Anemia of chronic kidney disease: novel physiological approaches to therapy based on simulation of hypoxic response

Cover Page

Cite item

Abstract

Anemia is a modifiable risk factor for the progression of chronic kidney disease (CKD) and is characterized by a  decrease in the hemoglobin level, the hematocrit, and the number of circulating red blood cells. In the pre-erythropoietin era blood transfusion was a  common practice for the adequate correction of anemia in patients with CKD. However, a  recombinant human erythropoietin, that was developed and implemented into a clinical practice three decades ago, made a revolution in the renal anemia treatment. Today the management of anemia is based on the use of exogenous erythropoiesis-stimulating agents, such as erythropoietin and its analogues, as well as an oral or parenteral administration of iron. Nevertheless, despite of the high efficacy in the majority of patients this approach has a  negative side. The hemoglobin excursions, increased risk of cardiovascular complications, as well as the development of iron deficiency and chronic inflammation become additional factors in the pathogenesis of anemia associated with the renal failure. In this regard, the development of effective and safe methods of anemia management in CKD is of immediate interest. New medications based mainly on physiological approach are developed. A pharmacological activation of hypoxia-inducible factor (HIF) response is one of them. HIF is the main hormonal regulator of erythropoiesis that stimulates the production of endogenous erythropoietin. It is known that in patients with renal failure, the activation of this factor in response to hypoxia is compromised, resulting in a lack of erythropoietin production. This review covers the new mechanistic views on the hypoxic regulation of erythropoiesis and the production of erythropoietin by the kidneys, and presents the newly discovered interactions between the synthesis of erythropoietin, iron metabolism, and the chronic inflammation. Besides that, ongoing clinical trials of pharmacological HIF activators, such as FG-4592, GSK1278863, AKB-6548, BAY85-3934 are also discussed as a  new comprehensive and physiological approach for the treatment of anemia associated with CKD. Preliminary results of the clinical trials demonstrated a high efficiency of HIF activators in the treatment of renal anemia including a high tolerability, an increase in hemoglobin level and its maintenance in the target range, an increase in general capacity for iron binding and a reduction in the serum levels of both ferritin and hepcidin. However, there are some safety-related problems that include proangiogenic and adverse cardiovascular and metabolic complications, so the possibility of their development should be thoroughly studied in long-term clinical trials. 

About the authors

K. A. Aitbaev

Scientific and Research Institute of Molecular Biology and Medicine

Email: fake@neicon.ru

MD, Professor

3 Togolok Moldo str., Bishkek, 720040

Kyrgyzstan

I. T. Murkamilov

Kyrgyz State Medical Academy named after I.K. Akhunbaev

Author for correspondence.
Email: murkamilov.i@mail.ru

PhD, Nephrologist, Assistant, Chair of Faculty Therapy named after M.E. Volsky – M.M. Mirrahimova

Tel.: 0312 620991, 0557 221983

92 Akhunbaev str., Bishkek, 720020

Kyrgyzstan

V. V. Fomin

I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation

Email: fake@neicon.ru

MD, PhD, Professor, Corr. Member of Russ. Acad. Sci., Head of Chair of Faculty Therapy No. 1, Director of the Clinic of Faculty Therapy named after V.N. Vinogradov

8/2 Trubetskaya ul., Moscow, 119991

Russian Federation

References

  1. Nangaku M, Eckardt KU. Pathogenesis of renal anemia. Semin Nephrol. 2006;26(4):261–8. doi: 10.1016/j.semnephrol.2006.06.001.
  2. Erslev AJ. Erythropoietin. N Engl J Med. 1991;324(19):1339–44. doi: 10.1056/ NEJM199105093241907.
  3. Querbes W, Bogorad RL, Moslehi J, Wong J, Chan AY, Bulgakova E, Kuchimanchi S, Akinc A, Fitzgerald K, Koteliansky V, Kaelin WG Jr. Treatment of erythropoietin deficiency in mice with systemically administered siRNA. Blood. 2012;120(9):1916–22. doi: 10.1182/ blood-2012-04-423715.
  4. Miró-Murillo M, Elorza A, Soro-Arnáiz I, Albacete-Albacete L, Ordoñez A, Balsa E, Vara-Vega A, Vázquez S, Fuertes E, Fernández-Criado C, Landázuri MO, Aragonés J. Acute Vhl gene inactivation induces cardiac HIF-dependent erythropoietin gene expression. PLoS One. 2011;6(7):e22589. doi: 10.1371/journal. pone.0022589.
  5. Rankin EB, Wu C, Khatri R, Wilson TL, Andersen R, Araldi E, Rankin AL, Yuan J, Kuo CJ, Schipani E, Giaccia AJ. The HIF signaling pathway in osteoblasts directly modulates erythropoiesis through the production of EPO. Cell. 2012;149(1):63–74. doi: 10.1016/j. cell.2012.01.051.
  6. Maxwell PH, Eckardt KU. HIF prolyl hydroxylase inhibitors for the treatment of renal anaemia and beyond. Nat Rev Nephrol. 2016;12(3):157– 68. doi: 10.1038/nrneph.2015.193.
  7. Santos FR, Moysés RM, Montenegro FL, Jorgetti V, Noronha IL. IL-1beta, TNF-alpha, TGF-beta, and bFGF expression in bone biopsies before and after parathyroidectomy. Kidney Int. 2003;63(3):899–907. doi: 10.1046/j.1523- 1755.2003.00835.x.
  8. Miller CB, Jones RJ, Piantadosi S, Abeloff MD, Spivak JL. Decreased erythropoietin response in patients with the anemia of cancer. N Engl J Med. 1990;322(24):1689–92. doi: 10.1056/ NEJM199006143222401.
  9. Frede S, Fandrey J, Pagel H, Hellwig T, Jelkmann W. Erythropoietin gene expression is suppressed after lipopolysaccharide or interleukin-1 beta injections in rats. Am J Physiol. 1997;273(3 Pt 2):R1067–71.
  10. Souma T, Yamazaki S, Moriguchi T, Suzuki N, Hirano I, Pan X, Minegishi N, Abe M, Kiyomoto H, Ito S, Yamamoto M. Plasticity of renal erythropoietin-producing cells governs fibrosis. J Am Soc Nephrol. 2013;24(10):1599–616. doi: 10.1681/ASN.2013010030.
  11. Weiss G, Goodnough LT. Anemia of chronic disease. N Engl J Med. 2005;352(10):1011–23. doi: 10.1056/NEJMra041809.
  12. Libregts SF, Gutiérrez L, de Bruin AM, Wensveen FM, Papadopoulos P, van Ijcken W, Ozgür Z, Philipsen S, Nolte MA. Chronic IFN-γ production in mice induces anemia by reducing erythrocyte life span and inhibiting erythropoiesis through an IRF-1/PU.1 axis. Blood. 2011;118(9):2578–88. doi: 10.1182/ blood-2010-10-315218.
  13. Suehiro Y, Muta K, Nakashima M, Abe Y, Shiratsuchi M, Shiokawa S, Ikuyama S, Yoshikawa Y, Watanabe T, Nishimura J. A novel mechanism in suppression of erythropoiesis during inflammation: a crucial role of RCAS1. Eur J Haematol. 2005;74(5):365–73. doi: 10.1111/j.1600- 0609.2004.00389.
  14. Besson-Fournier C, Latour C, Kautz L, Bertrand J, Ganz T, Roth MP, Coppin H. 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. doi: 10.1182/ blood-2012-02-411470.
  15. Nemeth E, Tuttle MS, Powelson J, Vaughn MB, Donovan A, Ward DM, Ganz T, Kaplan J. Science. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. 2004;306(5704):2090–3. doi: 10.1126/science.1104742.
  16. Besarab A, Coyne DW. Iron supplementation to treat anemia in patients with chronic kidney disease. Nat Rev Nephrol. 2010;6(12):699–710. doi: 10.1038/nrneph.2010.139.
  17. Fudin R, Jaichenko J, Shostak A, Bennett M, Gotloib L. Correction of uremic iron deficiency anemia in hemodialyzed patients: a prospective study. Nephron. 1998;79(3):299–305.
  18. Paulson RF, Shi L, Wu DC. Stress erythropoiesis: new signals and new stress progenitor cells. Curr Opin Hematol. 2011;18(3):139–45. doi: 10.1097/MOH.0b013e32834521c8.
  19. Rouault TA. The role of iron regulatory proteins in mammalian iron homeostasis and disease. Nat Chem Biol. 2006;2(8):406–14. doi: 10.1038/ nchembio807.
  20. Wilkinson N, Pantopoulos K. IRP1 regulates erythropoiesis and systemic iron homeostasis by controlling HIF2α mRNA translation. Blood. 2013;122(9):1658–68. doi: 10.1182/ blood-2013-03-492454.
  21. Ghosh MC, Zhang DL, Jeong SY, Kovtunovych G, Ollivierre-Wilson H, Noguchi A, Tu T, Senecal T, Robinson G, Crooks DR, Tong WH, Ramaswamy K, Singh A, Graham BB, Tuder RM, Yu ZX, Eckhaus M, Lee J, Springer DA, Rouault TA. Deletion of iron regulatory protein 1 causes polycythemia and pulmonary hypertension in mice through translational derepression of HIF2α. Cell Metab. 2013;17(2): 271–81. doi: 10.1016/j.cmet.2012.12.016.
  22. Anderson SA, Nizzi CP, Chang YI, Deck KM, Schmidt PJ, Galy B, Damnernsawad A, Broman AT, Kendziorski C, Hentze MW, Fleming MD, Zhang J, Eisenstein RS. The IRP1-HIF2α axis coordinates iron and oxygen sensing with erythropoiesis and iron absorption. Cell Metab. 2013;17(2):282–90. doi: 10.1016/j. cmet.2013.01.007.
  23. Ponka P. Tissue-specifi regulation of iron metabolism and heme synthesis: distinct control mechanisms in erythroid cells. Blood. 1997;89(1):1–25.
  24. Chen JJ. Regulation of protein synthesis by the heme-regulated eIF2alpha kinase: relevance to anemias. Blood. 2007;109(7):2693–9. doi: 10.1182/blood-2006-08-041830.
  25. Besarab A, Frinak S, Yee J. What is so bad about a hemoglobin level of 12 to 13 g/dL for chronic kidney disease patients anyway? Adv Chronic Kidney Dis. 2009;16(2):131–42. doi: 10.1053/j. ackd.2008.12.007.
  26. Pfeffer MA, Burdmann EA, Chen CY, Cooper ME, de Zeeuw D, Eckardt KU, Feyzi JM, Ivanovich P, Kewalramani R, Levey AS, Lewis EF, McGill JB, McMurray JJ, Parfrey P, Parving HH, Remuzzi G, Singh AK, Solomon SD, Toto R; TREAT Investigators. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med. 2009;361(21):2019–32. doi: 10.1056/NEJMoa0907845.
  27. Goldberg MA, Glass GA, Cunningham JM, Bunn HF. The regulated expression of erythropoietin by two human hepatoma cell lines. Proc Natl Acad Sci USA. 1987;84(22):7972–6.
  28. Wang GL, Semenza GL. General involvement of hypoxia-inducible factor 1 in transcriptional response to hypoxia. Proc Natl Acad Sci USA. 1993;90(9):4304–8.
  29. Ebert B, Jelkmann W. Intolerability of cobalt salt as erythropoietic agent. Drug Test Anal. 2014;6(3):185–9. doi: 10.1002/dta.1528.
  30. Vengellur A, Woods BG, Ryan HE, Johnson RS, LaPres JJ. Gene expression profiling of the hypoxia signaling pathway in hypoxia-inducible factor 1alpha null mouse embryonic fibroblasts. Gene Expr. 2003;11(3–4):181–97.
  31. Jefferson JA, Escudero E, Hurtado ME, Pando J, Tapia R, Swenson ER, Prchal J, Schreiner GF, Schoene RB, Hurtado A, Johnson RJ. Excessive erythrocytosis, chronic mountain sickness, and serum cobalt levels. Lancet. 2002;359(9304): 407–8. doi: 10.1016/S0140-6736(02)07594-3.
  32. Barrett TD, Palomino HL, Brondstetter TI, Kanelakis KC, Wu X, Haug PV, Yan W, Young A, Hua H, Hart JC, Tran DT, Venkatesan H, Rosen MD, Peltier HM, Sepassi K, Rizzolio MC, Bembenek SD, Mirzadegan T, Rabinowitz MH, Shankley NP. Pharmacological characterization of 1-(5-chloro-6-(trifluoromethoxy)-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid (JNJ-42041935), a potent and selective hypoxia-inducible factor prolyl hydroxylase inhibitor. Mol Pharmacol. 2011;79(6):910–20. doi: 10.1124/mol.110.070508.
  33. Spinowitz В, Pergola PE, Haase VH, Farmer TM, Hartman CS, Maroni B. Hemoglobin response in a phase 2b study of vadadustat for the treatment of anemia in patients with non-dialysis dependent chronic kidney disease [Internet]. Available from: http:// akebia.com/wp-content/themes/akebia/ img/media-kit/abstracts-posters-presentations/20151102-Ph2b_Subgroups_Oral_ ASN_2015_Final_no-b-u.pdf.
  34. GlaxoSmithKline. GSK Study Register [Internet]. Available from: http://www.gsk-clinicalstudyregister.com.
  35. Semenza GL. Oxygen sensing, hypoxia-inducible factors, and disease pathophysiology. Annu Rev Pathol. 2014;9:47–71. doi: 10.1146/ annurev-pathol-012513-104720.
  36. Shimoda LA, Laurie SS. HIF and pulmonary vascular responses to hypoxia. J Appl Physiol (1985). 2014;116(7):867–74. doi: 10.1152/japplphysiol.00643.2013.
  37. Cowburn AS, Takeda N, Boutin AT, Kim JW, Sterling JC, Nakasaki M, Southwood M, Goldrath AW, Jamora C, Nizet V, Chilvers ER, Johnson RS. HIF isoforms in the skin differentially regulate systemic arterial pressure. Proc Natl Acad Sci U S A. 2013;110(43):17570–5. doi: 10.1073/pnas.1306942110.
  38. Bertout JA, Patel SA, Simon MC. The impact of O2 availability on human cancer. Nat Rev Cancer. 2008;8(12):967–75. doi: 10.1038/nrc2540.
  39. Semenza GL. HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations. J Clin Invest. 2013;123(9): 3664–71. doi: 10.1172/JCI67230.
  40. Keith B, Johnson RS, Simon MC. HIF1α and HIF2α: sibling rivalry in hypoxic tumour growth and progression. Nat Rev Cancer. 2011;12(1): 9–22. doi: 10.1038/nrc3183.
  41. Krock BL, Skuli N, Simon MC. Hypoxia-induced angiogenesis: good and evil. Genes Cancer. 2011;2(12):1117–33. doi: 10.1177/1947601911423654.
  42. Astellas Pharma Inc. News release: the FDA accepts the complete response for clinical holds of FG-2216*/FG-4592 for the treatment of anemia [Internet]. Available from: http://www.astellas. com/en/corporate/news/pdf/080402_eg.pdf.
  43. Rabinowitz MH. Inhibition of hypoxia-inducible factor prolyl hydroxylase domain oxygen sensors: tricking the body into mounting orchestrated survival and repair responses. J Med Chem. 2013;56(23):9369–402. doi: 10.1021/ jm400386j.
  44. Klaus S, Langsetmo I, Neff T, Lin A, Liu D. Beneficial pharmacodynamic effects resulting from ‘complete erythropoiesis’ induced by novel HIF prolyl hydroxylase inhibitors FG-2216 and FG-4592 [abstract]. J Am Soc Nephrol. 2008;19:524A.
  45. Provenzano R, Besarab A, Sun CH, Diamond SA, Durham JH, Cangiano JL, Aiello JR, Novak JE, Lee T, Leong R, Roberts BK, Saikali KG, Hemmerich S, Szczech LA, Yu KH, Neff TB. Oral Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor Roxadustat (FG-4592) for the Treatment of Anemia in Patients with CKD. Clin J Am Soc Nephrol. 2016;11(6):982–91. doi: 10.2215/ CJN.06890615.
  46. Hsieh MM, Linde NS, Wynter A, Metzger M, Wong C, Langsetmo I, Lin A, Smith R, Rodgers GP, Donahue RE, Klaus SJ, Tisdale JF. HIF prolyl hydroxylase inhibition results in endogenous erythropoietin induction, erythrocytosis, and modest fetal hemoglobin expression in rhesus macaques. Blood. 2007;110(6):2140– 7. doi: 10.1182/blood-2007-02-073254.
  47. Besarab A, Szczech L, Yu KHP, Neff NB. Impact of iron regimen on iron indices and hepcidin during roxadustat anemia correction in incident dialysis patients [abstract]. J Am Soc Nephrol. 2014;25:304A.
  48. Frohna PA, Milwee S, Pinkett J, Lee T, Moore-Perry K, Chou J, Ellison RH. Preliminary results from a randomized, single-blind, placebo-controlled trial of FG-4592, a novel hypoxia inducible factor prolyl hydroxylase inhibitor, in subjects with CKD anemia [abstract]. J Am Soc Nephrol. 2007;18:763A.
  49. Kindler J, Eckardt KU, Ehmer B, Jandeleit K, Kurtz A, Schreiber A, Scigalla P, Sieberth HG. Single-dose pharmacokinetics of recombinant human erythropoietin in patients with various degrees of renal failure. Nephrol Dial Transplant. 1989;4(5):345–9.
  50. Kapitsinou PP, Liu Q, Unger TL, Rha J, Davidoff O, Keith B, Epstein JA, Moores SL, Erickson-Miller CL, Haase VH. Hepatic HIF-2 regulates erythropoietic responses to hypoxia in renal anemia. Blood. 2010;116(16):3039–48. doi: 10.1182/blood-2010-02-270322.
  51. Kapitsinou PP, Jaffe J, Michael M, Swan CE, Duffy KJ, Erickson-Miller CL, Haase VH. Preischemic targeting of HIF prolyl hydroxylation inhibits fibrosis associated with acute kidney injury. Am J Physiol Renal Physiol. 2012;302(9):F1172–9. doi: 10.1152/ajprenal.00667.2011.
  52. Brigandi RA.The prolyl-hydroxylase inhibitor, GSK1278863A, induced EPO in vitro and efficient erythropoiesis leading to increased hemoglobin in vivo [abstract]. J Am Soc Nephrol. 2010;21:722A.
  53. Brigandi RA, Russ SF, Al-Banna M, Zhang J, Erickson-Miller CL, Peng B. Prolyl-hydroxylase inhibitor modulation of erythropoietin in a randomized placebo controlled trial [abstract]. J Am Soc Nephrol. 2010;21:390A.
  54. Brigandi RA, Johnson B, Oei C, Westerman ME, Olbina G, Kumar S, Russ SF. Induction of erythropoiesis in anemic patients by prolyl-hydroxylase inhibitor in a repeat dose, randomized placebo controlled trial [abstract]. J Am Soc Nephrol. 2012;2:662A.
  55. Olson E, Demopoulos L, Haws TF, Hu E, Fang Z, Mahar KM, Qin P, Lepore J, Bauer TA, Hiatt WR. Short-term treatment with a novel HIF-prolyl hydroxylase inhibitor (GSK1278863) failed to improve measures of performance in subjects with claudication-limited peripheral artery disease. Vasc Med. 2014;19(6):473–82. doi: 10.1177/1358863X14557151.
  56. Shalwitz R, Hartman C, Flinn C, Shalwitz I, Logan DK. AKB-6548, a novel hypoxia-inducible factor prolyl-hydroxylase inhibitor reduces hepcidin and ferritin while it increases reticulocyte production and total iron binding capacity in healthy adults [abstract]. J Am Soc Nephrol. 2011;22:435A.
  57. Hartman C, Smith MT, Flinn C, Shalwitz I, Peters KG, Shalwitz RA, Haase V. AKB-6548, a new hypoxia-inducible factor prolyl-hydroxylase inhibitor increases hemoglobin while decreasing ferritin in a 28-day, phase 2a dose escalation study in stage 3 and 4 chronic kidney disease patients with anemia [abstract]. J Am Soc Nephrol. 2011;22:435A.
  58. Hartman CS, Farmer TM, Annis K, Kazazi F, Pollack P, Shalwitz R. Phase 2 study of AKB-6548, a novel hypoxia-inducible factor Prolyl-hydroxylase inhibitor (HIF-PHI) in patients with end stage renal disease (ESRD) undergoing hemodialysis (HD) [Internet]. Available from: http://akebia.com/wp-content/themes/akebia/img/media-kit/abstracts-posters-presentations/20141106_Akebia_ASN_Informational_Poster-FINAL.pdf.
  59. Baillie JK, Bates MG, Thompson AA, Waring WS, Partridge RW, Schnopp MF, Simpson A, Gulliver-Sloan F, Maxwell SR, Webb DJ. Endogenous urate production augments plasma antioxidant capacity in healthy lowland subjects exposed to high altitude. Chest. 2007;131(5): 1473–8. doi: 10.1378/chest.06-2235.
  60. 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. doi: 10.1371/journal. pone.0111838.
  61. Boettcher MF, Lentini S, Kaiser A, Flamme I, Kubitza D, Wensing G. First-in-man study with BAY 85-3934 – a new oral selective HIF-PH inhibitor for the treatment of renal anemia [abstract]. J Am Soc Nephrol. 2013;24:347A.

Copyright (c) 2018 Aitbaev K.A., Murkamilov I.T., Fomin V.V.

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.

This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies