When should erythropoietin (EPO) be initiated in patients with chronic kidney disease (CKD)?

When to Initiate Erythropoietin in CKD

Initiate erythropoietin therapy when hemoglobin falls below 10 g/dL (100 g/L) after correcting iron deficiency and excluding other reversible causes of anemia. 1, 2, 3

Pre-Treatment Requirements (Must Complete Before Starting ESA)

Before initiating any erythropoietin therapy, you must systematically address the following:

Iron Status Correction

• Verify transferrin saturation >20% AND serum ferritin >100 ng/mL (or mcg/L) before starting ESA therapy 1, 2, 3
• The majority of CKD patients will require supplemental iron during ESA therapy 2, 3
• Iron deficiency is the most common cause of ESA resistance 4

Exclude Reversible Causes of Anemia

Rule out the following before attributing anemia to CKD: 1, 4, 2, 3

• Vitamin B12 or folate deficiency
• Active bleeding
• Severe hyperparathyroidism
• Hypothyroidism
• Aluminum toxicity
• Inflammatory conditions (check C-reactive protein, as inflammation increases ESA requirements) 5

Baseline Blood Pressure Assessment

• Measure and control blood pressure before initiating therapy, as ESAs increase hypertension risk 1, 4

Initiation Thresholds by Patient Population

Adult Dialysis Patients (Hemodialysis or Peritoneal Dialysis)

• Initiate when hemoglobin is sustained below 10 g/dL 1, 2, 3
• Starting dose: 50-100 Units/kg three times weekly (intravenous route preferred for hemodialysis patients) 2, 3

Adult Non-Dialysis CKD Patients

• Consider initiating only when hemoglobin <10 g/dL AND both of the following apply: 2, 3
  • The rate of hemoglobin decline indicates likelihood of requiring RBC transfusion
  • Reducing the risk of alloimmunization and/or other RBC transfusion-related risks is a treatment goal
• Starting dose: 50-100 Units/kg three times weekly (intravenous or subcutaneous) 2, 3
• Do not start ESAs in asymptomatic non-dialysis patients until hemoglobin falls below 10 g/dL 1

Pediatric CKD Patients (≥1 month old)

• Initiate only when hemoglobin <10 g/dL 2, 3
• Starting dose: 50 Units/kg three times weekly (intravenous or subcutaneous) 2, 3

Target Hemoglobin Range

Target hemoglobin of 11 g/dL (110 g/L), with an acceptable range of 10-12 g/dL (100-120 g/L). 1, 4

Critical Safety Thresholds

• Never target hemoglobin >13 g/dL - this increases all-cause mortality (risk ratio 1.17), arteriovenous access thrombosis (risk ratio 1.34), and stroke risk 1, 6
• Reduce or interrupt ESA dose if hemoglobin approaches or exceeds 11 g/dL in dialysis patients 2, 3
• Reduce or interrupt ESA dose if hemoglobin exceeds 10 g/dL in non-dialysis patients 2, 3
• For pediatric patients, reduce or interrupt if hemoglobin approaches or exceeds 12 g/dL 2, 3

Monitoring Protocol

Initial Phase

• Monitor hemoglobin weekly after starting therapy or changing doses until stable 2, 3
• Once stable, monitor at least monthly 2, 3

Dose Adjustments

• Do not increase dose more frequently than once every 4 weeks (decreases can occur more frequently) 2, 3
• If hemoglobin rises rapidly (>1 g/dL in any 2-week period), reduce dose by 25% or more 2, 3
• If hemoglobin increases <1 g/dL after 4 weeks, increase dose by 25% 2, 3
• If no adequate response over 12 weeks of escalation, further dose increases are unlikely to help and may increase risks - discontinue ESA 2, 3

Route of Administration

Dialysis Patients

• Intravenous route is recommended for hemodialysis patients 2, 3
• Either intravenous or subcutaneous acceptable for peritoneal dialysis patients 1

Non-Dialysis and Peritoneal Dialysis Patients

• Subcutaneous route is preferred based on improved efficacy (requires 30% lower dose than IV) and convenience 1
• Subcutaneous administration requires 50% lower doses than intravenous if tolerated 4

Common Pitfalls to Avoid

Starting ESAs Too Early

• Do not initiate ESAs before correcting iron deficiency - this is the most common cause of poor response 4
• Asymptomatic non-dialysis patients should not receive ESAs until hemoglobin falls below 10 g/dL 1

Targeting Hemoglobin Too High

• Large randomized trials (CHOIR, CREATE, TREAT) demonstrated that targeting hemoglobin >13 g/dL provides no quality-of-life benefit and significantly increases cardiovascular events, stroke, and death 1, 6
• Even targeting 11-13 g/dL showed increased risks compared to 10-11 g/dL 1

Rapid Correction of Anemia

• Avoid hemoglobin increases >3 g/dL per month - this raises cardiovascular risk 4
• Reduce dose by 25% if hemoglobin increases >1 g/dL in any 2-week period 2, 3

Ignoring Blood Pressure

• ESAs increase hypertension risk - monitor and treat blood pressure aggressively throughout therapy 1, 4

Continuing ESAs Despite Non-Response

• If no response after 12 weeks of dose escalation, continuing ESAs increases risks without benefit 2, 3
• Evaluate for other causes of anemia and consider discontinuation 2, 3

Special Considerations

Diabetic CKD Patients

• Use ESAs cautiously in diabetic patients with CKD, as they have increased stroke risk (TREAT trial showed hazard ratio 1.92 for stroke in higher hemoglobin group) 6
• Low endogenous erythropoietin concentrations are a major factor in diabetic nephropathy 5

Patients with Cardiovascular Disease

• The risk-benefit ratio is less favorable in patients with existing cardiovascular disease 6
• Weigh the benefits of reducing transfusions against increased cardiovascular risks 2, 3

ESA Resistance

• Inflammation (elevated C-reactive protein) significantly increases ESA requirements 5
• Women often require higher ESA doses than men, possibly related to androgen level differences 5
• Functional iron deficiency is the principal reason for lack of ESA response - ensure adequate iron supplementation 1