Vadadustat, a novel oral HIF stabilizer, provides effective anemia treatment in nondialysis-dependent chronic kidney disease

Kidney International

Volumn 90, Issue 5, 2016, Pages 1115-1122

  Pergola, Pablo E ^a   Spinowitz, Bruce S ^b   Hartman, Charlotte S ^c   Maroni, Bradley J ^c   Haase, Volker H ^d  

^a Renal Associates   (United States)

^b Department of Medicine   (United States)

^c AKEBIA THERAPEUTICS   (United States)

^d VANDERBILT UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

anemia; chronic kidney disease; erythropoietin; hypoxia inducible factor; prolyl 4 hydroxylase

Indexed keywords

FERRITIN; HEMOGLOBIN; HEPCIDIN; PLACEBO; VADADUSTAT; GLYCINE; HYPOXIA INDUCIBLE FACTOR PROLINE DIOXYGENASE; PICOLINIC ACID DERIVATIVE;

ACUTE KIDNEY FAILURE; AGED; ANEMIA; ARTICLE; CHRONIC KIDNEY DISEASE; CHRONIC KIDNEY FAILURE; CONSTIPATION; CONTROLLED STUDY; DIARRHEA; DIZZINESS; DOUBLE BLIND PROCEDURE; DRUG EFFICACY; DRUG FATALITY; DRUG SAFETY; DRUG WITHDRAWAL; DYSPNEA; FATIGUE; FEMALE; FERRITIN BLOOD LEVEL; GASTROINTESTINAL HEMORRHAGE; HEADACHE; HUMAN; HYPERKALEMIA; HYPERTENSION; HYPOTENSION; IRON BINDING CAPACITY; MAJOR CLINICAL STUDY; MALE; MORBIDITY; MULTICENTER STUDY; NAUSEA; PERIPHERAL EDEMA; PHASE 2 CLINICAL TRIAL; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL; RETICULOCYTE; UPPER RESPIRATORY TRACT INFECTION; URINARY TRACT INFECTION; ANALOGS AND DERIVATIVES; ANTAGONISTS AND INHIBITORS; CLINICAL TRIAL; COMPLICATION; MIDDLE AGED; OUTCOME ASSESSMENT;

AGED; ANEMIA; DOUBLE-BLIND METHOD; FEMALE; GLYCINE; HUMANS; HYPOXIA-INDUCIBLE FACTOR-PROLINE DIOXYGENASES; MALE; MIDDLE AGED; OUTCOME ASSESSMENT (HEALTH CARE); PICOLINIC ACIDS; RENAL INSUFFICIENCY, CHRONIC;

EID: 84994143390     PISSN: 00852538     EISSN: 15231755     Source Type: Journal    
DOI: 10.1016/j.kint.2016.07.019     Document Type: Article

References (46)

1. 1 Fishbane, S., Nissenson, A.R., Anemia management in chronic kidney disease. Kidney Int Suppl(117), 2010, S3–S9.
2. 2 Koury, M.J., Haase, V.H., Anaemia in kidney disease: harnessing hypoxia responses for therapy. Nat Rev Nephrol 11 (2015), 394–410.
3. 3 Stauffer, M.E., Fan, T., Prevalence of anemia in chronic kidney disease in the United States. PLoS One, 9, 2014, e84943.
4. 4 Efstratiadis, G., Konstantinou, D., Chytas, I., Vergoulas, G., Cardio-renal anemia syndrome. Hippokratia 12 (2008), 11–16.
5. 5 Finkelstein, F.O., Story, K., Firanek, C., et al. Health-related quality of life and hemoglobin levels in chronic kidney disease patients. Clin J Am Soc Nephrol 4 (2009), 33–38.
6. 6 Portoles, J., Gorriz, J.L., Rubio, E., et al. The development of anemia is associated to poor prognosis in NKF/KDOQI stage 3 chronic kidney disease. BMC Nephrol, 14, 2013, 2.
7. 7 van Nooten, F.E., Green, J., Brown, R., et al. Burden of illness for patients with non-dialysis chronic kidney disease and anemia in the United States: review of the literature. J Med Econ 13 (2010), 241–256.
8. 8 Macdougall, I.C., Bircher, A.J., Eckardt, K.U., et al. Iron management in chronic kidney disease: conclusions from a “Kidney Disease: Improving Global Outcomes” (KDIGO) Controversies Conference. Kidney Int 89 (2016), 28–39.
9. 9 Padhi, S., Glen, J., Pordes, B.A., et al. Management of anaemia in chronic kidney disease: summary of updated NICE guidance. BMJ, 350, 2015, h2258.
10. 10 Singh, A.K., Szczech, L., Tang, K.L., et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med 355 (2006), 2085–2098.
11. 11 Pfeffer, M.A., Burdmann, E.A., Chen, C.Y., et al., for the TREAT Investigators. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med 361 (2009), 2019–2032.
12. 12 Palmer, S.C., Saglimbene, V., Mavridis, D., et al. Erythropoiesis-stimulating agents for anaemia in adults with chronic kidney disease: a network meta-analysis. Cochrane Database Syst Rev, 12, 2014, CD010590.
13. 13 Weinhandl, E.D., Gilbertson, D.T., Collins, A.J., Association of mean weekly epoetin alfa dose with mortality risk in a retrospective cohort study of Medicare hemodialysis patients. Am J Nephrol 34 (2011), 298–308.
14. 14 Kalantar-Zadeh, K., Lee, G.H., Miller, J.E., et al. Predictors of hyporesponsiveness to erythropoiesis-stimulating agents in hemodialysis patients. Am J Kidney Dis 53 (2009), 823–834.
15. 15 McCullough, P.A., Barnhart, H.X., Inrig, J.K., et al. Cardiovascular toxicity of epoetin-alfa in patients with chronic kidney disease. Am J Nephrol 37 (2013), 549–558.
16. 16 Inrig, J.K., Sapp, S., Barnhart, H., et al. Impact of higher hemoglobin targets on blood pressure and clinical outcomes: a secondary analysis of CHOIR. Nephrol Dial Transplant 27 (2012), 3606–3614.
17. 17 Okazaki, M., Komatsu, M., Kawaguchi, H., et al. Erythropoietin resistance index and the all-cause mortality of chronic hemodialysis patients. Blood Purif 37 (2014), 106–112.
18. 18 Kilpatrick, R.D., Critchlow, C.W., Fishbane, S., et al. Greater epoetin alfa responsiveness is associated with improved survival in hemodialysis patients. Clin J Am Soc Nephrol 3 (2008), 1077–1083.
19. 19 Hung, S.C., Tarng, D.C., ESA and iron therapy in chronic kidney disease: a balance between patient safety and hemoglobin target. Kidney Int 86 (2014), 676–678.
20. 20 Liles, A.M., Intravenous versus oral iron for treatment of iron deficiency in non-hemodialysis-dependent patients with chronic kidney disease. Am J Health Syst Pharm 69 (2012), 1206–1211.
21. 21 Kaelin, W.G. Jr., Ratcliffe, P.J., Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol Cell 30 (2008), 393–402.
22. 22 Yousaf, F., Spinowitz, B., Hypoxia-inducible factor stabilizers: a new avenue for reducing BP while helping hemoglobin?. Curr Hypertens Rep, 18, 2016, 23.
23. 23 Hartman, C., Smith, M.T., Flinn, C., et al. 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. J Am Soc Nephrol, 22, 2011, 435A (FR-PO1392).
24. 24 Shalwitz, R., Hartman, C., Flinn, C., et al. 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. J Am Soc Nephrol, 22, 2011, 435A (FR-OR186).
25. 25 Unger, E.F., Thompson, A.M., Blank, M.J., Temple, R., Erythropoiesis-stimulating agents—time for a reevaluation. N Engl J Med 362 (2010), 189–192.
26. 26 Vaziri, N.D., Zhou, X.J., Potential mechanisms of adverse outcomes in trials of anemia correction with erythropoietin in chronic kidney disease. Nephrol Dial Transplant 24 (2009), 1082–1088.
27. 27 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 16 (2009), 131–142.
28. 28 Bigham, A.W., Lee, F.S., Human high-altitude adaptation: forward genetics meets the HIF pathway. Genes Dev 28 (2014), 2189–2204.
29. 29 Besarab, A., Bolton, W.K., Browne, J.K., 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 339 (1998), 584–590.
30. 30 Boudville, N.C., Djurdjev, O., Macdougall, I.C., et al. Hemoglobin variability in nondialysis chronic kidney disease: examining the association with mortality. Clin J Am Soc Nephrol 4 (2009), 1176–1182.
31. 31 Drueke, T.B., Locatelli, F., Clyne, N., et al. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med 355 (2006), 2071–2084.
32. 32 Mastrogiannaki, M., Matak, P., Keith, B., et al. HIF-2alpha, but not HIF-1alpha, promotes iron absorption in mice. J Clin Invest 119 (2009), 1159–1166.
33. 33 Anderson, E.R., Xue, X., Shah, Y.M., Intestinal hypoxia-inducible factor-2alpha (HIF-2alpha) is critical for efficient erythropoiesis. J Biol Chem 286 (2011), 19533–19540.
34. 34 Anderson, E.R., Taylor, M., Xue, X., et al. Intestinal HIF2alpha promotes tissue-iron accumulation in disorders of iron overload with anemia. Proc Natl Acad Sci U S A 110 (2013), E4922–E4930.
35. 35 Liu, Q., Davidoff, O., Niss, K., Haase, V.H., Hypoxia-inducible factor regulates hepcidin via erythropoietin-induced erythropoiesis. J Clin Invest 122 (2012), 4635–4644.
36. 36 Mastrogiannaki, M., Matak, P., Mathieu, J.R., et al. Hepatic hypoxia-inducible factor-2 down-regulates hepcidin expression in mice through an erythropoietin-mediated increase in erythropoiesis. Haematologica 97 (2012), 827–834.
37. 37 Talbot, N.P., Smith, T.G., Lakhal-Littleton, S., et al. Suppression of plasma hepcidin by venesection during steady-state hypoxia. Blood 127 (2016), 1206–1207.
38. 38 Saran, R., Li, Y., Robinson, B., et al. US Renal Data System 2015 Annual Data Report: Epidemiology of Kidney Disease in the United States. Am J Kidney Dis, 67(3 Suppl 1), 2016 Svii, S1–305.
39. 39 Semenza, G.L., Regulation of metabolism by hypoxia-inducible factor 1. Cold Spring Harbor Symp Quant Biol 76 (2011), 347–353.
40. 40 Haase, V.H., Renal cancer: oxygen meets metabolism. Exp Cell Res 318 (2012), 1057–1067.
41. 41 Girgis, C.M., Cheng, K., Scott, C.H., Gunton, J.E., Novel links between HIFs, type 2 diabetes, and metabolic syndrome. Trends Endocrinol Metab 23 (2012), 372–380.
42. 42 Provenzano, R., Besarab, A., Wright, S., 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 67 (2016), 912–924.
43. 43 Krock, B.L., Skuli, N., Simon, M.C., Hypoxia-induced angiogenesis: good and evil. Genes Cancer 2 (2011), 1117–1133.
44. 44 Keith, B., Johnson, R.S., Simon, M.C., HIF1α and HIF2α: sibling rivalry in hypoxic tumour growth and progression. Nat Rev Cancer 12 (2012), 9–22.
45. 45 Semenza, G.L., Oxygen sensing, hypoxia-inducible factors, and disease pathophysiology. Annu Rev Pathol 9 (2014), 47–71.
46. 46 Kapitsinou, P.P., Rajendran, G., Astleford, L., et al. The endothelial prolyl-4-hydroxylase domain 2/hypoxia-inducible factor 2 axis regulates pulmonary artery pressure in mice. Mol Cell Biol 36 (2016), 1584–1594.