Skip to main content Skip to main navigation menu Skip to site footer

Anemia on Chronic Kidney Disease: The Role of Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors

  • Ni Wayan Anantika Riani ,
  • I Gde Raka Widiana ,


Anemia is one of the homeostatic abnormalities caused by chronic kidney disease and also frequently problem encountered in end-stage renal disease patients, regardless of the hemodialysis treatment. Anemia in chronic kidney disease significantly impairs kidney function, increases morbidity and mortality risk, and deteriorates the quality of life. Chronic kidney disease’s patients with anemia conditions are affected by numerous factors, including decreased production of endogenous erythropoietin, functional and absolute iron deficiency, and elevated hepcidin levels due to inflammation, particularly in hemodialysis patients. Treatment options for anemia in chronic kidney disease include exogenous erythropoietin and iron supplementation. A new mechanism known as the "hypoxia-sensing system" termed a mediator of erythropoietin synthesis, has been proposed to boost endogenous erythropoietin synthesis. The hypoxia-inducible factor activates specific gene expression and contributes to a physiological response to lower tissue oxygen levels. Chronic kidney disease’s patients who are contraindicated or are hyporesponsive to therapy with erythropoiesis-stimulating drugs may utilize this mechanism as an alternative.


  1. Wish JB, Anker SD, Butler J, et al. Iron Deficiency in CKD Without Concomitant Anemia. Kidney Int Reports 2021; 6(11): 2752–2762.
  2. McMurray JJV, Parfrey PS, Adamson JW, et al. Kidney Disease: Improving Global Outcomes (KDIGO) Anemia Work Group. KDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease. Kidney Int Suppl 2012; 2: 279–335.
  3. 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.
  4. Sofue T, Nakagawa N, Kanda E, et al. Prevalence of anemia in patients with chronic kidney disease in Japan: A nationwide, cross-sectional cohort study using data from the Japan Chronic Kidney Disease Database (J-CKD-DB). PLoS One 2020; 15(7): e0236132.
  5. Wittbrodt ET, James G, Kumar S, et al. Contemporary outcomes of anemia in US patients with chronic kidney disease. Clin Kidney J 2022; 15(2): 244–252.
  6. Gafter-Gvili A, Schechter A, Rozen-Zvi B. Iron Deficiency Anemia in Chronic Kidney Disease. Acta Haematol 2019; 142(1): 44–50.
  7. Gupta N, Wish JB. Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors: A Potential New Treatment for Anemia in Patients With CKD. Am J Kidney Dis 2017; 69(6): 815–826.
  8. Singh AK, Szczech L, Tang KL, et al. Correction of Anemia with Epoetin Alfa in Chronic Kidney Disease. N Engl J Med 2006; 355(20): 2085–2098.
  9. Drüeke TB, Locatelli F, Clyne N, et al. Normalization of Hemoglobin Level in Patients with Chronic Kidney Disease and Anemia. N Engl J Med 2006; 355(20): 2071–2084.
  10. Locatelli F, Bárány P, Covic A, 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; 28(6): 1346–1359.
  11. Hirota K. HIF-α prolyl hydroxylase inhibitors and their implications for biomedicine: A comprehensive review. Biomedicines 2021; 9(5): 468.
  12. Fujikawa R, Nagao Y, Fujioka M, et al. Treatment of anemia associated with chronic kidney disease with the HIF prolyl hydroxylase inhibitor enarodustat: A review of the evidence. Ther Apher Dial 2022; 26(4): 679–693.
  13. Sanghani NS, Haase VH. Hypoxia-Inducible Factor Activators in Renal Anemia: Current Clinical Experience. Adv Chronic Kidney Dis 2019; 26(4): 253–266.
  14. Wang B, Li ZL, Zhang YL, et al. Hypoxia and chronic kidney disease. eBioMedicine 2022; 77: 103942.
  15. Miao M, Wu M, Li Y, et al. Clinical Potential of Hypoxia Inducible Factors Prolyl Hydroxylase Inhibitors in Treating Nonanemic Diseases. Front Pharmacol 2022; 13: 837249.
  16. Schönberger T, Fandrey J, Prost-Fingerle K. Ways into understanding HIF inhibition. Cancers (Basel) 2021; 13(1): 159.
  17. 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(2): 389.
  18. Hirakawa Y, Tanaka T, Nangaku M. Renal hypoxia in CKD; Pathophysiology and detecting methods. Front Physiol 2017; 8: 99.
  19. Wyatt CM, Drüeke TB. HIF stabilization by prolyl hydroxylase inhibitors for the treatment of anemia in chronic kidney disease. Kidney Int 2016; 90(5): 923–925.
  20. Haase VH. Hypoxia-inducible factor–prolyl hydroxylase inhibitors in the treatment of anemia of chronic kidney disease. Kidney Int Suppl 2021; 11(1): 8–25.
  21. Souza E, Cho KH, Harris ST, et al. Hypoxia-inducible factor prolyl hydroxylase inhibitors: a paradigm shift for treatment of anemia in chronic kidney disease? Expert Opin Investig Drugs 2020; 29(8): 831–844.
  22. Liu Q, Davidoff O, Niss K, et al. Hypoxia-inducible factor regulates hepcidin via erythropoietin-induced erythropoiesis. J Clin Invest 2012; 122(12): 4635–4644.
  23. Martin ER, Smith MT, Maroni BJ, et al. Clinical Trial of Vadadustat in Patients with Anemia Secondary to Stage 3 or 4 Chronic Kidney Disease. Am J Nephrol 2017; 45(5): 380–388.
  24. Chertow GM, Pergola PE, Farag YMK, et al. Vadadustat in Patients with Anemia and Non–Dialysis-Dependent CKD. N Engl J Med 2021; 384(17): 1589–1600.
  25. Eckardt K-U, Agarwal R, Aswad A, et al. Safety and Efficacy of Vadadustat for Anemia in Patients Undergoing Dialysis. N Engl J Med 2021; 384: 1601–1612.
  26. Chen N, Qian J, Chen J, et al. Phase 2 studies of oral hypoxia-inducible factor prolyl hydroxylase inhibitor FG-4592 for treatment of anemia in China. Nephrol Dial Transplant 2017; 32(8): 1373–1386.
  27. Akizawa T, Iwasaki M, Otsuka T, et al. Roxadustat Treatment of Chronic Kidney Disease-Associated Anemia in Japanese Patients Not on Dialysis: A Phase 2, Randomized, Double-Blind, Placebo-Controlled Trial. Adv Ther 2019; 36(6): 1438–1454.
  28. Singh AK, Carroll K, Perkovic V, et al. Daprodustat for the Treatment of Anemia in Patients Undergoing Dialysis. N Engl J Med 2021; 385(25): 2325–2335.
  29. Meadowcroft AM, Cizman B, Holdstock L, et al. Daprodustat for anemia: A 24-week, open-label, randomized controlled trial in participants on hemodialysis. Clin Kidney J 2019; 12(1): 139–148.
  30. Locatelli F, Fishbane S, Block GA, et al. Targeting Hypoxia-Inducible Factors for the Treatment of Anemia in Chronic Kidney Disease Patients. Am J Nephrol 2017; 45(3): 187–199.
  31. Pergola PE, Spinowitz BS, Hartman CS, et al. Vadadustat, a novel oral HIF stabilizer, provides effective anemia treatment in nondialysis-dependent chronic kidney disease. Kidney Int 2016; 90(5): 1115–1122.

How to Cite

Ni Wayan Anantika Riani, & I Gde Raka Widiana. (2022). Anemia on Chronic Kidney Disease: The Role of Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors. Intisari Sains Medis, 13(3), 694–697.




Search Panel

Ni Wayan Anantika Riani
Google Scholar
ISM Journal

I Gde Raka Widiana
Google Scholar
ISM Journal