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The challenge

  • Understanding anaemia of CKD

    Anaemia is a common feature of chronic kidney disease,1 and one of the hallmarks of advanced CKD.2,3

    The prevalence of anaemia increases as CKD progresses, from 42.5% at stage 3b CKD to 83.7% in people with stage 5 CKD.4

    Anaemia is known to be caused by a number of factors, including:1,6-9

    Illustration of kidneys

    Disrupted oxygen sensing in the kidney

    Illustration of red blood cells

    Reduced erythropoietin production

    Illustration of liver

    Chronic inflammation resulting in increased hepcidin levels

    Illustration of blood droplet with arrow

    Iron deficiency

    1_1_HIF mechanism_GIF_CKD

    Figure made by Astellas based on Locatelli ref 5

    Inverse relationship between Hepcidin (Hep) and available iron (Fe) and plasma Erythropoetin (EPO) concentration. With inflammation and Hep production red blood cell (RBC) production and Hb decreases.

    As CKD progresses:5
    • EPO production decreases, leading to a reduction in red blood cells and haemoglobin
    • Hepcidin levels are elevated due to inflammation and decreased renal excretion
    • Elevated hepcidin leads to a reduction in absorption, recycling and mobilisation of iron

    CKD, chronic kidney disease; EPO, erythropoietin.

    References

    • Babitt JL, Lin HY. Mechanisms of anemia in CKD. J Am Soc Nephrol. 2012;(10)23:1631-1634.
    • Del Vecchio L, Locatelli F. Roxadustat in the treatment of anaemia in chronic kidney disease. Expert Opin Investig Drugs. 2018;27(1):125-133.
    • Koury MJ, Haase VH. Anaemia in kidney disease: harnessing hypoxia responses for therapy. Nat Rev Nephrol. 2015;11:394–410.
    • Evans M, Bower H, Cockburn E et al. Contemporary management of anaemia, erythropoietin resistance and cardiovascular risk in patients with advanced chronic kidney disease: a nationwide analysis. Clin Kidney J. 2020;13(5):821-827.
    • Locatelli F, Fishbane S, Block GA, Macdougall IC. Targeting Hypoxia-Inducible Factors for the Treatment of Anemia in Chronic Kidney Disease Patients. Am J Nephrol. 2017;45:187-199.
    • Wenger RH, Hoogewijs D. Regulated oxygen sensing by protein hydroxylation in renal erythropoietin-producing cells. Am J Physiol Renal Physiol. 2010;298: F1287–F1296.
    • Fishbane S, Spinowitz B. Update on Anemia in ESRD and Earlier Stages of CKD: Core Curriculum 2018. Am J Kidney Dis. 2018;71(3):423–435.
    • Peyssonnaux C, Nizet V, Johnson RS. Role of the hypoxia inducible factors HIF in iron metabolism. Cell Cycle. 2008;7:28–32.
    • Kaplan JM, Sharma N, Dikdan S. Hypoxia-Inducible Factor and Its Role in the Management of Anemia in Chronic Kidney Disease. Int J Mol Sci. 2018;19:389.

  • Treatment challenges

    A specialist's view

    The burden of anaemia of CKD and challenges in its management

    What do patients want from their treatment?

    Management of anaemia of CKD can be sub-optimal.1-3

    Treatment of anaemia of CKD is based on iron supplements and ESAs (erythropoiesis-stimulating agents).1

    These treatments target individual factors of anaemia of CKD.

    CKD, chronic kidney disease; ESA, erythropoiesis-stimulating agent.

    References

    • Del Vecchio L, LocateIIi F. Investigational hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHI) for the treatment of anemia associated with chronic kidney disease. Expert Opin Investig Drugs. 2018;27(7):613-621.
    • Guedes M, Robinson BM, Obrador G et al. Management of Anemia in Nondialysis Chronic Kidney Disease: Current Recommendations, Real-World Practice, and Patient Perspectives. Kidney360. 2020;(1):855-62.
    • Lopes MB, Tu C, Zee J et al. A real-world longitudinal study of anemia management in non-dialysis-dependent chronic kidney disease patients: a multinational analysis of CKDopps. Nature Scientific Reports. 2021;11:1784.

  • The need for an alternative treatment option

    Limitations of current therapies have driven a search for alternative treatment options.1

    Advances in the study of CKD-associated anaemia have focused on the pathophysiology of anaemia with the hope of discovering more targeted and physiological therapies.1-4

    The discovery of hypoxia-inducible factors (HIFs) has led to the development of a class of drugs that stimulate erythropoiesis by activating the HIF pathway.1,4,5

    Discover the HIF pathway

    CKD, chronic kidney disease; HIF, hypoxia-inducible factor.

    References

    • Locatelli F, Fishbane S, Block GA, Macdougall IC. Targeting Hypoxia-Inducible Factors for the Treatment of Anemia in Chronic Kidney Disease Patients. Am J Nephrol. 2017;45:187-199.
    • Babitt JL, Lin HY. Mechanisms of anemia in CKD. J Am Soc Nephrol. 2012;(10)23:1631-1634.
    • Koury MJ, Haase VH. Anaemia in kidney disease: harnessing hypoxia responses for therapy. Nat Rev Nephrol. 2015;11:394–410.
    • Haase VH. HIF-prolyl hydroxylases as therapeutic targets in erythropoiesis and iron metabolism. Hemodial Int. 2017;21:S110–S124.
    • Del Vecchio L, LocateIIi F. Investigational hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHI) for the treatment of anemia associated with chronic kidney disease. Expert Opin Investig Drugs. 2018;27(7):613-621