Correspondence *Department of Internal Medicine, Meander Medical Center, PO Box 1502, 3800 BM Amersfoort, The Netherlands

Email cajm.gaillard@meandermc.nl

Introduction

Anemia is common in patients with both heart failure and chronic kidney disease (CKD) and is associated with a negative outcome. Whether treatment with erythropoietin (EPO) is of benefit is the subject of several ongoing studies. Therapy with EPO does not increase hemoglobin levels in a considerable proportion of patients. This fact is clinically important because resistance to EPO is associated with an increased risk of death in people with CKD. In this Review, we address these issues with a focus on the mechanisms that modulate the response to EPO. First, we briefly discuss the pathogenesis of the cardiorenal syndrome, and explore the causes and consequences of anemia in CKD, heart failure and the combination of the two. Thereafter, we elucidate the physiological role of EPO and discuss the mechanisms that might underlie the variability in sensitivity to endogenous, as well as exogenous, EPO.

Erythropoietin and the cardiorenal syndrome

We recently proposed a model for the pathogenesis of the cardiorenal syndrome, in which cardiac and renal dysfunction mutually amplify progressive failure of both systems.¹ Inflammation, the balance between nitric oxide and reactive oxygen species, the sympathetic nervous system, and the renin–angiotensin system (RAS), are the 'cardiorenal connectors', cornerstones in the pathophysiology of the cardiorenal syndrome (Figure 1).¹ More recently, we have expanded the model and explored the hypothesis that EPO could dampen the cardiorenal connectors.² In this Review, we address the means by which the cardiorenal connectors influence the function of EPO. In acknowledgment of its pivotal role, we will specifically focus on the mechanism by which inflammation affects the physiological function of EPO. The other cardiorenal connectors are only discussed when relevant to this mechanism.

Figure 1 The pathophysiology of the cardiorenal syndrome and its effect on erythropoietin.

The cardiorenal syndrome is characterized by an imbalance between nitric oxide and reactive oxygen species, by increased inflammation, by increased activity of the renin–angiotensin system, and by increased activity of the sympathetic nervous system. Together, these 'cardiorenal connectors' decrease sensitivity to EPO. Abbreviations: EPO, erythropoietin; NO, nitric oxide; RAS, renin–angiotensin system; ROS, reactive oxygen species; SNS, sympathetic nervous system.

Full figure and legend (14K)Figures & Tables indexDownload Power Point slide (128K)

Anemia in CKD, heart failure and the cardiorenal syndrome

Erythropoietin, erythropoiesis and beyond

EPO acts as an erythropoietic protein; it is produced in the kidneys by peritubular cells and can also be produced in the liver.⁴⁵ The primary stimulus for production of EPO is hypoxia. A deficiency in tissue oxygen levels increases the activity of hypoxia-inducible factor 2, which binds to hypoxia-responsive elements located in the enhancer region of the EPO gene in order to activate transcription.^{46, 47} Other transcription factors, such as GATA2 and nuclear factor kappa B (NFB), can modulate EPO expression; evidence indicates that both factors inhibit transcription of the EPO gene.^{48, 49} The transcription factor Sox6 has been shown in mice to be an important enhancer of erythropoiesis at multiple levels.⁵⁰ In the bone marrow, EPO acts synergistically with stem cell factor, granulocyte macrophage colony-stimulating factor, interleukin (IL)-3, IL-4, IL-9 and insulin-like growth factor 1 on erythroid progenitor cells to prevent their programmed cell death, thereby stimulating proliferation and maturation of erythroid progenitors through the normoblast stage into reticulocytes and mature erythrocytes.⁵¹ The EPO receptor is expressed primarily on erythroid cells that are between the colony-forming-unit erythroid stage and the pronormoblast stage of development. The number of EPO receptors per cell gradually decreases during erythroid differentiation.⁵²

In addition to acting as an erythropoietic factor, EPO has been shown to have an important role in tissues outside of the erythropoietic system. Expression of EPO receptors and a biological response to EPO have been observed in endothelial, neural, cardiac and other cell types.^{53, 54, 55} One non-hematopoietic effect of EPO is its stimulation of dose-dependent proliferation and chemotaxis of endothelial progenitor cells in vitro, which promotes vascular reparative processes and neoangiogenesis.⁵⁶ This process has also been shown to occur in patients with CKD⁵⁷ and in patients with CHF.⁵⁸ EPO can also induce nitric oxide production by endothelial cells, which might exert anti-apoptotic effects.^{2, 59} EPO protects cardiomyocytes against ischemic injury by inhibiting apoptosis.⁶⁰ Administration of EPO to ischemic renal cells reduced apoptosis and enhanced regeneration in a study by Vesey and colleagues.⁶¹ Thus, local binding of EPO to endothelial cells, cardiac cells and renal cells exerts cytoprotective and proliferative effects.

Erythropoietic agents were introduced in about 1990 for the treatment of anemia associated with CKD. Nowadays, EPO is also registered for use in patients with nonmyeloid malignancies treated with chemotherapy, in AIDS patients with anemia due to treatment with zidovudine, and in the perioperative stage for surgical patients. Several studies that aim to define the role of EPO treatment in CHF, in the combination of CHF and CKD, and in acute myocardial infarction, are underway.

Erythropoietin resistance

In 1979, Caro et al. measured endogenous EPO levels in healthy people with or without anemia and compared these with levels in CKD patients with anemia.⁶² It seemed that EPO levels were higher in patients with CKD than in those without CKD, but were inappropriately low for the degree of anemia. Serum levels of EPO in normal individuals range between 1 and 27 mU/ml (mean 6.2 4.3 mU/ml), whereas those in patients with CKD are between 4.2 and 102 mU/ml (mean 29.5 4.0 mU/ml);⁶³ anemia persists in patients with CKD despite average EPO levels being approximately five times higher than those in healthy individuals. This disparity indicates that, in addition to relative EPO deficiency, bone marrow response to endogenous EPO is suppressed in people with CKD. Erythropoietic agents have been used since the 1990s to treat patients with CKD, in an effort to overcome the relative EPO deficiency. Up to 10% of patients, however, have an inadequate response to therapy.⁶⁴ This finding is clinically important, because resistance to EPO is associated with an increased risk of death in patients with CKD. This effect persists after adjustment for the generally decreased hematocrit in these patients.²⁹

EPO levels have also been measured in people with CHF, and have been found to be high.^{65, 66, 67} Analogous to the situation in patients with CKD, the high EPO levels in patients with CHF are inappropriately low for the degree of anemia.⁶⁸ These data indicate that in CHF, as well as in CKD, there is a relative EPO deficiency as well as resistance of bone marrow to endogenous EPO.

Several mechanisms for resistance to endogenous, as well as exogenous, EPO have been proposed. The processes that cause anemia of chronic disease have a role. The primary hypothesis is that proinflammatory cytokines antagonize the actions of endogenous and exogenous EPO by directly inhibiting erythroid progenitor cells and by disrupting iron metabolism. Interaction between EPO and its receptor, and intracellular EPO signaling, could also have a role. Little is known about the putative contribution of neocytolysis (selective hemolysis of young circulating red blood cells) to EPO resistance. These possible causes of EPO resistance are discussed in the following section.

Mechanisms of Erythropoietin resistance

Cytokines and erythropoiesis

CKD involves a chronic inflammatory state. Patients with CKD have increased levels of markers of inflammation such as C-reactive protein and the cytokines IL-1, IL-6, interferon (IFN)- and tumor necrosis factor (TNF).^{69, 70} Increased levels of TNF and IL-6 have also been measured in patients with heart failure.^{71, 72, 73} These cytokines inhibit the growth of erythroid precursor cells in vitro, an effect that is probably brought about through cytokine-mediated induction of apoptosis.^{74, 75} Taniguchi et al. showed that IFN- downregulates messenger RNA for EPO receptor expression, indicating that the number of EPO receptors can influence apoptosis of erythroid precursor cells.⁷⁶ In addition, IL-1 and TNF have been shown to inhibit EPO production, another mechanism by which cytokines induce apoptosis of precursor cells.⁷⁷ Moreover, cytokines have a direct toxic effect on progenitor cells, which is generated at least in part by inducing the labile free radical nitric oxide, produced by inducible nitric oxide synthase.⁷⁸

In addition to their direct inhibitory effect on erythroid progenitor cells, cytokines can cause EPO resistance by disrupting iron metabolism (Figure 2). Iron is essential for the production of hemoglobin. Iron homeostasis involves the following three sources that supply the plasma compartment: iron absorption from the diet; recycled iron from red blood cells; and iron moved from storage sites in the liver (Figure 3). As most of the body's iron is contained in red blood cells, nearly all of the iron for erythropoiesis is supplied by the recycling of iron from senescent red cells. Macrophages phagocytize erythrocytes, and iron is released from hemoglobin in the phagolysosome. From the macrophage, iron is transferred to the circulation by the carrier protein ferroportin.⁷⁹ Iron is transported in the plasma by transferrin, which donates iron to cells through its interaction with a specific membrane receptor, the transferrin receptor.⁸⁰

Figure 2 The role of cytokines in erythropoietin resistance.

Proinflammatory cytokines induce EPO resistance by exerting both direct inhibitory effects on erythroid progenitor cells, and indirect inhibitory effects by upregulating hepcidin. Cytokines also induce EPO resistance by disrupting iron metabolism. This effect occurs via upregulation of hepcidin and via a direct effect of proinflammatory cytokines on iron homeostasis. Abbreviation: EPO, erythropoietin.

Full figure and legend (17K)Figures & Tables indexDownload Power Point slide (130K)

Figure 3 Iron homeostasis and the role of hepcidin.

Fe³⁺ is reduced to Fe²⁺ and moves into the enterocyte via DMT1. In the enterocyte, iron can either be stored as ferritin or can be transported out by ferroportin. In plasma, Fe²⁺ is oxidized to Fe³⁺, which can bind to transferrin. Macrophages take up iron by phagocytosis of erythrocytes, as Fe²⁺ via DMT1, and from transferrin via the transferrin receptor. In the macrophage, iron is stored as ferritin or is transported to the circulation via ferroportin. Hepcidin negatively regulates ferroportin in the enterocyte and macrophage, and the expression of DMT1 in the enterocyte, leading to decreased plasma iron availability. Abbreviations: DMT1, divalent metal transporter 1; TfR, transferrin receptor.

Full figure and legend (22K)Figures & Tables indexDownload Power Point slide (202K)

Proinflammatory cytokines, mainly IL-6, affect iron metabolism by stimulating the synthesis of hepcidin. Hepcidin is a type II acute-phase protein produced in the liver that has been proposed to be the central regulator of iron metabolism (Figure 3).⁸¹ Hepcidin is thought to control the efflux of iron into plasma transferrin by downregulating ferroportin, the efflux channel for iron in macrophages and enterocytes. It has also been suggested that hepcidin negatively regulates the expression of the apical divalent metal transporter 1 in the enterocyte.⁸² The synthesis of hepcidin thus leads to inhibition of iron absorption in the small intestine and sequestering of iron in macrophages. These actions lead to a decreased iron concentration in the circulation. In addition to its effect on iron metabolism, hepcidin might contribute to EPO resistance by directly inhibiting erythroid-progenitor proliferation and survival (Figure 2).⁸³ In accordance with these findings, it has been shown that levels of hepcidin, as well as of pro-hepcidin (the precursor of hepcidin), are negatively correlated with hematocrit in hemodialysis patients.^{84, 85}

Proinflammatory cytokines also have a direct effect on iron homeostasis (Figure 2). TNF, IL-1 and IL-6 upregulate the expression of divalent metal transporter 1 in macrophages, induce ferritin expression, and downregulate ferroportin. In addition, cytokines stimulate an increase in transferrin-receptor-mediated uptake of transferrin-bound iron into macrophages. TNF and IL-1 damage erythrocyte membranes and stimulate erythrophagocytosis. Together, these processes promote intracellular iron storage and decrease the plasma concentration of iron.⁵

To sum up, the chronic inflammatory state of CKD plus CHF limits the availability of iron for erythropoiesis, thereby leading to EPO resistance via upregulation of hepcidin and the direct effects of cytokines on iron homeostasis.

Receptor interactions

Binding of EPO to the EPO receptor is essential for the production of mature red blood cells. The EPO receptor is a type 1 transmembrane protein that belongs to the hematopoietic cytokine receptor superfamily. The EPO-bound receptor is a dimer; however, there has been debate about whether, in the absence of ligand, the EPO receptor is a monomer or oligomer. One model proposes that two monomeric receptors become a dimer after the binding of EPO, resulting in signal transduction.⁸⁶ Another model describes a process whereby the EPO receptor appears at the cell surface as a preformed dimer. In this now generally accepted scheme, binding of ligand shifts the receptor from an inactive to an active conformation (Figure 4).^{87, 88} Activation of the EPO receptor is transient; it is rapidly deactivated by downregulating mechanisms, including receptor internalization and degradation.

Figure 4 Overview of erythropoietin receptor activation and intracellular pathways.

The EPO receptor is a preformed dimer ([1]). Binding of EPO leads to activation of JAK2 by transphosphorylation ([2]) and subsequent tyrosine phosphorylation of the cytoplasmic domain of the EPO receptor ([3]). This phosphorylation leads to the initiation of intracellular signaling with activation of STAT5, Ras/MAP, PI3K and NFB ([4]). STAT5 induces SOCS/CIS, which attenuates EPO signaling by binding to JAK2 and by inhibiting phosphorylation of STAT5 ([5]). EPO signaling is terminated by HCP, which dephosphorylates JAK2 ([6]). The EPO–EPO-receptor complex is internalized following dephosphorylation of the receptor ([7]). The receptor is then degraded in the proteosome ([8]) or recycled to the cell surface ([9]). Abbreviations: CIS, cytokine-inducible SH2-containing protein; EPO, erythropoietin; HCP, hematopoietic cell phosphatase; JAK2, Janus kinase 2; MAP, mitogen-activated protein; NFB, nuclear factor kappa B; PI3K, phosphatidylinositol 3 kinase; SOCS, suppressor of cytokine signaling; STAT5, signal transducer and activator of transcription 5.

Full figure and legend (25K)Figures & Tables indexDownload Power Point slide (138K)

Mechanisms that might underlie EPO resistance are defective dimerization or defective activation of the EPO receptor. It has been shown that the transmembrane domain of the EPO receptor has a powerful ligand-independent dimerizing capacity.⁸⁷ Although the role of preformed dimers is still unclear, it could be that the dimerizing activity of the EPO receptor transmembrane domain sensitizes the EPO receptor such that it functions at low EPO concentrations. According to this model, absence of spontaneous dimerization of the EPO receptor could lead to EPO resistance.

Naranda et al. described how the EPO receptor can be activated in the absence of its natural ligand by a peptide that binds to a domain that differs from the EPO-binding site.⁸⁹ Mimetic peptides that bind to the EPO-binding site activate the same signaling pathways as EPO itself.^{90, 91} EPO resistance could be induced by the presence of antagonistic peptides that bind to the EPO receptor. For example, it has been shown that cytokine-inducible SH2-containing protein (CIS) binds directly to the cytoplasmic domain of the EPO receptor and inhibits EPO-dependent proliferation.⁹² CIS production is induced by cytokines such as IFN-, IL-2 and IL-6. As such, cytokines might cause EPO resistance in cardiorenal failure.

Another possible cause of blunted EPO response is a decreased number of EPO receptors. IFN- inhibits messenger RNA for EPO-receptor expression. The number of EPO receptors can also drop in response to receptor internalization and degradation, which are poorly understood mechanisms of downregulation. Beckman et al. studied the contribution of EPO-induced receptor internalization to modulation of EPO intracellular signals.⁹³ They showed that neither EPO activation of Janus kinase 2 (JAK2), nor tyrosine phosphorylation of the EPO receptor, was required for EPO-induced receptor downregulation. So, in contrast to other classes of growth factor receptors,⁹⁴ internalization of the EPO receptor seems to be regulated independently to EPO signaling. An increase in the rate of internalization could decrease the number of EPO receptors and lead to EPO resistance. The means by which ligand-occupied EPO-receptor internalization is regulated, and whether cytokines have a role in this process, is unknown.

After internalization, proteosomes and lysosomes degrade both EPO and the EPO receptor, thereby regulating the degree of EPO signaling. In contrast to internalization, EPO and EPO-receptor degradation has been shown to be dependent on JAK2 activity; blocking JAK2-induced recycling of internalized EPO–EPO-receptor complexes to the cell, indicating perturbation of degradative processes.⁹⁵ Enhanced degradation of the EPO receptor could be important to the development of EPO resistance as it would diminish the rate of EPO–EPO-receptor-complex recycling; however, no data are available to support this hypothesis.

Conclusions

The pathophysiological basis of the frequently occurring phenomenon of cardiorenal anemia is complex, and includes inadequate EPO production as well as EPO resistance. We propose that inflammation has a key role in EPO resistance. Cardiorenal failure is a low-grade inflammatory condition in which proinflammatory cytokines antagonize the action of EPO by directly inhibiting erythroid progenitor cells and by disrupting iron metabolism, in which hepcidin has a central role. EPO resistance could also be caused by inflammation-induced changes in EPO-receptor properties, assembly and recycling, and by interference with post-receptor signaling routes. This latter subject is largely unexplored. Neocytolysis might also have a role in EPO resistance.

Recombinant human EPO has been registered for more than a decade for the treatment of renal anemia in patients with CKD, and has proven to be a safe and beneficial therapy. Less clear is whether treatment with EPO in patients with heart failure and kidney disease is effective and safe. Resistance to exogenous EPO is associated with an increased risk of death in hemodialysis patients. It is, therefore, important to understand in more detail how cardiorenal failure affects EPO production and function.

Acknowledgments

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

References

1. Bongartz LG et al. (2005) The severe cardiorenal syndrome: 'Guyton revisited'. Eur Heart J 26: 11–17 | Article | PubMed |
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 | PubMed | ChemPort |
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 | PubMed | ISI | ChemPort |
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
5. Weiss G and Goodnough LT (2005) Anemia of chronic disease. N Engl J Med 352: 1011–1023 | Article | PubMed | ISI | ChemPort |
6. Eckhardt KU (2000) Pathophysiology of renal anemia. Clin Nephrol 53 (Suppl 1): S2–S8
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 |
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 |
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 | PubMed | ISI | ChemPort |
10. Saudan P et al. (2006) ACE inhibitors or angiotensin II receptor blockers in dialysed patients and erythropoietin resistance. J Nephrol 19: 91–96 | PubMed | ChemPort |
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 | ISI |
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 | PubMed | ChemPort |
13. Anand IS (2005) Pathogenesis of anemia in cardiorenal disease. Rev Cardiovasc Med 6 (Suppl 3): S13–S21
14. Mrug M et al. (1997) Angiotensin II stimulates proliferation of normal early erythroid progenitors. J Clin Invest 100: 2310–2314 | Article | PubMed | ISI | ChemPort |
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 | PubMed | ISI | ChemPort |
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 | PubMed | ChemPort |
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 | PubMed | ISI | ChemPort |
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 | PubMed | ISI | ChemPort |
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 | PubMed | ChemPort |
20. Androne AS et al. (2003) Hemodilution is common in patients with advanced heart failure. Circulation 107: 226–229 | Article | PubMed | ISI |
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
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 | PubMed | ISI | ChemPort |
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 | PubMed | ISI | ChemPort |
24. Ma JZ et al. (1999) Hematocrit level and associated mortality in hemodialysis patients. J Am Soc Nephrol 10: 610–619 | PubMed | ISI | ChemPort |
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 | ISI |
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 | PubMed | ISI | ChemPort |
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 | ISI |
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 | ISI |
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 | PubMed | ISI | ChemPort |
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 | PubMed | ISI | ChemPort |
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 | PubMed | ISI | ChemPort |
32. Frank H et al. (2004) Effect of erythropoietin on cardiovascular prognosis parameters in hemodialysis patients. Kidney Int 66: 832–840 | Article | PubMed | ChemPort |
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 | PubMed | ISI | ChemPort |
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 | PubMed | ISI | ChemPort |
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 | PubMed | ISI | ChemPort |
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 | Article |
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
38. Anand I et al. (2004) Anemia and its relationship to clinical outcome in heart failure. Circulation 110: 149–154 | Article | PubMed |
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 | PubMed | ChemPort |
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 | PubMed | ISI | ChemPort |
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 | PubMed | ISI | ChemPort |
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 | PubMed | ChemPort |
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 |
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 | PubMed | ISI | ChemPort |
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 | PubMed | ISI | ChemPort |
47. Scortegagna M et al. (2005) HIF-2alpha regulates murine hematopoietic development in an erythropoietin-dependent manner. Blood 105: 3133–3140 | Article | PubMed | ChemPort |
48. Imagawa S et al. (1997) Negative regulation of the erythropoietin gene expression by the GATA transcription factors. Blood 89: 1430–1439 | PubMed | ISI | ChemPort |
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 | PubMed | ISI | ChemPort |
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 | PubMed | ChemPort |
51. Fisher JW (2003) Erythropoietin: physiology and pharmacology update. Exp Biol Med (Maywood) 228: 1–14 | PubMed | ChemPort |
52. Wickrema A et al. (1992) Differentiation and erythropoietin receptor gene expression in human erythroid progenitor cells. Blood 80: 1940–1949 | PubMed | ISI | ChemPort |
53. Anagnostou A et al. (1994) Erythropoietin receptor mRNA expression in human endothelial cells. Proc Natl Acad Sci USA 91: 3974–3978 | Article | PubMed | ChemPort |
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 | PubMed | ISI | ChemPort |
55. Henry DH et al. (2004) Epoetin alfa: clinical evolution of a pleiotropic cytokine. Arch Intern Med 164: 262–276 | Article | PubMed | ChemPort |
56. Bahlmann FH et al. (2004) Erythropoietin regulates endothelial progenitor cells. Blood 103: 921–926 | Article | PubMed | ISI | ChemPort |
57. Bahlmann FH et al. (2003) Endothelial progenitor cell proliferation and differentiation is regulated by erythropoietin. Kidney Int 64: 1648–1652 | Article | PubMed | ISI | ChemPort |
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 | PubMed | ISI | ChemPort |
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 | PubMed | ISI | ChemPort |
60. Parsa CJ et al. (2003) A novel protective effect of erythropoietin in the infarcted heart. J Clin Invest 112: 999–1007 | Article | PubMed | ISI | ChemPort |
61. Vesey DA et al. (2004) Erythropoietin protects against ischaemic acute renal injury. Nephrol Dial Transplant 19: 348–355 | Article | PubMed | ISI | ChemPort |
62. Caro J et al. (1979) Erythropoietin levels in uremic nephric and anephric patients. J Lab Clin Med 93: 449–458 | PubMed | ISI | ChemPort |
63. Mason-Garcia M et al. (1990) Development of a new radioimmunoassay for erythropoietin using recombinant erythropoietin. Kidney Int 38: 969–975 | Article | PubMed | ChemPort |
64. Macdougall IC (1995) Poor response to erythropoietin: practical guidelines on investigation and management. Nephrol Dial Transplant 10: 607–614 | PubMed | ISI | ChemPort |
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 | PubMed | ISI | ChemPort |
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 | PubMed | ChemPort |
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 | PubMed | ChemPort |
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 | PubMed | ChemPort |
69. Stenvinkel P (2001) Inflammatory and atherosclerotic interactions in the depleted uremic patient. Blood Purif 19: 53–61 | Article | PubMed | ISI | ChemPort |
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 | PubMed | ISI | ChemPort |
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 | PubMed | ISI | ChemPort |
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 | PubMed | ISI | ChemPort |
73. Dutka DP et al. (1993) Tumour necrosis factor alpha in severe congestive cardiac failure. Br Heart J 70: 141–143 | Article | PubMed | ChemPort |
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
75. Means RT Jr (2003) Recent developments in the anemia of chronic disease. Curr Hematol Rep 2: 116–121 | PubMed |
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 | PubMed | ChemPort |
77. Jelkmann W (1998) Proinflammatory cytokines lowering erythropoietin production. J Interferon Cytokine Res 18: 555–559 | PubMed | ISI | ChemPort |
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 | PubMed | ISI | ChemPort |
79. Donovan A et al. (2005) The iron exporter ferroportin/Slc40a1 is essential for iron homeostasis. Cell Metab 1: 191–200 | Article | PubMed | ISI | ChemPort |
80. Lawrence CM et al. (1999) Crystal structure of the ectodomain of human transferrin receptor. Science 286: 779–782 | Article | PubMed | ISI | ChemPort |
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 | PubMed | ISI | ChemPort |
82. Mena NP et al. (2006) Regulation of transepithelial transport of iron by hepcidin. Biol Res 39: 191–193 | PubMed | ChemPort |
83. Dallalio G et al. (2006) Hepcidin inhibits in vitro erythroid colony formation at reduced erythropoietin concentrations. Blood 107: 2702–2704 | Article | PubMed | ChemPort |
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 | PubMed | ChemPort |
85. Eleftheriadis T et al. (2006) Does hepcidin affect erythropoiesis in hemodialysis patients? Acta Haematol 116: 238–244 | Article | PubMed | ChemPort |
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 | PubMed | ISI | ChemPort |
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 | PubMed | ChemPort |
88. Rossert J and Eckardt KU (2005) Erythropoietin receptors: their role beyond erythropoiesis. Nephrol Dial Transplant 20: 1025–1028 | Article | PubMed | ChemPort |
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 | PubMed | ChemPort |
90. Wrighton NC et al. (1996) Small peptides as potent mimetics of the protein hormone erythropoietin. Science 273: 458–464 | Article | PubMed | ISI | ChemPort |
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 | PubMed | ISI | ChemPort |
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 | PubMed | ISI | ChemPort |
93. Beckman DL et al. (1999) Activation of the erythropoietin receptor is not required for internalization of bound erythropoietin. Blood 94: 2667–2675 | PubMed | ChemPort |
94. Sorkin A and Waters CM (1993) Endocytosis of growth factor receptors. Bioessays 15: 375–382 | Article | PubMed | ISI | ChemPort |
95. Walrafen P et al. (2005) Both proteasomes and lysosomes degrade the activated erythropoietin receptor. Blood 105: 600–608 | Article | PubMed | ISI | ChemPort |
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 | PubMed | ISI | ChemPort |
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 | PubMed | ISI | ChemPort |
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 |
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 | PubMed | ISI | ChemPort |
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 | PubMed | ISI | ChemPort |
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 | PubMed | ISI | ChemPort |
102. Miura Y et al. (1994) Activation of the mitogen-activated protein kinase pathway by the erythropoietin receptor. J Biol Chem 269: 29962–29969 | PubMed | ISI | ChemPort |
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 | PubMed | ISI | ChemPort |
104. Miura O et al. (1994) Erythropoietin-dependent association of phosphatidylinositol 3-kinase with tyrosine-phosphorylated erythropoietin receptor. J Biol Chem 269: 614–620 | PubMed | ISI | ChemPort |
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 | PubMed | ISI | ChemPort |
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 | PubMed | ISI | ChemPort |
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 | PubMed | ChemPort |
108. Rice L et al. (1999) Neocytolysis contributes to the anemia of renal disease. Am J Kidney Dis 33: 59–62 | PubMed | ISI | ChemPort |

Contact the journal about this article

Subject areas under which this article appears: Progression of renal disease