Narrative Review
New Treatment Approaches for the Anemia of CKD

https://doi.org/10.1053/j.ajkd.2015.06.030Get rights and content

Normocytic normochromic anemia is a common complication in chronic kidney disease and is associated with many adverse clinical consequences. Erythropoiesis-stimulating agents (ESAs) and adjuvant iron therapy represent the primary treatment for anemia in chronic kidney disease. The introduction of ESAs into clinical practice was a success story, mediating an increase in hemoglobin concentrations without the risk for recurrent blood transfusions and improving quality of life substantially. However, recombinant ESAs are still expensive and require a parenteral route of administration. Moreover, concern has arisen following randomized clinical trials showing that higher hemoglobin targets and/or high ESA doses may cause significant harm. This, together with changes in ESA reimbursement policy in some countries, has resulted in a significant reduction in ESA prescribing and the hemoglobin level targeted during therapy. Several attempts are being made to develop new drugs with improved characteristics and/or easier manufacturing processes compared with currently available ESAs, including new treatment approaches that may indirectly improve erythropoiesis. We give an update on the new investigational strategies for increasing erythropoiesis, examining in depth their characteristics and possible advantages in the clinical setting and the caveats to be aware of at the present stage of development.

Section snippets

Hypoxia-Inducible Factor Stabilizers

Hypoxia-inducible factors (HIFs) coordinate the physiologic response to systemic hypoxia by altering gene expression in certain cell types, leading to an increase in EPO production in the kidney and liver, improved uptake and use of iron, and changes to the bone marrow microenvironment that encourage erythroid progenitor maturation and proliferation.26

HIFs are heterodimers consisting of an oxygen-sensitive α subunit and a constitutively expressed β subunit. There are 3 HIF α subunits in

EPO Mimetic Peptides

EPO mimetic peptides (EMPs) are a group of synthetic cyclic peptides capable of stimulating the EPO receptor though their amino acid sequence is completely different from the hormone.85, 86 EMP-1, an oligopeptide containing 20 amino acids joined by a disulfide bridge between 2 cysteine residues, was synthesized in 1998.87 However, its short in vivo half-life and relatively weak binding to the EPO receptor hampered its clinical use.

In order to increase effectiveness, peptide dimers that use

Conclusions

The development of new strategies to treat anemia is still an evolving and fascinating area of experimental and clinical research. At present, the most promising class of agents seems to be HIF stabilizers, as evident in the number of molecules currently under development. This class of drug stimulates erythropoiesis by physiologic concentrations of endogenous EPO, which may translate into a clinical advantage because concerns for ESA safety are higher at the high doses. However, these

Acknowledgements

Support: None.

Financial Disclosure: Dr Del Vecchio has served on the advisory board of Astellas. Dr Locatelli has served on the advisory boards of Akebia, Amgen, Astellas, Fibrogen, Genzyme, GSK, Fresenius Medical Care, Janssen Cilag, Pharmacosmos, Keryx, and ZS Pharma and has been a speaker at a meeting supported by Amgen, Asahi Casei, Roche, and ZS Pharma. The remaining authors declare that they have no relevant financial interests.

References (103)

  • S. Elliott et al.

    Activation of the erythropoietin (EPO) receptor by bivalent anti-EPO receptor antibodies

    J Biol Chem

    (1996)
  • V.H. Haase

    Regulation of erythropoiesis by hypoxia-inducible factors

    Blood Rev

    (2013)
  • G.L. Semenza

    Hypoxia-inducible factors in physiology and medicine

    Cell

    (2012)
  • P.P. Kapitsinou et al.

    Hepatic HIF-2 regulates erythropoietic responses to hypoxia in renal anemia

    Blood

    (2010)
  • M. Scortegagna et al.

    HIF-2alpha regulates murine hematopoietic development in an erythropoietin-dependent manner

    Blood

    (2005)
  • A.J. Majmundar et al.

    Hypoxia-inducible factors and the response to hypoxic stress

    Mol Cell

    (2010)
  • A. Priyadarshi et al.

    Effects of reduction of renal mass on renal oxygen tension and erythropoietin production in the rat

    Kidney Int

    (2002)
  • J. Krishnan et al.

    Activation of a HIF1alpha-PPARgamma axis underlies the integration of glycolytic and lipid anabolic pathways in pathologic cardiac hypertrophy

    Cell Metab

    (2009)
  • S.F. Rimoldi et al.

    Systemic vascular dysfunction in patients with chronic mountain sickness

    Chest

    (2012)
  • V. Maguer-Satta et al.

    Regulation of human erythropoiesis by activin A, BMP2, and BMP4, members of the TGFbeta family

    Exp Cell Res

    (2003)
  • Y. Zermati et al.

    Transforming growth factor inhibits erythropoiesis by blocking proliferation and accelerating differentiation of erythroid progenitors

    Exp Hematol

    (2000)
  • J. Yu et al.

    Characterization of the potentiation effect of activin on human erythroid colony formation in vitro

    Blood

    (1989)
  • l Shao et al.

    Effect of activin A on globin gene expression in purified human erythroid progenitors

    Blood

    (1992)
  • C. Besson-Fournier 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)
  • K.E. Finberg et al.

    Down-regulation of Bmp/Smad signaling by Tmprss6 is required for maintenance of systemic iron homeostasis

    Blood

    (2010)
  • J. Truksa et al.

    Two BMP responsive elements, STAT, and bZIP/HNF4/COUP motifs of the hepcidin promoter are critical for BMP, SMAD1, and HJV responsiveness

    Blood

    (2009)
  • S. Lotinun et al.

    A soluble activin receptor type IIA fusion protein (ACE-011) increases bone mass via a dual anabolic-antiresorptive effect in Cynomolgus monkeys

    Bone

    (2010)
  • M.B. Leonard

    A structural approach to skeletal fragility in chronic kidney disease

    Semin Nephrol

    (2009)
  • C. Huang

    Receptor-Fc fusion therapeutics, traps, and MIMETIBODY technology

    Curr Opin Biotechnol

    (2009)
  • J. Schuurman et al.

    The inter-heavy chain disulfide bonds of IgG4 are in equilibrium with intra-chain disulfide bonds

    Mol Immunol

    (2001)
  • A.T. Kausz et al.

    The care of patients with chronic kidney disease

    J Gen Intern Med

    (2002)
  • W. Jelkmann

    The ESA scenario gets complex: from biosimilar epoetins to activin traps

    Nephrol Dial Transplant

    (2015)
  • A.K. Singh et al.

    Correction of anemia with epoetin alfa in chronic kidney disease

    N Engl J Med

    (2006)
  • T.B. Drüeke et al.

    Normalization of hemoglobin level in patients with chronic kidney disease and anemia

    N Engl J Med

    (2006)
  • M.A. Pfeffer et al.

    A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease

    N Engl J Med

    (2009)
  • KDIGO clinical practice guideline for anemia in chronic kidney disease

    Kidney Int Suppl

    (2012)
  • F. Locatelli et al.

    Kidney Disease: Improving Global Outcomes guidelines on anaemia management in chronic kidney disease: a European Renal Best Practice position statement

    Nephrol Dial Transplant

    (2013)
  • P.J. Bugelski et al.

    Differential effects of long-lived erythropoietin receptor agonists in rats

    Pharm Anal Acta

    (2011)
  • A. Greindl et al.

    AGEM400(HES), a novel erythropoietin mimetic peptide conjugated to hydroxyethyl starch with excellent in vitro efficacy

    Open Hematol J

    (2010)
  • F.A. Fares et al.

    Development of a long-acting erythropoietin by fusing the carboxyl-terminal peptide of human chorionic gonadotropin beta-subunit to the coding sequence of human erythropoietin

    Endocrinology

    (2007)
  • F. Fares et al.

    Designing a long acting erythropoietin by fusing three carboxyl-terminal peptides of human chorionic gonadotropin β subunit to the n-terminal coding sequence

    Int J Cell Biol

    (2011)
  • C.A. Penno et al.

    Production of recombinant human erythropoietin/Fc fusion protein by genetically manipulated chickens

    Transgenic Res

    (2010)
  • S.E. Lacy et al.

    The potency of erythropoietin-mimic antibodies correlates inversely with affinity

    J Immunol

    (2008)
  • N. Suzuki et al.

    In vivo regulation of erythropoiesis by chemically inducible dimerization of the erythropoietin receptor intracellular domain

    PLoS One

    (2015)
  • M. Mastrogiannaki et al.

    HIF-2alpha, but not HIF-1alpha, promotes iron absorption in mice

    J Clin Invest

    (2009)
  • M.H. Rabinowitz

    Inhibition of hypoxia-inducible factor prolyl hydroxylase domain oxygen sensors: tricking the body into mounting orchestrated survival and repair responses

    J Med Chem

    (2013)
  • A. Kato et al.

    Erythropoietin production in patients with chronic renal failure

    Ren Fail

    (1994)
  • S. Shimizu et al.

    Erythropoietin response to acute hypobaric or anaemic hypoxia in gentamicin-administered rats

    Acta Physiol Scand

    (1994)
  • E.F. Unger et al.

    Erythropoiesis stimulating agents—time for a reevaluation

    N Engl J Med

    (2010)
  • A. Besarab et al.

    FG-4592, an oral hypoxia-inducible factor propyl hydroxylase inhibitor, corrects anemia without iron supplementation in incident dialysis patients

    J Am Soc Nephrol

    (2012)
  • Cited by (80)

    View all citing articles on Scopus
    View full text