Iron Deficiency in Chronic Kidney Disease

Iron deficiency is present in 25 to 50% of patients with chronic kidney disease and in up to 70% of those on haemodialysis. It takes two forms. Absolute iron deficiency is depletion of body stores through blood loss and poor absorption.

Functional iron deficiency is the situation where stores are adequate (ferritin normal or high) but iron cannot be released to the marrow, because inflammation raises hepcidin, which blocks intestinal absorption and ferroportin mediated release from macrophages. Erythropoiesis stimulating agents unmask functional deficiency because they increase iron demand beyond what can be mobilised.

Causes of iron loss in CKD

• Gastrointestinal bleeding (uraemic platelet dysfunction, gastritis, angiodysplasia, antiplatelet and anticoagulant use).
• Haemodialysis: 1 to 3 mL of blood is lost at each session in the circuit and needle sites, a total of 1 to 2 g of iron annually; frequent blood sampling.
• Reduced absorption: hepcidin excess, proton pump inhibitors, phosphate binders (calcium, aluminium), gastroparesis, low dietary intake from protein restriction.
• Menstruation, pregnancy.

• Fatigue, reduced exercise tolerance, dyspnoea, palpitations, impaired concentration, hair loss, pagophagia (craving for ice), restless legs syndrome, brittle or spoon shaped nails (koilonychia), angular stomatitis, glossitis.
• Reduced response to erythropoiesis stimulating agents requiring escalating doses.
• Worsening heart failure symptoms (iron deficiency reduces exercise capacity independent of haemoglobin).

Red flags

• Iron deficiency in an adult man or post-menopausal woman without a dialysis explanation: investigate for gastrointestinal malignancy.
• Melaena, rectal bleeding, weight loss, change in bowel habit, dysphagia.
• Failure to respond to adequate iron therapy: consider ongoing blood loss, malabsorption, coeliac disease, or Helicobacter pylori infection.

Iron indices

• Ferritin: acute phase reactant, so a normal or raised value does not exclude deficiency in inflammation. Absolute deficiency: ferritin below 100 microg/L in non-dialysis chronic kidney disease; below 200 microg/L in haemodialysis. Iron replacement is also indicated when transferrin saturation is below 20%.
• Transferrin saturation: below 20% indicates inadequate iron supply to the marrow. Test fasting where possible, because serum iron has diurnal variation.
• Percentage of hypochromic red cells above 6%, or reticulocyte haemoglobin content below 29 pg, are early and sensitive markers of functional deficiency.
• MCV and MCH fall late; a normal MCV does not exclude deficiency.

Distinguishing features

• Anaemia of inflammation: ferritin high or normal, transferrin saturation low, CRP raised.
• Thalassaemia trait: low MCV with high red cell count, normal ferritin, abnormal haemoglobin electrophoresis.
• Aluminium toxicity: microcytosis in dialysis patients with raised serum aluminium.
• Sideroblastic anaemia, lead poisoning: basophilic stippling.

Source of loss. Faecal occult blood, upper and lower gastrointestinal endoscopy (indicated in all men and post-menopausal women, and in any patient with symptoms), coeliac serology, Helicobacter pylori test, review of drugs (antiplatelets, anticoagulants, NSAIDs, SSRIs).

Treat the source. Investigate the gastrointestinal tract by endoscopy, stop NSAIDs, treat Helicobacter pylori, minimise phlebotomy volumes (paediatric tubes), and optimise dialysis needling and circuit return.

Oral iron (non-dialysis chronic kidney disease, mild deficiency)

• Ferrous fumarate 210 mg (about 65 mg elemental iron) once daily, or on alternate days to improve fractional absorption and tolerability, taken apart from phosphate binders, calcium and tea. Alternative: ferric maltol 30 mg twice daily on an empty stomach, or ferric citrate 1 g with each meal (also lowers phosphate).
• Reassess haemoglobin and ferritin after 4 to 8 weeks. Failure to achieve a haemoglobin rise of at least 10 g/L, intolerance, or ongoing losses should prompt a move to intravenous iron.

Intravenous iron

• Haemodialysis: iron sucrose 100 mg intravenously at each of 10 consecutive sessions, then 100 mg once weekly to once every 2 weeks as maintenance with monitoring of ferritin and transferrin saturation every 1 to 3 months. Replace iron when ferritin is below 200 microg/L or transferrin saturation is below 20%.
• Non-dialysis and peritoneal dialysis: iron sucrose 200 mg 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, infused over at least 20 minutes).
• A proactive high dose regimen (iron sucrose 400 mg monthly in haemodialysis) lets the ESA dose fall by about 20% but needs ferritin kept under 700 microg/L and transferrin saturation under 40%. With the conventional maintenance regimen, withhold iron if ferritin exceeds 500 microg/L or transferrin saturation exceeds 40%, and recheck in 3 months.
• Contraindications: active bacteraemia, previous anaphylaxis to the same product, haemosiderosis. Delay during acute infection.

Adverse reactions

• Fishbane reaction (flushing, chest tightness, back pain, no hypotension or bronchospasm): stop the infusion, give nothing further for 15 minutes, restart at half the rate.
• Anaphylaxis (airway compromise, hypotension): stop infusion; adrenaline 500 microg intramuscularly (0.5 mL of 1 in 1000), repeated after 5 minutes if needed; chlorphenamine 10 mg and hydrocortisone 200 mg intravenously; oxygen and fluids.
• Hypophosphataemia after ferric carboxymaltose: check phosphate 2 to 4 weeks after repeat doses; replace phosphate if below 0.6 mmol/L.

Monitoring. Haemoglobin, ferritin and transferrin saturation at 4 weeks after a course, then every 1 to 3 months in dialysis and every 3 months in non-dialysis disease.

Referral and escalation. Gastroenterology for suspected gastrointestinal loss. Haematology if ferritin is low but haemoglobin does not rise after intravenous iron, or if unexplained marrow disorders are suspected.

Special groups

• Children: oral elemental iron 2 to 3 mg/kg daily, or intravenous iron sucrose 2 to 3 mg/kg for each dose weekly for 5 doses (avoid high bolus doses).
• Pregnancy: oral iron first; intravenous iron from the second trimester if intolerant or not responding.
• Heart failure: intravenous iron improves symptoms when ferritin is below 100 microg/L, or 100 to 299 microg/L with transferrin saturation below 20%.
• Transplant recipients: correct deficiency to reduce post-transplant anaemia, using oral iron unless intolerant.