This is a multi-center, randomized (1:1), open-label, active-controlled, pragmatic study of the efficacy of vadadustat administered three times a week compared to standard of care erythropoiesis-stimulating agent for the treatment of anemia in in-center hemodialysis participants with end-stage kidney disease (ESKD). A subset of sites will participate in a red blood cell (RBC) sub-study where changes in the phenotype of RBCs in response to vadadustat treatment relative to methoxy polyethylene glycol-epoetin beta treatment in DD-CKD participants with anemia will be assessed. A separate informed consent form (ICF) will be signed by these participants who opt to be in the RBC sub-study. Of the 350 participants in the main study, approximately 28 participants will also be enrolled into the RBC sub-study. The total duration of the study is approximately 35 Weeks including screening and follow-up.

Inclusion Criteria:

• Adult participants ≥18 years of age.
• Receiving outpatient in-center hemodialysis for ESKD at least three times a week.
• Currently prescribed or meets criteria for ESA based on approved facility policy.
• Hb > 8 grams per deciliter (g/dl).
• Serum ferritin ≥100 nanograms per milliliter (ng/mL) and transferrin saturation (TSAT) ≥20%.
• Understands the procedures and requirements of the study and provides written informed consent and authorization for protected health information disclosure.
• For selected sites, individuals who opt to participate in the RBC sub-study must meet the following inclusion criteria:
• Currently prescribed or will be prescribed methoxy polyethylene glycol-epoetin beta.
• Hb <11.5 g/dL

Exclusion Criteria:

• Contraindication to receive vadadustat per United States prescribing information (USPI) as determined by the treating health care provider.
• Concomitant use of any hypoxia-inducible factor prolyl hydroxylase inhibitor(HIF-PHI).
• Known cirrhosis or active, acute liver disease.
• Unable to comply with study requirements or compliance with attending dialysis treatments as prescribed, or in the opinion of the treating physician or Investigator, not clinically stable to participate in the study.
• Pregnant at the time of consent (per participant self-report).
• Any other reason, which in the opinion of the Investigator, would make the participants unsuitable for participation in the study.
• For selected sites, individuals who opt to participate in the RBC sub-study must also not meet the following exclusion criteria:
• History of, or currently diagnosed with, any hematological disease, such as sickle cell disease, thalassemia, hemochromatosis, Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency, myelodysplastic syndromes, or any other blood disorder that could interfere with the study outcomes.
• Participants will receive a blood transfusion within 3 months prior to the initiation of the study.
• History of or currently diagnosed with chronic lung disease