- Email: [email protected]
Erythropoiesis-stimulating agents: Past and future
http://www.kidney-international.org & 2007 International Society of Nephrology
Erythropoiesis-stimulating agents: Past and future M Nangaku1 and D Fliser2 1 2
Division of Nephrology and Endocrinology, Department of Internal Medicine, University of Tokyo School of Medicine, Tokyo, Japan and Division of Nephrology, Department of Internal Medicine, Hannover Medical School, Hannover, Germany
Renal anemia is a well-recognized complication of chronic kidney disease (CKD), and the deficiency of erythropoietin (EPO) is the primary cause. Observational population-based studies continue to demonstrate the association of low hemoglobin with adverse outcomes, and renal failure, cardiac failure, and anemia all may interact to cause or worsen each other, the so-called cardio-renal anemia syndrome. Treatment of anemia can be successfully achieved with the use of erythropoiesis-stimulating agents (ESAs). From a mechanistic point of view, however, the therapeutic benefits of ESA could be far beyond the correction of anemia. ESA modulates a broad array of cellular processes that include progenitor stem cell development, cellular integrity, and angiogenesis. A pleiotropic effect of EPO has been shown in the central nervous system, the cardiovascular system, and the kidney. While recent results of randomized controlled trials have established that there is little support for normalizing hemoglobin in CKD patients, the results of these studies do not negate renoprotective effects of EPO. A large number of patients with CKD will benefit from early recognition and appropriate correction of anemia with ESA. Kidney International (2007) 72, S1–S3; doi:10.1038/sj.ki.5002480 KEYWORDS: darbepoetin; erythropoietin; hypoxia; chronic kidney disease
Renal anemia is a well-recognized complication of chronic kidney disease (CKD). Although mechanisms involved in the pathogenesis of renal anemia include chronic inflammation, iron deficiency, and shortened half-life of erythrocytes, the primary cause is the deficiency of erythropoietin (EPO).1 Large observational population-based studies continue to demonstrate the association of low hemoglobin with adverse outcomes. Many morbidity conditions observed in patients with CKD are cardiovascular complications, and it is suggested that renal failure, cardiac failure, and anemia all interact to cause or worsen each other, the so-called cardiorenal anemia syndrome.2 Treatment of anemia can be successfully achieved with the use of erythropoiesis-stimulating agents (ESAs). On the basis of the epidemiological data, Iseki and Kohagura3 gave a comprehensive review on the role of anemia on CKD management. From a mechanistic point of view, however, a steadily growing body of evidence indicates that the therapeutic benefits of ESA could be far beyond the correction of anemia.4–7 ESA modulates a broad array of cellular processes that include progenitor stem cell development, cellular integrity, and angiogenesis. As a result, organ protection by EPO is remarkable in association with inhibition of apoptosis and amelioration of inflammation. An opportunity to address nonhematopoietic mechanisms of organ protection by ESA arose when the Pharmaceutical Division of Kirin Brewery and AMGEN-Europe invited us to chair a symposium focused on ESA. Their support enabled an ancillary symposium of the World Congress of Nephrology, which took place in Rio de Janeiro, 24 April 2007. Entitled ‘Erythropoiesis stimulating agents—past and future,’ it gathered together clinical scientists undertaking research at both the molecular and tissue levels. NEUROPROTECTION
Correspondence: M Nangaku, Division of Nephrology and Endocrinology, Department of Internal Medicine, University of Tokyo School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. E-mail: [email protected] Kidney International (2007) 72, S1–S3
The central nervous system is the first in which a pleiotropic effect of EPO was demonstrated.8–10 Research during the past years has clearly demonstrated that EPO is a potent promoter of neuronal survival. In vitro and in vivo studies have shown that EPO has the ability to cross the blood–brain barrier and provide neuroprotection by limiting damage to the central nervous system following injury. In vivo, the administration of recombinant EPO reduced brain injury associated with stroke, blunt trauma, cytotoxicity, and experimental autoimmune encephalomyelitis, and prevented spinal cord injury. S1
M Nangaku and D Fliser: Erythropoiesis-stimulating agents
CARDIOPROTECTION
Control of anemia can also become a valuable addition to the therapeutic armamentarium in patients with congestive heart failure. In an open uncontrolled study, Silverberg et al.11,12 investigated the effect of correcting anemia with EPO in patients suffering from congestive heart failure. The treatment caused an improvement in cardiac function and a reduction in the need for hospitalization. Furthermore, renal function was stabilized by the treatment of anemia. Long-term studies on the correction of renal anemia in patients on maintenance hemodialysis with EPO demonstrated a mitigation of oxidative stress during this therapy.13 During periods of 1 and 2 years, it was observed that the serum levels of 4-hydroxy-2-nonenal and malondialdehyde could be reduced. Amelioration of oxidative stress may have a direct positive effect on a variety of cardiovascular diseases as well as kidney diseases. RENOPROTECTION
Because chronic hypoxia in the tubulointerstitium is a final common pathway to end-stage renal disease,14 therapeutic approaches that target chronic hypoxia of renal tissue should prove effective against a broad range of kidney diseases. Correction of anemia by EPO and the subsequent improvement in oxygen delivery to the kidney should theoretically delay the progression of renal failure. Furthermore, ESA may activate various ‘surviving’ intracellular pathways in renal tissue and protect the kidney via nonhematopoietic mechanisms. This expectation was supported by several studies that suggested that progression might be delayed by an improvement in anemia by treatment with EPO. Kuriyama et al.15 were the first to raise the possibility that EPO therapy might actually delay progression of kidney disease. Tapolyai et al.16 reported that the mean slope of change in monthly reciprocal of the serum creatinine was significantly lower after correction of the hematocrit. Dean et al.17performed observational, before and after analysis using electronic medical records from the Veterans Administration. The analysis of 122 patients revealed that EPO treatment among older patients with moderate to severe kidney disease ameliorated deterioration of renal function. Gouva et al.18 recently conducted a randomized controlled trial of early versus deferred initiation of EPO in nondiabetic predialysis patients. The results clearly showed that early initiation of EPO significantly slows the progression of kidney disease. However, a major limitation to this trial was the systematic avoidance of renin–angiotensin blockers in the management of these patients. Thus, it remains to be clarified whether early treatment of renal anemia with EPO can retard progression of renal failure in otherwise optimally managed patients. While these clinical studies support a role of anemia treatment in protection of residual renal function, the recent meta-analysis of the available evidence, while continuing to support a role for correction of renal anemia on improvement of quality of life, failed to demonstrate a conclusive benefit of EPO on the progression of kidney disease.19 In S2
addition, recent results of randomized controlled trials have established that there is little support for normalizing hemoglobin in CKD patients.20–22 The results of these studies should not be misinterpreted to negate renoprotective effects of EPO, however. On the basis of the previous studies, current therapeutic targets of maintaining hemoglobin over 11 g/dl are likely appropriate, and what these studies demonstrated is that we did not get additional benefits by the normalization of hemoglobin levels in CKD patients. MECHANISMS OF ORGAN PROTECTION BY ESA
To support the notion that ESA protects organs via nonhematopoietic mechanisms, EPO analogues that maintain tissue-protective effects but are devoid of the action on erythropoiesis like carbamylated EPO have already been tested in experimental animals, revealing tissue-protective properties without any effect on hematocrit.23–25 Even at this moment, papers on renoprotection by ESA are published online before print.26,27 The three sections of this supplement address the broad issue of mechanisms of organ protection by ESA. Bahlmann et al.28 reviewed the data on the nonhematological effects of ESA in different experimental settings of acute and chronic kidney injury, and discussed pivotal intracellular pathways induced by ESA. Katavetin et al.29 focused on the antioxidative stress effects of ESA. Rabelink and colleagues30 described effects of endothelial precursor cell recruitment by ESA. These papers give us important insights that explain why the therapeutic benefits of ESA could be far more widereaching than anticipated by ameliorating of anemia and accompanying tissue hypoxia. CONCLUSION
While renal anemia deteriorates patient well-being, renal anemia is also likely to contribute to progression of kidney disease and aggravation of cardiovascular disease. ESA can protect organs via hematopoiesis-dependent and -independent manner. Recent studies have elucidated multiple molecular mechanisms of organ protection by ESA. A large number of patients with CKD will benefit from early recognition and appropriate correction of anemia with ESA. DISCLOSURE
Masaomi Nangaku has received lecture fees and grant support from Kirin Brewery Co. Ltd. Danilo Fliser has received consulting fees from Amgen (Munich, Germany), Roche (Mannheim, Germany), and Janssen Cilag/Ortho Biotech. He has also received lecture fees from Roche and Amgen and grant support from the German Research Foundation, the German Ministry for Education and Research and Janssen Cilag/Ortho Biotech (Neuss, Germany). REFERENCES 1. 2.
3.
Nangaku M, Eckdardt KU. Pathogenesis of renal anemia. Semin Nephrol 2006; 26: 261–268. Silverberg DS, Wexler D, Iaina A, Schwartz D. The interaction between heart failure and other heart diseases, renal failure, and anemia. Semin Nephrol 2006; 26: 296–306. Iseki K, Kohagura K. Anemia as a risk factor for chronic kidney disease. Kidney Int (this issue). Kidney International (2007) 72, S1–S3
M Nangaku and D Fliser: Erythropoiesis-stimulating agents
4. Fliser D, Bahlmann FH, deGroot K, Haller H. Mechanisms of disease: erythropoietin—an old hormone with a new mission? Nat Clin Pract Cardiovasc Med 2006; 3: 563–572. 5. Fliser D, Bahlmann FH, Haller H. EPO: renoprotection beyond anemia correction. Pediatr Nephrol 2006; 21: 1785–1789. 6. Brines M, Cerami A. Discovering erythropoietin’s extra-hematopoietic functions: biology and clinical promise. Kidney Int 2006; 70: 246–250. 7. Maiese K, Li F, Chong ZZ. New avenues of exploration for erythropoietin. JAMA 2005; 293: 90–95. 8. Brines ML, Ghezzi P, Keenan S et al. Erythropoietin crosses the blood–brain barrier to protect against experimental brain injury. Proc Natl Acad Sci USA 2000; 97: 10526–10531. 9. Digicaylioglu M, Lipton SA. Erythropoietin-mediated neuroprotection involves cross-talk between Jak2 and NF-kappaB signalling cascades. Nature 2001; 412: 641–647. 10. Grimm C, Wenzel A, Groszer M et al. HIF-1-induced erythropoietin in the hypoxic retina protects against light-induced retinal degeneration. Nat Med 2002; 8: 718–724. 11. Silverberg DS, Wexler D, Blum M et al. The effect of correction of anaemia in diabetics and non-diabetics with severe resistant congestive heart failure and chronic renal failure by subcutaneous erythropoietin and intravenous iron. Nephrol Dial Transplant 2003; 18: 141–146. 12. Silverberg DS, Wexler D, Blum M et al. The interaction between heart failure, renal failure and anemia—the cardio-renal anemia syndrome. Kidney Blood Press Res 2005; 28: 41–47. 13. Siems W, Carluccio F, Radenkovic S et al. Oxidative stress in renal anemia of hemodialysis patients is mitigated by epoetin treatment. Kidney Blood Press Res 2005; 28: 295–301. 14. Nangaku M. Chronic hypoxia and tubulointerstitial injury: a final common pathway to end-stage renal failure. J Am Soc Nephrol 2006; 17: 17–25. 15. Kuriyama S, Tomonari H, Yoshida H et al. Reversal of anemia by erythropoietin therapy retards the progression of chronic renal failure, especially in nondiabetic patients. Nephron 1997; 77: 176–185. 16. Tapolyai M, Kadomatsu S, Perera-Chong M. r.hu-erythropoietin (EPO) treatment of pre-ESRD patients slows the rate of progression of renal decline. BMC Nephrol 2003; 4: 3. 17. Dean BB, Dylan M, Gano Jr A et al. Erythropoiesis-stimulating protein therapy and the decline of renal function: a retrospective analysis of patients with chronic kidney disease. Curr Med Res Opin 2005; 21: 981–987.
Kidney International (2007) 72, S1–S3
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28. 29. 30.
Gouva C, Nikolopoulos P, Ioannidis JP, Siamopoulos KC. Treating anemia early in renal failure patients slows the decline of renal function: a randomized controlled trial. Kidney Int 2004; 66: 753–760. Cody J, Daly C, Campbell M et al. Recombinant human erythropoietin for chronic renal failure anaemia in pre-dialysis patients. Cochrane Database Syst Rev 2005; 3: CD003266. Drueke TB, Locatelli F, Clyne N et al. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med 2006; 355: 2071–2084. Singh SK, Szczech L, Tang KL et al. Correction of anemia with epoetin alpha in chronic kidney disease. N Engl J Med 2006; 355: 2085–2098. Ritz E, Laville M, Bilous RW et al. Target level for hemoglobin correction in patients with diabetes and CKD: primary results of the Anemia Correction in Diabetes (ACORD) Study. Am J Kidney Dis 2007; 49: 194–207. Leist M, Ghezzi P, Grasso G et al. Derivatives of erythropoietin that are tissue protective but not erythropoietic. Science 2004; 305: 239–242. Coleman TR, Westenfelder C, Togel FE et al. Cytoprotective doses of erythropoietin or carbamylated erythropoietin have markedly different procoagulant and vasoactive activities. Proc Natl Acad Sci USA 2006; 103: 5965–5970. Imamura R, Isaka Y, Ichimaru N et al. Carbamylated erythropoietin protects the kidneys from ischemia-reperfusion injury without stimulating erythropoiesis. Biochem Biophys Res Commun 2007; 353: 786–792. Eto N, Wada T, Inagi R et al. Podocyte protection by darbepoetin: preservation of the cytoskeleton and nephrin expression. Kidney Int; E-pub ahead of print. Mitra A, Bansal S, Wang W et al. Erythropoietin ameliorates renal dysfunction during endotoxaemia. Nephrol Dial Transplant 2007; 22: 2349–2353. Bahlmann FH, Kielstein JT, Haller H, Fliser D. Erythropoietin and progression of CKD. Kidney Int (this issue). Katavetin P, Tungsanga K, Eiam-Ong S, Nangaku M. Antioxidative effects of erythropoietin. Kidney Int (this issue). Aydin Z, Duijs J, Bajema IM, Van Zonneveld AJ, Rabelink TJ. Erythropoietin, progenitors, and repair. Kidney Int (this issue).
S3
Erythropoiesis-stimulating agents: Past and future M Nangaku1 and D Fliser2 1 2
Division of Nephrology and Endocrinology, Department of Internal Medicine, University of Tokyo School of Medicine, Tokyo, Japan and Division of Nephrology, Department of Internal Medicine, Hannover Medical School, Hannover, Germany
Renal anemia is a well-recognized complication of chronic kidney disease (CKD), and the deficiency of erythropoietin (EPO) is the primary cause. Observational population-based studies continue to demonstrate the association of low hemoglobin with adverse outcomes, and renal failure, cardiac failure, and anemia all may interact to cause or worsen each other, the so-called cardio-renal anemia syndrome. Treatment of anemia can be successfully achieved with the use of erythropoiesis-stimulating agents (ESAs). From a mechanistic point of view, however, the therapeutic benefits of ESA could be far beyond the correction of anemia. ESA modulates a broad array of cellular processes that include progenitor stem cell development, cellular integrity, and angiogenesis. A pleiotropic effect of EPO has been shown in the central nervous system, the cardiovascular system, and the kidney. While recent results of randomized controlled trials have established that there is little support for normalizing hemoglobin in CKD patients, the results of these studies do not negate renoprotective effects of EPO. A large number of patients with CKD will benefit from early recognition and appropriate correction of anemia with ESA. Kidney International (2007) 72, S1–S3; doi:10.1038/sj.ki.5002480 KEYWORDS: darbepoetin; erythropoietin; hypoxia; chronic kidney disease
Renal anemia is a well-recognized complication of chronic kidney disease (CKD). Although mechanisms involved in the pathogenesis of renal anemia include chronic inflammation, iron deficiency, and shortened half-life of erythrocytes, the primary cause is the deficiency of erythropoietin (EPO).1 Large observational population-based studies continue to demonstrate the association of low hemoglobin with adverse outcomes. Many morbidity conditions observed in patients with CKD are cardiovascular complications, and it is suggested that renal failure, cardiac failure, and anemia all interact to cause or worsen each other, the so-called cardiorenal anemia syndrome.2 Treatment of anemia can be successfully achieved with the use of erythropoiesis-stimulating agents (ESAs). On the basis of the epidemiological data, Iseki and Kohagura3 gave a comprehensive review on the role of anemia on CKD management. From a mechanistic point of view, however, a steadily growing body of evidence indicates that the therapeutic benefits of ESA could be far beyond the correction of anemia.4–7 ESA modulates a broad array of cellular processes that include progenitor stem cell development, cellular integrity, and angiogenesis. As a result, organ protection by EPO is remarkable in association with inhibition of apoptosis and amelioration of inflammation. An opportunity to address nonhematopoietic mechanisms of organ protection by ESA arose when the Pharmaceutical Division of Kirin Brewery and AMGEN-Europe invited us to chair a symposium focused on ESA. Their support enabled an ancillary symposium of the World Congress of Nephrology, which took place in Rio de Janeiro, 24 April 2007. Entitled ‘Erythropoiesis stimulating agents—past and future,’ it gathered together clinical scientists undertaking research at both the molecular and tissue levels. NEUROPROTECTION
Correspondence: M Nangaku, Division of Nephrology and Endocrinology, Department of Internal Medicine, University of Tokyo School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. E-mail: [email protected] Kidney International (2007) 72, S1–S3
The central nervous system is the first in which a pleiotropic effect of EPO was demonstrated.8–10 Research during the past years has clearly demonstrated that EPO is a potent promoter of neuronal survival. In vitro and in vivo studies have shown that EPO has the ability to cross the blood–brain barrier and provide neuroprotection by limiting damage to the central nervous system following injury. In vivo, the administration of recombinant EPO reduced brain injury associated with stroke, blunt trauma, cytotoxicity, and experimental autoimmune encephalomyelitis, and prevented spinal cord injury. S1
M Nangaku and D Fliser: Erythropoiesis-stimulating agents
CARDIOPROTECTION
Control of anemia can also become a valuable addition to the therapeutic armamentarium in patients with congestive heart failure. In an open uncontrolled study, Silverberg et al.11,12 investigated the effect of correcting anemia with EPO in patients suffering from congestive heart failure. The treatment caused an improvement in cardiac function and a reduction in the need for hospitalization. Furthermore, renal function was stabilized by the treatment of anemia. Long-term studies on the correction of renal anemia in patients on maintenance hemodialysis with EPO demonstrated a mitigation of oxidative stress during this therapy.13 During periods of 1 and 2 years, it was observed that the serum levels of 4-hydroxy-2-nonenal and malondialdehyde could be reduced. Amelioration of oxidative stress may have a direct positive effect on a variety of cardiovascular diseases as well as kidney diseases. RENOPROTECTION
Because chronic hypoxia in the tubulointerstitium is a final common pathway to end-stage renal disease,14 therapeutic approaches that target chronic hypoxia of renal tissue should prove effective against a broad range of kidney diseases. Correction of anemia by EPO and the subsequent improvement in oxygen delivery to the kidney should theoretically delay the progression of renal failure. Furthermore, ESA may activate various ‘surviving’ intracellular pathways in renal tissue and protect the kidney via nonhematopoietic mechanisms. This expectation was supported by several studies that suggested that progression might be delayed by an improvement in anemia by treatment with EPO. Kuriyama et al.15 were the first to raise the possibility that EPO therapy might actually delay progression of kidney disease. Tapolyai et al.16 reported that the mean slope of change in monthly reciprocal of the serum creatinine was significantly lower after correction of the hematocrit. Dean et al.17performed observational, before and after analysis using electronic medical records from the Veterans Administration. The analysis of 122 patients revealed that EPO treatment among older patients with moderate to severe kidney disease ameliorated deterioration of renal function. Gouva et al.18 recently conducted a randomized controlled trial of early versus deferred initiation of EPO in nondiabetic predialysis patients. The results clearly showed that early initiation of EPO significantly slows the progression of kidney disease. However, a major limitation to this trial was the systematic avoidance of renin–angiotensin blockers in the management of these patients. Thus, it remains to be clarified whether early treatment of renal anemia with EPO can retard progression of renal failure in otherwise optimally managed patients. While these clinical studies support a role of anemia treatment in protection of residual renal function, the recent meta-analysis of the available evidence, while continuing to support a role for correction of renal anemia on improvement of quality of life, failed to demonstrate a conclusive benefit of EPO on the progression of kidney disease.19 In S2
addition, recent results of randomized controlled trials have established that there is little support for normalizing hemoglobin in CKD patients.20–22 The results of these studies should not be misinterpreted to negate renoprotective effects of EPO, however. On the basis of the previous studies, current therapeutic targets of maintaining hemoglobin over 11 g/dl are likely appropriate, and what these studies demonstrated is that we did not get additional benefits by the normalization of hemoglobin levels in CKD patients. MECHANISMS OF ORGAN PROTECTION BY ESA
To support the notion that ESA protects organs via nonhematopoietic mechanisms, EPO analogues that maintain tissue-protective effects but are devoid of the action on erythropoiesis like carbamylated EPO have already been tested in experimental animals, revealing tissue-protective properties without any effect on hematocrit.23–25 Even at this moment, papers on renoprotection by ESA are published online before print.26,27 The three sections of this supplement address the broad issue of mechanisms of organ protection by ESA. Bahlmann et al.28 reviewed the data on the nonhematological effects of ESA in different experimental settings of acute and chronic kidney injury, and discussed pivotal intracellular pathways induced by ESA. Katavetin et al.29 focused on the antioxidative stress effects of ESA. Rabelink and colleagues30 described effects of endothelial precursor cell recruitment by ESA. These papers give us important insights that explain why the therapeutic benefits of ESA could be far more widereaching than anticipated by ameliorating of anemia and accompanying tissue hypoxia. CONCLUSION
While renal anemia deteriorates patient well-being, renal anemia is also likely to contribute to progression of kidney disease and aggravation of cardiovascular disease. ESA can protect organs via hematopoiesis-dependent and -independent manner. Recent studies have elucidated multiple molecular mechanisms of organ protection by ESA. A large number of patients with CKD will benefit from early recognition and appropriate correction of anemia with ESA. DISCLOSURE
Masaomi Nangaku has received lecture fees and grant support from Kirin Brewery Co. Ltd. Danilo Fliser has received consulting fees from Amgen (Munich, Germany), Roche (Mannheim, Germany), and Janssen Cilag/Ortho Biotech. He has also received lecture fees from Roche and Amgen and grant support from the German Research Foundation, the German Ministry for Education and Research and Janssen Cilag/Ortho Biotech (Neuss, Germany). REFERENCES 1. 2.
3.
Nangaku M, Eckdardt KU. Pathogenesis of renal anemia. Semin Nephrol 2006; 26: 261–268. Silverberg DS, Wexler D, Iaina A, Schwartz D. The interaction between heart failure and other heart diseases, renal failure, and anemia. Semin Nephrol 2006; 26: 296–306. Iseki K, Kohagura K. Anemia as a risk factor for chronic kidney disease. Kidney Int (this issue). Kidney International (2007) 72, S1–S3
M Nangaku and D Fliser: Erythropoiesis-stimulating agents
4. Fliser D, Bahlmann FH, deGroot K, Haller H. Mechanisms of disease: erythropoietin—an old hormone with a new mission? Nat Clin Pract Cardiovasc Med 2006; 3: 563–572. 5. Fliser D, Bahlmann FH, Haller H. EPO: renoprotection beyond anemia correction. Pediatr Nephrol 2006; 21: 1785–1789. 6. Brines M, Cerami A. Discovering erythropoietin’s extra-hematopoietic functions: biology and clinical promise. Kidney Int 2006; 70: 246–250. 7. Maiese K, Li F, Chong ZZ. New avenues of exploration for erythropoietin. JAMA 2005; 293: 90–95. 8. Brines ML, Ghezzi P, Keenan S et al. Erythropoietin crosses the blood–brain barrier to protect against experimental brain injury. Proc Natl Acad Sci USA 2000; 97: 10526–10531. 9. Digicaylioglu M, Lipton SA. Erythropoietin-mediated neuroprotection involves cross-talk between Jak2 and NF-kappaB signalling cascades. Nature 2001; 412: 641–647. 10. Grimm C, Wenzel A, Groszer M et al. HIF-1-induced erythropoietin in the hypoxic retina protects against light-induced retinal degeneration. Nat Med 2002; 8: 718–724. 11. Silverberg DS, Wexler D, Blum M et al. The effect of correction of anaemia in diabetics and non-diabetics with severe resistant congestive heart failure and chronic renal failure by subcutaneous erythropoietin and intravenous iron. Nephrol Dial Transplant 2003; 18: 141–146. 12. Silverberg DS, Wexler D, Blum M et al. The interaction between heart failure, renal failure and anemia—the cardio-renal anemia syndrome. Kidney Blood Press Res 2005; 28: 41–47. 13. Siems W, Carluccio F, Radenkovic S et al. Oxidative stress in renal anemia of hemodialysis patients is mitigated by epoetin treatment. Kidney Blood Press Res 2005; 28: 295–301. 14. Nangaku M. Chronic hypoxia and tubulointerstitial injury: a final common pathway to end-stage renal failure. J Am Soc Nephrol 2006; 17: 17–25. 15. Kuriyama S, Tomonari H, Yoshida H et al. Reversal of anemia by erythropoietin therapy retards the progression of chronic renal failure, especially in nondiabetic patients. Nephron 1997; 77: 176–185. 16. Tapolyai M, Kadomatsu S, Perera-Chong M. r.hu-erythropoietin (EPO) treatment of pre-ESRD patients slows the rate of progression of renal decline. BMC Nephrol 2003; 4: 3. 17. Dean BB, Dylan M, Gano Jr A et al. Erythropoiesis-stimulating protein therapy and the decline of renal function: a retrospective analysis of patients with chronic kidney disease. Curr Med Res Opin 2005; 21: 981–987.
Kidney International (2007) 72, S1–S3
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28. 29. 30.
Gouva C, Nikolopoulos P, Ioannidis JP, Siamopoulos KC. Treating anemia early in renal failure patients slows the decline of renal function: a randomized controlled trial. Kidney Int 2004; 66: 753–760. Cody J, Daly C, Campbell M et al. Recombinant human erythropoietin for chronic renal failure anaemia in pre-dialysis patients. Cochrane Database Syst Rev 2005; 3: CD003266. Drueke TB, Locatelli F, Clyne N et al. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med 2006; 355: 2071–2084. Singh SK, Szczech L, Tang KL et al. Correction of anemia with epoetin alpha in chronic kidney disease. N Engl J Med 2006; 355: 2085–2098. Ritz E, Laville M, Bilous RW et al. Target level for hemoglobin correction in patients with diabetes and CKD: primary results of the Anemia Correction in Diabetes (ACORD) Study. Am J Kidney Dis 2007; 49: 194–207. Leist M, Ghezzi P, Grasso G et al. Derivatives of erythropoietin that are tissue protective but not erythropoietic. Science 2004; 305: 239–242. Coleman TR, Westenfelder C, Togel FE et al. Cytoprotective doses of erythropoietin or carbamylated erythropoietin have markedly different procoagulant and vasoactive activities. Proc Natl Acad Sci USA 2006; 103: 5965–5970. Imamura R, Isaka Y, Ichimaru N et al. Carbamylated erythropoietin protects the kidneys from ischemia-reperfusion injury without stimulating erythropoiesis. Biochem Biophys Res Commun 2007; 353: 786–792. Eto N, Wada T, Inagi R et al. Podocyte protection by darbepoetin: preservation of the cytoskeleton and nephrin expression. Kidney Int; E-pub ahead of print. Mitra A, Bansal S, Wang W et al. Erythropoietin ameliorates renal dysfunction during endotoxaemia. Nephrol Dial Transplant 2007; 22: 2349–2353. Bahlmann FH, Kielstein JT, Haller H, Fliser D. Erythropoietin and progression of CKD. Kidney Int (this issue). Katavetin P, Tungsanga K, Eiam-Ong S, Nangaku M. Antioxidative effects of erythropoietin. Kidney Int (this issue). Aydin Z, Duijs J, Bajema IM, Van Zonneveld AJ, Rabelink TJ. Erythropoietin, progenitors, and repair. Kidney Int (this issue).
S3