Therapeutic Advancements in Anemia of Chronic Kidney Disease and End Stage Kidney Disease
Main Article Content
Abstract
Anemia is a frequent complication during the late stages of chronic kidney disease, reaching an almost universal prevalence among those with end stage kidney disease. There is a clear association between anemia and an increased risk for decline in the estimated glomerular filtration rate, cardiovascular events, and all-cause mortality. The main mechanisms for the development of anemia related to chronic kidney disease are a relative erythropoietin deficiency and disordered iron homeostasis related to chronic inflammation. Recent improvements in the understanding of the pathophysiology of anemia in chronic kidney disease have advanced the diagnosis and treatment of anemia in chronic kidney disease. While the cornerstone of the diagnosis of anemia related to chronic kidney disease remains excluding other etiologies of anemia, newer diagnostic resources include population-informed cutoffs for traditional measures of iron storage as well as evolving diagnostics of the reticulocyte hemoglobin index and percent hypochromic red blood cells in plasma. Intravenous iron has emerged as a novel tool for both the diagnosis and treatment of disordered iron homeostasis in the anemia of chronic kidney disease. Outside of iron replacement, the treatment of the anemia of chronic kidney disease has traditionally relied on erythropoiesis stimulating agents. A newer class of medications, the Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors, are an emerging therapy that work by stimulating the transcription of the erythropoietin gene in the Kidney and Liver. These agents are oral therapy, unlike erythropoiesis-stimulating agents, and are used in those who fail to respond to traditional therapy. Additional novel and experimental therapies include SGLT2 inhibitors, inhibitors of hepcidin production, and novel oral and intravenous iron formulations. This review encompasses the highlights of the epidemiology, pathophysiology, and the recent diagnostic and therapeutic advancements for anemia in chronic kidney disease.
Article Details
How to Cite
SHARMA, Neeraj et al.
Therapeutic Advancements in Anemia of Chronic Kidney Disease and End Stage Kidney Disease.
Medical Research Archives, [S.l.], v. 12, n. 10, oct. 2024.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/5815>. Date accessed: 22 dec. 2024.
doi: https://doi.org/10.18103/mra.v12i10.5815.
Section
Review Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
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2. Ryu SR, Park SK, Jung JY, et al. The Prevalence and Management of Anemia in Chronic Kidney Disease Patients: Result from the KoreaN Cohort Study for Outcomes in Patients With Chronic Kidney Disease (KNOW-CKD). J Korean Med Sci. 2017;32(2):249-256. doi:10.3346/jkms.2017.32.2.249
3. Stauffer ME, Fan T. Prevalence of Anemia in Chronic Kidney Disease in the United States. PLOS ONE. 2014;9(1):e84943. doi:10.1371/journal.pone.0084943
4. Babitt JL, Lin HY. Mechanisms of Anemia in CKD. J Am Soc Nephrol JASN. 2012;23(10):1631-1634. doi:10.1681/ASN.2011111078
5. Nutritional anaemias. Report of a WHO scientific group. World Health Organ Tech Rep Ser. 1968;405:5-37.
6. Chisholm H. Encyclopædia Britannic. In: Christison, Sir Robert. Vol 6. 11th ed. ; 1911:292-293.
7. On Granular Degeneration of the Kidneys, and Its Connection with Dropsy, Inflammation, and Other Diseases. Edinb Med Surg J. 1840;54(144):234-244.
8. Foley RN, Parfrey PS, Harnett JD, Kent GM, Murray DC, Barre PE. The impact of anemia on cardiomyopathy, morbidity, and and mortality in end-stage renal disease. Am J Kidney Dis Off J Natl Kidney Found. 1996;28(1):53-61. doi:10.1016/s0272-6386(96)90130-4
9. Liang R, Ghaffari S. Advances in understanding the mechanisms of erythropoiesis in homeostasis and disease. Br J Haematol. 2016;174(5):661-673. doi:10.1111/bjh.14194
10. Babitt JL, Eisenga MF, Haase VH, et al. Controversies in optimal anemia management: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Conference. Kidney Int. 2021;99(6):1280-1295. doi:10.1016/j.kint.2021.03.020
11. Jadoul M, Aoun M, Masimango Imani M. The major global burden of chronic kidney disease. Lancet Glob Health. 2024;12(3):e342-e343. doi:10.1016/S2214-109X(24)00050-0
12. United States Renal Data System. 2023 USRDS Annual Data Report: Chronic Kidney Disease. Published online 2023.
13. Nissenson AR, Wade S, Goodnough T, Knight K, Dubois RW. Economic burden of anemia in an insured population. J Manag Care Pharm JMCP. 2005;11(7):565-574. doi:10.18553/jmcp.2005.11.7.565
14. Kovesdy CP, Davis JR, Duling I, Little DJ. Prevalence of anaemia in adults with chronic kidney disease in a representative sample of the United States population: analysis of the 1999-2018 National Health and Nutrition Examination Survey. Clin Kidney J. 2023;16(2):303-311. doi:10.1093/ckj/sfac240
15. Evans M, Bower H, Cockburn E, Jacobson SH, Barany P, Carrero JJ. Contemporary management of anaemia, erythropoietin resistance and cardiovascular risk in patients with advanced chronic kidney disease: a nationwide analysis. Clin Kidney J. 2020;13(5):821-827. doi:10.1093/ckj/sfaa054
16. Jacobson LO, Goldwasser E, Fried W, Plzak L. Role of the kidney in erythropoiesis. Nature. 1957;179(4560):633-634. doi:10.1038/179633a0
17. Fried W. Erythropoietin and the kidney. Nephron. 1975;15(3-5):327-349. doi:10.1159/000180519
18. Shih HM, Wu CJ, Lin SL. Physiology and pathophysiology of renal erythropoietin-producing cells. J Formos Med Assoc Taiwan Yi Zhi. 2018;117(11):955-963. doi:10.1016/j.jfma.2018.03.017
19. Vuori K, Pihlajaniemi T, Marttila M, Kivirikko KI. Characterization of the human prolyl 4-hydroxylase tetramer and its multifunctional protein disulfide-isomerase subunit synthesized in a baculovirus expression system. Proc Natl Acad Sci U S A. 1992;89(16):7467-7470. doi:10.1073/pnas.89.16.7467
20. McGonigle RJ, Wallin JD, Shadduck RK, Fisher JW. Erythropoietin deficiency and inhibition of erythropoiesis in renal insufficiency. Kidney Int. 1984;25(2):437-444. doi:10.1038/ki.1984.36
21. Rege AB, Brookins J, Fisher JW. A radioimmunoassay for erythropoietin: serum levels in normal human subjects and patients with hemopoietic disorders. J Lab Clin Med. 1982;100(6):829-843.
22. KDOQI, National Kidney Foundation. KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease. Am J Kidney Dis Off J Natl Kidney Found. 2006;47(5 Suppl 3):S11-145. doi:10.1053/j.ajkd.2006.03.010
23. Gafter-Gvili A, Schechter A, Rozen-Zvi B. Iron Deficiency Anemia in Chronic Kidney Disease. Acta Haematol. 2019;142(1):44-50. doi:10.1159/000496492
24. Tsukamoto T, Matsubara T, Akashi Y, Kondo M, Yanagita M. Annual Iron Loss Associated with Hemodialysis. Am J Nephrol. 2016;43(1):32-38. doi:10.1159/000444335
25. Shepshelovich D, Rozen-Zvi B, Avni T, Gafter U, Gafter-Gvili A. Intravenous Versus Oral Iron Supplementation for the Treatment of Anemia in CKD: An Updated Systematic Review and Meta-analysis. Am J Kidney Dis Off J Natl Kidney Found. 2016;68(5):677-690. doi:10.1053/j.ajkd.2016.04.018
26. Leung AKC, Lam JM, Wong AHC, Hon KL, Li X. Iron Deficiency Anemia: An Updated Review. Curr Pediatr Rev. 2024;20(3):339-356. doi:10.2174/1573396320666230727102042
27. Santos-Silva A, Ribeiro S, Reis F, Belo L. Hepcidin in chronic kidney disease anemia. Vitam Horm. 2019;110:243-264. doi:10.1016/bs.vh.2019.01.012
28. Camaschella C, Nai A, Silvestri L. Iron metabolism and iron disorders revisited in the hepcidin era. Haematologica. 2020;105(2):260-272. doi:10.3324/haematol.2019.232124
29. Madu AJ, Ughasoro MD. Anaemia of Chronic Disease: An In-Depth Review. Med Princ Pract. 2017;26(1):1-9. doi:10.1159/000452104
30. J Z, B Y, Hj W, et al. Hepcidin--a potential novel biomarker for iron status in chronic kidney disease. Clin J Am Soc Nephrol CJASN. 2009;4(6). doi:10.2215/CJN.05931108
31. Hanudel MR, Rappaport M, Gabayan V, et al. Increased serum hepcidin contributes to the anemia of chronic kidney disease in a murine model. Haematologica. 2017;102(3):e85-e88. doi:10.3324/haematol.2016.150433
32. Guedes M, Muenz DG, Zee J, et al. Serum Biomarkers of Iron Stores Are Associated with Increased Risk of All-Cause Mortality and Cardiovascular Events in Nondialysis CKD Patients, with or without Anemia. J Am Soc Nephrol. 2021;32(8):2020-2030. doi:10.1681/ASN.2020101531
33. Astor BC, Muntner P, Levin A, Eustace JA, Coresh J. Association of kidney function with anemia: the Third National Health and Nutrition Examination Survey (1988-1994). Arch Intern Med. 2002;162(12):1401-1408. doi:10.1001/archinte.162.12.1401
34. Válka J, Čermák J. Differential diagnosis of anemia. Vnitr Lek. 2018;64(5):468-475.
35. Stancu S, Bârsan L, Stanciu A, Mircescu G. Can the Response to Iron Therapy Be Predicted in Anemic Nondialysis Patients with Chronic Kidney Disease? Clin J Am Soc Nephrol. 2010;5(3):409-416. doi:10.2215/CJN.04280609
36. Ratcliffe LEK, Thomas W, Glen J, et al. Diagnosis and Management of Iron Deficiency in CKD: A Summary of the NICE Guideline Recommendations and Their Rationale. Am J Kidney Dis Off J Natl Kidney Found. 2016;67(4):548-558. doi:10.1053/j.ajkd.2015.11.012
37. Macdougall IC. What is the most appropriate strategy to monitor functional iron deficiency in the dialysed patient on rhEPO therapy? Merits of percentage hypochromic red cells as a marker of functional iron deficiency. Nephrol Dial Transplant Off Publ Eur Dial Transpl Assoc - Eur Ren Assoc. 1998;13(4):847-849. doi:10.1093/ndt/13.4.847
38. Macdougall IC, White C, Anker SD, et al. Intravenous Iron in Patients Undergoing Maintenance Hemodialysis. N Engl J Med. 2019;380(5):447-458. doi:10.1056/NEJMoa1810742
39. Hu X, Xie J, Chen N. Hypoxia-Inducible Factor-Proline Hydroxylase Inhibitor in the Treatment of Renal Anemia. Kidney Dis Basel Switz. 2021;7(1):1-9. doi:10.1159/000510587
40. 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. doi:10.1056/NEJMoa2113379
41. Coyne DW, Singh AK, Lopes RD, et al. Three Times Weekly Dosing of Daprodustat versus Conventional Epoetin for Treatment of Anemia in Hemodialysis Patients: ASCEND-TD: A Phase 3 Randomized, Double-Blind, Noninferiority Trial. Clin J Am Soc Nephrol CJASN. 2022;17(9):1325-1336. doi:10.2215/CJN.00550122
42. Akizawa T, Iwasaki M, Yamaguchi Y, Majikawa Y, Reusch M. Phase 3, Randomized, Double-Blind, Active-Comparator (Darbepoetin Alfa) Study of Oral Roxadustat in CKD Patients with Anemia on Hemodialysis in Japan. J Am Soc Nephrol JASN. 2020;31(7):1628-1639. doi:10.1681/ASN.2019060623
43. Liu J, Zhang A, Hayden JC, et al. Roxadustat (FG-4592) treatment for anemia in dialysis-dependent (DD) and not dialysis-dependent (NDD) chronic kidney disease patients: A systematic review and meta-analysis. Pharmacol Res. 2020;155:104747. doi:10.1016/j.phrs.2020.104747
44. Eckardt KU, Agarwal R, Aswad A, et al. Safety and Efficacy of Vadadustat for Anemia in Patients Undergoing Dialysis. N Engl J Med. 2021;384(17):1601-1612. doi:10.1056/NEJMoa2025956
45. KDOQI, National Kidney Foundation. KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease. Am J Kidney Dis Off J Natl Kidney Found. 2006;47(5 Suppl 3):S11-145. doi:10.1053/j.ajkd.2006.03.010
46. Cizman B, Sykes AP, Paul G, Zeig S, Cobitz AR. An Exploratory Study of Daprodustat in Erythropoietin-Hyporesponsive Subjects. Kidney Int Rep. 2018;3(4):841-850. doi:10.1016/j.ekir.2018.02.009
47. Chen P, Nirula A, Heller B, et al. SARS-CoV-2 Neutralizing Antibody LY-CoV555 in Outpatients with Covid-19. N Engl J Med. Published online October 28, 2020. doi:10.1056/NEJMoa2029849
48. Shutov E, Sułowicz W, Esposito C, et al. Roxadustat for the treatment of anemia in chronic kidney disease patients not on dialysis: a Phase 3, randomized, double-blind, placebo-controlled study (ALPS). Nephrol Dial Transplant Off Publ Eur Dial Transpl Assoc - Eur Ren Assoc. 2021;36(9):1629-1639. doi:10.1093/ndt/gfab057
49. Fishbane S, El-Shahawy MA, Pecoits-Filho R, et al. Roxadustat for Treating Anemia in Patients with CKD Not on Dialysis: Results from a Randomized Phase 3 Study. J Am Soc Nephrol JASN. 2021;32(3):737-755. doi:10.1681/ASN.2020081150
50. 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. doi:10.1056/NEJMoa2035938
51. Cunningham JW, Claggett BL, Lopes RD, et al. Daprodustat and Heart Failure in CKD. J Am Soc Nephrol JASN. 2024;35(5):607-617. doi:10.1681/ASN.0000000000000321
52. Kanbay M, Tapoi L, Ureche C, et al. Effect of sodium-glucose cotransporter 2 inhibitors on hemoglobin and hematocrit levels in type 2 diabetes: a systematic review and meta-analysis. Int Urol Nephrol. 2022;54(4):827-841. doi:10.1007/s11255-021-02943-2
53. The EMPA-KIDNEY Collaborative Group. Empagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2023;388(2):117-127. doi:10.1056/NEJMoa2204233
2. Ryu SR, Park SK, Jung JY, et al. The Prevalence and Management of Anemia in Chronic Kidney Disease Patients: Result from the KoreaN Cohort Study for Outcomes in Patients With Chronic Kidney Disease (KNOW-CKD). J Korean Med Sci. 2017;32(2):249-256. doi:10.3346/jkms.2017.32.2.249
3. Stauffer ME, Fan T. Prevalence of Anemia in Chronic Kidney Disease in the United States. PLOS ONE. 2014;9(1):e84943. doi:10.1371/journal.pone.0084943
4. Babitt JL, Lin HY. Mechanisms of Anemia in CKD. J Am Soc Nephrol JASN. 2012;23(10):1631-1634. doi:10.1681/ASN.2011111078
5. Nutritional anaemias. Report of a WHO scientific group. World Health Organ Tech Rep Ser. 1968;405:5-37.
6. Chisholm H. Encyclopædia Britannic. In: Christison, Sir Robert. Vol 6. 11th ed. ; 1911:292-293.
7. On Granular Degeneration of the Kidneys, and Its Connection with Dropsy, Inflammation, and Other Diseases. Edinb Med Surg J. 1840;54(144):234-244.
8. Foley RN, Parfrey PS, Harnett JD, Kent GM, Murray DC, Barre PE. The impact of anemia on cardiomyopathy, morbidity, and and mortality in end-stage renal disease. Am J Kidney Dis Off J Natl Kidney Found. 1996;28(1):53-61. doi:10.1016/s0272-6386(96)90130-4
9. Liang R, Ghaffari S. Advances in understanding the mechanisms of erythropoiesis in homeostasis and disease. Br J Haematol. 2016;174(5):661-673. doi:10.1111/bjh.14194
10. Babitt JL, Eisenga MF, Haase VH, et al. Controversies in optimal anemia management: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Conference. Kidney Int. 2021;99(6):1280-1295. doi:10.1016/j.kint.2021.03.020
11. Jadoul M, Aoun M, Masimango Imani M. The major global burden of chronic kidney disease. Lancet Glob Health. 2024;12(3):e342-e343. doi:10.1016/S2214-109X(24)00050-0
12. United States Renal Data System. 2023 USRDS Annual Data Report: Chronic Kidney Disease. Published online 2023.
13. Nissenson AR, Wade S, Goodnough T, Knight K, Dubois RW. Economic burden of anemia in an insured population. J Manag Care Pharm JMCP. 2005;11(7):565-574. doi:10.18553/jmcp.2005.11.7.565
14. Kovesdy CP, Davis JR, Duling I, Little DJ. Prevalence of anaemia in adults with chronic kidney disease in a representative sample of the United States population: analysis of the 1999-2018 National Health and Nutrition Examination Survey. Clin Kidney J. 2023;16(2):303-311. doi:10.1093/ckj/sfac240
15. Evans M, Bower H, Cockburn E, Jacobson SH, Barany P, Carrero JJ. Contemporary management of anaemia, erythropoietin resistance and cardiovascular risk in patients with advanced chronic kidney disease: a nationwide analysis. Clin Kidney J. 2020;13(5):821-827. doi:10.1093/ckj/sfaa054
16. Jacobson LO, Goldwasser E, Fried W, Plzak L. Role of the kidney in erythropoiesis. Nature. 1957;179(4560):633-634. doi:10.1038/179633a0
17. Fried W. Erythropoietin and the kidney. Nephron. 1975;15(3-5):327-349. doi:10.1159/000180519
18. Shih HM, Wu CJ, Lin SL. Physiology and pathophysiology of renal erythropoietin-producing cells. J Formos Med Assoc Taiwan Yi Zhi. 2018;117(11):955-963. doi:10.1016/j.jfma.2018.03.017
19. Vuori K, Pihlajaniemi T, Marttila M, Kivirikko KI. Characterization of the human prolyl 4-hydroxylase tetramer and its multifunctional protein disulfide-isomerase subunit synthesized in a baculovirus expression system. Proc Natl Acad Sci U S A. 1992;89(16):7467-7470. doi:10.1073/pnas.89.16.7467
20. McGonigle RJ, Wallin JD, Shadduck RK, Fisher JW. Erythropoietin deficiency and inhibition of erythropoiesis in renal insufficiency. Kidney Int. 1984;25(2):437-444. doi:10.1038/ki.1984.36
21. Rege AB, Brookins J, Fisher JW. A radioimmunoassay for erythropoietin: serum levels in normal human subjects and patients with hemopoietic disorders. J Lab Clin Med. 1982;100(6):829-843.
22. KDOQI, National Kidney Foundation. KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease. Am J Kidney Dis Off J Natl Kidney Found. 2006;47(5 Suppl 3):S11-145. doi:10.1053/j.ajkd.2006.03.010
23. Gafter-Gvili A, Schechter A, Rozen-Zvi B. Iron Deficiency Anemia in Chronic Kidney Disease. Acta Haematol. 2019;142(1):44-50. doi:10.1159/000496492
24. Tsukamoto T, Matsubara T, Akashi Y, Kondo M, Yanagita M. Annual Iron Loss Associated with Hemodialysis. Am J Nephrol. 2016;43(1):32-38. doi:10.1159/000444335
25. Shepshelovich D, Rozen-Zvi B, Avni T, Gafter U, Gafter-Gvili A. Intravenous Versus Oral Iron Supplementation for the Treatment of Anemia in CKD: An Updated Systematic Review and Meta-analysis. Am J Kidney Dis Off J Natl Kidney Found. 2016;68(5):677-690. doi:10.1053/j.ajkd.2016.04.018
26. Leung AKC, Lam JM, Wong AHC, Hon KL, Li X. Iron Deficiency Anemia: An Updated Review. Curr Pediatr Rev. 2024;20(3):339-356. doi:10.2174/1573396320666230727102042
27. Santos-Silva A, Ribeiro S, Reis F, Belo L. Hepcidin in chronic kidney disease anemia. Vitam Horm. 2019;110:243-264. doi:10.1016/bs.vh.2019.01.012
28. Camaschella C, Nai A, Silvestri L. Iron metabolism and iron disorders revisited in the hepcidin era. Haematologica. 2020;105(2):260-272. doi:10.3324/haematol.2019.232124
29. Madu AJ, Ughasoro MD. Anaemia of Chronic Disease: An In-Depth Review. Med Princ Pract. 2017;26(1):1-9. doi:10.1159/000452104
30. J Z, B Y, Hj W, et al. Hepcidin--a potential novel biomarker for iron status in chronic kidney disease. Clin J Am Soc Nephrol CJASN. 2009;4(6). doi:10.2215/CJN.05931108
31. Hanudel MR, Rappaport M, Gabayan V, et al. Increased serum hepcidin contributes to the anemia of chronic kidney disease in a murine model. Haematologica. 2017;102(3):e85-e88. doi:10.3324/haematol.2016.150433
32. Guedes M, Muenz DG, Zee J, et al. Serum Biomarkers of Iron Stores Are Associated with Increased Risk of All-Cause Mortality and Cardiovascular Events in Nondialysis CKD Patients, with or without Anemia. J Am Soc Nephrol. 2021;32(8):2020-2030. doi:10.1681/ASN.2020101531
33. Astor BC, Muntner P, Levin A, Eustace JA, Coresh J. Association of kidney function with anemia: the Third National Health and Nutrition Examination Survey (1988-1994). Arch Intern Med. 2002;162(12):1401-1408. doi:10.1001/archinte.162.12.1401
34. Válka J, Čermák J. Differential diagnosis of anemia. Vnitr Lek. 2018;64(5):468-475.
35. Stancu S, Bârsan L, Stanciu A, Mircescu G. Can the Response to Iron Therapy Be Predicted in Anemic Nondialysis Patients with Chronic Kidney Disease? Clin J Am Soc Nephrol. 2010;5(3):409-416. doi:10.2215/CJN.04280609
36. Ratcliffe LEK, Thomas W, Glen J, et al. Diagnosis and Management of Iron Deficiency in CKD: A Summary of the NICE Guideline Recommendations and Their Rationale. Am J Kidney Dis Off J Natl Kidney Found. 2016;67(4):548-558. doi:10.1053/j.ajkd.2015.11.012
37. Macdougall IC. What is the most appropriate strategy to monitor functional iron deficiency in the dialysed patient on rhEPO therapy? Merits of percentage hypochromic red cells as a marker of functional iron deficiency. Nephrol Dial Transplant Off Publ Eur Dial Transpl Assoc - Eur Ren Assoc. 1998;13(4):847-849. doi:10.1093/ndt/13.4.847
38. Macdougall IC, White C, Anker SD, et al. Intravenous Iron in Patients Undergoing Maintenance Hemodialysis. N Engl J Med. 2019;380(5):447-458. doi:10.1056/NEJMoa1810742
39. Hu X, Xie J, Chen N. Hypoxia-Inducible Factor-Proline Hydroxylase Inhibitor in the Treatment of Renal Anemia. Kidney Dis Basel Switz. 2021;7(1):1-9. doi:10.1159/000510587
40. 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. doi:10.1056/NEJMoa2113379
41. Coyne DW, Singh AK, Lopes RD, et al. Three Times Weekly Dosing of Daprodustat versus Conventional Epoetin for Treatment of Anemia in Hemodialysis Patients: ASCEND-TD: A Phase 3 Randomized, Double-Blind, Noninferiority Trial. Clin J Am Soc Nephrol CJASN. 2022;17(9):1325-1336. doi:10.2215/CJN.00550122
42. Akizawa T, Iwasaki M, Yamaguchi Y, Majikawa Y, Reusch M. Phase 3, Randomized, Double-Blind, Active-Comparator (Darbepoetin Alfa) Study of Oral Roxadustat in CKD Patients with Anemia on Hemodialysis in Japan. J Am Soc Nephrol JASN. 2020;31(7):1628-1639. doi:10.1681/ASN.2019060623
43. Liu J, Zhang A, Hayden JC, et al. Roxadustat (FG-4592) treatment for anemia in dialysis-dependent (DD) and not dialysis-dependent (NDD) chronic kidney disease patients: A systematic review and meta-analysis. Pharmacol Res. 2020;155:104747. doi:10.1016/j.phrs.2020.104747
44. Eckardt KU, Agarwal R, Aswad A, et al. Safety and Efficacy of Vadadustat for Anemia in Patients Undergoing Dialysis. N Engl J Med. 2021;384(17):1601-1612. doi:10.1056/NEJMoa2025956
45. KDOQI, National Kidney Foundation. KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease. Am J Kidney Dis Off J Natl Kidney Found. 2006;47(5 Suppl 3):S11-145. doi:10.1053/j.ajkd.2006.03.010
46. Cizman B, Sykes AP, Paul G, Zeig S, Cobitz AR. An Exploratory Study of Daprodustat in Erythropoietin-Hyporesponsive Subjects. Kidney Int Rep. 2018;3(4):841-850. doi:10.1016/j.ekir.2018.02.009
47. Chen P, Nirula A, Heller B, et al. SARS-CoV-2 Neutralizing Antibody LY-CoV555 in Outpatients with Covid-19. N Engl J Med. Published online October 28, 2020. doi:10.1056/NEJMoa2029849
48. Shutov E, Sułowicz W, Esposito C, et al. Roxadustat for the treatment of anemia in chronic kidney disease patients not on dialysis: a Phase 3, randomized, double-blind, placebo-controlled study (ALPS). Nephrol Dial Transplant Off Publ Eur Dial Transpl Assoc - Eur Ren Assoc. 2021;36(9):1629-1639. doi:10.1093/ndt/gfab057
49. Fishbane S, El-Shahawy MA, Pecoits-Filho R, et al. Roxadustat for Treating Anemia in Patients with CKD Not on Dialysis: Results from a Randomized Phase 3 Study. J Am Soc Nephrol JASN. 2021;32(3):737-755. doi:10.1681/ASN.2020081150
50. 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. doi:10.1056/NEJMoa2035938
51. Cunningham JW, Claggett BL, Lopes RD, et al. Daprodustat and Heart Failure in CKD. J Am Soc Nephrol JASN. 2024;35(5):607-617. doi:10.1681/ASN.0000000000000321
52. Kanbay M, Tapoi L, Ureche C, et al. Effect of sodium-glucose cotransporter 2 inhibitors on hemoglobin and hematocrit levels in type 2 diabetes: a systematic review and meta-analysis. Int Urol Nephrol. 2022;54(4):827-841. doi:10.1007/s11255-021-02943-2
53. The EMPA-KIDNEY Collaborative Group. Empagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2023;388(2):117-127. doi:10.1056/NEJMoa2204233