-E2. Cell Growth Differ. 1997;8:1317–28.PubMedGoogle Scholar
  39. 39.
    Steinberg M, Benz E. Pathobiology of the human erythrocyte and its hemoglobins. In: Hoffman N, editor. Hematology: Basic Principles and Practice. Edinburgh: Churchill Livingstone; 2000.Google Scholar
  40. 40.
    Telen M. In: Cann C, editors. Wintrobe’s clinical hematology, vol. 1. Malvern: Lea & Febiger; 1993. p. 101–133.Google Scholar
  41. 41.
    Wu SG, et al. Red blood cell osmotic fragility in chronically hemodialyzed patients. Nephron. 1998;78:28–32.PubMedGoogle Scholar
  42. 42.
    Icardi A, et al. Red cell membrane during erythropoietin therapy in hemodialysis and in hemodiafiltration. Int J Artif Organs. 1991;14:147–9.PubMedGoogle Scholar
  43. 43.
    Rodriguez-Commes JL, Tabernero JM, Martin-Vasallo P, De Castro S, Battaner E. Metabolism of red blood cells in chronic renal failure. I. Glycolytic enzyme levels. Nephron. 1979;24:21–4.PubMedGoogle Scholar
  44. 44.
    Bohler T, Leo A, Stadler A, Linderkamp O. Mechanical fragility of erythrocyte membrane in neonates and adults. Pediatr Res. 1992;32:92–6.PubMedGoogle Scholar
  45. 45.
    Muller-Wiefel DE, Sinn H, Gilli G, Scharer K. Hemolysis and blood loss in children with chronic renal failure. Clin Nephrol. 1977;8:481–6.PubMedGoogle Scholar
  46. 46.
    Ponka P. Tissue-specific regulation of iron metabolism and heme synthesis: distinct control mechanisms in erythroid cells. Blood. 1997;89:1–25.PubMedGoogle Scholar
  47. 47.
    Ponka P, Beaumont C, Richardson DR. Function and regulation of transferrin and ferritin. Semin Hematol. 1998;35:35–54.PubMedGoogle Scholar
  48. 48.
    Conrad ME, Parmley RT, Osterloh K. Small intestinal regulation of iron absorption in the rat. J Lab Clin Med. 1987;110:418–26.PubMedGoogle Scholar
  49. 49.
    Roughead ZK, Hunt JR. Adaptation in iron absorption: iron supplementation reduces nonheme-iron but not heme-iron absorption from food. Am J Clin Nutr. 2000;72:982–9.PubMedGoogle Scholar
  50. 50.
    McKie AT, et al. An iron-regulated ferric reductase associated with the absorption of dietary iron. Science (New York). 2001;291:1755–9.Google Scholar
  51. 51.
    Fleming MD, et al. Nramp2 is mutated in the anemic Belgrade (b) rat: evidence of a role for Nramp2 in endosomal iron transport. Proc Natl Acad Sci USA. 1998;95:1148–53.Google Scholar
  52. 52.
    Harrison PM, Arosio P. The ferritins: molecular properties, iron storage function and cellular regulation. Biochim Biophys Acta. 1996;1275:161–203.PubMedGoogle Scholar
  53. 53.
    Ponka P, Lok CN. The transferrin receptor: role in health and disease. Int J Biochem Cell Biol. 1999;31:1111–37.PubMedGoogle Scholar
  54. 54.
    Aisen P. Transferrin receptor 1. Int J Biochem Cell Biol. 2004;36:2137–43.PubMedGoogle Scholar
  55. 55.
    Koorts AM, Viljoen M. Ferritin and ferritin isoforms I: Structure-function relationships, synthesis, degradation and secretion. Arch Physiol Biochem. 2007;113:30–54.PubMedGoogle Scholar
  56. 56.
    Besarab A, Kaiser JW, Frinak S. A study of parenteral iron regimens in hemodialysis patients. Am J Kidney Dis. 1999;34:21–8.PubMedGoogle Scholar
  57. 57.
    Hudson JQ, Comstock TJ. Considerations for optimal iron use for anemia due to chronic kidney disease. Clin Ther. 2001;23:1637–71.PubMedGoogle Scholar
  58. 58.
    Park CH, Valore EV, Waring AJ, Ganz T. Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J Biol Chem. 2001;276:7806–10.PubMedGoogle Scholar
  59. 59.
    Pigeon C, et al. A new mouse liver-specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload. J Biol Chem. 2001;276:7811–9.PubMedGoogle Scholar
  60. 60.
    Hunter HN, Fulton DB, Ganz T, Vogel HJ. The solution structure of human hepcidin, a peptide hormone with antimicrobial activity that is involved in iron uptake and hereditary hemochromatosis. J Biol Chem. 2002;277:37597–603.PubMedGoogle Scholar
  61. 61.
    Nemeth E, et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science (New York). 2004;306: 2090–3.Google Scholar
  62. 62.
    Papanikolaou G, et al. Hepcidin in iron overload disorders. Blood. 2005;105:4103–5.PubMedGoogle Scholar
  63. 63.
    Nemeth E, et al. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J Clin Invest. 2004;113:1271–6.PubMedGoogle Scholar
  64. 64.
    Babitt JL, et al. Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression. Nat Genet. 2006;38:531–9.PubMedGoogle Scholar
  65. 65.
    Lin L, et al. Iron transferrin regulates hepcidin synthesis in primary hepatocyte culture through hemojuvelin and BMP2/4. Blood. 2007;110:2182–9.PubMedGoogle Scholar
  66. 66.
    Babitt JL, et al. Modulation of bone morphogenetic protein signaling in vivo regulates systemic iron balance. J Clin Invest. 2007;117:1933–9.PubMedGoogle Scholar
  67. 67.
    Schmidt PJ, Toran PT, Giannetti AM, Bjorkman PJ, Andrews NC. The transferrin receptor modulates Hfe-dependent regulation of hepcidin expression. Cell Metab. 2008;7:205–14.PubMedGoogle Scholar
  68. 68.
    Goswami T, Andrews NC. Hereditary hemochromatosis protein, HFE, interaction with transferrin receptor 2 suggests a molecular mechanism for mammalian iron sensing. J Biol Chem. 2006;281:28494–8.PubMedGoogle Scholar
  69. 69.
    Vokurka M, Krijt J, Sulc K, Necas E. Hepcidin mRNA levels in mouse liver respond to inhibition of erythropoiesis. Physiol Res/Acad Sci Bohemoslov. 2006;55:667–74.Google Scholar
  70. 70.
    Pak M, Lopez MA, Gabayan V, Ganz T, Rivera S. Suppression of hepcidin during anemia requires erythropoietic activity. Blood. 2006;108:3730–5.PubMedGoogle Scholar
  71. 71.
    Ashby DR, et al. Plasma hepcidin levels are elevated but responsive to erythropoietin therapy in renal disease. Kidney Int. 2009;75:976–81.PubMedGoogle Scholar
  72. 72.
    Zaritsky J, et al. Hepcidin – a potential novel biomarker for iron status in chronic kidney disease. Clin J Am Soc Nephrol. 2009;4:1051–6.PubMedGoogle Scholar
  73. 73.
    Sato T, Maekawa T, Watanabe S, Tsuji K, Nakahata T. Erythroid progenitors differentiate and mature in response to endogenous erythropoietin. J Clin Invest. 2000;106:263–70.PubMedGoogle Scholar
  74. 74.
    Bachmann S, Le Hir M, Eckardt KU. Co-localization of erythropoietin mRNA and ecto-5′-nucleotidase immunoreactivity in peritubular cells of rat renal cortex indicates that fibroblasts produce erythropoietin. J Histochem Cytochem. 1993;41:335–41.PubMedGoogle Scholar
  75. 75.
    Maxwell PH, et al. Identification of the renal erythropoietin-producing cells using transgenic mice. Kidney Int. 1993;44:1149–62.PubMedGoogle Scholar
  76. 76.
    Liapis H, et al. In situ hybridization of human erythropoietin in pre- and postnatal kidneys. Pediatr Pathol Lab Med. 1995;15:875–83.PubMedGoogle Scholar
  77. 77.
    Juul SE, Yachnis AT, Christensen RD. Tissue distribution of erythropoietin and erythropoietin receptor in the developing human fetus. Early Hum Dev. 1998;52:235–49.PubMedGoogle Scholar
  78. 78.
    Schuster SJ, Wilson JH, Erslev AJ, Caro J. Physiologic regulation and tissue localization of renal erythropoietin messenger RNA. Blood. 1987;70:316–8.PubMedGoogle Scholar
  79. 79.
    Norman JT, Orphanides C, Garcia P, Fine LG. Hypoxia-induced changes in extracellular matrix metabolism in renal cells. Exp Nephrol. 1999;7:463–9.PubMedGoogle Scholar
  80. 80.
    Koury ST, Bondurant MC, Koury MJ, Semenza GL. Localization of cells producing erythropoietin in murine liver by in situ hybridization. Blood. 1991;77:2497–503.PubMedGoogle Scholar
  81. 81.
    Jacobs K, et al. Isolation and characterization of genomic and cDNA clones of human erythropoietin. Nature. 1985;313:806–10.PubMedGoogle Scholar
  82. 82.
    Chandra M, Clemons G, Sahdev I, McVicar M, Bluestone P. Intraperitoneal production of erythropoietin with continuous ambulatory peritoneal dialysis. Pediatr Nephrol. 1993;7:281–3.PubMedGoogle Scholar
  83. 83.
    Juul SE, Joyce AE, Zhao Y, Ledbetter DJ. Why is erythropoietin present in human milk? Studies of erythropoietin receptors on enterocytes of human and rat neonates. Pediatr Res. 1999;46:263–8.PubMedGoogle Scholar
  84. 84.
    Watkins PC, et al. Regional assignment of the erythropoietin gene to human chromosome region 7pter–q22. Cytogenet Cell Genet. 1986;42:214–8.PubMedGoogle Scholar
  85. 85.
    Law, ML, et al. Chromosomal assignment of the human erythropoietin gene and its DNA polymorphism. Proc Natl Acad Sci USA. 1986;83:6920–4.Google Scholar
  86. 86.
    Powell JS, Berkner KL, Lebo RV, Adamson JW. Human erythropoietin gene: high level expression in stably transfected mammalian cells and chromosome localization. Proc Natl Acad Sci USA. 1986;83: 6465–9.Google Scholar
  87. 87.
    Wang GL, Semenza GL. General involvement of hypoxia-inducible factor 1 in transcriptional response to hypoxia. Proc Natl Acad Sci USA. 1993;90: 4304–8.Google Scholar
  88. 88.
    Gleadle JM, Ratcliffe PJ. Induction of hypoxia-inducible factor-1, erythropoietin, vascular endothelial growth factor, and glucose transporter-1 by hypoxia: evidence against a regulatory role for Src kinase. Blood. 1997;89:503–9.PubMedGoogle Scholar
  89. 89.
    Erslev AJ. Erythropoietin. N Engl J Med. 1991;324: 1339–44.PubMedGoogle Scholar
  90. 90.
    Wang GL, Jiang BH, Rue EA, Semenza GL. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci USA. 1995;92:5510–4.PubMedGoogle Scholar
  91. 91.
    Paliege A, et al. Hypoxia-inducible factor-2alpha-expressing interstitial fibroblasts are the only renal cells that express erythropoietin under hypoxia-inducible factor stabilization. Kidney Int. 2010;77:312–8.PubMedGoogle Scholar
  92. 92.
    Wiesener MS, et al. Widespread hypoxia-inducible expression of HIF-2alpha in distinct cell populations of different organs. FASEB J. 2003;17:271–3.PubMedGoogle Scholar
  93. 93.
    Percy MJ, et al. Novel exon 12 mutations in the HIF2A gene associated with erythrocytosis. Blood. 2008;111:5400–2.PubMedGoogle Scholar
  94. 94.
    Furlow PW, et al. Erythrocytosis-associated HIF-2alpha mutations demonstrate a critical role for residues C-terminal to the hydroxylacceptor proline. J Biol Chem. 2009;284:9050–8.PubMedGoogle Scholar
  95. 95.
    Konietzny R, et al. Molecular imaging: into in vivo interaction of HIF-1alpha and HIF-2alpha with ARNT. Ann N Y Acad Sci. 2009;1177:74–81.PubMedGoogle Scholar
  96. 96.
    Semenza GL, Wang GL. A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol Cell Biol. 1992;12:5447–54.PubMedGoogle Scholar
  97. 97.
    Huang LE, Bunn HF. Regulation of erythropoietin gene expression. Curr Opin Hematol. 1995;2: 125–31.PubMedGoogle Scholar
  98. 98.
    Wang GL, Semenza GL. Molecular basis of hypoxia-induced erythropoietin expression. Curr Opin Hematol. 1996;3:156–62.PubMedGoogle Scholar
  99. 99.
    Jiang BH, Semenza GL, Bauer C, Marti HH. Hypoxia-inducible factor 1 levels vary exponentially over a physiologically relevant range of O2 tension. Am J Physiol. 1996;271:C1172–80.PubMedGoogle Scholar
  100. 100.
    Jaakkola P, et al. Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science. 2001; 292:468–72.PubMedGoogle Scholar
  101. 101.
    Pappalardi MB, et al. Biochemical characterization of human prolyl hydroxylase domain protein 2 variants associated with erythrocytosis. Biochemistry (Mosc). 2008;47:11165–7.Google Scholar
  102. 102.
    Al-Sheikh M, Moradkhani K, Lopez M, Wajcman H, Prehu C. Disturbance in the HIF-1alpha pathway associated with erythrocytosis: further evidences brought by frameshift and nonsense mutations in the prolyl hydroxylase domain protein 2 (PHD2) gene. Blood Cells Mol Dis. 2008;40:160–5.PubMedGoogle Scholar
  103. 103.
    Percy MJ, et al. A novel erythrocytosis-associated PHD2 mutation suggests the location of a HIF binding groove. Blood. 2007;110:2193–6.PubMedGoogle Scholar
  104. 104.
    Percy MJ, et al. A family with erythrocytosis establishes a role for prolyl hydroxylase domain protein 2 in oxygen homeostasis. Proc Natl Acad Sci USA. 2006;103:654–9.PubMedGoogle Scholar
  105. 105.
    Mole DR, et al. 2-oxoglutarate analogue inhibitors of HIF prolyl hydroxylase. Bioorg Med Chem Lett. 2003;13:2677–80.PubMedGoogle Scholar
  106. 106.
    McNeill LA, et al. The use of dioxygen by HIF prolyl hydroxylase (PHD1). Bioorg Med Chem Lett. 2002;12:1547–50.PubMedGoogle Scholar
  107. 107.
    Bernhardt WM, Wiesener MS, Schmieder RE, Gunzler V, Eckardt K-U. The Prolyl Hydroxylase Inhibitor FG-2216 Stimulates EPO Production in Nephric and Anephric Dialysis Patients–Evidence for an Underutilized Production Capacity in Liver and Kidneys. J Am Soc Nephrol. 2007;18:515A.Google Scholar
  108. 108.
    Fraser JK, Lin FK, Berridge MV. Expression of high affinity receptors for erythropoietin on human bone marrow cells and on the human erythroleukemic cell line. HEL. Exp Hematol. 1988;16:836–42.PubMedGoogle Scholar
  109. 109.
    Wu H, Liu X, Jaenisch R, Lodish HF. Generation of committed erythroid BFU-E and CFU-E progenitors does not require erythropoietin or the erythropoietin receptor. Cell. 1995;83:59–67.PubMedGoogle Scholar
  110. 110.
    Vannucchi AM, Grossi A, Rafanelli D, Vannucchi L, Rossi Ferrini P. Binding of recombinant human 125I-erythropoietin to CFU-E from the spleen of anemic mice. Haematologica. 1990;75:21–6.PubMedGoogle Scholar
  111. 111.
    Sinclair AM, et al. Functional erythropoietin receptor is undetectable in endothelial, cardiac, neuronal, and renal cells. Blood. 2010;115(21):4264–72.Google Scholar
  112. 112.
    Anagnostou A, et al. Erythropoietin receptor mRNA expression in human endothelial cells. Proc Natl Acad Sci USA. 1994;91:3974–8.PubMedGoogle Scholar
  113. 113.
    Wright GL, et al. Erythropoietin receptor expression in adult rat cardiomyocytes is associated with an acute cardioprotective effect for recombinant erythropoietin during ischemia-reperfusion injury. FASEB J. 2004;18:1031–3.PubMedGoogle Scholar
  114. 114.
    Echigoya MH, Obikane K, Nakashima T, Sasaki S. Glomerular localization of erythropoietin receptor mRNA and protein in neonatal and mature mouse kidney. Nephron Exp Nephrol. 2005;100:e21–9.PubMedGoogle Scholar
  115. 115.
    Wallach I, et al. Erythropoietin-receptor gene regulation in neuronal cells. Pediatr Res. 2009;65:619–24.PubMedGoogle Scholar
  116. 116.
    Masuda S, et al. Functional erythropoietin receptor of the cells with neural characteristics. Comparison with receptor properties of erythroid cells. J Biol Chem. 1993;268:11208–16.PubMedGoogle Scholar
  117. 117.
    Yu X, et al. Erythropoietin receptor signalling is required for normal brain development. Development. 2002;129:505–16.PubMedGoogle Scholar
  118. 118.
    Wu H, Lee SH, Gao J, Liu X, Iruela-Arispe ML. Inactivation of erythropoietin leads to defects in cardiac morphogenesis. Development. 1999;126:3597–605.PubMedGoogle Scholar
  119. 119.
    Cheetham JC, et al. NMR structure of human erythropoietin and a comparison with its receptor bound conformation. Nat Struct Biol. 1998;5:861–6.PubMedGoogle Scholar
  120. 120.
    Broudy VC, Lin N, Brice M, Nakamoto B, Papayannopoulou T. Erythropoietin receptor characteristics on primary human erythroid cells. Blood. 1991;77:2583–90.PubMedGoogle Scholar
  121. 121.
    Caravella JA, Lyne PD, Richards WG. A partial model of the erythropoietin receptor complex. Proteins. 1996;24:394–401.PubMedGoogle Scholar
  122. 122.
    Maouche L, Cartron JP, Chretien S. Different domains regulate the human erythropoietin receptor gene transcription. Nucleic Acids Res. 1994;22:338–46.PubMedGoogle Scholar
  123. 123.
    McCaffery PJ, Fraser JK, Lin FK, Berridge MV. Subunit structure of the erythropoietin receptor. J Biol Chem. 1989;264:10507–12.PubMedGoogle Scholar
  124. 124.
    Wilson IA, Jolliffe LK. The structure, organization, activation and plasticity of the erythropoietin receptor. Curr Opin Struct Biol. 1999;9:696–704.PubMedGoogle Scholar
  125. 125.
    Vadas O, Hartley O, Rose K. Characterization of new multimeric erythropoietin receptor agonists. Biopolymers. 2008;90:496–502.PubMedGoogle Scholar
  126. 126.
    Vadas O, Rose K. Multimeric peptides as agonists of the erythropoietin receptor. Adv Exp Med Biol. 2009;611:505–6.PubMedGoogle Scholar
  127. 127.
    Kirito K, et al. Identification of the human erythropoietin receptor region required for Stat1 and Stat3 activation. Blood. 2002;99:102–10.PubMedGoogle Scholar
  128. 128.
    Torti M, Marti KB, Altschuler D, Yamamoto K, Lapetina EG. Erythropoietin induces p21ras activation and p120GAP tyrosine phosphorylation in human erythroleukemia cells. J Biol Chem. 1992;267:8293–8.PubMedGoogle Scholar
  129. 129.
    Komatsu N, et al. Erythropoietin rapidly induces tyrosine phosphorylation in the human erythropoietin-dependent cell line, UT-7. Blood. 1992;80:53–9.PubMedGoogle Scholar
  130. 130.
    Nosaka Y, Arai A, Miyasaka N, Miura O. CrkL mediates Ras-dependent activation of the Raf/ERK pathway through the guanine nucleotide exchange factor C3G in hematopoietic cells stimulated with erythropoietin or interleukin-3. J Biol Chem. 1999;274: 30154–62.PubMedGoogle Scholar
  131. 131.
    Arai A, Kanda E, Miura O. Rac is activated by erythropoietin or interleukin-3 and is involved in activation of the Erk signaling pathway. Oncogene. 2002;21:2641–51.PubMedGoogle Scholar
  132. 132.
    Chen C, Sytkowski AJ. Erythropoietin activates two distinct signaling pathways required for the initiation and the elongation of c-myc. J Biol Chem. 2001;276:38518–26.PubMedGoogle Scholar
  133. 133.
    Kubota Y, et al. Src transduces erythropoietin-induced differentiation signals through phosphatidylinositol 3-kinase. EMBO J. 2001;20:5666–77.PubMedGoogle Scholar
  134. 134.
    Neri LM, et al. Erythropoietin-induced erythroid differentiation of K562 cells is accompanied by the nuclear translocation of phosphatidylinositol 3-kinase and intranuclear generation of phosphatidylinositol (3,4,5) trisphosphate. Cell Signal. 2002; 14:21–9.PubMedGoogle Scholar
  135. 135.
    Cheng CK, Chan J, Cembrowski GS, van Assendelft OW. Complete blood count reference interval diagrams derived from NHANES III: stratification by age, sex, and race. Lab Hematol. 2004;10:42–53.PubMedGoogle Scholar
  136. 136.
    Robins EB, Blum S. Hematologic reference values for African American children and adolescents. Am J Hematol. 2007;82:611–4.PubMedGoogle Scholar
  137. 137.
    Dallman PR, Yip R, Johnson C. Prevalence and causes of anemia in the United States, 1976 to 1980. Am J Clin Nutr. 1984;39:437–45.PubMedGoogle Scholar
  138. 138.
    Yip R, Schwartz S, Deinard AS. Hematocrit values in white, black, and American Indian children with comparable iron status. Evidence to support uniform diagnostic criteria for anemia among all races. Am J Dis Child. 1984;138:824–7.PubMedGoogle Scholar
  139. 139.
    Anonymous. NKF-DOQI clinical practice guidelines for the treatment of anemia of chronic renal failure. National Kidney Foundation-Dialysis Outcomes Quality Initiative [see comments]. Am J Kidney Dis. 1997;30:S192–240.Google Scholar
  140. 140.
    Anonymous. IV. NKF-K/DOQI Clinical Practice Guidelines for Anemia of Chronic Kidney Disease: update 2000. Am J Kidney Dis [Online]. 2001;37: S182–238.Google Scholar
  141. 141.
    Henry J. Clinical diagnosis and management by laboratory methods. In: Methods hematology: basic methodology. Philadelphia: Saunders; 1996. p. 578–625.Google Scholar
  142. 142.
    Holt JT, DeWandler MJ, Arvan DA. Spurious elevation of the electronically determined mean corpuscular volume and hematocrit caused by hyperglycemia. Am J Clin Pathol. 1982;77:561–7.PubMedGoogle Scholar
  143. 143.
    Paterakis G, et al. The effect of red cell shape on the measurement of red cell volume. A proposed method for hte comparison assessment of this effect among various haematology analysers. Clin Lab Haematol. 1994;16:235–45.PubMedGoogle Scholar
  144. 144.
    Chandra M, Clemons GK, McVicar MI. Relation of serum erythropoietin levels to renal excretory function: evidence for lowered set point for erythropoietin production in chronic renal failure. J Pediatr. 1988;113:1015–21.PubMedGoogle Scholar
  145. 145.
    von Lilien T, Salusky IB, Boechat I, Ettenger RB, Fine RN. Five years’ experience with continuous ambulatory or continuous cycling peritoneal dialysis in children. J Pediatr. 1987;111:513–8.Google Scholar
  146. 146.
    Nissenson AR. National cooperative rHu erythropoietin study in patients with chronic renal failure: a phase IV multicenter study. Report of National Cooperative rHu Erythropoietin Study Group. Am J Kidney Dis.1991;18:24–33.Google Scholar
  147. 147.
    Aljama P, et al. Serum ferritin concentration: a ­reliable guide to iron overload in uremic and hemodialyzed patients. Clin Nephrol. 1978;10:101–4.PubMedGoogle Scholar
  148. 148.
    Moreb J, Popovtzer MM, Friedlaender MM, Konijn AM, Hershko C. Evaluation of iron status in patients on chronic hemodialysis: relative usefulness of bone marrow hemosiderin, serum ferritin, transferrin saturation, mean corpuscular volume and red cell protoporphyrin. Nephron. 1983;35:196–200.PubMedGoogle Scholar
  149. 149.
    Gomez E, et al. Serum ferritin in haemodialysis patients: role of blood transfusions and ‘haemochromatosis alleles’ HLA A3, B7 and B14. Nephron. 1984;36:106–10.PubMedGoogle Scholar
  150. 150.
    Taccone-Gallucci M, et al. Risk of iron overload and ‘hemochromatosis allele(s)’ in patients on maintenance hemodialysis. Am J Nephrol. 1987;7:28–32.PubMedGoogle Scholar
  151. 151.
    Chavers BM, Sullivan EK, Tejani A, Harmon WE. Pre-transplant blood transfusion and renal allograft outcome: a report of the North American Pediatric Renal Transplant Cooperative Study. Pediatr Transplant. 1997;1:22–28.Google Scholar
  152. 152.
    Temple RM, Deary IJ, Winney RJ. Recombinant erythropoietin improves cognitive function in patients maintained on chronic ambulatory peritoneal dialysis. Nephrol Dial Transplant. 1995;10: 1733–8.PubMedGoogle Scholar
  153. 153.
    Kambova L. Recombinant erythropoietin improves cognitive function in chronic haemodialysis patients [letter]. Nephrol Dial Transplant. 1998;13:229–30.PubMedGoogle Scholar
  154. 154.
    Marsh JT, et al. rHuEPO treatment improves brain and cognitive function of anemic dialysis patients. Kidney Int. 1991;39:155–63.PubMedGoogle Scholar
  155. 155.
    Nelson M. Anaemia in adolescent girls: effects on cognitive function and activity. Proc Nutr Soc. 1996;55:359–67.PubMedGoogle Scholar
  156. 156.
    Nissenson AR. Recombinant human erythropoietin: impact on brain and cognitive function, exercise tolerance, sexual potency, and quality of life. Semin Nephrol. 1989;9:25–31.PubMedGoogle Scholar
  157. 157.
    Temple RM, Langan SJ, Deary IJ, Winney RJ. Recombinant erythropoietin improves cognitive function in chronic haemodialysis patients. Nephrol Dial Transplant. 1992;7:240–5.PubMedGoogle Scholar
  158. 158.
    Weiskopf RB, et al. Acute severe isovolemic anemia impairs cognitive function and memory in humans. Anesthesiology. 2000;92:1646–52.PubMedGoogle Scholar
  159. 159.
    Wolcott DL, Marsh JT, La Rue A, Carr C, Nissenson AR. Recombinant human erythropoietin treatment may improve quality of life and cognitive function in chronic hemodialysis patients. Am J Kidney Dis. 1989;14:478–85.PubMedGoogle Scholar
  160. 160.
    Lozoff B, Jimenez E, Hagen J, Mollen E, Wolf AW. Poorer behavioral and developmental outcome more than 10 years after treatment for iron deficiency in infancy. Pediatrics. 2000;105:E51.PubMedGoogle Scholar
  161. 161.
    Guthrie M, et al. Effects of erythropoietin on strength and functional status of patients on hemodialysis. Clin Nephrol. 1993;39:97–102.PubMedGoogle Scholar
  162. 162.
    Warady BA, Sabath RJ, Smith CA, Alon U, Hellerstein S. Recombinant human erythropoietin therapy in pediatric patients receiving long-term peritoneal dialysis. Pediatr Nephrol. 1991;5: 718–23.PubMedGoogle Scholar
  163. 163.
    Campos A, Garin EH. Therapy of renal anemia in children and adolescents with recombinant human erythropoietin (rHuEPO). Clin Pediatr (Phila). 1992;31:94–9.Google Scholar
  164. 164.
    Portoles J, Lopez-Gomez JM, Aljama P. A prospective multicentre study of the role of anaemia as a risk factor in haemodialysis patients: the MAR Study. Nephrol Dial Transplant. 2007;22:500–7.PubMedGoogle Scholar
  165. 165.
    Nelson M, Bakaliou F, Trivedi A. Iron-deficiency anaemia and physical performance in adolescent girls from different ethnic backgrounds. Br J Nutr. 1994;72:427–33.PubMedGoogle Scholar
  166. 166.
    Kapoor RK, et al. Cardiovascular responses to treadmill exercise testing in anemia. Indian Pediatr. 1997;34:607–12.PubMedGoogle Scholar
  167. 167.
    Martin GR, Ongkingo JR, Turner ME, Skurow ES, Ruley EJ. Recombinant erythropoietin (Epogen) improves cardiac exercise performance in children with end-stage renal disease. Pediatr Nephrol. 1993;7:276–80.PubMedGoogle Scholar
  168. 168.
    Morris KP, Sharp J, Watson S, Coulthard MG. Non-cardiac benefits of human recombinant erythropoietin in end stage renal failure and anaemia. Arch Dis Child. 1993;69:580–6.PubMedGoogle Scholar
  169. 169.
    Navarro M, Alonso A, Avilla JM, Espinosa L. Anemia of chronic renal failure: treatment with erythropoietin. Child Nephrol Urol. 1991;11:146–51.PubMedGoogle Scholar
  170. 170.
    Jabs K. The effects of recombinant human erythropoietin on growth and nutritional status. Pediatr Nephrol. 1996;10:324–7.PubMedGoogle Scholar
  171. 171.
    Boehm M, et al. Early erythropoietin therapy is associated with improved growth in children with chronic kidney disease. Pediatr Nephrol. 2007;22:1189–93.PubMedGoogle Scholar
  172. 172.
    Steinhauer HB, Lubrich-Birkner I, Dreyling KW, Horl WH, Schollmeyer P. Increased ultrafiltration after erythropoietin-induced correction of renal anemia in patients on continuous ambulatory peritoneal dialysis. Nephron. 1989;53:91–2.PubMedGoogle Scholar
  173. 173.
    Schollmeyer P, Lubrich-Birkner I, Steinhauer HB. Effect of recombinant human erythropoietin on anemia and dialysis: efficiency in patients undergoing CAPD. Contrib Nephrol. 1990;87:95–104.PubMedGoogle Scholar
  174. 174.
    Lubrich-Birkner I, Schollmeyer P, Steinhauer HB. One year experience with subcutaneous human erythropoietin in CAPD: correction of renal anemia and increased ultrafiltration. Adv Perit Dial. 1990;6:302–7.PubMedGoogle Scholar
  175. 175.
    Bessman J, Gilmer Jr P, Gardner F. Improved classification of anemias by MCV and RDW. Am J Clin Pathol. 1983;80:322–6.PubMedGoogle Scholar
  176. 176.
    Fialon P, Leaute AG, Sassier P, Vallot C, Wone C. Use of red blood cell indices (MCV, MCH, RDW) in monitoring chronic hemodialysis patients treated with recombinant erythropoietin. Pathol Biol. 1993; 41:931–5.PubMedGoogle Scholar
  177. 177.
    Besarab A, Caro J, Jarrell BE, Francos G, Erslev AJ. Dynamics of erythropoiesis following renal transplantation. Kidney Int. 1987;32:526–36.PubMedGoogle Scholar
  178. 178.
    Erslev AJ. Erythropoietin titers in health and disease. Semin Hematol. 1991;28:2–7. discussion 7–8.PubMedGoogle Scholar
  179. 179.
    Feinstein S, et al. Erythropoietin deficiency causes anemia in nephrotic children with normal kidney function. Am J Kidney Dis [Online]. 2001;37: 736–42.Google Scholar
  180. 180.
    KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease. Am J Kidney Dis. 2006;47:S11–145.Google Scholar
  181. 181.
    Linder MC, et al. Serum ferritin: does it differ from tissue ferritin? J Gastroenterol Hepatol. 1996;11: 1033–6.PubMedGoogle Scholar
  182. 182.
    Worwood M. Ferritin. Blood Rev. 1990;4:259–69.PubMedGoogle Scholar
  183. 183.
    Kwak EL, Larochelle DA, Beaumont C, Torti SV, Torti FM. Role for NF-kappa B in the regulation of ferritin H by tumor necrosis factor-alpha. J Biol Chem. 1995;270:15285–93.PubMedGoogle Scholar
  184. 184.
    Rogers JT, et al. Translational control during the acute phase response. Ferritin synthesis in response to interleukin-1. J Biol Chem. 1990;265:14572–8.PubMedGoogle Scholar
  185. 185.
    Fishbane S, Kowalski EA, Imbriano LJ, Maesaka JK. The evaluation of iron status in hemodialysis patients. J Am Soc Nephrol. 1996;7:2654–7.PubMedGoogle Scholar
  186. 186.
    Kalantar-Zadeh K, et al. Diagnosis of iron deficiency anemia in renal failure patients during the post-erythropoietin era. Am J Kidney Dis. 1995;26: 292–9.PubMedGoogle Scholar
  187. 187.
    Tessitore N, et al. The role of iron status markers in predicting response to intravenous iron in haemodialysis patients on maintenance erythropoietin. Nephrol Dial Transplant. 2001;16:1416–23.PubMedGoogle Scholar
  188. 188.
    Kalantar-Zadeh K, Rodriguez RA, Humphreys MH. Association between serum ferritin and measures of inflammation, nutrition and iron in haemodialysis patients. Nephrol Dial Transplant. 2004;19:141–9.PubMedGoogle Scholar
  189. 189.
    Coyne DW, et al. Ferric gluconate is highly efficacious in anemic hemodialysis patients with high serum ferritin and low transferrin saturation: results of the dialysis patients’ response to IV iron with elevated ferritin (DRIVE) study. J Am Soc Nephrol. 2007;18:975–84.PubMedGoogle Scholar
  190. 190.
    Singh AK, Coyne DW, Shapiro W, Rizkala AR. Predictors of the response to treatment in anemic hemodialysis patients with high serum ferritin and low transferrin saturation. Kidney Int. 2007;71:1163–71.PubMedGoogle Scholar
  191. 191.
    Chuang CL, Liu RS, Wei YH, Huang TP, Tarng DC. Early prediction of response to intravenous iron supplementation by reticulocyte haemoglobin content and high-fluorescence reticulocyte count in haemodialysis patients. Nephrol Dial Transplant. 2003;18:370–7.PubMedGoogle Scholar
  192. 192.
    Mittman N, et al. Reticulocyte hemoglobin content predicts functional iron deficiency in hemodialysis patients receiving rHuEPO. Am J Kidney Dis. 1997;30:912–22.PubMedGoogle Scholar
  193. 193.
    Fishbane S, Shapiro W, Dutka P, Valenzuela OF, Faubert J. A randomized trial of iron deficiency testing strategies in hemodialysis patients. Kidney Int. 2001;60:2406–11.PubMedGoogle Scholar
  194. 194.
    Cullen P, et al. Hypochromic red cells and reticulocyte haemglobin content as markers of iron-deficient erythropoiesis in patients undergoing chronic haemodialysis. Nephrol Dial Transplant. 1999;14: 659–65.PubMedGoogle Scholar
  195. 195.
    Chiang WC, Tsai TJ, Chen YM, Lin SL, Hsieh BS. Serum soluble transferrin receptor reflects erythropoiesis but not iron availability in erythropoietin-treated chronic hemodialysis patients. Clin Nephrol. 2002;58:363–9.PubMedGoogle Scholar
  196. 196.
    Tarng DC, Huang TP. Determinants of circulating soluble transferrin receptor level in chronic haemodialysis patients. Nephrol Dial Transplant. 2002;17: 1063–9.PubMedGoogle Scholar
  197. 197.
    Fernandez-Rodriguez AM, et al. Diagnosis of iron deficiency in chronic renal failure. Am J Kidney Dis. 1999;34:508–13.PubMedGoogle Scholar
  198. 198.
    Ganz T. Molecular control of iron transport. J Am Soc Nephrol. 2007;18:394–400.PubMedGoogle Scholar
  199. 199.
    Domrongkitchaiporn S, Jirakranont B, Atamasrikul K, Ungkanont A, Bunyaratvej A. Indices of iron status in continuous ambulatory peritoneal dialysis patients. Am J Kidney Dis. 1999;34:29–35.PubMedGoogle Scholar
  200. 200.
    Lin FK, et al. Cloning and expression of the human erythropoietin gene. Proc Natl Acad Sci USA. 1985;82:7580–4Google Scholar
  201. 201.
    Miyake T, Kung CK, Goldwasser E. Purification of human erythropoietin. J Biol Chem. 1977;252: 5558–64.PubMedGoogle Scholar
  202. 202.
    Lai PH, Everett R, Wang FF, Arakawa T, Goldwasser E. Structural characterization of human erythropoietin. J Biol Chem. 1986;261:3116–21.PubMedGoogle Scholar
  203. 203.
    Deicher R, Horl WH. Differentiating factors between erythropoiesis-stimulating agents: a guide to selection for anaemia of chronic kidney disease. Drugs. 2004;64:499–509.PubMedGoogle Scholar
  204. 204.
    Sikole A, Spasovski G, Zafirov D, Polenakovic M. Epoetin omega for treatment of anemia in maintenance hemodialysis patients. Clin Nephrol. 2002;57:237–45.PubMedGoogle Scholar
  205. 205.
    Bren A, et al. A comparison between epoetin omega and epoetin alfa in the correction of anemia in hemodialysis patients: a prospective, controlled crossover study. Artif Organs. 2002;26:91–7.PubMedGoogle Scholar
  206. 206.
    Sinai-Trieman L, Salusky IB, Fine RN. Use of subcutaneous recombinant human erythropoietin in children undergoing continuous cycling peritoneal dialysis. J Pediatr. 1989;114:550–4.PubMedGoogle Scholar
  207. 207.
    Brem AS, Lambert C, Hill C, Kitsen J, Shemin DG. Outcome data on pediatric dialysis patients from the end-stage renal disease clinical indicators project. Am J Kidney Dis [Online]. 2000;36:310–7.Google Scholar
  208. 208.
    Alexander S, Benfield M, Fine RN, McDonald R, Warady B. North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) 2002 Annual Report. (2002).Google Scholar
  209. 209.
    Jabs K, Alexander S, McCabe D, Lerner G, Harmon WE. Primary results from the U.S. multicenter pediatric recombinant erythropoietin study. J Am Soc Nephrol. 1994;5:456 (abstract 484P).Google Scholar
  210. 210.
    Seeherunvong W, et al. Identification of poor responders to erythropoietin among children undergoing hemodialysis. J Pediatr. 2001;138:710–4.PubMedGoogle Scholar
  211. 211.
    Pollak A, et al. Effect of intravenous iron supplementation on erythropoiesis in erythropoietin-treated premature infants. Pediatrics. 2001;107:78–85.PubMedGoogle Scholar
  212. 212.
    Maier RF, et al. High-versus low-dose erythropoietin in extremely low birth weight infants. The European Multicenter rhEPO Study Group. J Pediatr. 1998; 132:866–70.PubMedGoogle Scholar
  213. 213.
    Brown MS, Jones MA, Ohls RK, Christensen RD. Single-dose pharmacokinetics of recombinant human erythropoietin in preterm infants after intravenous and subcutaneous administration. J Pediatr. 1993;122:655–7.PubMedGoogle Scholar
  214. 214.
    Bamgbola OF, Kaskel FJ, Coco M. Analyses of age, gender and other risk factors of erythropoietin resistance in pediatric and adult dialysis cohorts. Pediatr Nephrol. 2009;24:571–9.PubMedGoogle Scholar
  215. 215.
    Port RE, Mehls O. Erythropoietin dosing in children with chronic kidney disease: based on body size or on hemoglobin deficit? Pediatr Nephrol. 2009;24: 435–7.PubMedGoogle Scholar
  216. 216.
    Scigalla P, et al. Therapy of renal anemia with recombinant human erythropoietin in children with end-stage renal disease. Contrib Nephrol. 1989;76:227–40. discussion 240-221.PubMedGoogle Scholar
  217. 217.
    Cody J, et al. Frequency of administration of recombinant human erythropoietin for anaemia of end-stage renal disease in dialysis patients. Cochrane Database of Systematic Reviews: 2005(3).Google Scholar
  218. 218.
    Brandt JR, Avner ED, Hickman RO, Watkins SL. Safety and efficacy of erythropoietin in children with chronic renal failure [see comments]. Pediatr Nephrol. 1999;13:143–7.PubMedGoogle Scholar
  219. 219.
    Rusthoven E, van de Kar NC, Monnens LA, Schroder CH. Long-term effectiveness of intraperitoneal erythropoietin in children on NIPD by administration in small bags. Perit Dial Int. 2001;21:196–7.PubMedGoogle Scholar
  220. 220.
    Frenken LA, et al. Intraperitoneal administration of recombinant human erythropoietin. Perit Dial Int. 1992;12:378–83.PubMedGoogle Scholar
  221. 221.
    Rijk Y, Raaijmakers R, van de Kar N, Schroder C. Intraperitoneal treatment with darbepoetin for children on peritoneal dialysis. Pediatr Nephrol. 2007;22: 436–40.PubMedGoogle Scholar
  222. 222.
    Egrie JC, Browne JK. Development and characterization of novel erythropoiesis stimulating protein (NESP). Br J Cancer. 2001;84:3–10.PubMedGoogle Scholar
  223. 223.
    Macdougall IC, Chandler G, Elston O, Harchowal J. Beneficial effects of adopting an aggressive intravenous iron policy in a hemodialysis unit. Am J Kidney Dis. 1999;34:S40–6.PubMedGoogle Scholar
  224. 224.
    Vekeman F, et al. Dose and cost comparison of erythropoietic agents in the inpatient hospital setting. Am J Health Syst Pharm. 2007;64:1943–9.PubMedGoogle Scholar
  225. 225.
    Song X, Long SR, Marder WD, Sullivan SD, Kallich J. The impact of methodological approach on cost findings in comparison of epoetin alfa with darbepoetin alfa. Ann Pharmacother. 2009;43:1203–10.PubMedGoogle Scholar
  226. 226.
    Courtney AE, McNamee PT, Maxwell AP. Cost should be the principal determinant of choice of erythropoiesis-stimulating agent in chronic haemodialysis patients. Nephron Clin Pract. 2007;107: c14–9.PubMedGoogle Scholar
  227. 227.
    Schmitt CP, Nau B, Brummer C, Rosenkranz J, Schaefer F. Increased injection pain with darbepoetin-alpha compared to epoetin-beta in paediatric dialysis patients. Nephrol Dial Transplant. 2006;21: 3520–4.PubMedGoogle Scholar
  228. 228.
    Aljama P, et al. Practical guidelines for the use of NESP in treating renal anaemia. Nephrol Dial Transplant. 2001;16:22–8.PubMedGoogle Scholar
  229. 229.
    Lerner G, et al. Pharmacokinetics of darbepoetin alfa in pediatric patients with chronic kidney disease. Pediatr Nephrol. 2002;17:933–7.PubMedGoogle Scholar
  230. 230.
    Hutchinson FN, Jones WJ. A cost-effectiveness analysis of anemia screening before erythropoietin in patients with end-stage renal disease. Am J Kidney Dis. 1997;29:651–7.PubMedGoogle Scholar
  231. 231.
    Kaufman JS. Subcutaneous erythropoietin therapy: efficacy and economic implications. Am J Kidney Dis. 1998;32:S147–51.PubMedGoogle Scholar
  232. 232.
    Buckner FS, Eschbach JW, Haley NR, Davidson RC, Adamson JW. Hypertension following erythropoietin therapy in anemic hemodialysis patients. Am J Hypertens. 1990;3:947–55.PubMedGoogle Scholar
  233. 233.
    Abraham PA, Macres MG. Blood pressure in ­hemodialysis patients during amelioration of anemia with erythropoietin. J Am Soc Nephrol. 1991;2: 927–36.PubMedGoogle Scholar
  234. 234.
    Van Geet C, et al. Recombinant human erythropoietin increases blood pressure, platelet aggregability and platelet free calcium mobilisation in uraemic children: a possible link? Thromb Haemost. 1990;64: 7–10.PubMedGoogle Scholar
  235. 235.
    Yalcinkaya F, Tumer N, Cakar N, Ozkaya N. Low-dose erythropoietin is effective and safe in children on continuous ambulatory peritoneal dialysis. Pediatr Nephrol. 1997;11:350–2.PubMedGoogle Scholar
  236. 236.
    Scharer K, Klare B, Braun A, Dressel P, Gretz N. Treatment of renal anemia by subcutaneous erythropoietin in children with preterminal chronic renal failure. Acta Paediatr. 1993;82:953–8.PubMedGoogle Scholar
  237. 237.
    Vaziri ND. Cardiovascular effects of erythropoietin and anemia correction. Curr Opin Nephrol Hypertens. 2001;10:633–7.PubMedGoogle Scholar
  238. 238.
    Raine AE, Roger SD. Effects of erythropoietin on blood pressure. Am J Kidney Dis. 1991;18:76–83.PubMedGoogle Scholar
  239. 239.
    Zhou XJ, Pandian D, Wang XQ, Vaziri ND. Erythropoietin-induced hypertension in rat is not mediated by alterations of plasma endothelin, vasopressin, or atrial natriuretic peptide levels. J Am Soc Nephrol. 1997;8:901–5.PubMedGoogle Scholar
  240. 240.
    Cogar AA, Hartenberger CH, Ohls RK. Endothelin concentrations in preterm infants treated with human recombinant erythropoietin. Biol Neonate. 2000;77: 105–8.PubMedGoogle Scholar
  241. 241.
    Raine AE. Hypertension, blood viscosity, and cardiovascular morbidity in renal failure: implications of erythropoietin therapy. Lancet. 1988;1:97–100.PubMedGoogle Scholar
  242. 242.
    Ni Z, Wang XQ, Vaziri ND. Nitric oxide metabolism in erythropoietin-induced hypertension: effect of calcium channel blockade. Hypertension. 1998;32:724–9.PubMedGoogle Scholar
  243. 243.
    Vaziri ND, et al. Role of nitric oxide resistance in erythropoietin-induced hypertension in rats with chronic renal failure. Am J Physiol. 1996;271:E113–22.PubMedGoogle Scholar
  244. 244.
    Schiffl H, Lang SM. Hypertension induced by recombinant human erythropoietin (rHU-EPO) can be prevented by indomethacin. Pathogenetic role of cytosolic calcium. Eur J Med Res. 1997;2:97–100.PubMedGoogle Scholar
  245. 245.
    Allegra A, et al. Administration of recombinant erythropoietin determines increase of peripheral resistances in patients with hypovolemic shock. Nephron. 1996;74:431–2.PubMedGoogle Scholar
  246. 246.
    Abiose AK, et al. Increased vascular alpha1-adrenergic sensitivity in patients with renal failure: receiving recombinant erythropoeitin. Am J Ther. 2007;14:427–34.PubMedGoogle Scholar
  247. 247.
    Fritschka E, et al. Effect of erythropoietin on parameters of sympathetic nervous activity in patients undergoing chronic haemodialysis. Br J Clin Pharmacol. 1990;30:135S–8.PubMedGoogle Scholar
  248. 248.
    Ksiazek A, Zaluska WT, Ksiazek P. Effect of recombinant human erythropoietin on adrenergic activity in normotensive hemodialysis patients. Clin Nephrol. 2001;56:104–10.PubMedGoogle Scholar
  249. 249.
    Hand MF, Haynes WG, Johnstone HA, Anderton JL, Webb DJ. Erythropoietin enhances vascular responsiveness to norepinephrine in renal failure. Kidney Int. 1995;48:806–13.PubMedGoogle Scholar
  250. 250.
    Vaziri ND. Mechanism of erythropoietin-induced hypertension. Am J Kidney Dis. 1999;33:821–8.PubMedGoogle Scholar
  251. 251.
    Jabs K, Harmon WE. Recombinant human erythropoietin therapy in children on dialysis. Adv Ren Replace Ther. 1996;3:24–36.PubMedGoogle Scholar
  252. 252.
    Luft FC. Erythropoietin and arterial hypertension. Clin Nephrol. 2000;53:S61–4.PubMedGoogle Scholar
  253. 253.
    De Marchi S, et al. Long-term effects of erythropoietin therapy on fistula stenosis and plasma concentrations of PDGF and MCP-1 in hemodialysis patients. J Am Soc Nephrol. 1997;8:1147–56.PubMedGoogle Scholar
  254. 254.
    Wirtz JJ, van Esser JW, Hamulyak K, Leunissen KM, van Hooff JP. The effects of recombinant human erythropoietin on hemostasis and fibrinolysis in hemodialysis patients. Clin Nephrol. 1992;38:277–82.PubMedGoogle Scholar
  255. 255.
    Eschbach JW, et al. Recombinant human erythropoietin in anemic patients with end-stage renal disease. Results of a phase III multicenter clinical trial. Ann Intern Med. 1989;111:992–1000.PubMedGoogle Scholar
  256. 256.
    Kooistra MP, van Es A, Marx JJ, Hertsig ML, Struyvenberg A. Low-dose aspirin does not prevent thrombovascular accidents in low-risk haemodialysis patients during treatment with recombinant human erythropoietin. Nephrol Dial Transplant. 1994;9:1115–20.PubMedGoogle Scholar
  257. 257.
    Metry G, et al. Effect of normalization of hematocrit on brain circulation and metabolism in hemodialysis patients. J Am Soc Nephrol. 1999;10:854–63.PubMedGoogle Scholar
  258. 258.
    Jaar B, et al. Effects of long-term treatment with recombinant human erythropoietin on physiologic inhibitors of coagulation. Am J Nephrol. 1997;17: 399–405.PubMedGoogle Scholar
  259. 259.
    Tassies D, et al. Effect of recombinant human erythropoietin treatment on circulating reticulated platelets in uremic patients: association with early improvement in platelet function. Am J Hematol. 1998;59:105–9.PubMedGoogle Scholar
  260. 260.
    el-Shahawy MA, Francis R, Akmal M, Massry SG. Recombinant human erythropoietin shortens the bleeding time and corrects the abnormal platelet aggregation in hemodialysis patients. Clin Nephrol. 1994;41:308–13.PubMedGoogle Scholar
  261. 261.
    Eschbach JW, Egrie JC, Downing MR, Browne JK, Adamson JW. Correction of the anemia of end-stage renal disease with recombinant human erythropoietin. Results of a combined phase I and II clinical trial [see comments]. N Engl J Med. 1987;316:73–8.PubMedGoogle Scholar
  262. 262.
    Lewis NP, et al. Effects of the correction of renal anaemia by erythropoietin on physiological changes during exercise. Eur J Clin Invest. 1993;23:423–7.PubMedGoogle Scholar
  263. 263.
    Shinaberger JH, Miller JH, Gardner PW. Erythropoietin alert: risks of high hematocrit hemodialysis. ASAIO Trans. 1988;34:179–84.PubMedGoogle Scholar
  264. 264.
    Granolleras C, Leskopf W, Shaldon S, Fourcade J. Experience of pain after subcutaneous administration of different preparations of recombinant human erythropoietin: a randomized, double-blind crossover study. Clin Nephrol. 1991;36:294–8.PubMedGoogle Scholar
  265. 265.
    Frenken LA, et al. Identification of the component part in an epoetin alfa preparation that causes pain after subcutaneous injection. Am J Kidney Dis. 1993;22:553–6.PubMedGoogle Scholar
  266. 266.
    Frenken LA, van Lier HJ, Koene RA. Analysis of the efficacy of measures to reduce pain after subcutaneous administration of epoetin alfa. Nephrol Dial Transplant. 1994;9:1295–8.PubMedGoogle Scholar
  267. 267.
    Takemasa A, Yorioka N, Yamakido M. Investigation of the influenza-like symptoms associated with recombinant human erythropoietin therapy. J Int Med Res. 1997;25:127–34.PubMedGoogle Scholar
  268. 268.
    Kuriyama S, et al. Evidence for amelioration of endothelial cell dysfunction by erythropoietin therapy in predialysis patients. Am J Hypertens. 1996;9: 426–31.PubMedGoogle Scholar
  269. 269.
    Krmar RT, Gretz N, Klare B, Wuhl E, Scharer K. Renal function in predialysis children with chronic renal failure treated with erythropoietin. Pediatr Nephrol. 1997;11:69–73.PubMedGoogle Scholar
  270. 270.
    Albertazzi A, Di Liberato L, Daniele F, Battistel V, Colombi L. Efficacy and tolerability of recombinant human erythropoietin treatment in pre-dialysis patients: results of a multicenter study. Int J Artif Organs. 1998;21:12–8.PubMedGoogle Scholar
  271. 271.
    Jelkmann W. Erythropoiesis stimulating agents and techniques: a challenge for doping analysts. Curr Med Chem. 2009;16:1236–47.PubMedGoogle Scholar
  272. 272.
    Monahan JB, et al. Bivalent binding and signaling characteristics of Leridistim, a novel chimeric dual agonist of interleukin-3 and granulocyte colony-stimulating factor receptors. Exp Hematol. 2001; 29:416–24.PubMedGoogle Scholar
  273. 273.
    Nabholtz JM, et al. Phase III trial comparing granulocyte colony-stimulating factor to leridistim in the prevention of neutropenic complications in breast cancer patients treated with docetaxel/doxorubicin/cyclophosphamide: results of the BCIRG 004 trial. Clin Breast Cancer. 2002;3:268–75.PubMedGoogle Scholar
  274. 274.
    Abegg AL, et al. The enhanced in vitro hematopoietic activity of leridistim, a chimeric dual G-CSF and IL-3 receptor agonist. Leukemia. 2002;16: 316–26.PubMedGoogle Scholar
  275. 275.
    Farese AM, et al. Leridistim, a chimeric dual G-CSF and IL-3 receptor agonist, enhances multilineage hematopoietic recovery in a nonhuman primate model of radiation-induced myelosuppression: effect of schedule, dose, and route of administration. Stem Cells. 2001;19:522–33.PubMedGoogle Scholar
  276. 276.
    Farese AM, et al. A single dose of pegylated leridistim significantly improves neutrophil recovery in sublethally irradiated rhesus macaques. Stem Cells. 2001;19:514–21.PubMedGoogle Scholar
  277. 277.
    Nishino T, et al. Ex vivo expansion of human hematopoietic stem cells by a small-molecule agonist of c-MPL. Exp Hematol. 2009;37:1364–77. e1364.PubMedGoogle Scholar
  278. 278.
    Kessler M, et al. C.E.R.A. once every 4 weeks in patients with chronic kidney disease not on dialysis: the ARCTOS extension study. Hemodial Int. 2009;14:233–9.PubMedGoogle Scholar
  279. 279.
    Canaud B, et al. Intravenous C.E.R.A. maintains stable haemoglobin levels in patients on dialysis previously treated with darbepoetin alfa: results from STRIATA, a randomized phase III study. Nephrol Dial Transplant. 2008;23:3654–61.PubMedGoogle Scholar
  280. 280.
    Macdougall IC, et al. C.E.R.A. corrects anemia in patients with chronic kidney disease not on dialysis: results of a randomized clinical trial. Clin J Am Soc Nephrol. 2008;3:337–47.PubMedGoogle Scholar
  281. 281.
    Klinger M, et al. Efficacy of intravenous methoxy polyethylene glycol-epoetin beta administered every 2 weeks compared with epoetin administered 3 times weekly in patients treated by hemodialysis or peritoneal dialysis: a randomized trial. Am J Kidney Dis. 2007;50:989–1000.PubMedGoogle Scholar
  282. 282.
    Spinowitz B, et al. C.E.R.A. maintains stable control of hemoglobin in patients with chronic kidney disease on dialysis when administered once every two weeks. Am J Nephrol. 2008;28:280–9.PubMedGoogle Scholar
  283. 283.
    Locatelli F, Reigner B. C.E.R.A.: pharmacodynamics, pharmacokinetics and efficacy in patients with chronic kidney disease. Expert Opin Investig Drugs. 2007;16:1649–61.PubMedGoogle Scholar
  284. 284.
    Sulowicz W, et al. Once-monthly subcutaneous C.E.R.A. maintains stable hemoglobin control in patients with chronic kidney disease on dialysis and converted directly from epoetin one to three times weekly. Clin J Am Soc Nephrol. 2007;2:637–46.PubMedGoogle Scholar
  285. 285.
    Macdougall IC, et al. Pharmacokinetics and pharmacodynamics of intravenous and subcutaneous continuous erythropoietin receptor activator (C.E.R.A.) in patients with chronic kidney disease. Clin J Am Soc Nephrol. 2006;1:1211–5.PubMedGoogle Scholar
  286. 286.
    Besarab A, et al. Efficacy and tolerability of intravenous continuous erythropoietin receptor activator: a 19-week, phase II, multicenter, randomized, open-label, dose-finding study with a 12-month extension phase in patients with chronic renal disease. Clin Ther. 2007;29:626–39.PubMedGoogle Scholar
  287. 287.
    Provenzano R, et al. The continuous erythropoietin receptor activator (C.E.R.A.) corrects anemia at extended administration intervals in patients with chronic kidney disease not on dialysis: results of a phase II study. Clin Nephrol. 2007;67:306–17.PubMedGoogle Scholar
  288. 288.
    de Francisco AL, et al. Continuous Erythropoietin Receptor Activator (C.E.R.A.) administered at extended administration intervals corrects anaemia in patients with chronic kidney disease on dialysis: a randomised, multicentre, multiple-dose, phase II study. Int J Clin Pract. 2006;60:1687–96.PubMedGoogle Scholar
  289. 289.
    Locatelli F, et al. C.E.R.A. safety profile: a pooled analysis in patients with chronic kidney disease. Clin Nephrol. 2010;73:94–103.PubMedGoogle Scholar
  290. 290.
    Hamad I, Hunter AC, Szebeni J, Moghimi SM. Poly(ethylene glycol)s generate complement activation products in human serum through increased alternative pathway turnover and a MASP-2-dependent process. Mol Immunol. 2008;46:225–32.PubMedGoogle Scholar
  291. 291.
    Laine GA, Hossain SM, Solis RT, Adams SC. Polyethylene glycol nephrotoxicity secondary to prolonged high-dose intravenous lorazepam. Ann Pharmacother. 1995;29:1110–4.PubMedGoogle Scholar
  292. 292.
    Lee DE, Son W, Ha BJ, Oh MS, Yoo OJ. The prolonged half-lives of new erythropoietin derivatives via peptide addition. Biochem Biophys Res Commun. 2006;339:380–5.PubMedGoogle Scholar
  293. 293.
    Lu B, Liu X, Huang P. Construction of a fusion protein between N-terminal 153 peptide of thrombopoietin and erythropoietin. Sci China C Life Sci. 1998;41:426–34.PubMedGoogle Scholar
  294. 294.
    Penno CA, Kawabe Y, Ito A, Kamihira M. Production of recombinant human erythropoietin/Fc fusion protein by genetically manipulated chickens. Transgenic Res. 2010;19:187–95.PubMedGoogle Scholar
  295. 295.
    Joung CH, et al. Production and characterization of long-acting recombinant human albumin-EPO fusion protein expressed in CHO cell. Protein Expr Purif. 2009;68:137–45.PubMedGoogle Scholar
  296. 296.
    Lacy SE, et al. The potency of erythropoietin-mimic antibodies correlates inversely with affinity. J Immunol. 2008;181:1282–7.PubMedGoogle Scholar
  297. 297.
    Schriebl K, et al. Biochemical characterization of rhEpo-Fc fusion protein expressed in CHO cells. Protein Expr Purif. 2006;49:265–75.PubMedGoogle Scholar
  298. 298.
    Sytkowski AJ, Lunn ED, Risinger MA, Davis KL. An erythropoietin fusion protein comprised of identical repeating domains exhibits enhanced biological properties. J Biol Chem. 1999;274:24773–8.PubMedGoogle Scholar
  299. 299.
    Dumont JA, et al. Delivery of an erythropoietin-Fc fusion protein by inhalation in humans through an immunoglobulin transport pathway. J Aerosol Med. 2005;18:294–303.PubMedGoogle Scholar
  300. 300.
    Bitonti AJ, et al. Pulmonary delivery of an erythropoietin Fc fusion protein in non-human primates through an immunoglobulin transport pathway. Proc Natl Acad Sci USA. 2004;101:9763–8.PubMedGoogle Scholar
  301. 301.
    Lee JY. Purification of biologically active human erythropoietin-binding protein and detection of its binding sites. Ann Clin Lab Sci. 2007;37:63–70.PubMedGoogle Scholar
  302. 302.
    Bugelski PJ, et al. CNTO 530: molecular pharmacology in human UT-7EPO cells and pharmacokinetics and pharmacodynamics in mice. J Biotechnol. 2008;134:171–80.PubMedGoogle Scholar
  303. 303.
    Bouman-Thio E, et al. A phase I, single and fractionated, ascending-dose study evaluating the safety, pharmacokinetics, pharmacodynamics, and immunogenicity of an erythropoietin mimetic antibody fusion protein (CNTO 528) in healthy male subjects. J Clin Pharmacol. 2008;48:1197–207.PubMedGoogle Scholar
  304. 304.
    Stead RB, et al. 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. 2006;108:1830–4.PubMedGoogle Scholar
  305. 305.
    Macdougall IC, et al. A peptide-based erythropoietin-receptor agonist for pure red-cell aplasia. N Engl J Med. 2009;361:1848–55.PubMedGoogle Scholar
  306. 306.
    Woodburn KW, Schatz PJ, Fong KL, Beaumier P. Erythropoiesis equivalence, pharmacokinetics and immune response following repeat hematide™ administration in cynomolgus monkeys. Int J Immu­nopathol Pharmacol. 2010;23:121–9.PubMedGoogle Scholar
  307. 307.
    Woodburn KW, et al. A subchronic murine intravenous pharmacokinetic and toxicity study of Hematide, a PEGylated peptidic erythropoiesis-stimulating agent. Drug Chem Toxicol. 2010;33:28–37.PubMedGoogle Scholar
  308. 308.
    Minamishima YA, et al. Somatic inactivation of the PHD2 prolyl hydroxylase causes polycythemia and congestive heart failure. Blood. 2008;111:3236–44.PubMedGoogle Scholar
  309. 309.
    Ladroue C, et al. PHD2 mutation and congenital erythrocytosis with paraganglioma. N Engl J Med. 2008;359:2685–92.PubMedGoogle Scholar
  310. 310.
    Hsieh MM, et al. HIF prolyl hydroxylase inhibition results in endogenous erythropoietin induction, erythrocytosis, and modest fetal hemoglobin expression in rhesus macaques. Blood. 2007;110:2140–7.PubMedGoogle Scholar
  311. 311.
    Provenzano RW, et al. A Novel Oral HIF-PHI, Stimulates Erythropoiesis and Increases Hemoglobin Concentration in Patients with Non-Dialysis CKD. Am J Kidney Dis. 2008;51:B80.FG2216.Google Scholar
  312. 312.
    Klaus S, et al. Beneficial Pharmacodynamic Effects Resulting from ‘Complete Erythropoiesis’ Induced by Novel HIF Prolyl Hydroxylase Inhibitors FG-2216 and FG-4592. Presented at the 41st Annual Meeting of the American Society of Nephrology (Abstract F-PO1835) 2008.Google Scholar
  313. 313.
    Hewitson KS, et al. Structural and mechanistic studies on the inhibition of the hypoxia-inducible transcription factor hydroxylases by tricarboxylic acid cycle intermediates. J Biol Chem. 2007;282:3293–301.PubMedGoogle Scholar
  314. 314.
    Hewitson KS, et al. Hypoxia-inducible factor (HIF) asparagine hydroxylase is identical to factor inhibiting HIF (FIH) and is related to the cupin structural family. J Biol Chem. 2002;277:26351–5.PubMedGoogle Scholar
  315. 315.
    Obara N, et al. Repression via the GATA box is essential for tissue-specific erythropoietin gene expression. Blood. 2008;111:5223–32.PubMedGoogle Scholar
  316. 316.
    Nakano Y, et al. Oral administration of K-11706 inhibits GATA binding activity, enhances hypoxia-inducible factor 1 binding activity, and restores indicators in an in vivo mouse model of anemia of chronic disease. Blood. 2004;104:4300–7.PubMedGoogle Scholar
  317. 317.
    Yaqub MS, Leiser J, Molitoris BA. Erythropoietin requirements increase following hospitalization in end-stage renal disease patients. Am J Nephrol. 2001;21:390–6.PubMedGoogle Scholar
  318. 318.
    Vreugdenhil G, Wognum AW, van Eijk HG, Swaak AJ. Anaemia in rheumatoid arthritis: the role of iron, vitamin B12, and folic acid deficiency, and erythropoietin responsiveness. Ann Rheum Dis. 1990;49:93–8.PubMedGoogle Scholar
  319. 319.
    Remacha AF, et al. Erythroid abnormalities in rheumatoid arthritis: the role of erythropoietin. J Rheumatol. 1992;19:1687–91.PubMedGoogle Scholar
  320. 320.
    Macdougall IC, Cooper A. The inflammatory response and epoetin sensitivity. Nephrol Dial Transplant. 2002;17:48–52.PubMedGoogle Scholar
  321. 321.
    Pixley JS, MacKintosh FR, Smith EA, Zanjani ED. Anemia of inflammation: role of T lymphocyte activating factor. Pathobiology. 1992;60:309–15.PubMedGoogle Scholar
  322. 322.
    Souweine B, et al. Serum erythropoietin and reticulocyte counts in inflammatory process. Ann Med Interne. 1995;146:8–12.Google Scholar
  323. 323.
    Jelkmann WE, Fandrey J, Frede S, Pagel H. Inhibition of erythropoietin production by cytokines. Implications for the anemia involved in inflammatory states. Ann N Y Acad Sci. 1994;718:300–9. discussion 309–311.PubMedGoogle Scholar
  324. 324.
    Jelkmann W, Pagel H, Wolff M, Fandrey J. Monokines inhibiting erythropoietin production in human hepatoma cultures and in isolated perfused rat kidneys. Life Sci. 1992;50:301–8.PubMedGoogle Scholar
  325. 325.
    Faquin WC, Schneider TJ, Goldberg MA. Effect of inflammatory cytokines on hypoxia-induced erythropoietin production. Blood. 1992;79:1987–94.PubMedGoogle Scholar
  326. 326.
    Fandrey J, Jelkmann WE. Interleukin-1 and tumor necrosis factor-alpha inhibit erythropoietin production in vitro. Ann N Y Acad Sci. 1991;628:250–5.PubMedGoogle Scholar
  327. 327.
    Jelkmann W, Wolff M, Fandrey J. Modulation of the production of erythropoietin by cytokines: in vitro studies and their clinical implications. Contrib Nephrol. 1990;87:68–77.PubMedGoogle Scholar
  328. 328.
    Winter SS, Howard T, Ware RE. Regulation of expression of the human erythropoietin receptor gene. Blood Cells Mol Dis. 1996;22:214–24. discussion 224a.PubMedGoogle Scholar
  329. 329.
    Lu L, et al. Effects of recombinant human tumor necrosis factor alpha, recombinant human gamma-interferon, and prostaglandin E on colony formation of human hematopoietic progenitor cells stimulated by natural human pluripotent colony-stimulating factor, pluripoietin alpha, and recombinant erythropoietin in serum-free cultures. Cancer Res. 1986;46: 4357–61.PubMedGoogle Scholar
  330. 330.
    Yip R, Dallman PR. The roles of inflammation and iron deficiency as causes of anemia. Am J Clin Nutr. 1988;48:1295–300.PubMedGoogle Scholar
  331. 331.
    Gunnell J, Yeun JY, Depner TA, Kaysen GA. Acute-phase response predicts erythropoietin resistance in hemodialysis and peritoneal dialysis patients. Am J Kidney Dis [Online]. 1999;33:63–72.Google Scholar
  332. 332.
    Kim JK, et al. The predictive parameters of erythropoietin hyporesponsiveness in patients on continuous ambulatory peritoneal dialysis. Korean J Intern Med. 2001;16:110–7.PubMedGoogle Scholar
  333. 333.
    Barany P, Divino Filho JC, Bergstrom J. High C-reactive protein is a strong predictor of resistance to erythropoietin in hemodialysis patients. Am J Kidney Dis. 1997;29:565–8.PubMedGoogle Scholar
  334. 334.
    Kooistra MP, et al. Iron absorption in erythropoietin-treated haemodialysis patients: effects of iron availability, inflammation and aluminium. Nephrol Dial Transplant. 1998;13:82–8.PubMedGoogle Scholar
  335. 335.
    Ahsan N, Holman MJ, Gocke CD, Groff JA, Yang HC. Pure red cell aplasia due to parvovirus B19 infection in solid organ transplantation. Clin Transplant. 1997;11:265–70.PubMedGoogle Scholar
  336. 336.
    Bertoni E, et al. Severe aplastic anaemia due to B19 parvovirus infection in renal transplant recipient. Nephrol Dial Transplant. 1995;10:1462–3.PubMedGoogle Scholar
  337. 337.
    Bertoni E, et al. Aplastic anemia due to B19 parvovirus infection in cadaveric renal transplant recipients: an underestimated infectious disease in the immunocompromised host. J Nephrol. 1997;10:152–6.PubMedGoogle Scholar
  338. 338.
    Tonelli M, Blake PG, Muirhead N. Predictors of erythropoietin responsiveness in chronic hemodialysis patients. ASAIO J. 2001;47:82–5.PubMedGoogle Scholar
  339. 339.
    Coen G, et al. Parathyroidectomy in chronic renal failure: short- and long-term results on parathyroid function, blood pressure and anemia. Nephron. 2001;88:149–55.PubMedGoogle Scholar
  340. 340.
    Mandolfo S, et al. Parathyroidectomy and response to erythropoietin therapy in anaemic patients with chronic renal failure. Nephrol Dial Transplant. 1998;13:2708–9.PubMedGoogle Scholar
  341. 341.
    Rault R, Magnone M. The effect of parathyroidectomy on hematocrit and erythropoietin dose in patients on hemodialysis. ASAIO J. 1996;42:M901–3.PubMedGoogle Scholar
  342. 342.
    Barbour GL. Effect of parathyroidectomy on anemia in chronic renal failure. Arch Intern Med. 1979;139:889–91.PubMedGoogle Scholar
  343. 343.
    Zingraff J, et al. Anemia and secondary hyperparathyroidism. Arch Intern Med. 1978;138:1650–2.PubMedGoogle Scholar
  344. 344.
    Podjarny E, et al. Is anemia of chronic renal failure related to secondary hyperparathyroidism? Arch Intern Med. 1981;141:453–5.PubMedGoogle Scholar
  345. 345.
    Grutzmacher P, Radtke HW, Fassbinder W, Koch KM, Schoeppe W. Effect of secondary hyperparathyroidism on the anaemia of end-stage renal failure: in vivo and in vitro studies. Proceedings of the European Dialysis & Transplant Association 1983, vol. 20, p. 739–745.Google Scholar
  346. 346.
    Geary DF, et al. Hyperparathyroidism and anemia in chronic renal failure. Eur J Pediatr. 1982;139:296–8.PubMedGoogle Scholar
  347. 347.
    Kcomt J, Sotelo C, Raja R. Influence of adynamic bone disease on responsiveness to recombinant human erythropoietin in peritoneal dialysis patients. Adv Perit Dial. 2000;16:294–6.PubMedGoogle Scholar
  348. 348.
    Nazem AK, Mako J. The effect of calcitriol on renal anaemia in patients undergoing long-term dialysis. Int Urol Nephrol. 1997;29:119–27.PubMedGoogle Scholar
  349. 349.
    Goicoechea M, et al. Intravenous calcitriol improves anaemia and reduces the need for erythropoietin in haemodialysis patients. Nephron. 1998;78:23–7.PubMedGoogle Scholar
  350. 350.
    Massry SG. Pathogenesis of the anemia of uremia: role of secondary hyperparathyroidism. Kidney Int Suppl. 1983;16:S204–7.PubMedGoogle Scholar
  351. 351.
    Gallieni M, Corsi C, Brancaccio D. Hyperparathyroidism and anemia in renal failure. Am J Nephrol. 2000;20:89–96.PubMedGoogle Scholar
  352. 352.
    Foulks CJ, Mills GM, Wright LF. Parathyroid hormone and anaemia – an erythrocyte osmotic fragility study in primary and secondary hyperparathyroidism. Postgrad Med J. 1989;65:136–9.PubMedGoogle Scholar
  353. 353.
    Zachee P, Chew SL, Daelemans R, Lins RL. Erythropoietin resistance due to vitamin B12 deficiency. Case report and retrospective analysis of B12 levels after erythropoietin treatment. Am J Nephrol. 1992;12:188–91.PubMedGoogle Scholar
  354. 354.
    Sunder-Plassmann G, Horl WH. Novel aspects of erythropoietin response in renal failure patients. Nephrol Dial Transplant. 2001;16:40–4.PubMedGoogle Scholar
  355. 355.
    Nemeth I, Turi S, Haszon I, Bereczki C. Vitamin E alleviates the oxidative stress of erythropoietin in uremic children on hemodialysis. Pediatr Nephrol. 2000;14:13–7.PubMedGoogle Scholar
  356. 356.
    Graafland AD, Doorenbos CJ, van Saase JC. Enalapril-induced anemia in two kidney transplant recipients. Transpl Int. 1992;5:51–3.PubMedGoogle Scholar
  357. 357.
    Kuriyama R, et al. Angiotensin converting enzyme inhibitor induced anemia in a kidney transplant recipient. Transplant Proc. 1996;28:1635.PubMedGoogle Scholar
  358. 358.
    Le Meur Y, et al. Plasma levels and metabolism of AcSDKP in patients with chronic renal failure: relationship with erythropoietin requirements. Am J Kidney Dis [Online]. 2001;38:510–7.Google Scholar
  359. 359.
    Eiselt J, Racek J, Opatrny Jr K. The effect of hemodialysis and acetate-free biofiltration on anemia. Int J Artif Organs. 2000;23:173–80.PubMedGoogle Scholar
  360. 360.
    Geerlings W, et al. Factors influencing anaemia in dialysis patients. A special survey by the EDTA-ERA Registry. Nephrol Dial Transplant. 1993;8: 585–9.PubMedGoogle Scholar
  361. 361.
    Losekann A, et al. Aluminium intoxication in the rat induces partial resistance to the effect of recombinant human erythropoietin. Nephrol Dial Transplant. 1990;5:258–63.PubMedGoogle Scholar
  362. 362.
    Fulton B, Jeffery EH. Heme oxygenase induction. A possible factor in aluminum-associated anemia. Biol Trace Elem Res. 1994;40:9–19.PubMedGoogle Scholar
  363. 363.
    Gonella M, Pratesi G, Calabrese G, Vagelli G, Mazzotta A. Improvement of anemia in patients on chronic dialysis treated by hemodiafiltration. Blood Purif. 1989;7:186–91.PubMedGoogle Scholar
  364. 364.
    Steuer RR, Leypoldt JK, Cheung AK, Senekjian HO, Conis JM. Reducing symptoms during hemodialysis by continuously monitoring the hematocrit. Am J Kidney Dis. 1996;27:525–32.PubMedGoogle Scholar
  365. 365.
    Coli L, et al. Evidence of profiled hemodialysis efficacy in the treatment of intradialytic hypotension. Int J Artif Organs. 1998;21:398–402.PubMedGoogle Scholar
  366. 366.
    Besarab A, et al. The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin [see comments]. N Engl J Med. 1998;339:584–90.PubMedGoogle Scholar
  367. 367.
    Madore F, et al. Anemia in hemodialysis patients: variables affecting this outcome predictor. J Am Soc Nephrol. 1997;8:1921–9.PubMedGoogle Scholar
  368. 368.
    Casadevall N, et al. Pure red-cell aplasia and antierythropoietin antibodies in patients treated with recombinant erythropoietin. N Engl J Med. 2002;346:469–75.PubMedGoogle Scholar
  369. 369.
    Warady BA, et al. Iron therapy in the pediatric hemodialysis population. Pediatr Nephrol (Berlin). 2004;19:655–61.Google Scholar
  370. 370.
    Aggarwal HK, et al. Comparison of oral versus intravenous iron therapy in predialysis patients of chronic renal failure receiving recombinant human erythropoietin. J Assoc Physicians India. 2003;51: 170–4.PubMedGoogle Scholar
  371. 371.
    Stoves J, Inglis H, Newstead CG. A randomized study of oral vs intravenous iron supplementation in patients with progressive renal insufficiency treated with erythropoietin. Nephrol Dial Transplant. 2001;16:967–74.PubMedGoogle Scholar
  372. 372.
    Pru C, Eaton J, Kjellstrand C. Vitamin C intoxication and hyperoxalemia in chronic hemodialysis patients. Nephron. 1985;39:112–6.PubMedGoogle Scholar
  373. 373.
    Boggs DR. Fate of a ferrous sulfate prescription. Am J Med. 1987;82:124–8.PubMedGoogle Scholar
  374. 374.
    Wingard RL, Parker RA, Ismail N, Hakim RM. Efficacy of oral iron therapy in patients receiving recombinant human erythropoietin. Am J Kidney Dis. 1995;25:433–9.PubMedGoogle Scholar
  375. 375.
    Nissenson AR, et al. Clinical evaluation of heme iron polypeptide: sustaining a response to rHuEPO in hemodialysis patients. Am J Kidney Dis. 2003;42:325–30.PubMedGoogle Scholar
  376. 376.
    Barraclough KA, et al. Rationale and design of the oral HEMe iron polypeptide Against Treatment with Oral Controlled Release Iron Tablets trial for the correction of anaemia in peritoneal dialysis patients (HEMATOCRIT trial). BMC Nephrol. 2009;10:20.PubMedGoogle Scholar
  377. 377.
    Fishbane S, Frei GL, Maesaka J. Reduction in recombinant human erythropoietin doses by the use of chronic intravenous iron supplementation. Am J Kidney Dis. 1995;26:41–6.PubMedGoogle Scholar
  378. 378.
    Fudin R, Jaichenko J, Shostak A, Bennett M, Gotloib L. Correction of uremic iron deficiency anemia in hemodialyzed patients: a prospective study. Nephron. 1998;79:299–305.PubMedGoogle Scholar
  379. 379.
    Macdougall IC, et al. A randomized controlled study of iron supplementation in patients treated with erythropoietin. Kidney Int. 1996;50:1694–9.PubMedGoogle Scholar
  380. 380.
    Ruiz-Jaramillo Mde L, Guizar-Mendoza JM, Gutierrez-Navarro Mde J, Dubey-Ortega LA, Amador-Licona N. Intermittent versus maintenance iron therapy in children on hemodialysis: a randomized study. Pediatr Nephrol (Berlin). 2004;19: 77–81.Google Scholar
  381. 381.
    Warady BA, Zobrist RH, Wu J, Finan E. Sodium ferric gluconate complex therapy in anemic children on hemodialysis. Pediatr Nephrol (Berlin). 2005;20: 1320–7.Google Scholar
  382. 382.
    Bastani B, Rahman S, Gellens M. Lack of reaction to ferric gluconate in hemodialysis patients with a history of severe reaction to iron dextran. ASAIO J. 2002;48:404–6.PubMedGoogle Scholar
  383. 383.
    Hamstra RD, Block MH, Schocket AL. Intravenous iron dextran in clinical medicine. JAMA. 1980;243:1726–31.PubMedGoogle Scholar
  384. 384.
    Ifudu O. Parenteral iron: pharmacology and clinical use. Nephron. 1998;80:249–56.PubMedGoogle Scholar
  385. 385.
    Coyne DW, et al. Sodium ferric gluconate complex in hemodialysis patients. II. Adverse reactions in iron dextran-sensitive and dextran-tolerant patients. Kidney Int. 2003;63:217–24.PubMedGoogle Scholar
  386. 386.
    Silverstein SB, Rodgers GM. Parenteral iron therapy options. Am J Hematol. 2004;76:74–8.PubMedGoogle Scholar
  387. 387.
    Faich G, Strobos J. Sodium ferric gluconate complex in sucrose: safer intravenous iron therapy than iron dextrans. Am J Kidney Dis. 1999;33: 464–70.PubMedGoogle Scholar
  388. 388.
    Warady BA, Zobrist RH, Finan E. Sodium ferric gluconate complex maintenance therapy in children on hemodialysis. Pediatr Nephrol (Berlin). 2006;21: 553–60.Google Scholar
  389. 389.
    Charytan C, Qunibi W, Bailie GR. Comparison of intravenous iron sucrose to oral iron in the treatment of anemic patients with chronic kidney disease not on dialysis. Nephron Clin Pract. 2005;100:c55–62.PubMedGoogle Scholar
  390. 390.
    Singh H, Reed J, Noble S, Cangiano JL, Van Wyck DB. Effect of intravenous iron sucrose in peritoneal dialysis patients who receive erythropoiesis-­stimulating agents for anemia: a randomized, controlled trial. Clin J Am Soc Nephrol. 2006;1:475–82.PubMedGoogle Scholar
  391. 391.
    Leijn E, Monnens LA, Cornelissen EA. Intravenous iron supplementation in children on hemodialysis. J Nephrol. 2004;17:423–6.PubMedGoogle Scholar
  392. 392.
    Morgan HE, Gautam M, Geary DF. Maintenance intravenous iron therapy in pediatric hemodialysis patients. Pediatr Nephrol (Berlin). 2001;16:779–83.Google Scholar
  393. 393.
    Coyne DW. Ferumoxytol for treatment of iron deficiency anemia in patients with chronic kidney disease. Expert Opin Pharmacother. 2009;10:2563–8.PubMedGoogle Scholar
  394. 394.
    Provenzano R, et al. Ferumoxytol as an intravenous iron replacement therapy in hemodialysis patients. Clin J Am Soc Nephrol. 2009;4:386–93.PubMedGoogle Scholar
  395. 395.
    Singh A, et al. Safety of ferumoxytol in patients with anemia and CKD. Am J Kidney Dis. 2008;52:907–15.PubMedGoogle Scholar
  396. 396.
    Spinowitz BS, et al. Ferumoxytol for treating iron deficiency anemia in CKD. J Am Soc Nephrol. 2008;19:1599–605.PubMedGoogle Scholar
  397. 397.
    Kalantar-Zadeh K, Don BR, Rodriguez RA, Humphreys MH. Serum ferritin is a marker of morbidity and mortality in hemodialysis patients. Am J Kidney Dis. 2001;37:564–72.PubMedGoogle Scholar
  398. 398.
    Kalantar-Zadeh K, Regidor DL, McAllister CJ, Michael B, Warnock DG. Time-dependent associations between iron and mortality in hemodialysis patients. J Am Soc Nephrol. 2005;16:3070–80.PubMedGoogle Scholar
  399. 399.
    Rambod M, Kovesdy CP, Kalantar-Zadeh K. Combined high serum ferritin and low iron saturation in hemodialysis patients: the role of inflammation. Clin J Am Soc Nephrol. 2008;3:1691–701.PubMedGoogle Scholar
  400. 400.
    Besarab A. Resolving the paradigm crisis in intravenous iron and erythropoietin management. Kidney Int Suppl. 2006;101:S13–8.PubMedGoogle Scholar
  401. 401.
    Powell LW, George DK, McDonnell SM, Kowdley KV. Diagnosis of hemochromatosis. Ann Intern Med. 1998;129:925–31.PubMedGoogle Scholar
  402. 402.
    Carmel R, Denson TA, Mussell B. Anemia. Textbook vs practice. JAMA. 1979;242:2295–7.PubMedGoogle Scholar
  403. 403.
    Abernathy KA, Meuleman JR. Appropriateness of iron prescribing: a retrospective study. Pharmacotherapy. 1996;16:473–6.PubMedGoogle Scholar
  404. 404.
    Shinton N. CRC Desk Reference for Hematology. 1st ed. Boca Raton, FL: CRC Press; 1998. p. 740.Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Division of NephrologyUniversity of California-San Diego School of MedicineSan DiegoUSA
  2. 2.Department of PediatricsMattel Children’s Hospital at UCLALos AngelesUSA

Personalised recommendations