Emerging drugs for the treatment of kidney disease-induced anemia

Expert Opinion on Emerging Drugs

Volumn 21, Issue 3, 2016, Pages 315-330

  Malyszko, Jolanta ^a   Malyszko, Jacek S ^a  

^a MEDICAL UNIVERSITY OF BIALYSTOK   (Poland)

Author keywords

Chronic kidney disease; dialysis; erythropoietin; hepcidin; HIF stabilizers; iron; renal anemia

Indexed keywords

ANTIANEMIC AGENT; EPOMIMETIC AGENT; FERROPORTIN; HEMOGLOBIN; HEPCIDIN; HYPOXIA INDUCIBLE FACTOR; HYPOXIA INDUCIBLE FACTOR STABILIZER; IRON; PHOSPHATE; UNCLASSIFIED DRUG; BASIC HELIX LOOP HELIX TRANSCRIPTION FACTOR; ENDOTHELIAL PAS DOMAIN-CONTAINING PROTEIN 1; HYPOXIA INDUCIBLE FACTOR 1; IRON DERIVATIVE;

ANEMIA; BONE MARROW; CHRONIC KIDNEY DISEASE; CONTROLLED CLINICAL TRIAL (TOPIC); DRUG INDICATION; DRUG SAFETY; ERYTHROPOIESIS; HUMAN; IRON THERAPY; MULTICENTER STUDY (TOPIC); PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; RISK BENEFIT ANALYSIS; ANIMAL; CHRONIC KIDNEY FAILURE; COMPLICATION; DRUG DESIGN; METABOLISM;

ANEMIA; ANIMALS; BASIC HELIX-LOOP-HELIX TRANSCRIPTION FACTORS; DRUG DESIGN; HEMATINICS; HUMANS; HYPOXIA-INDUCIBLE FACTOR 1; IRON COMPOUNDS; KIDNEY FAILURE, CHRONIC;

EID: 84985001729     PISSN: 14728214     EISSN: 17447623     Source Type: Journal    
DOI: 10.1080/14728214.2016.1220537     Document Type: Review

References (116)

1. I.C.Macdougall Clinical aspects and overview of renal anaemia. In:N.Turner, N.Lameire, D.J.Goldsmith, et al., editors. Oxford textbook of clinical nephrology. 4th ed. Oxford University Press; 2015. doi:10.1093/med/9780199592548.003.0125.
2. P.Zhang, G.Behre, J.Pan, et al. Negative cross-talk between hematopoietic regulators:GATA proteins repress PU.1. Proc Natl Acad Sci U S A. 1999;96:8705–8710.
3. J.Yu, L.Shao, J.Vaughan, et al. Characterization of the potentiation effect of activin on human erythroid colony formation in vitro. Blood. 1989;73:952–960.
4. R.F.Paulson. Targeting a new regulator of erythropoiesis to alleviate anemia. Nat Med. 2014;20:334–335.
5. M.Dussiot, T.T.Maciel, A.Fricot, et al. An activin receptor IIA ligand trap corrects ineffective erythropoiesis in β-thalassemia. Nat Med. 2014;20:398–407.
6. J.Malik, A.R.Kim, K.A.Tyre, et al. Erythropoietin critically regulates the terminal maturation of murine and human primitive erythroblasts. Haematologica. 2013;98:1778–1787.
7. W.Jelkmann. Erythropoietin:structure, control of production, and function. Physiol Rev. 1992;72:449–489.
8. D.L.Porter, M.A.Goldberg. Regulation of erythropoietin production. Exp Hematol. 1993;21:399–404.
9. H.F.Bunn, J.Gu, L.E.Huang, et al. Erythropoietin:a model system for studying oxygen-dependent gene regulation. J Exp Biol. 1998;201:1197–1201.
10. G.L.Semenza, G.L.Wang. A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol Cell Biol. 1992;12:5447–5454.
11. G.L.Semenza. Oxygen sensing, homeostasis, and disease. N Engl J Med. 2011;365:537–547.
12. A.Krause, S.Neitz, H.J.Magert, et al. LEAP-1, a novel highly disulfide-bonded human peptide exhibits antimicrobial activity. FEBS Lett. 2000;480:147–150.
13. C.H.Park, E.V.Valore, A.J.Waring, et al. Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J Biol Chem. 2001;276:7806–7810.
14. T.Ganz, E.Nemeth. Iron balance and the role of hepcidin in chronic kidney disease. Semin Nephrol. 2016;36:87–93.•• Excellent review on iron and hepcidin in kidney diseases.
15. J.Malyszko, M.Mysliwiec. Hepcidin in anemia and inflammation in chronic kidney disease. Kidney Blood Press Res. 2007;30:15–30.
16. M.Safran, W.G.KaelinJr. HIF hydroxylation and the mammalian oxygen-sensing pathway. J Clin Invest. 2003;111:779–783.
17. B.Courselaud, C.Pigeon, Y.I.Inoue, et al. C/EBP alpha regulates hepatic transcription of hepcidin, an antimicrobial peptide and regulator of iron metabolism. Cross-talk between C/EBP pathway and iron metabolism. J Biol Chem. 2002;277:41163–41170.
18. C.Rosenberger, S.Mandriota, J.S.Jurgensen, et al. Expression of hypoxia-inducible factor–1α and –2α in hypoxic and ischemic rat kidneys. J Am Soc Nephrol. 2002;13:1721–1732.
19. R.K.Bruick, S.L.McKnight. A conserved family of prolyl-4-hydroxylases that modify HIF. Science. 2001;294:1337–1340.
20. A.C.R.Epstein, J.M.Gleadle, L.A.McNeill, et al. C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell. 2001;107:43–54.
21. M.S.Wiesener, H.Turley, W.E.Allen, et al. Induction of endothelial PAS domain protein-1 by hypoxia:characterization and comparison with hypoxia-inducible factor–1α. Blood. 1998;92:2260–2268.
22. E.Muchnik, J.Kaplan. HIF prolyl hydroxylase inhibitors for anemia. Expert Opin Investig Drugs. 2011;20:645–656.
23. 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;56:9369–9402.
24. A.Besarab, W.K.Bolton, J.K.Browne, 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;339:584–590.
25. A.K.Singh, L.Szczech, K.L.Tang, et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med. 2006;355:2085–2098.
26. T.B.Drüeke, F.Locatelli, N.Clyne, et al. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med. 2006;355:2071–2084.
27. M.A.Pfeffer, E.A.Burdmann, C.Y.Chen, et al. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med. 2009;361:2019–2032.
28. D.Goldsmith. 2009:a requiem for rHuEPOs – but should we nail down the coffin in 2010? Clin J Am Soc Nephrol. 2010;5:929–935.
29. F.K.Lin, S.Suggs, C.H.Lin, et al. Cloning and expression of the human erythropoietin gene. Proc Natl Acad Sci U S A. 1985;82:7580–7584.
30. KIDGO clinical practice guideline for anemia in chronic kidney disease. Kidney Int Suppl. 2012;2:279–335.
31. H.Ledford. ‘Biosimilar’ drugs poised to penetrate market. Draft regulations will pave the way for copycat antibodies and other large molecules. Nature. 2010;468:18–19.
32. R.Nellore. Regulatory considerations for biosimilars. Perspect Clin Res. 2010;1:11–14.
33. M.J.Lopez, G.Antonino, I.Vicente, et al. Erythropoietic factors in renal chronic disease:economic management. Int J Clin Pharm. 2012;34:221–222.
34. F.Bocquet, P.Paubel, I.Fusier, et al. Biosimilar versus patented erythropoietins:learning from 5 years of European and Japanese experience. Appl Health Econ Health Policy. 2015;13:47–59.
35. I.V.Pearson, K.I.Johnson. A cost minimization analysis of epoetin zeta for the treatment of anemia associated with chronic kidney disease. Value Health. 2008;11:A304.
36. R.Minutolo, M.Borzumati, S.Sposini, et al. Dosing penalty of erythropoiesis-stimulating agents after switching from originator to biosimilar preparations in stable hemodialysis patients. Am J Kidney Dis. 2016;68:170–172.
37. J.Rottembourg, A.Kadri, E.Leonard, et al. Do two intravenous iron sucrose preparations have the same efficacy? Nephrol Dial Transplant. 2011;26:3262–3267.
38. H.Schmid, W.Jelkmann. Investigational therapies for renal disease-induced anemia. Expert Opin Investig Drugs. 2016;21:1–16.
39. M.Bonomini, L.Del Vecchio, V.Sirolli, et al. New treatment approaches for the anemia of CKD. Am J Kidney Dis. 2016;67:133–142.• Elegant overview on epomimetics and other new anti-anemia agents.
40. J.Małyszko, I.C.Macdougall. Iron matabolism in chronic kidney disease. In:N.Turner, N.Lameire, D.J.Goldsmith, et al., editors. Oxford textbook of clinical nephrology. 4th ed. Oxford University Press; 2015. doi:10.1093/med/9780199592548.003.0125.
41. D.A.Allen, C.Breen, M.M.Yaqoob, et al. Inhibition of CFU-E colony formation in uremic patients with inflammatory disease:role of IFN-gamma and TNF-alpha. J Investig Med. 1999;47:204–211.
42. Y.Zhang, M.Thamer, K.Stefanik, et al. Epoetin requirements predict mortality in hemodialysis patients. Am J Kidney Dis. 2004;44:866–876.
43. A.T.Kausz, C.Solid, B.J.G.Pereira, et al. Intractable anemia among hemodialysis patients:a sign of suboptimal management or a marker of disease? Am J Kidney Dis. 2005;45:136–147.
44. L.A.Szczech, H.X.Barnhart, J.K.Inrig, et al. Secondary analysis of the CHOIR trial epoetin-α dose and achieved hemoglobin outcomes. Kidney Int. 2008;74:791–798.
45. S.D.Solomon, H.Uno, E.F.Lewis, et al.; Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT) Investigators. Erythropoietic response and outcomes in kidney disease and type 2 diabetes. N Engl J Med. 2010;363(12):1146–1155.
46. M.M.Suttorp, T.Hoekstra, M.Mittelman, et al. Treatment with high dose of erythropoiesis-stimulating agents and mortality:analysis with a sequential Cox approach and a marginal structural model. Pharmacoepidemiol Drug Saf. 2015;24:1068–1075.
47. W.M.Bernhardt, M.S.Wiesener, P.Scigalla, et al. Inhibition of prolyl hydroxylases increases erythropoietin production in ESRD. J Am Soc Nephrol. 2010;21:2151–2156.
48. A.Besarab, R.Provenzano, J.Hertel, et al. Randomized placebo-controlled dose-ranging and pharmacodynamics study of roxadustat (FG-4592) to treat anemia in nondialysis-dependent chronic kidney disease (NDD-CKD) patients. Nephrol Dial Transplant. 2015;30:1665–1673.
49. R.P.Ross, J.B.McCrea, A.Besarab. Erythropoietin response to blood loss in hemodialysis patients is blunted but preserved. ASAIO J. 1994;40:M880–M885.
50. J.S.Milledge, P.M.Cotes. Serum erythropoietin in humans at high altitude and its relation to plasma renin. J Appl Physiol. 1985;59:360–364.
51. R.Provenzano, A.Besarab, C.H.Sun, et al. 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;11:982–991.
52. C.Peyssonnaux, A.S.Zinkernagel, R.A.Schuepbach, et al. Regulation of iron homeostasis by the hypoxia-inducible transcription factors (HIFs). J Clin Invest. 2007;117:1926–1932.
53. Y.M.Shah, T.Matsubara, S.Ito, et al. Intestinal hypoxia-inducible transcription factors are essential for iron absorption following iron deficiency. Cell Metab. 2009;9:152–164.
54. E.R.Anderson, X.Xue, Y.M.Shah. Intestinal hypoxia-inducible factor-2α (HIF-2α) is critical for efficient erythropoiesis. J Biol Chem. 2011;286:19533–19540.
55. A.Besarab, E.Chernyavskaya, I.Motylev, et al. Roxadustat (FG-4592):correction of anemia in incident dialysis patients. J Am Soc Nephrol. 2016;27:1225–1233.
56. R.Provenzano, A.Besarab, S.Wright, et al. Roxadustat (FG-4592) versus epoetin alfa for anemia in patients receiving maintenance hemodialysis:a phase 2, randomized, 6- to 19-week, open-label, active-comparator, dose-ranging, safety and exploratory efficacy study. Am J Kidney Dis. 2016;67:912–924.
57. I.Flamme, F.Oehme, P.Ellinghaus, et al. Mimicking hypoxia to treat anemia:HIF stabilizer BAY 85-3934 (Molidustat) stimulates erythropoietin production without hypertensive effects. PLoS One. 2014;9:e111838.
58. I.Macdougall, T.Akizawa, J.Berns, et al. Safety and efficacy of molidustat in erythropoiesis stimulating agents (esa) pre-treated anaemic patients with chronic kidney disease not on dialysis (ckd-nd). 53rd Congress ERA-EDTA; 2016 May 21–24; Vienna. abstract Sp309.
59. I.Macdougall, T.Akizawa, J.Berns, et al. Molidustat increases haemoglobin in erythropoiesis stimulating agents (esa)-naive anaemic patients with chronic kidney disease not on dialysis (ckd-nd). 53rd Congress ERA-EDTA; 2016 May 21–24; Vienna. abstract So036.
60. http://ir.akebia.com/releasedetail.cfm?releaseid=972288
61. http://ir.akebia.com/releasedetail.cfm?ReleaseID5878191
62. G.A.Chandorkar, R.Farzaneh-Far, A.Buch, et al. A drug-drug interaction study to evaluate the effect of vadadustat on the pharmacokinetics of celecoxib, a cyp2c9 substrate in healthy volunteers. 53rd Congress ERA-EDTA; 2016 May 21–24; Vienna. abstract SP322.
63. http://ir.akebia.com/releasedetail.cfm?releaseid=935299
64. R.A.Brigandi, B.Johnson, C.Oei, et al.; PHI112844 Investigators. A novel hypoxia-inducible factor-prolyl hydroxylase inhibitor (GSK1278863) for anemia in CKD:a 28-day, phase 2A randomized trial. Am J Kidney Dis. 2016;67:861–871.
65. Safety, tolerability, PK and PD study of JTZ-951 in anemic subjects with end-stage renal disease. U.S. National Institutes of Health. Available from:https://clinicaltrials.gov/ct2/show?term5jtz-951&rank52.
66. Pilot PK/PD study of DS-1093a in patients with chronic kidney disease. U.S. National Institutes of Health. Available from:https://clinicaltrials.gov/ct2/show?term5ds1093a&rank51.
67. Y.Morikami, A.Fujimori, S.Okada, et al. Comparison of 2-week versus 4-week dosing intervals of epoetin beta pegol on erythropoiesis and iron metabolism in hemodialysis patients. Ther Apher Dial. 2014;18:414–420.
68. S.Shoji, M.Inaba, N.Tomosugi, et al. Greater potency of darbepoetin-α than erythropoietin in suppression of serum hepcidin-25 and utilization of iron for erythropoiesis in hemodialysis patients. Eur J Haematol. 2013;90:237–244.
69. G.Weiss, I.Theurl, S.Eder, et al. Serum hepcidin concentration in chronic haemodialysis patients:associations and effects of dialysis, iron and erythropoietin therapy. Eur J Clin Invest. 2009;39:883–890.
70. D.R.Ashby, D.P.Gale, M.Busbridge, et al. Plasma hepcidin levels are elevated but responsive to erythropoietin therapy in renal disease. Kidney Int. 2009;75:976–981.
71. J.Ferezou, J.P.Richalet, T.Coste, et al. Changes in plasma lipids and lipoprotein cholesterol during a high altitude mountaineering expedition (4800 m). Eur J Appl Physiol Occup Physiol. 1988;57:740–745.
72. S.Fishbane, A.Mathew, N.D.Vaziri. Iron toxicity:relevance for dialysis patients. Nephrol Dial Transplant. 2014;29:255–259.• Excellent review on dark side of iron in kidney diseases.
73. Affymax and Takeda announce a nationwide voluntary recall of all lots of OMONTYS (peginesatide) Injection. Available from:http://www.takeda.com/news/2013/20130224_5664.html.
74. S.Imagawa, Y.Nakano, N.Obara, et al. A GATA-specific inhibitor (K-7174) rescues anemia induced by IL-1beta, TNF-alpha, or L-NMMA. FASEB J. 2003;17:1742–1754.
75. T.Fujiwara, T.Ikeda, Y.Nagasaka, et al. A low-molecular-weight compound K7174 represses hepcidin:possible therapeutic strategy against anemia of chronic disease. PLoS One. 2013;8:e75568.
76. Y.Nakano, S.Imagawa, K.Matsumoto, et al. Oral administration of K-11706 inhibits GATA binding activity, enhances hypoxia-inducible factor 1 binding activity, and restores indicators in an in vivo mouse model of anemia of chronic disease. Blood. 2004;104:4300–4307.
77. Y.Lippin, M.Dranitzki-Elhalel, E.Brill-Almon, et al. Human erythropoietin gene therapy for patients with chronic renal failure. Blood. 2005;106:2280–2286.
78. E.Bouman-Thio, K.Franson, B.Miller, et al. A Phase I, single and fractionated, ascending-dose study evaluating the safety, pharmacokinetics, pharmacodynamics, and immunogenicity of an erythropoietin mimetic antibody fusion protein (CNTO 528) in healthy male subjects. J Clin Pharmacol. 2008;48:1197–1207.
79. J.J.Perez-Ruixo, W.Krzyzanski, E.Bouman-Thio, et al. Pharmacokinetics and pharmacodynamics of the erythropoietin Mimetibody construct CNTO 528 in healthy subjects. Clin Pharmacokinet. 2009;48:601–613.
80. P.Sathyanarayana, E.Houde, D.Marshall, et al. CNTO 530 functions as a potent EPO mimetic via unique sustained effects on bone marrow proerythroblast pools. Blood. 2009;113:4955–4962.
81. R.N.V.S.Suragani, S.M.Cawley, R.Li, et al. Modified activin receptor IIB ligand trap mitigates ineffective erythropoiesis and disease complications in murine β-thalassemia. Blood. 2014;123:3864–3872.
82. R.N.V.S.Suragani, S.M.Cadena, S.M.Cawley, et al. Transforming growth factor-β superfamily ligand trap ACE-536 corrects anemia by promoting late-stage erythropoiesis. Nat Med. 2014;20:408–414.
83. M.L.Sherman, N.G.Borgstein, L.Mook, et al. Multiple-dose, safety, pharmacokinetic, and pharmacodynamic study of sotatercept (ActRIIA-IgG1), a novel erythropoietic agent, in healthy postmenopausal women. J Clin Pharmacol. 2013;53:1121–1130.
84. K.M.Attie, M.J.Allison, T.McClure, et al. A phase 1 study of ACE-536, a regulator of erythroid differentiation, in healthy volunteers. Am J Hematol. 2014;89:766–770.
85. S.Lotinun, R.S.Pearsall, M.V.Davies, 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;46:1082–1088.
86. S.J.Im, S.I.Yang, S.H.Yang, et al. Natural form of noncytolytic flexible human Fc as a long-acting carrier of agonistic ligand, erythropoietin. PLoS One. 2011;6:e24574.
87. S.H.Yang, S.I.Yang, Y.-K.Chung. A long-acting erythropoietin fused with noncytolytic human Fc for the treatment of anemia. Arch Pharm Res. 2012;35:757–759.
88. http://genexine.com/m62.php?cate=1 [cited 2016 May 29].
89. V.G.Sankaran, M.J.Weiss. Anemia:progress in molecular mechanisms and therapies. Nat Med. 2015;21:221–230.
90. B.J.Sasu, K.S.Cooke, T.L.Arvedson, et al. Antihepcidin antibody treatment modulates iron metabolism and is effective in a mouse model of inflammation-induced anemia. Blood. 2010;115:3616–3624.
91. K.S.Cooke, B.Hinkle, H.Salimi-Moosavi, et al. A fully human anti-hepcidin antibody modulates iron metabolism in both mice and nonhuman primates. Blood. 2013;122:3054–3061.
92. C.C.Sun, V.Vaja, J.L.Babitt, et al. Targeting the hepcidin-ferroportin axis to develop new treatment strategies for anemia of chronic disease and anemia of inflammation. Am J Hematol. 2012;87:392–400.•• Interesting overview on hepcidin–ferroportin axis therapeutic targets.
93. K.Chua, E.Fung, E.D.Micewicz, et al. Small cyclic agonists of iron regulatory hormone hepcidin. Bioorg Med Chem Lett. 2015;25:4961–4969.
94. E.Fung, K.Chua, T.Ganz, et al. Thiol-derivatized minihepcidins retain biological activity. Bioorg Med Chem Lett. 2015;25:763–766.
95. L.Kautz, G.Jung, E.Nemeth, et al. Erythroferrone contributes to recovery from anemia of inflammation. Blood. 2014;124:2569–2574.
96. A.Vater, S.Klussmann. Turning mirror-image oligonucleotides into drugs:the evolution of Spiegelmer(®) therapeutics. Drug Discov Today. 2015;20:147–155.
97. L.T.van Eijk, A.S.E.John, F.Schwoebel, et al. Effect of the antihepcidin Spiegelmer lexaptepid on inflammation-induced decrease in serum iron in humans. Blood. 2014;124:2643–2646.
98. S.Schlehuber, A.Skerra. Lipocalins in drug discovery:from natural ligand-binding proteins to “anticalins”. Drug Discov Today. 2005;10:23–33.
99. Pieris. Preclinical Pipeline PRS-080. [cited 2016 May 29]. Available from:http://www.pieris.com/pipeline/proprietary-programs/prs-080.
100. http://www.pieris.com/news-and-events/press-releases/detail/524/ [cited 2016 May 29].
101. C.Hsu, S.Patel, E.Young. New phosphate binding agents:ferric compounds. J Am Soc Nephrol. 1999;10:1274–1280.
102. W.Yang, C.Yang, C.Hou, et al. An open-label, crossover study of a new phosphate-binding agent in haemodialysis patients:ferric citrate. Nephrol Dial Transplant. 2002;17:265–270.
103. J.Lewis, M.Sika, M.Koury, et al. Ferric citrate controls phosphorus and delivers iron in patients on dialysis. J Am Soc Nephrol. 2015;26:493–503.
104. K.Umanath, D.I.Jalal, B.A.Greco, et al.; Collaborative Study Group. Ferric citrate reduces intravenous iron and erythropoiesis-stimulating agent use in ESRD. J Am Soc Nephrol. 2015;26:2578–2587.
105. R.Rodby, K.Umanath, R.Niecestro, et al.; Collaborative Study Group. Phosphorus binding with ferric citrate is associated with fewer hospitalizations and reduced hospitalization costs. Expert Rev Pharmacoecon Outcomes Res. 2015;15:545–550.
106. K.Yokoyama, T.Akiba, M.Fukagawa, et al. Long-term safety and efficacy of a novel iron-containing phosphate binder, JTT-751, in patients receiving hemodialysis. J Ren Nutr. 2014;24:261–267.
107. G.Block, S.Fishbane, M.Rodriguez, et al. A 12-week, double-blind, placebo-controlled trial of ferric citrate for the treatment of iron deficiency anemia and reduction of serum phosphate in patients with CKD stages 3–5. Am J Kidney Dis. 2014;65:728–736.
108. J.Floege, A.C.Covic, M.Ketteler, et al.; PA21 Study Group. A phase III study of the efficacy and safety of a novel iron-based phosphate binder in dialysis patients. Kidney Int. 2014;86:638–647.
109. J.Floege, A.C.Covic, M.Ketteler, et al.; Sucroferric Oxyhydroxide Study Group. Long-term effects of the iron-based phosphate binder, sucroferric oxyhydroxide, in dialysis patients. Nephrol Dial Transplant. 2015;30:1037–1046.
110. A.B.Pai, S.M.Jang, N.Wegrzyn. Iron-based phosphate binders – a new element in management of hyperphosphatemia. Expert Opin Drug Metab Toxicol. 2015;16:1–13.
111. A.Gupta, N.B.Amin, A.Besarab, et al. Dialysate iron therapy:infusion of soluble ferric pyrophosphate via the dialysate during hemodialysis. Kidney Int. 1999;55:1891–1898.
112. A.Gupta, V.Lin, C.Guss, et al. Ferric pyrophosphate citrate administered via dialysate reduces erythropoiesis-stimulating agent use and maintains hemoglobin in hemodialysis patients. Kidney Int. 2015;88:1187–1194.
113. G.L.Semenza. Targeting hypoxia-inducible factor 1 to stimulate tissue vascularization. J Investig Med. 2016;64:361–363.
114. G.L.Semenza. Molecular mechanisms mediating metastasis of hypoxic breast cancer cells. Trends Mol Med. 2012;18:534–543.
115. K.Praditpornsilpa, K.Tiranathanagul, P.Kupatawintu, et al. Biosimilar recombinant human erythropoietin induces the production of neutralizing antibodies. Kidney Int. 2011;80:88–92.
116. I.C.Macdougall, M.Ashenden. Current and upcoming erythropoiesis-stimulating agents, iron products, and other novel anemia medications. Adv Chronic Kidney Dis. 2009;16:117–130.