Anaemia of Chronic Kidney Disease

Anaemia of chronic kidney disease is the reduction in red cell mass, defined by haemoglobin below 130 g/L in men and below 120 g/L in women, that develops as kidney function declines. Prevalence rises from about 10% at stage G3a to more than 50% at stage G5. The central mechanism is relative erythropoietin deficiency, because peritubular interstitial fibroblasts lose their capacity to produce erythropoietin in response to hypoxia.

Contributing factors are absolute and functional iron deficiency (raised hepcidin), chronic inflammation, shortened red cell survival (uraemic toxins), blood loss (gastrointestinal, dialysis circuit, phlebotomy), vitamin B12 and folate deficiency, secondary hyperparathyroidism (marrow fibrosis), aluminium toxicity, hypothyroidism, renin angiotensin system blockade and haemoglobinopathies.

Consequences. Fatigue, reduced exercise tolerance, impaired cognition, left ventricular hypertrophy, heart failure, reduced quality of life, increased hospitalisation and mortality, and reduced transplant success if repeated transfusion causes sensitisation.

• Fatigue, lethargy, dyspnoea on exertion, palpitations, headache, poor concentration, cold intolerance, reduced libido, sleep disturbance, restless legs (iron deficiency).
• Pallor of conjunctivae and palms, tachycardia, flow murmur, signs of heart failure, postural dizziness.
• Features of iron deficiency (glossitis, koilonychia, pica) or B12 deficiency (neuropathy, glossitis).

Red flags

• Haemoglobin below 70 g/L, or symptomatic angina or heart failure with any anaemia.
• Rapidly falling haemoglobin (more than 20 g/L within a month) or melaena, haematemesis, rectal bleeding.
• Anaemia disproportionate to renal function (haemoglobin below 100 g/L when eGFR is above 45): search for another cause, including myeloma, haemolysis, marrow failure or malignancy.
• Sudden severe transfusion dependent anaemia in a patient on an erythropoiesis stimulating agent for more than 8 weeks with reticulocytes below 10 x 10⁹/L: pure red cell aplasia.

Frequency of testing. Haemoglobin at least annually in stage G3, twice yearly in stages G4 to G5 not on dialysis, and every 1 to 3 months in haemodialysis and peritoneal dialysis. Test whenever symptoms arise.

Initial investigation

• Full blood count with indices (MCV, MCH), reticulocyte count, blood film, ferritin, transferrin saturation, C-reactive protein, vitamin B12, folate, thyroid function, parathyroid hormone, bicarbonate, liver tests.
• Haemolysis screen (lactate dehydrogenase, bilirubin, haptoglobin, direct antiglobulin test) when MCV and reticulocytes are not explained.
• Serum protein electrophoresis and serum free light chains when anaemia is out of proportion to kidney function.
• Stool occult blood or endoscopy in iron deficiency not explained by dialysis loss, in men and post-menopausal women.
• Haemoglobin electrophoresis in ethnic groups at risk. Aluminium level in dialysis patients with microcytosis and exposure.

Interpretation of iron status. Absolute deficiency: ferritin below 100 microg/L in non-dialysis chronic kidney disease or below 200 microg/L in haemodialysis, or transferrin saturation below 20%. Ferritin above 500 microg/L suggests inflammation or iron overload rather than deficiency.

Differential diagnosis

• Iron deficiency from gastrointestinal bleeding; thalassaemia trait (high red cell count, low MCV, normal ferritin); myelodysplasia; myeloma; B12 or folate deficiency; haemolytic anaemia; hypothyroidism; hyperparathyroid marrow fibrosis; aluminium toxicity; drug induced marrow suppression (azathioprine, mycophenolate, ribavirin).

Step 1: correct reversible causes before starting an erythropoiesis stimulating agent

• Replace iron, B12 (hydroxocobalamin 1 mg intramuscularly alternate days for 2 weeks, then every 3 months) and folate (5 mg daily for 4 months).
• Treat infection and inflammation, control parathyroid hormone, optimise dialysis adequacy (Kt/V of at least 1.2), stop or reduce ACE inhibitors only if anaemia is severe and unexplained.

Iron

• Non-dialysis: oral ferrous fumarate 210 mg (about 65 mg elemental iron) once daily or on alternate days for 1 to 3 months.
• If haemoglobin has not risen by at least 10 g/L or ferritin has not increased within 4 weeks, or if intolerant, move to intravenous iron.
• Intravenous options: iron sucrose 200 mg intravenously on 5 occasions over 14 days; or ferric carboxymaltose 15 mg/kg (maximum 1000 mg) as a single dose; or ferric derisomaltose 20 mg/kg (maximum 1000 mg in one infusion over at least 20 minutes).
• Haemodialysis: iron sucrose 100 mg intravenously at each of 10 consecutive sessions, then maintenance 100 mg once every 1 to 2 weeks adjusted to ferritin and transferrin saturation every 1 to 3 months.
• Replace iron when ferritin is below 200 microg/L or transferrin saturation is below 20%. Withhold when ferritin is above 500 microg/L or transferrin saturation above 40%, and reassess in 3 months.
• Observe patients for 30 minutes after infusion. Do not give intravenous iron during active systemic infection. Check phosphate 2 to 4 weeks after repeat doses of ferric carboxymaltose because of hypophosphataemia.

Erythropoiesis stimulating agents (start when haemoglobin is below 100 g/L, iron replete, and after weighing symptoms)

• Epoetin alfa 50 to 100 units/kg three times weekly subcutaneously or intravenously.
• Darbepoetin alfa 0.45 microg/kg once weekly subcutaneously or intravenously (or 0.75 microg/kg every 2 weeks).
• Methoxy polyethylene glycol epoetin beta 0.6 microg/kg every 2 weeks in patients not previously treated (when switching from another agent, the starting dose is calculated from the previous weekly dose).
• Target haemoglobin 100 to 120 g/L. Do not aim above 130 g/L because of stroke, thrombosis and cardiovascular risk; avoid ESAs where possible in active malignancy treated with curative intent, and use the lowest dose in a history of stroke.
• Monitor haemoglobin every 2 weeks until stable, then monthly. Aim for a rise of 10 to 20 g/L each month. Adjust the dose by 25%: increase when rise is under 10 g/L after 4 weeks, reduce when rise exceeds 20 g/L in 4 weeks or when haemoglobin exceeds 120 g/L; hold above 130 g/L until below 120 g/L.
• Monitor blood pressure (hypertension in 20 to 30%); treat before and during therapy.

Hyporesponsiveness. Defined as haemoglobin not at target after 4 months of ESA at epoetin more than 300 units/kg weekly (or 450 units/kg weekly intravenously) or darbepoetin more than 1.5 microg/kg weekly. Check iron, inflammation, infection, parathyroid hormone, dialysis dose, aluminium, B12 and folate, haemolysis, myeloma and haemoglobinopathy, bleeding, and adherence. Do not escalate beyond these doses without finding a cause.

Pure red cell aplasia. Anti-erythropoietin antibodies cause a sudden fall in haemoglobin (5 to 10 g/L each week) with reticulocytes below 10 x 10⁹/L. Stop all ESAs, confirm antibodies and marrow, and refer to haematology; immunosuppression (prednisolone with ciclosporin or cyclophosphamide) may restore response.

Alternative: hypoxia inducible factor prolyl hydroxylase inhibitor. Roxadustat 70 mg orally three times weekly (100 mg if weight is 70 kg or more), adjusted every 4 weeks in steps; maximum 3 mg/kg or 400 mg, whichever is lower. Haemoglobin must be monitored every 2 weeks initially. Risks include thrombosis, hypertension and seizure; avoid in prior thromboembolism, and do not use in active malignancy.

Transfusion. Reserve for haemoglobin below 70 g/L, symptomatic anaemia unresponsive to treatment, or acute blood loss. Transplant candidates should avoid transfusion to limit HLA sensitisation; use leucodepleted cells and give slowly during dialysis to control potassium and volume.

Referral and escalation. Refer to nephrology and haematology if haemoglobin is below 100 g/L with eGFR above 45, no response to ESAs, suspected pure red cell aplasia or monoclonal gammopathy.

Special groups

• Children: epoetin alfa 50 to 100 units/kg three times weekly; target haemoglobin 110 to 120 g/L.
• Malignancy: ESAs may promote tumour progression; use only after discussion with oncology.
• Pregnancy: oral or intravenous iron from second trimester, ESAs continued at minimum effective dose with a lower target haemoglobin of 100 to 110 g/L.
• Transplant: anaemia is common in the first year; treat iron deficiency, review mycophenolate, azathioprine, ACE inhibitors, and consider parvovirus B19 infection if reticulocytes are very low.