Management of Anaemia in Chronic Kidney Disease

Abstract

Anaemia is common in chronic kidney disease (CKD). Iron deficiency and erythropoietin deficiency are perhaps the most common causes of anaemia in patients with CKD, especially those requiring kidney replacement therapy (KRT/dialysis) (Centers for Disease Control and Prevention, https://www.cdc.gov/kidneydisease/publications-resources/2019-national-facts.html, 2019; The National Collaborating Centre for Chronic Kidney Disease: National Institute for Health and Clinical Excellence: Guidance. In: Chronic Kidney Disease: National Clinical Guideline for Early Identification and Management in Adults in Primary and Secondary Care, eds. Royal College of Physicians (UK). Royal College of Physicians of London, London, 2008; UK Renal Registry, UK renal registry 22nd annual report—data to 31/12/2018, Bristol; 2020. renal.org/audit-research/annual-report). The Renal National Service Framework and National Institute for Health and Clinical Excellence in the UK, and Kidney Disease Improving Global Outcomes (KDIGO), all advocate treatment of anaemia in patients with CKD (Locatelli et al., Kidney Int 74:1237–1240, 2008; Mikhail et al., BMC Nephrol 18:345, 2017; Locatelli et al., Nephrol Dial Transplant 28:1346–1359, 2013; National Clinical Guideline Centre: National Institute for Health and Care Excellence (NICE). Anaemia management in chronic kidney disease NG8. 2015. https://www.nice.org.uk/guidance/ng8/evidence/full-guideline-pdf-70545136). Intravenous (IV) Iron therapy leads to a reduction in the use of erythropoietin stimulating agents (ESA). This reduction in ESA use may be potentially beneficial in certain cases such as reducing cardiovascular risk. Also, the close relationship of anaemia, iron deficiency, CKD and cardiovascular disease make its therapy critical to improved clinical outcomes (De Silva et al., Am J Cardiol 98:391–398, 2006). ESA therapy remains important after iron repletion to optimise haemoglobin concentrations to a KDIGO target range of 100–115 g/L (Locatelli et al., Kidney Int 74:1237–1240, 2008; Locatelli et al., Nephrol Dial Transplant 28:1346–1359, 2013). Blood transfusions are infrequently required, and newer therapies such as Hypoxia-inducible factor (HIF) stabilisers are on the horizon (Besarab et al., Nephrol Dial Transplant 30:1665–1673, 2015; Singh et al., N Engl J Med 385:2313–24, 2021; Singh et al., N Engl J Med 385:2325–35, 2021).

Questions

• 1. A 59-year-old woman with CKD stage G4 secondary to type 2 diabetes mellitus attended clinic with increased lethargy and breathlessness.

  On examination, her blood pressure was 144/76 mmHg, and she was clinically pale.

  Investigations:

Haemoglobin	105 g/L (115–165)
Platelet count	154 × 109/L (150–400)
Serum ferritin	92 μg/L (15–300)
Transferrin saturation	19% (20–50)
Serum sodium	138 mmol/L (137–144)
Serum potassium	5.3 mmol/L (3.5–4.9)
Serum creatinine	326 μmol/L (60–110)
Estimated glomerular filtration rate (CKD Epi)	22 mL/min/1.73 m2 (>60)

What is the most appropriate next step in management of the anaemia according to the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines?

• A. Erythropoiesis-stimulating agent therapy

• B. Intravenous therapy repletion

• C. Observe for 3 months

• D. Trial of oral iron therapy

• E. Vitamin C therapy

Answer: D

• A. Incorrect. Always should correct iron deficiency before starting iron or any type

• B. Possible. Some clinicians may give IV iron due to poor compliance and tolerability of oral iron but KDIGO does suggest a trial while NICE gives more latitude.

• C. Incorrect. Patient is symptomatic and will benefit

• D. Correct. As stated in KDIGO

• E. Incorrect. Some suggest may improve iron absorption but data is weak and does not form part of guidelines.

• 2. A 68-year-old man with end-stage kidney disease secondary to IgA nephropathy, who was on regular haemodiafiltration, presented with symptoms suggestive of a transient ischaemic event. He also had increasing angina. His medication included Darbepoetin-alfa 40 μg fortnightly, Candesartan 8 mg daily and Bisoprolol 2.5 mg daily and Aspirin 75 mg daily.

  On examination, his blood pressure was 124/62 mmHg. He had a new focal weakness of the right leg.

  Investigations:

Haemoglobin	83 g/L (130–180)
Platelet count	169 × 109/L (150–400)
Serum ferritin	342 μg/L (15–300)
Transferrin saturation	23% (20–50)
Serum sodium	139 mmol/L (137–144)
Serum potassium	4.7 mmol/L (3.5–4.9)
Serum creatinine	558 μmol/L (60–110)

What is the most appropriate next step in management of the anaemia?

• A. Change Darbepoetin alfa to eprex three times a week

• B. Give intravenous iron 200 mg on dialysis

• C. Increase Darbepoetin-alfa dosage to 60 μg weekly

• D. Reduce Candesartan dosage to 4 mg/day

• E. Transfuse 1 unit of red cells

Answer: E

• A. Incorrect. The stroke and angina are relatively contra-indications to ESA use. Switching to a short acting ESA has been shown in observation Japanese cohorts to possibly reduced risk from lower peak levels in blood of ESA but not part of guidelines.

• B. Incorrect. Blood results show he is iron replete

• C. Incorrect. This will potentially increase cardiac and stroke risk

• D. Incorrect. On the contrary, candesartan is beneficial in the management of his cardiac disease

• E. Correct. Safest option in the current situation—forms part of guidelines.

• 3. A 45-year-old woman with end-stage kidney disease secondary to mesangiocapillary glomerulonephritis was found to have elevated hepcidin concentrations. Her medication included Eprex 400 units three times a week intravenously during each haemodiafiltration dialysis session, ramipril 10 mg daily and intravenous iron given proactively with an average dose of 400 mg per month on dialysis.

  On examination, her blood pressure was 150/82 mmHg. Her weight was 55 kg.

  Investigations:

Haemoglobin	142 g/L (115–165)
Platelet count	164 × 109/L (150–400)
Serum ferritin	420 μg/L (15–300)
Transferrin saturation	15% (20–50)
Serum sodium	141 mmol/L (137–144)
Serum potassium	4.6 mmol/L (3.5–4.9)
Serum creatinine	723 μmol/L (60–110)

What is the most likely cause of the elevated hepcidin concentrations?

• A. Chronic kidney disease

• B. Eprex therapy

• C. Haemodiafiltraion therapy

• D. Increased absorption of iron from macrophages

• E. Reduced absorption of iron from gastrointestinal tract

Answer: A

• A. Correct. Any inflammatory disorder including CKD leads to increase release of hepcidin from the liver

• B. Incorrect. No evidence and use would in theory reduce iron and lead to reduced hepcidin to allow more absorption and mobilisation of iron

• C. Incorrect. Dialysis has no significant impact of hepcidin but some data does suggest it may reduce it

• D. Incorrect. Hepcidin reduces absorption via effect on the ferroportin channels

• E. Incorrect. See above

• 4. Our 54-year-old patient with type 2 diabetes mellitus has a haemoglobin of 95 g/L and the haematinics indicate functional iron deficiency based on the serum ferritin and TSAT.

  What is the definition of functional iron deficiency anaemia in our patient with CKD not on dialysis?

  • A. TSAT% >20 and SF >100 μg/L

  • B. TSAT% >20 and SF <100 μg/L

  • C. TSAT% <20 and SF >100 μg/L

  • D. TSAT% <20 and SF <100 μg/L

  • E. TSAT% <30 and SF >100 μg/L

  Answer: C

  • A. Incorrect. This indicates both adequate iron stores and circulating iron.

  • B. Incorrect. Absolute iron deficiency with depleted iron stores

  • C. Correct. Based on KDIGO and NICE definition of reduced circulating iron (TSAT <20%) while having adequate iron stores (SF >100) due to inability to mobilize iron from stores. This is due to the effects of hepcidin

  • D. Incorrect. Absolute iron deficiency

  • E. Incorrect. Sufficient iron stores

• 5. A 54-year-old man with Stage G4A3 CKD secondary to insulin treated diabetes mellitus attended the renal outpatient clinic with increased lethargy and breathlessness. He had a previous history of a stroke, myocardial infarction, hypertension and had a fistula in situ

  His Hb had improved after a single dose of 1000 mg of IV iron, However, 6 months later his Hb falls to 76 g/L and he is more symptomatic with chest pain and shortness of breath (SOB), SF, 228 μg/L; and TSAT, 24%, Note: despite his high cardiovascular risk he is active on the kidney transplant list, How would you manage the anaemia?

  • A. Start ESA therapy

  • B. Give further IV iron therapy

  • C. Transfuse with blood

  • D. Observe

  • E. Start dialysis therapy

  Answer: C

  • A. Incorrect. The presence of a history of stroke and CVD would lead to caution in considering an ESA agent but also is not the most optimal to alleviate symptoms

  • B. Incorrect. The haematinics indicate sufficient iron repletion, and no functional iron deficiency so additional iron will not be required at present

  • C. Correct. The patients is symptomatic and with the background of cardiovascular disease, this will reduce risk although it is a balance given the risk of panel reactive antibodies and making future kidney transplantation more challenging

  • D. Incorrect. No in view of symptoms and cardiovascular disease

  • E. Incorrect. No indication for dialysis

• 6. A 65-year-old haemodialysis patient was seen in the dialysis clinic as a part of routine 3 monthly follow-up, having started dialysis in the last 6 months. He had suffered an anterior wall myocardial infarction 6 months previously. His blood pressure was 135/85 mmHg, pulse was 92/min regular and rest of the clinical examination was normal. He was on intravenous erythropoietin (ESA) once a week given during dialysis.

  Investigations:

Haemoglobin	108 g/L (130–180)
Platelet count	164 × 109/L (150–400)
Serum ferritin	220 μg/L (15–300)
Transferrin saturation	18% (20–50)
Serum sodium	140 mmol/L (137–144)
Serum potassium	5.1 mmol/L (3.5–4.9)
Serum creatinine	723 μmol/L (60–110)

What is the best step in management to improve his outcome?

• A. Convert IV ESA therapy to subcutaneous therapy

• B. IV iron therapy, given 400 mg over two dialysis sessions per month

• C. Transfuse blood

• D. IV iron 200 mg once only

• E. Increase ESA therapy to twice a week

Answer: B

• A. Incorrect. It may not help switching

• B. Correct. Results of PIVOTAL study shows benefit of high dose iron given as 400 mg monthly as long as SF <700 and TSAT <40% for incident patients (after an initial loading dose of 600 mg in the first month)

• C. Incorrect. The patients was asymptomatic and it adds to the risk of panel reactive antibodies and making future transplantation more challenging

• D. Incorrect. Needs higher dose based on PIVOTAL study for incident dialysis patients

• E. Incorrect. No benefit in outcome, especially as iron deplete and iron with reduce the need for ESA.

• 7. A 65-year-old haemodialysis patient was seen in the dialysis clinic as a part of routine 3 monthly follow-up, having started dialysis in the last 6 months. He had suffered an anterior wall myocardial infarction 6 months previously. His blood pressure was 135/85 mmHg, pulse was 92/min regular and rest of the clinical examination was normal. He was on intravenous erythropoietin (ESA) once a week.

  Investigations:

Haemoglobin	108 g/L (130–180)
Platelet count	164 × 109/L (150–400)
Serum ferritin	220 μg/L (15–300)
Transferrin saturation	15% (20–50)
Serum sodium	140 mmol/L (137–144)
Serum potassium	5.1 mmol/L (3.5–4.9)
Serum creatinine	723 μmol/L (60–110)

He was prescribed high dose intravenous iron to improve outcome.

What is most likely to be reduced with this high dose iron regime in incident dialysis patients?

• A. Deep venous thrombosis

• B. Heart failure

• C. Infective endocarditis

• D. Major bleeding

• E. Malnutrition

Answer: B

• A. Incorrect no evidence of increase or decrease but IV iron may reduce thrombocytosis.

• B. Correct. Results of PIVOTAL study show a reduction in heart failure and associated hospitalisations

• C. Incorrect—no impact

• D. Incorrect—no impact

• E. Incorrect.

• 8. A 73-year-old Indian female was referred to the kidney clinic with a declining eGFR and increased tiredness. Her daughter suffered from chronic kidney disease and anaemia. On examination she was pale, blood pressure 137/90 mmHg, pulse 90/min.

  Investigations:

Haemoglobin	98 g/L (115–165)
Platelet count	164 × 109/L (150–400)
Serum ferritin	120 μg/L (15–300)
Transferrin saturation	15% (20–50)
Mean corpuscular volume	72 fL (80–100)
Blood film	Microcytosis, hypochromic and target cells
Serum sodium	140 mmol/L (137–144)
Serum potassium	5.1 mmol/L (3.5–4.9)
Serum creatinine	323 μmol/L (60–110)

What is next best step in management?

• A. Start IV hypoxia inducible factor stabilizer

• B. Start subcutaneous erythropoietin

• C. Start intravenous iron

• D. Start intravenous erythropoietin

• E. Start oral iron

Correct answer C

• A. Incorrect—not part of clinical practice currently and no IV preparation available

• B. Incorrect—need to correct iron deficiency first

• C. Correct—a trial of intravenous iron as suggested by NICE probably the best option as the blood film consistent with Iron deficiency—haemoglobinopathy seems less likely given age but target cells present in both disorders.

• D. Incorrect—see B

• E. Incorrect

• 9. A 33-year-old Indian female was referred to the kidney clinic with declining eGFR and increasing tiredness. Her mother had suffered anaemia from an early age . On examination she was pale, blood pressure 137/90 mmHg, pulse 90/min. She was treated with 1000 mg of intravenous iron 2 months ago.

  Investigations:

Haemoglobin	98 g/L (115–165)
Platelet count	164 × 109/L (150–400)
Serum ferritin	450 μg/L (15–300)
Transferrin saturation	40% (20–50)
Mean corpuscular volume	72 fL (80–100)
RDW (red cell distribution width)	14.1% (12.2–16.1)
Blood film	Microcytosis, hypochromic and target cells
Serum sodium	140 mmol/L (137–144)
Serum potassium	5.1 mmol/L (3.5–4.9)
Serum creatinine	323 μmol/L (60–110)

What is the likely main cause of her anaemia?

• A. erythropoietin deficiency

• B. haemolytic anaemia

• C. iron deficiency

• D. sideroblastic anaemia

• E. vitamin B12 deficiency

Correct answer B

• A. Incorrect—would benefit to measure levels as probably contributing but not main cause

• B. Correct blood film and family history are suggestive of haemolytic anaemia; Haemoglobin electrophoresis demonstrated an alpha-thalassaemia. The RDW (red cell distribution width) tends to be higher in iron deficiency but not in the thalassaemias

• C. Incorrect—the patient has received iron therapy and iron markers normal

• D. Incorrect—no evidence of ringed sideroblasts on a peripheral smear which are pathognomic.

• E. Incorrect no evidence from blood film

• 10. A 88-year-old female was seen in acute medicine unit with weakness, poor appetite, weight loss and a fall. She suffered from constipation. On examination she was pale and in atrial fibrillation. She suffered no bony fractures. Her pulse was 110/min and irregular. Her BP was 120/68 mmHg. She was on bisoprolol, atorvastatin, bendroflumethiazide.

Haemoglobin	82 g/L (115–165)
Platelet count	220 × 109/L (150–400)
Serum ferritin	98 μg/L (15–300)
Mean corpuscular volume	78 fL (80–100)
Serum sodium	125 mmol/L (137–144)
Serum potassium	5.1 mmol/L (3.5–4.9)
Serum creatinine	458 μmol/L (60–110)

What is the most appropriate next step in establishing the cause of anaemia

• A. measure blood vitamin B12 and folate levels

• B. serum coombs’ test

• C. bone marrow biopsy

• D. haemoglobin electrophoresis

• E. request CT colonoscopy

Correct answer: E

• A. Incorrect - MCV not raised

• B. Incorrect - unlikely in this age group with low MCV iron deficicency

• C. Incorrect

• D. Incorrect - unlikely in this age group with low MCV

• E. Correct a potential cause of iron deficiency anaemia is a colonic malignancy due to weight loss

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