What is the treatment approach for anemia in Chronic Kidney Disease (CKD)?

Treatment of Anemia in CKD

First-Line Treatment: Iron Therapy

Iron supplementation, particularly intravenous iron, should be the initial treatment for anemia in CKD patients before considering erythropoiesis-stimulating agents (ESAs), as IV iron alone can significantly improve hemoglobin levels and may eliminate the need for ESA therapy. 1, 2

Iron Status Assessment and Treatment Thresholds

• Measure hemoglobin, transferrin saturation (TSAT), and serum ferritin in all CKD patients with anemia 1
• Initiate a trial of IV iron when TSAT is ≤30% and ferritin is ≤500 ng/mL 3, 1, 2
• Absolute iron deficiency is defined as TSAT <20% with ferritin <100 mg/L in non-dialysis patients or <200 mg/L in hemodialysis patients 3, 1
• Functional iron deficiency is defined as TSAT <20% with ferritin >100 mg/L in non-dialysis patients or >200 mg/L in hemodialysis patients 3, 1

Route of Iron Administration

For Non-Dialysis CKD (Stages 3-5):

• IV iron is superior to oral iron for achieving hemoglobin response >1 g/dL (risk ratio 1.61,95% CI 1.39-1.87) 4
• The FIND-CKD study demonstrated that IV iron dosed to target ferritin 400-600 mg/L was superior to oral iron or lower ferritin targets (100-200 mg/L) for achieving hemoglobin increase ≥1 g/dL 3
• For patients with milder anemia and TSAT <20% with ferritin <100 mg/L, a 1-3 month trial of oral iron is acceptable before escalating to IV iron 3, 1
• Oral iron is effective in only a minority of non-dialysis CKD patients due to inflammation-mediated hepcidin elevation limiting gut absorption 5

For Hemodialysis Patients (CKD Stage 5D):

• IV iron is strongly preferred over oral iron (risk ratio for hemoglobin response 2.14,95% CI 1.68-2.72) 4
• The PIVOTAL trial showed that proactive IV iron (administered unless ferritin >700 mg/L or TSAT >40%) was superior to reactive strategies (triggered only when TSAT <20% and ferritin <200 mg/L) 3
• Target TSAT ≥20% and ferritin ≥200 mg/L before considering ESA therapy 1

IV Iron Dosing Regimens

• Iron sucrose: 25-125 mg weekly for 8-10 weeks 3
• Iron dextran: 25-100 mg weekly for 10 weeks 3
• Ferric carboxymaltose: up to 1000 mg per week 1
• Ferumoxytol and ferric carboxymaltose appear to be among the most effective preparations based on network meta-analysis 6
• Administer IV iron as a course of treatment and monitor hemoglobin response 2 weeks after completion 2

Upper Safety Limits for Iron Therapy

• Withhold IV iron if ferritin >500 ng/mL and/or TSAT >30% 1, 2
• The upper limit of safety for ferritin and TSAT remains uncertain, though PIVOTAL used ferritin >700 mg/L and TSAT >40% as upper thresholds 3
• IV iron has been shown effective and safe across a wide ferritin range from <100 ng/mL to 800 ng/mL in dialysis patients 5
• Measure TSAT and ferritin no sooner than 2-7 days after the last dose for accurate monitoring; wait 14 days after doses ≥1 gram 3

Safety Considerations

• IV iron does not cause nephrotoxicity based on three randomized controlled trials 5
• IV iron carries higher risk of hypotension (RR 3.71,95% CI 1.74-7.94) but fewer gastrointestinal adverse events (RR 0.43,95% CI 0.28-0.67) compared to oral iron 4
• Monitor serum phosphate in patients receiving certain IV iron preparations, particularly in non-dialysis CKD and kidney transplant recipients 3
• Anaphylaxis is very rare but risk varies by formulation 3

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

Consider ESA therapy only after optimizing iron stores and if hemoglobin fails to improve adequately with IV iron alone. 2, 7

Indications for ESA Therapy

• Epoetin alfa (PROCRIT) is FDA-approved for treatment of anemia due to CKD in patients on dialysis and not on dialysis to decrease the need for RBC transfusion 8
• Initiate ESA only after ensuring all correctable causes of anemia have been addressed, including optimizing iron stores 2
• ESAs are most effective when iron stores are adequate (TSAT ≥20%, ferritin ≥100-200 mg/L depending on dialysis status) 3, 1

ESA Dosing and Iron Requirements

• ESAs increase iron utilization and decrease iron parameters, creating functional iron deficiency 3
• Most epoetin-treated hemodialysis patients require IV iron to maintain adequate iron stores 3
• A small percentage of hemodialysis patients and many peritoneal dialysis/non-dialysis CKD patients can maintain adequate iron stores with oral iron alone, possibly due to augmented intestinal absorption, smaller blood losses, and lower ESA requirements 3
• Frequent administration of low-dose IV iron (25-125 mg weekly) can reduce ESA requirements by 17-75% in hemodialysis patients 3

Limitations and Cautions

• ESAs have not been shown to improve quality of life, fatigue, or patient well-being 8
• Use ESAs with caution, balancing benefits of reducing transfusion needs against potential cardiovascular risks 2, 9
• Avoid ESAs in patients with active malignancy due to potential for tumor progression 9

Third-Line Treatment: Blood Transfusions

Reserve blood transfusions for specific clinical situations rather than reflexive use based solely on hemoglobin levels. 1, 2

Indications for Transfusion

• Patient becomes symptomatic from anemia 1, 2
• ESA therapy is ineffective or contraindicated 1, 2
• Rapid correction of anemia is required due to clinical deterioration 2
• Hemoglobin <7 g/dL with symptoms 9
• Acute decompensation or hemodynamic instability 9

Transfusion Risks

• Blood transfusions should generally be avoided when possible to minimize risks of allosensitization, which can complicate future kidney transplantation 1, 2
• Avoid reflexive transfusions based solely on hemoglobin level without considering patient's clinical status 1, 2

Emerging Therapies: HIF-Prolyl Hydroxylase Inhibitors (HIF-PHIs)

• HIF-PHIs are orally active agents that upregulate endogenous erythropoietin production and enhance iron availability by reducing hepcidin levels 7, 10
• These agents may have advantages in inflammatory conditions causing ESA resistance 7, 10
• Optimal iron management strategies for HIF-PHI therapy remain under investigation 3, 1
• Special consideration needed for specific populations including diabetic nephropathy with retinopathy and autosomal dominant polycystic kidney disease 3
• Long-term safety concerns exist and require further study 7

Monitoring Protocol

• For CKD patients with anemia not on ESA therapy: measure hemoglobin at least every 3 months 1, 2, 9
• Monitor iron status (ferritin, TSAT) before and after iron therapy to guide subsequent treatment decisions 1, 2
• Monitor iron parameters every 3 months during ongoing therapy 9
• Assess symptoms of anemia (fatigue, exercise tolerance, quality of life) at each visit 9

Common Pitfalls to Avoid

• Do not start ESAs before optimizing iron stores - this is the most common error in CKD anemia management 1, 2
• Do not continue IV iron when ferritin >500 ng/mL and TSAT >30% 1, 2
• Do not rely solely on ferritin levels in the setting of inflammation, as ferritin can be falsely elevated; TSAT provides better assessment of functional iron availability 3
• Do not transfuse based on hemoglobin number alone without considering clinical symptoms and transplant candidacy 1, 2
• Do not use oral iron as equivalent to IV iron in hemodialysis patients - IV iron is definitively superior 4