Inclusion Criteria:

Documentation of Anemia due to CKD

• Patients must have a Hb ≤ 9.5 g/dL on two separate occasions within 4 weeks prior to enrollment.
• Do not anticipate red cell transfusion within the following 4 weeks and no history of red cell transfusion in three weeks prior to enrollment.
• Ferritin ≥100 ng/mL and iron transferrin saturation (TSAT) ≥ 20%.
• Serum folate > 4 ng/mL
• Serum vitamin B12 > 250 pg/mL
• Patients may have received iron, B12 and folic acid repletion if initiated > 6 weeks prior to enrollment. Patients who are already on iron, B12 and folic acid repletion can continue throughout the trial.
• TSH, T4 within institutional normal limits. Documentation of Chronic Kidney Disease
• Chronic kidney disease defined as a GFR between 30-60 mL/min/1.73m2 for ≥ 3 months calculated by the 2021 CKD-EPI creatinine equation for eGFR, the 2021 CKD-EPI creatinine-cystatin C equation, or creatinine clearance measured by a 24-hour urine collection.

Prior Treatment with Erythrocyte Stimulating Agents (ESA)

• Eligible patients will not have had recent (within past 3 weeks) erythrocyte stimulating agents (ESA) prior to enrollment unless they are hyporesponsive to ESA therapy.
• Patients are eligible if they are either hyporesponsive to ESA therapy or unwilling to accept ESAs. defined by the Kidney Disease Outcomes Quality Initiative (KDOQI) as the inability to achieve/maintain a desired hemoglobin (herein defined as a hemoglobin of > 9.0 g/dL) using a maximum dose of erythropoietin (450 units/kg/week IV or 300 units/kg/week SQ or the darbepoetin equivalent using the conversion of 45,000 units/week of epoetin = 100 mcg/week of darbepoetin).
• Age ≥ 18
• ECOG Performance Status of ≤ 2
• Not Pregnant and Not Nursing Required Organ Function
• Adequate hematologic function defined as follows:
• Absolute neutrophil count (ANC) ≥ 1,000 cells/mm3
• Platelets ≥ 75,000 cells/mm3
• Adequate hepatic function defined as follows:
• Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) (patients with known Gilbert's disease who have bilirubin level ≤ 3 x ULN may be enrolled)
• AST and ALT ≤3 x institutional ULN
• Comorbid Conditions
• Patients with a history of a solid organ malignancy can be included if they have been in remission for at least 12 months.

Exclusion Criteria:

• Evidence of recent (within previous 4 weeks) bleeding including gastrointestinal to explain anemia.
• Evidence of hemolysis (LDH ≥ 2 x ULN and haptoglobin below lower limit of normal)
• Known diagnosis of myelodysplastic syndrome or any known hematologic malignancy [not including monoclonal of undetermined significance (MGUS) or monoclonal b-cell lymphocytosis (MBL)] not in remission
• GFR < 30 mL/min/1.73m2 or on dialysis (no available data for luspatercept on HD)
• Acute kidney injury ( ≤ 3 months)
• Uncontrolled hypertension: repeated elevations of SBP ≥ 150 mmHg and/or DBP ≥ 100 mmHg despite adequate treatment
• Known hemoglobinopathy.
• Known inherited or acquired thrombophilia.
• History of venous thromboembolism within past 2 years
• Cerebral vascular accident within past 2 years
• Recent (within 2 years) myocardial infarction
• Allergy to luspatercept components