Anaemia of Chronic Kidney Disease: What We Know Now

Main Article Content

Anoushka R. Krishnan
Debbie Trinder
Anita C. G. Chua
Aron Chakera
Grant A. Ramm
John K. Olynyk


anaemia, chronic kidney disease, iron metabolism, hepcidin, inflammation, erythropoietin-stimulating agents


Our understanding of the pathophysiology of the anaemia of chronic kidney disease (CKD) has improved considerably in the last decade with the discovery of the iron regulatory peptide hepcidin. Reduced clearance of hepcidin and the presence of achronic inflammatory state contribute to elevated hepcidin levels in kidney disease. The recent discovery of the various factors and signalling pathways regulating hepcidin has opened up an exciting avenue for research into the development of newer agents that could treat anaemia of CKD. This review highlights our current understanding of iron metabolism in health, the regulators of hepcidin, issues associated with the current available therapies for the treatment of anaemia in CKD and potential novel therapies that could be available in the near future targeting the various factors that regulate hepcidin.

Abstract 2641 | PDF Downloads 618 HTML Downloads 3222 XML Downloads 117


1. Xia H, Ebben J, Ma JZ, Collins AJ. Hematocrit levels and hospitalization risks in hemodialysis patients. J Am Soc Nephrol. 1999;10(6):1309–16.
2. Ma JZ, Ebben J, Xia H, Collins AJ. Hematocrit level and associated mortality in hemodialysis patients. J Am Soc Nephrol. 1999;10(3):610–19.
3. Nemeth E, Tuttle MS, Powelson J, Vaughn MB, Donovan A, Ward DM, et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science. 2004;306(5704):2090–3.
4. Olynyk JK, Trinder D, Ramm GA, Britton RS, Bacon BR. Hereditary hemochromatosis in the post-HFE era. Hepatology. 2008;48(3):991–1001.
5. Graham RM, Chua AC, Herbison CE, Olynyk JK, Trinder D. Liver iron transport. World J Gastroenterol. 2007;13(35):4725–36.
6. Chua AC, Graham RM, Trinder D, Olynyk JK. The regulation of cellular iron metabolism. Crit Rev Clin Lab Sci. 2007;44(5–6):413–59.
7. Beutler E, Hoffbrand AV, Cook JD. Iron deficiency and overload. Hematology Am Soc Hematol Educ Program. 2003:40–61.
8. Brittenham GM, Griffith PM, Nienhuis AW, McLaren CE, Young NS, Tucker EE, et al. Efficacy of deferoxamine in preventing complications of iron overload in patients with thalassemia major. N Engl J Med. 1994;331(9):567–73.
9. Park CH, Valore EV, Waring AJ, Ganz T. Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J Biol Chem. 2001;276(11):7806–10.
10. Ramey G, Deschemin JC, Durel B, Canonne-Hergaux F, Nicolas G, Vaulont S. Hepcidin targets ferroportin for degradation in hepatocytes. Haematologica. 2010;95(3):501–4.
11. Sow FB, Florence WC, Satoskar AR, Schlesinger LS, Zwilling BS, Lafuse WP. Expression and localization of hepcidin in macrophages: A role in host defense against tuberculosis. J Leukoc Biol. 2007;82(4):934–45.
12. De Domenico I, Zhang TY, Koening CL, Branch RW, London N, LO E, et al. Hepcidin mediates transcriptional changes that modulate acute cytokine-induced inflammatory responses in mice. J Clin Invest. 2010;120(7):2395–405.
13. Core AB, Canali S, Babitt JL. Hemojuvelin and bone morphogenetic protein (BMP) signaling in iron homeostasis. Front Pharmacol. 2014;5:104.
14. Ramos E, Kautz L, Rodriguez R, Hansen M, Gabayan V, Ginzburg Y, et al. Evidence for distinct pathways of hepcidin regulation by acute and chronic iron loading in mice. Hepatology. 2011;53(4):1333–41.
15. Corradini E, Meynard D, Wu Q, Chen S, Ventura P, Pietrangelo A, et al. Serum and liver iron differently regulate the bone morphogenetic protein 6 (BMP6)-SMAD signaling pathway in mice. Hepatology. 2011;54(1):273–84.
16. Bridle KR, Frazer DM, Wilkins SJ, Dixon JL, Purdie DM, Crawford DH, et al. Disrupted hepcidin regulation in HFE-associated haemochromatosis and the liver as a regulator of body iron homoeostasis. Lancet. 2003;361(9358):669–73.
17. Nemeth E, Roetto A, Garozzo G, Ganz T, Camaschella C. Hepcidin is decreased in TFR2 hemochromatosis. Blood. 2005;105(4):1803–6.
18. Nicolas G, Chauvet C, Viatte L, Danan JL, Bigard X, Devaux I, et al. The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation. J Clin Invest. 2002;110(7):1037–44.
19. Nemeth E, Rivera S, Gabayan V, Keller V, Taudorf S, Pedersen BK, et al. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J Clin Invest. 2004;113(9):1271–6.
20. Besson-Fournier C, Latour C, Kautz L, Bertrand J, Ganz T, Roth MP, et al. Induction of activin B by inflammatory stimuli up-regulates expression of the iron-regulatory peptide hepcidin through Smad1/5/8 signaling. Blood. 2012;120(2):431–9.
21. Semenza GL. HIF-1: Mediator of physiological and pathophysiological responses to hypoxia. J Appl Physiol (1985). 2000;88(4):1474–80.
22. Greijer AE, van der Groep P, Kemming D, Shvarts A, Semenza D, Meijer GA, et al. Up-regulation of gene expression by hypoxia is mediated predominantly by hypoxia-inducible factor 1 (HIF-1). J Pathol. 2005;206(3):291–304.
23. Fan C, Iacobas DA, Zhou D, Chen Q, Lai JK, Gavrialov O, et al. Gene expression and phenotypic characterization of mouse heart after chronic constant or intermittent hypoxia. Physiol Genomics. 2005;22(3):292–307.
24. Liu Q, Davidoff O, Niss K, Haase VH. Hypoxia-inducible factor regulates hepcidin via erythropoietin-induced erythropoiesis. J Clin Invest. 2012;122(12):4635–44.
25. Piperno A, Galimberti S, Mariani R, Pelucchi S, Ravasi G, Lombardi C, et al. Modulation of hepcidin production during hypoxia-induced erythropoiesis in humans in vivo: Data from the HIGHCARE project. Blood. 2011;117(10):2953–9.
26. Kautz L, Jung G, Valore EV, Rivella S, Nemeth E, Ganz T. Identification of erythroferrone as an erythroid regulator of iron metabolism. Nat Genet. 2014;46(7):678–84.
27. Kautz L, Nemeth E. Molecular liaisons between erythropoiesis and iron metabolism. Blood. 2014;124(4):479–82.
28. Shoji S, Inaba M, Tomosugi N, Okuno S, Ichii M, Yamakawa T, et al. Greater potency of darbepoetin-alpha than erythropoietin in suppression of serum hepcidin-25 and utilization of iron for erythropoiesis in hemodialysis patients. Eur J Haematol. 2013;90(3):237–44.
29. Onuma S, Honda H, Kobayashi Y, Yamamoto T, Michihata T, Shibagaki K, et al. Effects of long-term erythropoiesis-stimulating agents on iron metabolism in patients on hemodialysis. Ther Apher Dial. 2015;19(6):582–9.
30. Honda H, Kobayashi Y, Onuma S, Shibagaki K, Yuza T, Hirao K, et al. Associations among erythroferrone and biomarkers of erythropoiesis and iron metabolism, and treatment with long-term erythropoiesis-stimulating agents in patients on hemodialysis. PLoS One. 2016;11(3):e0151601.
31. McClellan WM, Flanders WD, Langston RD, Jurkovitz C, Presley R. Anemia and renal insufficiency are independent risk factors for death among patients with congestive heart failure admitted to community hospitals: A population-based study. J Am Soc Nephrol. 2002;13(7):1928–36.
32. Astor BC, Arnett DK, Brown A, Coresh J. Association of kidney function and hemoglobin with left ventricular morphology among African Americans: The Atherosclerosis Risk in Communities (ARIC) study. Am J Kidney Dis. 2004;43(5):836–45.
33. Panwar B, Gutierrez OM. Disorders of iron metabolism and anemia in chronic kidney disease. Semin Nephrol. 2016;36(4):252–61.
34. Young B, Zaritsky J. Hepcidin for clinicians. Clin J Am Soc Nephrol. 2009;4(8):1384–7.
35. Kuragano T, Shimonaka Y, Kida A, Furuta M, Nanami M, Otaki Y, et al. Determinants of hepcidin in patients on maintenance hemodialysis: Role of inflammation. Am J Nephrol. 2010;31(6):534–40.
36. Zaritsky J, Young B, Wang HJ, Westerman M, Olbina G, Nemeth E, et al. Hepcidin – A potential novel biomarker for iron status in chronic kidney disease. Clin J Am Soc Nephrol. 2009;4(6):1051–6.
37. Ashby DR, Gale DP, Busbridge M, Murphy KG, Duncan ND, Cairns TD, et al. Plasma hepcidin levels are elevated but responsive to erythropoietin therapy in renal disease. Kidney Int. 2009;75(9):976–81.
38. Weiss G, Theurl I, Eder S, Koppelstaetter C, Kurz K, Sonnweber T, et al. Serum hepcidin concentration in chronic haemodialysis patients: Associations and effects of dialysis, iron and erythropoietin therapy. Eur J Clin Invest. 2009;39(10):883–90.
39. Milward EA, Trinder D, Wilcox CE, Britton RS, Ramm GA, Olynyk JK. Is HFE involved in increased hepcidin expression and hypoferremia in inflammation and anemia of chronic disease? Hepatology. 2005;41(4):936–8.
40. Eleftheriadis T, Liakopoulos V, Antoniadi G, Kartsios C, Stefanidis I. The role of hepcidin in iron homeostasis and anemia in hemodialysis patients. Semin Dial. 2009;22(1):70–7.
41. Pecoits-Filho R, Lindholm B, Axelsson J, Stenvinkel P. Update on interleukin-6 and its role in chronic renal failure. Nephrol Dial Transplant. 2003;18(6):1042–5.
42. Ganz T, Olbina G, Girelli D, Nemeth E, Westerman M. Immunoassay for human serum hepcidin. Blood. 2008;112(10):4292–7.
43. Babitt JL, Lin HY. Molecular mechanisms of hepcidin regulation: Implications for the anemia of CKD. Am J Kidney Dis. 2010;55(4):726–41.
44. Vos FE, Schollum JB, Coulter CV, Doyle TC, Duffull SB, Walker RJ. Red blood cell survival in long-term dialysis patients. Am J Kidney Dis. 2011;58(4):591–8.
45. Eschbach JW Jr., Funk D, Adamson J, Kuhn I, Scribner BH, Finch CA. Erythropoiesis in patients with renal failure undergoing chronic dialysis. N Engl J Med. 1967;276(12):653–8.
46. Alon DB, Chaimovitz C, Dvilansky A, Lugassy G, Douvdevani A, Shany S, et al. Novel role of 1,25(OH)(2)D(3) in induction of erythroid progenitor cell proliferation. Exp Hematol. 2002;30(5):403–9.
47. Bacchetta J, Zaritsky JJ, Sea JL, Chun RF, Lisse TS, Zavala K, et al. Suppression of iron-regulatory hepcidin by vitamin D. J Am Soc Nephrol. 2014;25(3):564–72.
48. Sazawal S, Black RE, Ramsan M, Chwaya HM, Stoltzfus RJ, Dutta A, et al. Effects of routine prophylactic supplementation with iron and folic acid on admission to hospital and mortality in preschool children in a high malaria transmission setting: Community-based, randomised, placebo-controlled trial. Lancet. 2006;367(9505):133–43.
49. Boelaert JR, Vandecasteele SJ, Appelberg R, Gordeuk VR. The effect of the host’s iron status on tuberculosis. J Infect Dis. 2007;195(12):1745–53.
50. McDermid JM, Jaye A, Schim van der Loeff MF, Todd J, Bates C, Austin S, et al. Elevated iron status strongly predicts mortality in West African adults with HIV infection. J Acquir Immune Defic Syndr. 2007;46(4):498–507.
51. Litton E, Baker S, Erber W, French C, Ferrier J, Hawkins D, et al. The IRONMAN trial: A protocol for a multicentre randomised placebo-controlled trial of intravenous iron in intensive care unit patients with anaemia. Crit Care Resusc. 2014;16(4):285–90.
52. Barany P, Eriksson LC, Hultcrantz R, Pettersson E, Bergstrom J. Serum ferritin and tissue iron in anemic dialysis patients. Miner Electrolyte Metab. 1997;23(3–6):273–6.
53. Hentze MW, Muckenthaler MU, Andrews NC. Balancing acts: Molecular control of mammalian iron metabolism. Cell. 2004;117(3):285–97.
54. Saeed O, Otsuka F, Polavarapu R, Karmali V, Weiss D, Davis T, et al. Pharmacological suppression of hepcidin increases macrophage cholesterol efflux and reduces foam cell formation and atherosclerosis. Arterioscler Thromb Vasc Biol. 2012;32(2):299–307.
55. Wilson JG. Iron and glucose homeostasis: New lessons from hereditary haemochromatosis. Diabetologia. 2006;49(7):1459–61.
56. Drueke T, Witko-Sarsat V, Massy Z, Descamps-Latscha Z, Guerin AP, Marchais SJ, et al. Iron therapy, advanced oxidation protein products, and carotid artery intima-media thickness in end-stage renal disease. Circulation. 2002;106(17):2212–17.
57. van der Weerd NC, Grooteman MP, Bots ML, van den Dorpel MA, den Hoedt CH, Mazairac AH, et al. Hepcidin-25 is related to cardiovascular events in chronic haemodialysis patients. Nephrol Dial Transplant. 2013;28(12):3062–71.
58. Stadler N, Lindner RA, Davies MJ. Direct detection and quantification of transition metal ions in human atherosclerotic plaques: Evidence for the presence of elevated levels of iron and copper. Arterioscler Thromb Vasc Biol. 2004;24(5):949–54.
59. Finn AV, Nakano M, Polavarapu R, Karmal V, Saeed O, Zhao X, et al. Hemoglobin directs macrophage differentiation and prevents foam cell formation in human atherosclerotic plaques. J Am Coll Cardiol. 2012;59(2):166–77.
60. Del Vecchio L, Longhi S, Locatelli F. Safety concerns about intravenous iron therapy in patients with chronic kidney disease. Clin Kidney J. 2016;9(2):260–7.
61. Besarab A, Bolton WK, Browne JK, Egrie JC, Nissenson AR, Okamoto DM, et al. 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. 1998;339(9):584–90.
62. Besarab A, Goodkin DA, Nissenson AR, Normal Hematocrit Cardiac Trial Authors. The normal hematocrit study – Follow-up. N Engl J Med. 2008;358(4):433–4.
63. Levin NW, Lazarus JM, Nissenson AR. National cooperative rHu erythropoietin study in patients with chronic renal failure – An interim report. The national cooperative rHu erythropoietin study group. Am J Kidney Dis. 1993;22(2 Suppl 1):3–12.
64. Parfrey PS, Lauve M, Latremouille-Viau D, Lefebvre P. Erythropoietin therapy and left ventricular mass index in CKD and ESRD patients: A meta-analysis. Clin J Am Soc Nephrol. 2009;4(4):755–62.
65. Drueke TB, Locatelli F, Clyne N, Eckardt KU, Macdougall IC, Tsakiris D, et al. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med. 2006;355(20):2071–84.
66. Singh AK, Szczech L, Tang KL, Barnhart H, Sapp S, Wolfson M, et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med. 2006;355(20):2085–98.
67. Pfeffer MA, Burdmann EA, Chen CY, Cooper ME, de Zeeuw D, Eckardt KU, et al. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med. 2009;361(21):2019–32.
68. Winkelmayer WC. Against TREATing all patients alike: Lessons from an FDA advisory committee meeting. J Am Soc Nephrol. 2011;22(1):1–2.
69. Liu Y, Xu Y, Thilo F, Friis UG, Jensen BL, Scholze A, et al. Erythropoietin increases expression and function of transient receptor potential canonical 5 channels. Hypertension. 2011;58(2):317–24.
70. Janmaat ML, Heerkens JL, de Bruin AM, Klous A, de Waard V, de Vries CJ. Erythropoietin accelerates smooth muscle cell-rich vascular lesion formation in mice through endothelial cell activation involving enhanced PDGF-BB release. Blood. 2010;115(7):1453–60.
71. Hedley BD, Allan AL, Xenocostas A. The role of erythropoietin and erythropoiesis-stimulating agents in tumor progression. Clin Cancer Res. 2011;17(20):6373–80.
72. Hung SC, Lin YP, Tarng DC. Erythropoiesis-stimulating agents in chronic kidney disease: What have we learned in 25 years? J Formos Med Assoc. 2014;113(1):3–10.
73. Freitas JP, Filipe PM. Pentoxifylline. A hydroxyl radical scavenger. Biol Trace Elem Res. 1995;47(1–3):307–11.
74. Bienvenu J, Doche C, Gutowski MC, Lenoble M, Lepape A, Perdrix JP. Production of proinflammatory cytokines and cytokines involved in the TH1/TH2 balance is modulated by pentoxifylline. J Cardiovasc Pharmacol. 1995;25(Suppl 2): S80–4.
75. Benbernou N, Esnault S, Potron G, Guenounou M. Regulatory effects of pentoxifylline on T-helper cell-derived cytokine production in human blood cells. J Cardiovasc Pharmacol. 1995;25(Suppl 2): S75–9.
76. Johnson DW, Pascoe EM, Badve SV, Dalziel K, Cass A, Clarke P, et al. A randomized, placebo-controlled trial of pentoxifylline on erythropoiesis-stimulating agent hyporesponsiveness in anemic patients with CKD: The Handling Erythropoietin Resistance with Oxpentifylline (HERO) trial. Am J Kidney Dis. 2015;65(1):49–57.
77. Gummer J, Trengove R, Pascoe EM, Badve SV, Cass A, Clarke P, et al. Association between serum hepcidin-25 and primary resistance to erythropoiesis stimulating agents in chronic kidney disease: A secondary analysis of the HERO trial. Nephrology (Carlton). 2016. [Epub ahead of print].
78. Ferrari P, Mallon D, Trinder D, Olynyk JK. Pentoxifylline improves haemoglobin and interleukin-6 levels in chronic kidney disease. Nephrology (Carlton). 2010;15(3):344–9.
79. Bolignano D, D’Arrigo G, Pisano A, Coppolino G. Pentoxifylline for anemia in chronic kidney disease: A systematic review and meta-analysis. PLoS One. 2015;10(8):e0134104.
80. Besarab A, Chernyavskaya E, Motylev I, Shutov E, Kumbar LM, Gurevich K, et al. Roxadustat (FG-4592): Correction of anemia in incident dialysis patients. J Am Soc Nephrol. 2016;27(4):1225–33.
81. Pergola PE, Spinowitz BS, Hartman CS, Maroni BJ, Haase VH. Vadadustat, a novel oral HIF stabilizer, provides effective anemia treatment in nondialysis-dependent chronic kidney disease. Kidney Int. 2016;90(5):1115–22.
82. Flamme I, Oehme F, Ellinghaus P, Jeske M, Keldenich J, Thuss U. Mimicking hypoxia to treat anemia: HIF-stabilizer BAY 85-3934 (Molidustat) stimulates erythropoietin production without hypertensive effects. PLoS One. 2014;9(11):e111838.
83. Holdstock L, Meadowcroft AM, Maier R, Johnson BM, Jones D, Rastogi A, et al. Four-week studies of oral hypoxia-inducible factor-prolyl hydroxylase inhibitor GSK1278863 for treatment of anemia. J Am Soc Nephrol. 2016;27(4):1234–44.
84. Maxwell PH, Eckardt KU. HIF prolyl hydroxylase inhibitors for the treatment of renal anaemia and beyond. Nat Rev Nephrol. 2016;12(3):157–68.
85. Krock BL, Skuli N, Simon MC. Hypoxia-induced angiogenesis: Good and evil. Genes Cancer. 2011;2(12):1117–33.
86. Kapitsinou PP, Rajendran G, Astleford L, Michael M, Schonfeld MP, Fields T, et al. The endothelial prolyl-4-hydroxylase domain 2/hypoxia-inducible factor 2 axis regulates pulmonary artery pressure in mice. Mol Cell Biol. 2016;36(10):1584–94.
87. Semenza GL. Oxygen sensing, hypoxia-inducible factors, and disease pathophysiology. Annu Rev Pathol. 2014;9:47–71.
88. Cooke KS, Hinkle B, Salimi-Moosavi H, Foltz I, King C, Rathanaswami P, et al. A fully human anti-hepcidin antibody modulates iron metabolism in both mice and nonhuman primates. Blood. 2013;122(17):3054–61.
89. Badve SV, Palmer SC, Strippoli GF, Roberts MA, Teixeira- Pinto A, Boudville N, et al. The validity of left ventricular mass as a surrogate end point for all-cause and cardiovascular mortality outcomes in people with CKD: A systematic review and meta-analysis. Am J Kidney Dis. 2016;68(4):554–63.
90. Carvalho C, Isakova T, Collerone G, Olbina G, Wolf M, Westerman M, et al. Hepcidin and disordered mineral metabolism in chronic kidney disease. Clin Nephrol. 2011;76(2):90–8.
91. Icardi A, Paoletti E, De Nicola L, Mazzaferro S, Russo R, Cozzolino M. Renal anaemia and EPO hyporesponsiveness associated with vitamin D deficiency: The potential role of inflammation. Nephrol Dial Transplant. 2013;28(7):1672–9.
92. Zughaier SM, Alvarez JA, Sloan JH, Konrad RJ, Tangpricha V. The role of vitamin D in regulating the iron-hepcidin-ferroportin axis in monocytes. J Clin Transl Endocrinol. 2014;1(1):19–25.

Most read articles by the same author(s)