What medication should be given to a patient with Chronic Kidney Disease (CKD) and anemia?

Treatment of Anemia in CKD: Iron First, Then ESAs

For CKD patients with anemia, initiate treatment with iron supplementation (oral or intravenous) as first-line therapy, followed by erythropoiesis-stimulating agents (ESAs) only if hemoglobin remains below 10 g/dL after iron repletion, targeting hemoglobin levels of 10-12 g/dL to minimize cardiovascular risks and mortality. 1

Initial Evaluation and Iron Status Assessment

Before starting any anemia treatment, obtain baseline laboratory tests including complete blood count, absolute reticulocyte count, serum ferritin, transferrin saturation (TSAT), and vitamin B12/folate levels 1. Monitor iron parameters (TSAT and ferritin) at least every 3 months during ongoing treatment 2, 1.

Iron Deficiency Criteria in CKD

The diagnostic thresholds for iron deficiency differ in CKD compared to the general population:

• Absolute iron deficiency: TSAT ≤20% and ferritin ≤100 ng/mL (predialysis/peritoneal dialysis patients) or ≤200 ng/mL (hemodialysis patients) 3
• Functional iron deficiency: TSAT ≤20% with elevated ferritin levels 3

First-Line Treatment: Iron Supplementation

When to Initiate Iron Therapy

Start iron supplementation when TSAT ≤30% and ferritin ≤500 ng/mL in patients not yet receiving ESA therapy 2, 1. This applies to both dialysis and non-dialysis CKD patients.

Route of Administration

• Intravenous iron is preferred for hemodialysis patients and is generally more effective than oral iron 2, 3
• Oral iron may be attempted as a 1-3 month trial in non-dialysis CKD patients, though IV iron remains an acceptable alternative 2, 1
• Available IV formulations include iron dextran, sodium ferric gluconate complex, and iron sucrose 2

Critical safety consideration: When administering the initial dose of IV iron dextran, monitor patients for 60 minutes post-infusion with resuscitative facilities and trained personnel available 2. For non-dextran IV iron preparations, similar monitoring is suggested though with slightly less stringent requirements 2.

Second-Line Treatment: Erythropoiesis-Stimulating Agents (ESAs)

When to Initiate ESA Therapy

Begin ESA therapy only after:

1. Iron stores have been adequately corrected 2, 1
2. Other reversible causes of anemia have been addressed (vitamin B12/folate deficiency, hypothyroidism, hemoglobinopathies, blood loss) 2, 1
3. Hemoglobin remains below 10 g/dL despite iron repletion 1, 4

ESA Options and Dosing

For dialysis patients (hemoglobin <10 g/dL):

• Epoetin alfa: 50-100 units/kg subcutaneously three times weekly, or 40,000 units once weekly 5
• Darbepoetin alfa: 0.45 mcg/kg IV or subcutaneously weekly, or 0.75 mcg/kg every 2 weeks 4
• Intravenous route is recommended for hemodialysis patients 4

For non-dialysis CKD patients (hemoglobin <10 g/dL):

• Epoetin alfa: Same dosing as dialysis patients 5
• Darbepoetin alfa: 0.45 mcg/kg subcutaneously every 4 weeks 4
• Subcutaneous administration is preferred to preserve veins for potential future dialysis access 5, 6

Hemoglobin Targets and Monitoring

Target hemoglobin: 10-12 g/dL 2, 1, 5, 4. This range balances the benefits of reducing transfusions against the increased risks of death, stroke, and cardiovascular events associated with higher targets 2, 1, 4.

• Monitor hemoglobin at least weekly until stable, then monthly 4
• If hemoglobin rises >1 g/dL in any 2-week period, reduce ESA dose by 25% or more 4
• If hemoglobin approaches or exceeds 11 g/dL (dialysis patients) or 10 g/dL (non-dialysis patients), reduce or interrupt ESA dosing 4

Critical Contraindications and Cautions

Do not use ESAs or use with extreme caution in patients with:

• Active malignancy, particularly when cure is anticipated 2, 1
• History of stroke 2, 1
• Uncontrolled hypertension 1

The FDA explicitly warns that targeting hemoglobin >11 g/dL increases risks of death, serious cardiovascular reactions, and stroke 4.

Managing ESA Hyporesponsiveness

Classify patients as ESA-hyporesponsive if hemoglobin fails to increase after the first month of appropriate weight-based dosing 1. Do not escalate ESA doses beyond 12 weeks if no response occurs, as further increases are unlikely to help and may increase risks 4.

Investigate These Causes:

• Absolute or functional iron deficiency (most common) 1, 3
• Infection or chronic inflammation with elevated hepcidin 3, 7
• Hyperparathyroidism 1
• Aluminum toxicity 1
• Vitamin B12 or folate deficiency 1, 5
• Occult blood loss or hemolysis 1
• Bone marrow disorders or malignancy 1

Adjunctive Therapies: What NOT to Use

Avoid these agents due to lack of efficacy or safety concerns:

• Androgens: Associated with significant toxicity (virilization, hepatic dysfunction, hepatocellular carcinoma) without proven benefit 2
• L-carnitine: Insufficient evidence of efficacy despite some small trials 2, 5
• Vitamin C: Safety not established in CKD; concerns about pro-oxidant effects and oxalosis 2, 5

Emerging Therapies: HIF-Prolyl Hydroxylase Inhibitors

Newer oral agents like desidustat, roxadustat, and vadadustat represent an alternative to injectable ESAs 8, 7. These drugs increase endogenous erythropoietin production and improve iron availability by reducing hepcidin 7, 9.

Key considerations:

• Target the same hemoglobin range (10-12 g/dL) as with ESAs 8
• Contraindicated in polycystic kidney disease until more safety data emerge 8
• Not recommended for pediatric patients 8
• Long-term cardiovascular safety data remain limited compared to traditional ESAs 8, 9

Transfusion Therapy: Last Resort

Avoid red blood cell transfusions when possible to minimize allosensitization and transfusion-related risks 1. Consider transfusion only when ESA therapy is ineffective, risks of ESA therapy outweigh benefits, or immediate correction of anemia is required 1.

Common Pitfalls to Avoid

1. Starting ESAs before correcting iron deficiency: Iron must be repleted first 2, 1
2. Targeting hemoglobin >12 g/dL: This significantly increases cardiovascular risks and mortality 2, 4
3. Rapid hemoglobin increases: Rises >1 g/dL per 2 weeks require immediate dose reduction 4
4. Continuing to escalate ESA doses in non-responders: After 12 weeks without response, investigate other causes rather than increasing doses further 4
5. Using ESAs in patients with active malignancy: This can worsen outcomes, particularly when cure is the goal 2, 1