Abstract
Observational studies have shown a strong positive correlation between the severity of anemia and the risk of poor outcomes in patients with chronic kidney disease (CKD). This observation was initially taken to imply that adverse outcomes in CKD are caused by anemia. However, the assumption of causality ignores the possibility that anemia and adverse outcomes might be unrelated and that both are caused by underlying inflammation, oxidative stress and comorbid conditions. Randomized clinical trials of anemia correction have revealed an increased risk of adverse cardiovascular outcomes in patients assigned to normal, rather than subnormal, hemoglobin targets. As a result, correction of anemia is now considered potentially hazardous in patients with CKD. Notably, individuals who did not reach the target hemoglobin level in the clinical trials, despite receiving high doses of erythropoietin and iron, experienced a disproportionately large share of the adverse outcomes. These observations point to overdose of erythropoietin and iron, rather than anemia correction per se, as the likely culprit. This Review explores the reasons for the apparent contradiction between the findings of observational studies and randomized clinical trials of anemia treatment in CKD. I have focused on data from basic and translational studies, which are often overlooked in the design and interpretation of clinical studies and in the formulation of clinical guidelines.
Key Points
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Contrary to common perception, the observational association of anemia with cardiovascular and all-cause mortality in patients with chronic kidney disease (CKD) does not necessarily reflect causality; rather, anemia and adverse outcomes are both caused by inflammation and oxidative stress
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In addition to their well-known erythropoietic functions, erythropoietin and iron have many other actions that are essential when these agents are at physiological levels, but they are potentially hazardous when at high levels
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The increased risk of adverse outcomes observed in patients with CKD assigned to higher hemoglobin targets in randomized clinical trials is probably a result of the extra-erythropoietic actions of erythropoietin and/or iron that result from excessive dosing, as opposed to anemia correction per se
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The range of 'safe' hemoglobin levels varies widely among patients with CKD; consequently, the blanket application of arbitrary hemoglobin targets to all patients with CKD, as called for by clinical guidelines, is impractical and potentially harmful
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References
Besarab A (2001) Anemia of renal disease. In Diseases of the Kidney and Urinary Tract, edn 7, 2719–2734 (Ed. Schrier RW) Philadelphia: Lippincott, Williams & Wilkins
Stenvinkel P (2001) The role of inflammation in the anaemia of end-stage renal disease. Nephrol Dial Transplant 16: 36–40
Locatelli F et al. (2006) Nutritional-inflammation status and resistance to erythropoietin therapy in haemodialysis patients. Nephrol Dial Transplant 21: 991–998
Attallah N et al. (2006) Effect of intravenous ascorbic acid in hemodialysis patients with EPO-hyporesponsive anemia and hyperferritinemia. Am J Kidney Dis 47: 644–654
Lin CL et al. (2003) Low dose intravenous ascorbic acid for erythropoietin-hyporesponsive anemia in diabetic hemodialysis patients with iron overload. Ren Fail 25: 445–453
Himmelfarb J et al. (2002) The elephant in uremia: oxidant stress as a unifying concept of cardiovascular disease in uremia. Kidney Int 62: 1524–1538
Himmelfarb J and Hakim RM (2003) Oxidative stress in uremia. Curr Opin Nephrol Hypertens 12: 593–598
Stenvinkel P (2006) Inflammation in end-stage renal disease: the hidden enemy. Nephrology (Carlton) 11: 36–41
Lim PS et al. (2002) Mitochondrial DNA mutations and oxidative damage in skeletal muscle of patients with chronic uremia. J Biomed Sci 9: 549–560
Vaziri ND (2004) Oxidative stress in uremia: nature, mechanisms and potential consequences. Semin Nephrol 24: 469–473
Vaziri ND (2004) Roles of oxidative stress and antioxidant therapy in chronic renal disease and hypertension. Curr Opin Nephrol Hypertens 13: 93–99
Vaziri ND et al. (2007) Intra-renal angiotensin II/AT1 receptor, oxidative stress, inflammation and progressive injury in renal mass reduction. J Pharmacol Exp Ther 323: 85–93
Yoon JW et al. (2007) Spontaneous leukocyte activation and oxygen-free radical generation in end stage renal disease. Kidney Int 71: 167–172
Vaziri ND et al. (2003) Oxidative stress and dysregulation of superoxide dismutase and NAD(P)H oxidase in renal insufficiency. Kidney Int 63: 179–185
Vaziri ND et al. (2002) Enhanced nitric oxide inactivation and protein nitration by reactive oxygen species in renal insufficiency. Hypertension 39: 135–141
Quiroz Y et al. (2008) Melatonin ameliorates oxidative stress, inflammation, proteinuria and progression of renal damage in rats with renal mass reduction. Am J Physiol Renal Physiol 294: F336–F344
Herrera J et al. (2001) Melatonin prevents oxidative stress resulting from iron and erythropoietin administration. Am J Kidney Dis 37: 750–757
Chen HC et al. (1997) Recombinant human erythropoietin enhances superoxide production by FMLP-stimulated polymorphonuclear leukocytes in hemodialysis patients. Kidney Int 52: 1390–1394
Scalera F et al. (2005) Erythropoietin increases asymmetric dimethylarginine in endothelial cells: role of dimethylarginine dimethylaminohydrolase. J Am Soc Nephrol 16: 892–898
Lim CS and Vaziri ND (2004) Iron and oxidative stress in renal insufficiency. Am J Nephrol 24: 569–575
Lim CS and Vaziri ND (2004) The effects of iron dextran on the oxidative stress in cardiovascular tissues of rats with chronic renal failure. Kidney Int 65: 1802–1809
Lim PS et al. (1999) Enhanced oxidative stress in haemodialysis patients receiving intravenous iron therapy. Nephrol Dial Transplant 14: 2680–2687
Galleano M and Puntarulo S (1995) Role of antioxidants on the erythrocytes resistance to lipid peroxidation after acute iron overload in rats. Biochim Biophys Acta 1271: 321–326
Bishu K and Agarwal R (2006) Acute injury with intravenous iron and concerns regarding long-term safety. Clin J Am Soc Nephrol 1 (Suppl 1): S19–S23
Ma JZ et al. (1999) Hematocrit level and associated mortality in hemodialysis patients. J Am Soc Nephrol 10: 610–619
Xia H et al. (1999) Hematocrit levels and hospitalization risks in hemodialysis patients. J Am Soc Nephrol 10: 1309–1316
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
Li S and Collins AJ (2004) Association of hematocrit value with cardiovascular morbidity and mortality in incident hemodialysis patients. Kidney Int 65: 626–633
Ofsthun N et al. (2003) The effects of higher hemoglobin levels on mortality and hospitalization in hemodialysis patients. Kidney Int 63: 1908–1914
Li S et al. (2004) Anemia, hospitalization, and mortality in patients receiving peritoneal dialysis in the United States. Kidney Int 65: 1864–1869
Robinson BM et al. (2005) Anemia and mortality in hemodialysis patients: accounting for morbidity and treatment variables updated over time. Kidney Int 68: 2323–2330
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
Wolfe RA et al. (2005) Improvements in dialysis patient mortality are associated with improvements in urea reduction ratio and hematocrit, 1999 to 2002. Am J Kidney Dis 45: 127–135
[No authors listed] (2001) IV. NKF-K/DOQI clinical practice guidelines for anemia of chronic kidney disease: update 2000. Am J Kidney Dis 37 (Suppl 1): S182–S238
KDOQI (2006) KDOQI clinical practice guidelines and clinical practice recommendations for anemia in chronic kidney disease. Am J Kidney Dis 47 (Suppl 3): S11–S145
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
Drueke TB et al. (2006) Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med 355: 2071–2084
Singh AK et al. (2006) Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med 355: 2085–2098
Phrommintikul A et al. (2007) Mortality and target haemoglobin concentrations in anaemic patients with chronic kidney disease treated with erythropoietin: a meta-analysis. Lancet 369: 381–388
Strippoli GF et al. (2004) Hemoglobin targets for the anemia of chronic kidney disease: a meta-analysis of randomized, controlled trials. J Am Soc Nephrol 15: 3154–3165
Volkova N and Arab L (2006) Evidence-based systematic literature review of hemoglobin/hematocrit and all-cause mortality in dialysis patients. Am J Kidney Dis 47: 24–36
Parfrey PS (2006) Target hemoglobin level for EPO therapy in CKD. Am J Kidney Dis 47: 171–173
Pisoni RL et al. (2004) Anemia management and outcomes from 12 countries in the Dialysis Outcomes and Practice Patterns Study (DOPPS). Am J Kidney Dis 44: 94–111
KDOQI (2007) KDOQI clinical practice guideline and clinical practice recommendations for anemia in chronic kidney disease: 2007 update of hemoglobin target. Am J Kidney Dis 50: 471–530
Deng G et al. (2001) Increased tyrosine nitration of the brain in chronic renal insufficiency: reversal by antioxidant therapy and angiotensin-converting enzyme inhibition. J Am Soc Nephrol 12: 1892–1899
Vaziri ND et al. (1998) Role of increased oxygen free radical activity in the pathogenesis of uremic hypertension. Kidney Int 53: 1748–1754
Sindhu RK et al. (2004) Effect of chronic renal failure on caveolin-1, guanylate cyclase and AKT protein expression. Biochim Biophys Acta 1690: 231–237
Sindhu RK and Vaziri ND (2003) Upregulation of cytochrome P450 1A2 in chronic renal failure: does oxidized tryptophan play a role? Adv Exp Med Biol 527: 401–407
Rodriguez-Iturbe B et al. (2005) Early treatment with cGMP phosphodiesterase inhibitor ameliorates progression of renal damage. Kidney Int 68: 2131–2142
Vaziri ND and Khan M (2007) Interplay of reactive oxygen species and nitric oxide in the pathogenesis of experimental lead-induced hypertension. Clin Exp Pharmacol Physiol 34: 920–925
Schiffrin EL et al. (2007) Chronic kidney disease: effects on the cardiovascular system. Circulation 116: 85–97
Hansson GK (2005) Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 352: 1685–1695
Libby P (2002) Inflammation in atherosclerosis. Nature 420: 868–874
Shah PK (2003) Mechanisms of plaque vulnerability and rupture. J Am Coll Cardiol 41 (Suppl): S15–S22
Aikawa M and Libby P (2004) The vulnerable atherosclerotic plaque: pathogenesis and therapeutic approach. Cardiovasc Pathol 13: 125–138
Vaziri ND and Rodríguez-Iturbe B (2006) Mechanisms of Disease: oxidative stress and inflammation in the pathogenesis of hypertension. Nat Clin Pract Nephrol 2: 582–593
Yoon JW et al. (2006) Naïve and central memory T cell lymphopenia in end-stage renal disease. Kidney Int 70: 371–376
Ansell BJ et al. (2007) The paradox of dysfunctional high-density lipoprotein. Curr Opin Lipidol 18: 427–434
Navab M et al. (2006) Mechanisms of Disease: proatherogenic HDL—an evolving field. Nat Clin Pract Endocrinol Metab 2: 504–511
Kalantar-Zadeh K et al. (2007) HDL-inflammatory index correlates with poor outcome in hemodialysis patients. Kidney Int 72: 1149–1156
Ganz T (2007) Molecular control of iron transport. J Am Soc Nephrol 18: 394–400
Hardee ME et al. (2006) Erythropoietin biology in cancer. Clin Cancer Res 12: 332–339
Vaziri ND (1999) Mechanism of erythropoietin-induced hypertension. Am J Kidney Dis 33: 821–828
Vaziri ND (2001) Cardiovascular effects of erythropoietin and anemia correction. Curr Opin Nephrol Hypertens 10: 633–637
Lebel M et al. (1998) Hemodynamic and hormonal changes during erythropoietin therapy in hemodialysis patients. J Am Soc Nephrol 9: 97–104
Vaziri ND et al. (1996) Role of nitric oxide resistance in erythropoietin-induced hypertension in rats with chronic renal failure. Am J Physiol Endocrinol Metab 271: E113–E122
Vaziri ND et al. (1995) In vivo and in vitro pressor effects of erythropoietin in rats. Am J Physiol 269: F838–F845
Neusser M et al. (1993) Erythropoietin increases cytosolic free calcium concentration in vascular smooth muscle cells. Cardiovasc Res 27: 1233–1236
Kaupke CJ et al. (1994) Effect of erythrocyte mass on arterial blood pressure in dialysis patients receiving maintenance erythropoietin therapy. J Am Soc Nephrol 4: 1874–1878
Takahashi K et al. (1993) Plasma concentrations of immunoreactive-endothelin in patients with chronic renal failure treated with recombinant human erythropoietin. Clin Sci 84: 47–50
Bode-Böger SM et al. (1996) Recombinant human erythropoietin enhances vasoconstrictor tone via endothelin-1 and constrictor prostanoids. Kidney Int 50: 1255–1261
Carlini RG et al. (1993) Recombinant human erythropoietin (rHuEPO) increases endothelin-1 release by endothelial cells. Kidney Int 43: 1010–1014
Carlini RG et al. (1995) Endothelin-1 release by erythropoietin involves calcium signaling in endothelial cells. J Cardiovasc Pharmacol 26: 889–892
Lebel M et al. (1998) Plasma and blood vessel endothelin-1 concentrations in hypertensive uremic rats treated with erythropoietin. Clin Exp Hypertens 20: 939–951
Katoh K et al. (1994) Direct evidence for erythropoietin-induced release of endothelin from peripheral vascular tissue. Life Sci 54: 253–259
Brochu E et al. (1999) Differential effects of endothelin-1 antagonists on erythropoietin-induced hypertension in renal failure. J Am Soc Nephrol 10: 1440–1446
Eggena P et al. (1991) Influence of recombinant human erythropoietin on blood pressure and tissue renin-angiotensin systems. Am J Physiol 261: E642–E646
Barrett JD et al. (1998) Erythropoietin upregulates angiotensin receptors in cultured rat vascular smooth muscle cells. J Hypertens 16: 1749–1757
Kuriyama S et al. (2001) Association of angiotensinogen gene polymorphism with erythropoietin-induced hypertension: a preliminary report. Hypertens Res 24: 501–505
Lebel M et al. (2006) Antihypertensive and renal protective effects of renin–angiotensin system blockade in uremic rats treated with erythropoietin. Am J Hypertens 19: 1286–1292
Rodrigue ME et al. (2003) Relationship between eicosanoids and endothelin-1 in the pathogenesis of erythropoietin-induced hypertension in uremic rats. J Cardiovasc Pharmacol 41: 388–395
Rodrigue ME et al. (2005) Cyclooxygenase inhibition with acetylsalicylic acid unmasks a role for prostacyclin in erythropoietin-induced hypertension in uremic rats. Can J Physiol Pharmacol 83: 467–475
Anagnostou A et al. (1990) Erythropoietin has a mitogenic and positive chemotactic effect on endothelial cells. Proc Natl Acad Sci U S A 87: 5978–5982
Nagai T et al. (1995) Effects of rHuEpo on cellular proliferation and endothelin-1 production in cultured endothelial cells. Nephrol Dial Transplant 10: 1814–1819
Carlini RG et al. (1999) Effect of recombinant human erythropoietin on endothelial cell apoptosis. Kidney Int 55: 546–553
Wang XQ and Vaziri ND (1999) Erythropoietin depresses nitric oxide synthase expression by human endothelial cells. Hypertension 33: 894–899
Gogusev J et al. (1994) Effect of erythropoietin on DNA synthesis, proto-oncogene expression and phospholipase C activity in rat vascular smooth muscle cells. Biochem Biophys Res Commun 199: 977–983
Ammarguellat F et al. (1996) Direct effect of erythropoietin on rat vascular smooth-muscle cell via a putative erythropoietin receptor. Nephrol Dial Transplant 11: 687–692
Akimoto T et al. (2001) Involvement of erythropoietin-induced cytosolic free calcium mobilization in activation of mitogen-activated protein kinase and DNA synthesis in vascular smooth muscle cells. J Hypertens 19: 193–202
Carlini RG et al. (1995) Recombinant human erythropoietin stimulates angiogenesis in vitro. Kidney Int 47: 740–745
Satoh K et al. (2006) Important role of endogenous erythropoietin system in recruitment of endothelial progenitor cells in hypoxia-induced pulmonary hypertension in mice. Circulation 113: 1442–1450
Yatsiv I et al. (2005) Erythropoietin is neuroprotective, improves functional recovery, and reduces neuronal apoptosis and inflammation in a rodent model of experimental closed head injury. FASEB J 19: 1701–1703
van der Meer P et al. (2004) Erythropoietin improves left ventricular function and coronary flow in an experimental model of ischemia-reperfusion injury. Eur J Heart Fail 6: 853–859
Vaziri ND et al. (1994) Erythropoietin enhances recovery from cisplatin-induced acute renal failure. Am J Physiol 266: F360–F366
Zhu X and Perazella MA (2006) Nonhematologic complications of erythropoietin therapy. Semin Dial 19: 279–284
Kase S et al. (2007) Expression of erythropoietin receptor in human epiretinal membrane of proliferative diabetic retinopathy. Br J Ophthalmol 91: 1376–1378
Nagarajan S et al. (2007) Transplant reno-vascular stenoses associated with early erythropoietin use. Clin Transplant 21: 597–608
Bittorf T et al. (2001) Activation of the transcription factor NF-kappaB by the erythropoietin receptor: structural requirements and biological significance. Cell Signal 13: 673–681
Chen HC et al. (1997) Recombinant human erythropoietin enhances superoxide production by FMLP-stimulated polymorphonuclear leukocytes in hemodialysis patients. Kidney Int 52: 1390–1394
Kaupke CJ et al. (1996) Effect of recombinant human erythropoietin on platelet production in dialysis patients. J Am Soc Nephrol 3: 1672–1679
Stohlawetz PJ et al. (2000) Effects of erythropoietin on platelet reactivity and thrombopoiesis in humans. Blood 95: 2983–2989
Zhou XJ and Vaziri ND (2002) Defective calcium signalling in uraemic platelets and its amelioration with long-term erythropoietin therapy. Nephrol Dial Transplant 17: 992–997
Kahraman S et al. (2005) Impact of rHuEPO therapy initiation on soluble adhesion molecule levels in haemodialysis patients. Nephrology (Carlton) 10: 264–269
Nagai T et al. (1996) rHuEPO enhances the production of plasminogen activator inhibitor-1 in cultured endothelial cells. Kidney Int 50: 102–107
Borawski J et al. (2002) Tissue factor and thrombomodulin in hemodialysis patients: associations with endothelial injury, liver disease, and erythropoietin therapy. Clin Appl Thromb Hemost 8: 359–367
Fusté B et al. (2002) Erythropoietin triggers a signaling pathway in endothelial cells and increases the thrombogenicity of their extracellular matrices in vitro. Thromb Haemost 88: 678–685
Wang XQ and Vaziri ND (1999) Erythropoietin depresses nitric oxide synthase expression by human endothelial cells. Hypertension 33: 894–899
Ni Z et al. (1998) Nitric oxide metabolism in erythropoietin-induced hypertension: effect of calcium channel blockade. Hypertension 32: 724–729
Zager RA et al. (2002) Parenteral iron formulations: a comparative toxicologic analysis and mechanisms of cell injury. Am J Kidney Dis 40: 90–103
Tovbin D et al. (2002) Induction of protein oxidation by intravenous iron in hemodialysis patients: role of inflammation. Am J Kidney Dis 40: 1005–1012
Carlini RG et al. (2006) Apoptotic stress pathway activation mediated by iron on endothelial cells in vitro. Nephrol Dial Transplant 21: 3055–3061
Rooyakkers TM et al. (2002) Ferric saccharate induces oxygen radical stress and endothelial dysfunction in vivo. Eur J Clin Invest 32 (Suppl 1): 9–16
Drueke T et al. (2002) Iron therapy, advanced oxidation protein products, and carotid artery intima-media thickness in end-stage renal disease. Circulation 106: 2212–2217
Zhou XJ et al. (2000) Association of renal injury with increased oxygen free radical activity and altered nitric oxide metabolism in chronic experimental hemosiderosis. Lab Invest 80: 1905–1914
Agarwal R et al. (2004) Oxidative stress and renal injury with intravenous iron in patients with chronic kidney disease. Kidney Int 65: 2279–2289
Patruta SI and Hörl WH (1999) Iron and infection. Kidney Int Suppl 69: S125–S130
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Vaziri, N. Anemia and anemia correction: surrogate markers or causes of morbidity in chronic kidney disease?. Nat Rev Nephrol 4, 436–445 (2008). https://doi.org/10.1038/ncpneph0847
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DOI: https://doi.org/10.1038/ncpneph0847
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