Anemia of chronic kidney disease
ICD-10 D63.1 · ICD-11 3A71.2

Anemia of Chronic Kidney Disease (Not on Dialysis): What to Do When Erythropoiesis-Stimulating Agent Therapy Has Not Worked

This protocol addresses the next management step for patients with anemia complicating chronic kidney disease who are not receiving dialysis — including kidney transplant recipients — and in whom first-line erythropoiesis-stimulating agent (ESA) therapy has failed to produce the expected hemoglobin response.

Clinical scenario

The patient has anemia and chronic kidney disease and is not receiving dialysis (kidney transplant recipients are included). Selection of the appropriate hemoglobin threshold at which to act considers the presence of symptoms attributable to anemia and the relative harms of transfusion or ESA therapy.

Why this protocol — prior therapy did not reach its target

Previous treatment: Erythropoiesis-stimulating agent (ESA) therapy, initiated at an individualized hemoglobin concentration and administered with a target of keeping hemoglobin below 11.5 g/dl.

Goal not met: ESA therapy did not achieve an increase in hemoglobin concentration of 1.0 g/dl per month while maintaining hemoglobin below 11.5 g/dl — confirming ESA hyporesponsiveness.

This protocol defines the structured next step following that confirmed failure.

Next-line approach (partial overview)

In patients with confirmed ESA hyporesponsiveness, a trial course of a hypoxia-inducible factor–prolyl hydroxylase inhibitor (HIF-PHI) may be considered after discussion of potential risks and benefits. This class of agent is used alone — it is not combined with an ESA. Specific contraindications apply, including active malignancy and recent vascular events.

The full regimen — including which agents, starting doses, dose-adjustment rules, monitoring schedule, and discontinuation criteria — is available in the complete protocol.

Treatment goals

The aim is a desired erythropoietic response — a rise in hemoglobin — within 3–4 months. Hemoglobin is monitored 2–4 weeks after initiation and every 4 weeks thereafter. If the target response is not achieved by 3–4 months, discontinuation is indicated.

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References

DOI: 10.1016/j.kint.2025.06.006

In people with CKD not receiving dialysis, including kidney transplant recipients and children, the selection of Hb concentration at which ESA therapy is initiated should consider the presence of symptoms attributable to anemia, the potential benefits of higher Hb concentration, and the potential harms of RBC transfusions or ESA therapy (2D).

In people with CKD, anemia, and ESA hyporesponsiveness, if there is a desire to raise Hb to avoid transfusion or improve symptoms attributable to anemia, a trial course of HIF-PHI may be considered after discussion of potential risks and benefits (Figure 10).

In people with anemia and CKD not receiving dialysis or with CKD G5D who have active malignancy, a recent cardiovascular event, or recent vascular thrombosis, do not use HIF-PHIs.

In people with anemia and CKD, including those with ESA hyporesponsiveness, do not use ESAs and HIF-PHIs in combination.

In people with anemia and CKD, discontinue HIF-PHI after 3–4 months if a desired erythropoietic response has not been achieved.

In people with anemia and CKD, when administering HIF-PHIs, monitor Hb levels 2–4 weeks after initiation or dose adjustments and subsequently every 4 weeks during therapy.

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