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Mechanisms of Disease: erythropoietin resistance in patients with both heart and kidney failure

Nature Clinical Practice Nephrology volume 4, pages 47–57 (2008)Cite this article

Abstract

Anemia is common in patients who have both heart failure and chronic kidney disease, and there is an association between anemia and progression of both diseases. The main causes of anemia are deficient production of erythropoietin (EPO), iron deficiency, and chronic disease with endogenous EPO resistance. EPO has been successfully used for over a decade to treat anemia in patients with chronic kidney disease. Less obvious are the safety and efficacy of EPO treatment in patients with both heart failure and renal disease. Up to 10% of patients receiving EPO are hyporesponsive to therapy and require large doses of the agent. Several mechanisms could explain resistance to endogenous and exogenous EPO. Proinflammatory cytokines antagonize the action of EPO by exerting an inhibitory effect on erythroid progenitor cells and by disrupting iron metabolism (a process in which hepcidin has a central role). EPO resistance might also be caused by inflammation, which has a negative effect on EPO receptors. Furthermore, neocytolysis could have a role. As resistance to exogenous EPO is associated with an increased risk of death, it is important to understand how cardiorenal failure affects EPO production and function.

Key Points

  • Anemia is common in patients with chronic kidney disease and chronic heart failure, and is associated with a negative outcome

  • Resistance to erythropoietin is a major cause of the anemia that affects patients with both chronic heart failure and chronic kidney disease

  • Inflammation has a key role in resistance to erythropoietin

  • Resistance to exogenous erythropoietin is associated with an increased risk of death in patients with chronic kidney disease

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Figure 1: The pathophysiology of the cardiorenal syndrome and its effect on erythropoietin.
Figure 2: The role of cytokines in erythropoietin resistance.
Figure 3: Iron homeostasis and the role of hepcidin.
Figure 4: Overview of erythropoietin receptor activation and intracellular pathways.

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References

  1. Bongartz LG et al. (2005) The severe cardiorenal syndrome: 'Guyton revisited'. Eur Heart J 26: 11–17

    Article  PubMed  Google Scholar 

  2. Jie KE et al. (2006) Erythropoietin and the cardiorenal syndrome: cellular mechanisms on the cardiorenal connectors. Am J Physiol Renal Physiol 291: F932–F944

    Article  CAS  PubMed  Google Scholar 

  3. Fehr T et al. (2004) Interpretation of erythropoietin levels in patients with various degrees of renal insufficiency and anemia. Kidney Int 66: 1206–1211

    Article  CAS  PubMed  Google Scholar 

  4. Jacobs C et al. (2003) Results of the European Survey on Anaemia Management 2003 (ESAM 2003): current status of anaemia management in dialysis patients, factors affecting epoetin dosage and changes in anaemia management over the last 5 years. Nephrol Dial Transplant 20 (Suppl 3): Siii3–Siii24

    Google Scholar 

  5. Weiss G and Goodnough LT (2005) Anemia of chronic disease. N Engl J Med 352: 1011–1023

    Article  CAS  PubMed  Google Scholar 

  6. Eckhardt KU (2000) Pathophysiology of renal anemia. Clin Nephrol 53 (Suppl 1): S2–S8

    Google Scholar 

  7. Drueke TB and Eckardt KU (2002) Role of secondary hyperparathyroidism in erythropoietin resistance of chronic renal failure patients. Nephrol Dial Transplant 17 (Suppl 5): S28–S31

    Article  Google Scholar 

  8. de Silva R et al. (2006) Anemia, renal dysfunction, and their interaction in patients with chronic heart failure. Am J Cardiol 98: 391–398

    Article  PubMed  Google Scholar 

  9. Macdougall IC (1999) The role of ACE inhibitors and angiotensin II receptor blockers in the response to epoetin. Nephrol Dial Transplant 14: 1836–1841

    Article  CAS  PubMed  Google Scholar 

  10. Saudan P et al. (2006) ACE inhibitors or angiotensin II receptor blockers in dialysed patients and erythropoietin resistance. J Nephrol 19: 91–96

    CAS  PubMed  Google Scholar 

  11. Ezekowitz JA et al. (2003) Anemia is common in heart failure and is associated with poor outcomes: insights from a cohort of 12,065 patients with new-onset heart failure. Circulation 107: 223–225

    Article  PubMed  Google Scholar 

  12. Opasich C et al. (2005) Blunted erythropoietin production and defective iron supply for erythropoiesis as major causes of anaemia in patients with chronic heart failure. Eur Heart J 26: 2232–2237

    Article  CAS  PubMed  Google Scholar 

  13. Anand IS (2005) Pathogenesis of anemia in cardiorenal disease. Rev Cardiovasc Med 6 (Suppl 3): S13–S21

    PubMed  Google Scholar 

  14. Mrug M et al. (1997) Angiotensin II stimulates proliferation of normal early erythroid progenitors. J Clin Invest 100: 2310–2314

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Azizi M et al. (1996) Acute angiotensin-converting enzyme inhibition increases the plasma level of the natural stem cell regulator N-acetyl-seryl-aspartyl-lysyl-proline. J Clin Invest 97: 839–844

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. van der Meer P et al. (2005) Levels of hematopoiesis inhibitor N-acetyl-seryl-aspartyl-lysyl-proline partially explain the occurrence of anemia in heart failure. Circulation 112: 1743–1747

    Article  CAS  PubMed  Google Scholar 

  17. Albitar S et al. (1998) High dose enalapril impairs the response to erythropoietin treatment in haemodialysis patients. Nephrol Dial Transplant 13: 1206–1210

    Article  CAS  PubMed  Google Scholar 

  18. Erturk S et al. (1999) The impact of withdrawing ACE inhibitors on erythropoietin responsiveness and left ventricular hypertrophy in haemodialysis patients. Nephrol Dial Transplant 14: 1912–1916

    Article  CAS  PubMed  Google Scholar 

  19. Ishani A et al. (2005) Angiotensin-converting enzyme inhibitor as a risk factor for the development of anemia, and the impact of incident anemia on mortality in patients with left ventricular dysfunction. J Am Coll Cardiol 45: 391–399

    Article  CAS  PubMed  Google Scholar 

  20. Androne AS et al. (2003) Hemodilution is common in patients with advanced heart failure. Circulation 107: 226–229

    Article  PubMed  Google Scholar 

  21. Silverberg DS et al. (2002) The correction of anemia in severe resistant heart failure with erythropoietin and intravenous iron prevents the progression of both the heart and the renal failure and markedly reduces hospitalization. Clin Nephrol 58 (Suppl 1): S37–S45

    CAS  PubMed  Google Scholar 

  22. Levin A et al. (1999) Left ventricular mass index increase in early renal disease: impact of decline in hemoglobin. Am J Kidney Dis 34: 125–134

    Article  CAS  PubMed  Google Scholar 

  23. Foley RN et al. (1996) The impact of anemia on cardiomyopathy, morbidity, and mortality in end-stage renal disease. Am J Kidney Dis 28: 53–61

    Article  CAS  PubMed  Google Scholar 

  24. Ma JZ et al. (1999) Hematocrit level and associated mortality in hemodialysis patients. J Am Soc Nephrol 10: 610–619

    CAS  PubMed  Google Scholar 

  25. Parfrey PS et al. (2005) Double-blind comparison of full and partial anemia correction in incident hemodialysis patients without symptomatic heart disease. J Am Soc Nephrol 16: 2180–2189

    Article  PubMed  Google Scholar 

  26. Collins AJ et al. (2001) Death, hospitalization, and economic associations among incident hemodialysis patients with hematocrit values of 36 to 39%. J Am Soc Nephrol 12: 2465–2473

    CAS  PubMed  Google Scholar 

  27. Xue JL et al. (2002) Anemia treatment in the pre-ESRD period and associated mortality in elderly patients. Am J Kidney Dis 40: 1153–1161

    Article  PubMed  Google Scholar 

  28. Locatelli F et al. (2004) Anaemia in haemodialysis patients of five European countries: association with morbidity and mortality in the Dialysis Outcomes and Practice Patterns Study (DOPPS). Nephrol Dial Transplant 19: 121–132

    Article  PubMed  Google Scholar 

  29. Regidor DL et al. (2006) Associations between changes in hemoglobin and administered erythropoiesis-stimulating agent and survival in hemodialysis patients. J Am Soc Nephrol 17: 1181–1191

    Article  CAS  PubMed  Google Scholar 

  30. Jones M et al. (2004) Impact of epoetin alfa on clinical end points in patients with chronic renal failure: a meta-analysis. Kidney Int 65: 757–767

    Article  CAS  PubMed  Google Scholar 

  31. Goldberg N et al. (1992) Changes in left ventricular size, wall thickness, and function in anemic patients treated with recombinant human erythropoietin. Am Heart J 124: 424–427

    Article  CAS  PubMed  Google Scholar 

  32. Frank H et al. (2004) Effect of erythropoietin on cardiovascular prognosis parameters in hemodialysis patients. Kidney Int 66: 832–840

    Article  CAS  PubMed  Google Scholar 

  33. Besarab A et al. (1998) The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. N Engl J Med 339: 584–590

    Article  CAS  PubMed  Google Scholar 

  34. Drueke TB et al. for the CREATE Investigators (2006) Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med 355: 2071–2084

    Article  CAS  PubMed  Google Scholar 

  35. Singh AK et al. for the CHOIR Investigators (2006) Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med 355: 2085–2098

    Article  CAS  PubMed  Google Scholar 

  36. National Kidney Foundation (2006) KDOQI clinical practice guidelines and clinical practice recommendations for anemia in chronic kidney disease. Am J Kidney Dis 47 (Suppl 3): S11–S145

  37. Locatelli F et al. (2004) Revised European best practice guidelines for the management of anaemia in patients with chronic renal failure. Nephrol Dial Transplant 19 (Suppl 2): Sii1–Sii47

    Google Scholar 

  38. Anand I et al. (2004) Anemia and its relationship to clinical outcome in heart failure. Circulation 110: 149–154

    Article  PubMed  Google Scholar 

  39. Go AS et al. (2006) Hemoglobin level, chronic kidney disease, and the risks of death and hospitalization in adults with chronic heart failure: the Anemia in Chronic Heart Failure: Outcomes and Resource Utilization (ANCHOR) Study. Circulation 113: 2713–2723

    Article  CAS  PubMed  Google Scholar 

  40. Mancini DM et al. (2003) Effect of erythropoietin on exercise capacity in patients with moderate to severe chronic heart failure. Circulation 107: 294–299

    Article  CAS  PubMed  Google Scholar 

  41. Silverberg DS et al. (2001) The effect of correction of mild anemia in severe, resistant congestive heart failure using subcutaneous erythropoietin and intravenous iron: a randomized controlled study. J Am Coll Cardiol 37: 1775–1780

    Article  CAS  PubMed  Google Scholar 

  42. Ponikowski P et al. (2007) Effect of darbepoetin alfa on exercise tolerance in anemic patients with symptomatic chronic heart failure: a randomized, double-blind, placebo-controlled trial. J Am Coll Cardiol 49: 753–762

    Article  CAS  PubMed  Google Scholar 

  43. Palazzuoli A et al. (2006) Erythropoietin improves anemia exercise tolerance and renal function and reduces B-type natriuretic peptide and hospitalization in patients with heart failure and anemia. Am Heart J 152: 1096 e9–e15

    Article  CAS  Google Scholar 

  44. Ghali J et al. (2006) Randomized, double-blind, placebo-controlled trial to assess the impact of darbepoetin alfa treatment on exercise tolerance in anemic patients with symptomatic heart failure: results from STAMINA-HeFT (abstract #549). European Society of Cardiology Heart Failure Congress: 2006 17–20 June 2006, Helsinki, Finland

  45. Fisher JW et al. (1996) Erythropoietin production by interstitial cells of hypoxic monkey kidneys. Br J Haematol 95: 27–32

    Article  CAS  PubMed  Google Scholar 

  46. Warnecke C et al. (2004) Differentiating the functional role of hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha (EPAS-1) by the use of RNA interference: erythropoietin is a HIF-2alpha target gene in Hep3B and Kelly cells. FASEB J 18: 1462–1464

    Article  CAS  PubMed  Google Scholar 

  47. Scortegagna M et al. (2005) HIF-2alpha regulates murine hematopoietic development in an erythropoietin-dependent manner. Blood 105: 3133–3140

    Article  CAS  PubMed  Google Scholar 

  48. Imagawa S et al. (1997) Negative regulation of the erythropoietin gene expression by the GATA transcription factors. Blood 89: 1430–1439

    CAS  PubMed  Google Scholar 

  49. La Ferla K et al. (2002) Inhibition of erythropoietin gene expression signaling involves the transcription factors GATA-2 and NF-kappaB. FASEB J 16: 1811–1813

    Article  CAS  PubMed  Google Scholar 

  50. Dumitriu B et al. (2006) Sox6 cell-autonomously stimulates erythroid cell survival, proliferation, and terminal maturation and is thereby an important enhancer of definitive erythropoiesis during mouse development. Blood 108: 1198–1207

    Article  CAS  PubMed  Google Scholar 

  51. Fisher JW (2003) Erythropoietin: physiology and pharmacology update. Exp Biol Med (Maywood) 228: 1–14

    Article  CAS  Google Scholar 

  52. Wickrema A et al. (1992) Differentiation and erythropoietin receptor gene expression in human erythroid progenitor cells. Blood 80: 1940–1949

    CAS  PubMed  Google Scholar 

  53. Anagnostou A et al. (1994) Erythropoietin receptor mRNA expression in human endothelial cells. Proc Natl Acad Sci USA 91: 3974–3978

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Chong ZZ et al. (2002) Hematopoietic factor erythropoietin fosters neuroprotection through novel signal transduction cascades. J Cereb Blood Flow Metab 22: 503–514

    Article  CAS  PubMed  Google Scholar 

  55. Henry DH et al. (2004) Epoetin alfa: clinical evolution of a pleiotropic cytokine. Arch Intern Med 164: 262–276

    Article  CAS  PubMed  Google Scholar 

  56. Bahlmann FH et al. (2004) Erythropoietin regulates endothelial progenitor cells. Blood 103: 921–926

    Article  CAS  PubMed  Google Scholar 

  57. Bahlmann FH et al. (2003) Endothelial progenitor cell proliferation and differentiation is regulated by erythropoietin. Kidney Int 64: 1648–1652

    Article  CAS  PubMed  Google Scholar 

  58. George J et al. (2005) Erythropoietin promotes endothelial progenitor cell proliferative and adhesive properties in a PI 3-kinase-dependent manner. Cardiovasc Res 68: 299–306

    Article  CAS  PubMed  Google Scholar 

  59. Beleslin-Cokic BB et al. (2004) Erythropoietin and hypoxia stimulate erythropoietin receptor and nitric oxide production by endothelial cells. Blood 104: 2073–2080

    Article  CAS  PubMed  Google Scholar 

  60. Parsa CJ et al. (2003) A novel protective effect of erythropoietin in the infarcted heart. J Clin Invest 112: 999–1007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Vesey DA et al. (2004) Erythropoietin protects against ischaemic acute renal injury. Nephrol Dial Transplant 19: 348–355

    Article  CAS  PubMed  Google Scholar 

  62. Caro J et al. (1979) Erythropoietin levels in uremic nephric and anephric patients. J Lab Clin Med 93: 449–458

    CAS  PubMed  Google Scholar 

  63. Mason-Garcia M et al. (1990) Development of a new radioimmunoassay for erythropoietin using recombinant erythropoietin. Kidney Int 38: 969–975

    Article  CAS  PubMed  Google Scholar 

  64. Macdougall IC (1995) Poor response to erythropoietin: practical guidelines on investigation and management. Nephrol Dial Transplant 10: 607–614

    Article  CAS  PubMed  Google Scholar 

  65. Volpe M et al. (1994) Blood levels of erythropoietin in congestive heart failure and correlation with clinical, hemodynamic, and hormonal profiles. Am J Cardiol 74: 468–473

    Article  CAS  PubMed  Google Scholar 

  66. Jensen JD et al. (1993) Elevated level of erythropoietin in congestive heart failure relationship to renal perfusion and plasma renin. J Intern Med 233: 125–130

    Article  CAS  PubMed  Google Scholar 

  67. George J et al. (2005) Circulating erythropoietin levels and prognosis in patients with congestive heart failure: comparison with neurohormonal and inflammatory markers. Arch Intern Med 165: 1304–1309

    Article  CAS  PubMed  Google Scholar 

  68. van der Meer P et al. (2004) Prognostic value of plasma erythropoietin on mortality in patients with chronic heart failure. J Am Coll Cardiol 44: 63–67

    Article  CAS  PubMed  Google Scholar 

  69. Stenvinkel P (2001) Inflammatory and atherosclerotic interactions in the depleted uremic patient. Blood Purif 19: 53–61

    Article  CAS  PubMed  Google Scholar 

  70. Bergstrom J et al. (2000) What are the causes and consequences of the chronic inflammatory state in chronic dialysis patients? Semin Dial 13: 163–175

    Article  CAS  PubMed  Google Scholar 

  71. Deswal A et al. (2001) Cytokines and cytokine receptors in advanced heart failure: an analysis of the cytokine database from the Vesnarinone trial (VEST). Circulation 103: 2055–2059

    Article  CAS  PubMed  Google Scholar 

  72. Levine B et al. (1990) Elevated circulating levels of tumor necrosis factor in severe chronic heart failure. N Engl J Med 323: 236–241

    Article  CAS  PubMed  Google Scholar 

  73. Dutka DP et al. (1993) Tumour necrosis factor alpha in severe congestive cardiac failure. Br Heart J 70: 141–143

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Macdougall IC and Cooper AC (2002) Erythropoietin resistance: the role of inflammation and pro-inflammatory cytokines. Nephrol Dial Transplant 17 (Suppl 11): S39–S43

    Article  Google Scholar 

  75. Means RT Jr (2003) Recent developments in the anemia of chronic disease. Curr Hematol Rep 2: 116–121

    Article  PubMed  Google Scholar 

  76. Taniguchi S et al. (1997) Interferon gamma downregulates stem cell factor and erythropoietin receptors but not insulin-like growth factor-I receptors in human erythroid colony-forming cells. Blood 90: 2244–2252

    CAS  PubMed  Google Scholar 

  77. Jelkmann W (1998) Proinflammatory cytokines lowering erythropoietin production. J Interferon Cytokine Res 18: 555–559

    Article  CAS  PubMed  Google Scholar 

  78. Maciejewski JP et al. (1995) Nitric oxide suppression of human hematopoiesis in vitro: contribution to inhibitory action of interferon-gamma and tumor necrosis factor-alpha. J Clin Invest 96: 1085–1092

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Donovan A et al. (2005) The iron exporter ferroportin/Slc40a1 is essential for iron homeostasis. Cell Metab 1: 191–200

    Article  CAS  PubMed  Google Scholar 

  80. Lawrence CM et al. (1999) Crystal structure of the ectodomain of human transferrin receptor. Science 286: 779–782

    Article  CAS  PubMed  Google Scholar 

  81. Nemeth E et al. (2004) IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J Clin Invest 113: 1271–1276

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Mena NP et al. (2006) Regulation of transepithelial transport of iron by hepcidin. Biol Res 39: 191–193

    Article  CAS  PubMed  Google Scholar 

  83. Dallalio G et al. (2006) Hepcidin inhibits in vitro erythroid colony formation at reduced erythropoietin concentrations. Blood 107: 2702–2704

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Malyszko J et al. (2005) Is hepcidin a link between anemia, inflammation and liver function in hemodialyzed patients? Am J Nephrol 25: 586–590

    Article  CAS  PubMed  Google Scholar 

  85. Eleftheriadis T et al. (2006) Does hepcidin affect erythropoiesis in hemodialysis patients? Acta Haematol 116: 238–244

    Article  CAS  PubMed  Google Scholar 

  86. Philo JS et al. (1996) Dimerization of the extracellular domain of the erythropoietin (EPO) receptor by EPO: one high-affinity and one low-affinity interaction. Biochemistry 35: 1681–1691

    Article  CAS  PubMed  Google Scholar 

  87. Constantinescu SN et al. (2001) Ligand-independent oligomerization of cell-surface erythropoietin receptor is mediated by the transmembrane domain. Proc Natl Acad Sci USA 98: 4379–4384

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Rossert J and Eckardt KU (2005) Erythropoietin receptors: their role beyond erythropoiesis. Nephrol Dial Transplant 20: 1025–1028

    Article  CAS  PubMed  Google Scholar 

  89. Naranda T et al. (1999) Activation of erythropoietin receptor in the absence of hormone by a peptide that binds to a domain different from the hormone binding site. Proc Natl Acad Sci USA 96: 7569–7574

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Wrighton NC et al. (1996) Small peptides as potent mimetics of the protein hormone erythropoietin. Science 273: 458–464

    Article  CAS  PubMed  Google Scholar 

  91. Livnah O et al. (1996) Functional mimicry of a protein hormone by a peptide agonist: the EPO receptor complex at 2.8 A. Science 273: 464–471

    Article  CAS  PubMed  Google Scholar 

  92. Sasaki A et al. (2000) CIS3/SOCS-3 suppresses erythropoietin (EPO) signaling by binding the EPO receptor and JAK2. J Biol Chem 275: 29338–29347

    Article  CAS  PubMed  Google Scholar 

  93. Beckman DL et al. (1999) Activation of the erythropoietin receptor is not required for internalization of bound erythropoietin. Blood 94: 2667–2675

    CAS  PubMed  Google Scholar 

  94. Sorkin A and Waters CM (1993) Endocytosis of growth factor receptors. Bioessays 15: 375–382

    Article  CAS  PubMed  Google Scholar 

  95. Walrafen P et al. (2005) Both proteasomes and lysosomes degrade the activated erythropoietin receptor. Blood 105: 600–608

    Article  CAS  PubMed  Google Scholar 

  96. Witthuhn BA et al. (1993) JAK2 associates with the erythropoietin receptor and is tyrosine phosphorylated and activated following stimulation with erythropoietin. Cell 74: 227–236

    Article  CAS  PubMed  Google Scholar 

  97. Klingmuller U et al. (1995) Specific recruitment of SH-PTP1 to the erythropoietin receptor causes inactivation of JAK2 and termination of proliferative signals. Cell 80: 729–738

    Article  CAS  PubMed  Google Scholar 

  98. Akagi S et al. (2004) The critical role of SRC homology domain 2-containing tyrosine phosphatase-1 in recombinant human erythropoietin hyporesponsive anemia in chronic hemodialysis patients. J Am Soc Nephrol 15: 3215–3224

    Article  PubMed  Google Scholar 

  99. Silva M et al. (1996) Erythropoietin can promote erythroid progenitor survival by repressing apoptosis through Bcl-XL and Bcl-2. Blood 88: 1576–1582

    CAS  PubMed  Google Scholar 

  100. Matsumoto A et al. (1997) CIS, a cytokine inducible SH2 protein, is a target of the JAK-STAT5 pathway and modulates STAT5 activation. Blood 89: 3148–3154

    CAS  PubMed  Google Scholar 

  101. Peltola KJ et al. (2004) Pim-1 kinase inhibits STAT5-dependent transcription via its interactions with SOCS1 and SOCS3. Blood 103: 3744–3750

    Article  CAS  PubMed  Google Scholar 

  102. Miura Y et al. (1994) Activation of the mitogen-activated protein kinase pathway by the erythropoietin receptor. J Biol Chem 269: 29962–29969

    CAS  PubMed  Google Scholar 

  103. Carroll MP et al. (1991) Erythropoietin induces Raf-1 activation and Raf-1 is required for erythropoietin-mediated proliferation. J Biol Chem 266: 14964–14969

    CAS  PubMed  Google Scholar 

  104. Miura O et al. (1994) Erythropoietin-dependent association of phosphatidylinositol 3-kinase with tyrosine-phosphorylated erythropoietin receptor. J Biol Chem 269: 614–620

    CAS  PubMed  Google Scholar 

  105. Kashii Y et al. (2000) A member of Forkhead family transcription factor, FKHRL1, is one of the downstream molecules of phosphatidylinositol 3-kinase-Akt activation pathway in erythropoietin signal transduction. Blood 96: 941–949

    CAS  PubMed  Google Scholar 

  106. Rice L et al. (2001) Neocytolysis on descent from altitude: a newly recognized mechanism for the control of red cell mass. Ann Intern Med 134: 652–656

    Article  CAS  PubMed  Google Scholar 

  107. Trial J and Rice L (2004) Erythropoietin withdrawal leads to the destruction of young red cells at the endothelial-macrophage interface. Curr Pharm Des 10: 183–190

    Article  CAS  PubMed  Google Scholar 

  108. Rice L et al. (1999) Neocytolysis contributes to the anemia of renal disease. Am J Kidney Dis 33: 59–62

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The EPOCARES study is funded by the Dutch Heart Foundation, Grant #2005B192, The Hague, The Netherlands.

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Authors and Affiliations

  1. in the Department of Internal Medicine, K van der Putten is a Physician and Investigator for the EPOCARES study and CAJM Gaillard is a Nephrologist, Meander Medical Center, Amersfoort, The Netherlands.,

    Karien van der Putten & Carlo AJM Gaillard

  2. B Braam is Associate Professor of Medicine and Adjunct Associate Professor of Physiology in the Division of Nephrology and Immunology, Department of Medicine and Department of Physiology, University of Alberta, Edmonton, Canada.,

    Branko Braam

  3. KE Jie is Investigator for the EPOCARES study in the Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands.,

    Kim E Jie

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  1. Karien van der Putten
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Correspondence to Carlo AJM Gaillard.

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van der Putten, K., Braam, B., Jie, K. et al. Mechanisms of Disease: erythropoietin resistance in patients with both heart and kidney failure. Nat Rev Nephrol 4, 47–57 (2008). https://doi.org/10.1038/ncpneph0655

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