Erythropoiesis Stimulating Agents in Chronic Kidney Disease

Erythropoiesis stimulating agents treat anaemia of chronic kidney disease, which results from reduced erythropoietin production, iron restriction and inflammation. They are started after iron deficiency and other causes are corrected, usually when haemoglobin is persistently under 100 g/L, and they aim for a haemoglobin of 100 to 120 g/L. Targets above 130 g/L raise the risk of stroke, thrombosis and hypertension and are not advised.

Before starting. Exclude iron, vitamin B12 and folate deficiency, blood loss, haemolysis, infection, inflammation, malignancy, hyperparathyroidism and haemoglobinopathy.

Iron targets. Aim for ferritin over 100 micrograms/L (over 200 in haemodialysis) and transferrin saturation over 20 percent before and during treatment.

Hypertension. Control blood pressure before starting, because these agents raise it.

Agents. Epoetin alfa, epoetin beta, darbepoetin alfa and methoxy polyethylene glycol-epoetin beta, all given subcutaneously or intravenously. In haemodialysis the intravenous route is used, and in other patients the subcutaneous route is preferred. Biosimilar epoetins are equivalent options.

Oral option. Hypoxia-inducible factor prolyl hydroxylase inhibitors, such as roxadustat, are available in some regions and are used by specialist decision. They carry risks of thrombosis, stroke and cardiovascular events.

Avoid or use with care. Active malignancy where cure is intended, uncontrolled hypertension, previous stroke, and a history of pure red cell aplasia.

Special groups.

• Children: weight-based dosing under specialist care.

• Pregnancy: needs are higher, so use specialist advice.

• Transplant candidates: ESAs and iron limit the need for transfusion, which can cause sensitisation.

• East Africa: malaria, HIV, hookworm and tuberculosis cause anaemia and ESA resistance, so treat them. Epoetin must be kept at 2 to 8 degrees Celsius and never frozen or shaken, which matters where the cold chain is unreliable.

• Epoetin alfa: start 50 to 100 units/kg three times weekly, intravenously or subcutaneously. Increase by 25 units/kg each dose when haemoglobin rises under 10 g/L in 4 weeks.

• Darbepoetin alfa: start 0.45 micrograms/kg once weekly, or 0.75 micrograms/kg every 2 weeks. Increase the dose by 25 percent when haemoglobin rises under 10 g/L in 4 weeks.

• Methoxy polyethylene glycol-epoetin beta: start 0.6 micrograms/kg every 2 weeks in dialysis, or 1.2 micrograms/kg once monthly in non-dialysis disease.

• Dose changes: aim for a rise of 10 to 20 g/L each month. Reduce the dose by 25 to 50 percent if haemoglobin rises more than 20 g/L in a month or nears 120 g/L, and hold if it passes 130 g/L.

• Iron sucrose: 100 mg intravenously during dialysis, usually for 10 doses. Ferric carboxymaltose: 500 to 1000 mg intravenously as a single dose (maximum 20 mg/kg), with phosphate monitoring. Oral ferrous sulphate: 200 mg (65 mg elemental iron) once daily or on alternate days.

Monitoring. Check haemoglobin every 2 to 4 weeks during titration and every 1 to 3 months when stable, with ferritin and transferrin saturation every 3 months and blood pressure at each visit.

Stop rules. Stop the agent for uncontrolled hypertension, thrombosis, stroke, seizures, or a sudden severe fall in haemoglobin with low reticulocytes, which suggests pure red cell aplasia from neutralising antibodies.

Referral and escalation. Refer for resistance (no response after 4 months of appropriately increased doses), suspected pure red cell aplasia, haemoglobin needing doses over 300 units/kg weekly of epoetin, or any unexplained fall.

Common errors. Starting without iron repletion, aiming for a normal haemoglobin, skipping blood pressure checks, and giving subcutaneous doses to haemodialysis patients when intravenous access is available.