Anaemia in Chronic Renal Disease

Anaemia is defined as a haemoglobin concentration lower than 11 grams per decilitre (g/dl) for pregnant women and for children between 6 months and 5 years of age, less than 12 g/dl for non-pregnant women, and less than 13 g/dl in men.
In patients with chronic renal disease, normochromic normocytic anaemia mainly develops from decreased renal synthesis of erythropoietin. The anaemia becomes more severe as the GFR (glomerular filtration rate) progressively decreases. No reticulocyte response occurs, red blood cell survival is decreased, and there is an associated increased bleeding tendency due to ureamia-induced platelet dysfunction.
Iron deficiency is also common in patients with chronic renal disease. The iron deficiency may be absolute, often due to poor dietary intake or sometimes occult bleeding, or functional, when there is an imbalance between the iron requirements of the erythroid marrow and the actual iron supply. Iron deficiency leads to a reduction in formation of red cell haemoglobin, causing hypochromic microcytic anemia. Other causes for anaemia in chronic renal disease include the presence of uraemic inhibitors (e.g. parathyroid hormone, inflammatory cytokines), reduced half-life of circulating blood cells, and deficiencies of folate or Vitamin B12.

• Studies of patient with chronic kidney disease have shown that the prevalence of anaemia (defined as a haemoglobin level less than 12 g/dl in men and post-menopausal women and less than 11 g/dl in pre-menopausal women) is about 12.0%.¹
• Patients with diabetes and chronic renal failure are at a greater risk of developing anaemia than non-diabetic patients with chronic kidney disease.

• Often diagnosed by routine review blood tests.
• Renal anaemia may lead to the onset or aggravation of lethargy, cold intolerance and loss of stamina.
• Anaemia increases cardiac output, therefore contributing to the development of left ventricular hypertrophy and dilatation.

Causes of anaemia in patients with chronic kidney disease, other than renal failure itself, include:

• Chronic blood loss
• Iron deficiency
• Vitamin B₁₂ or folate deficiency
• Hypothyroidism
• Chronic infection or inflammation
• Hyperparathyroidism
• Aluminium toxicity
• Malignancy
• Haemolysis
• Bone marrow infiltration
• Pure red cell aplasia

Investigation involves assessment of the degree and cause of anaemia, assessment of renal function, assessment of any cardiovascular complications of anaemia and chronic renal disease, and identifying any other co-existant complications of chronic renal disease.

• Renal function, estimation of GFR and electrolytes.
• Full blood count, blood film, iron studies (iron, ferritin, total iron binding capacity), B12 and folate.
• Other investigations will be determined by likely alternative diagnoses and cardiovascular effects of anaemia, e.g. B₁₂, folate, thyroid function tests, renal ultrasound, echocardiography, investigations for gastrointestinal bleeding.

• Any patient with chronic renal disease presenting with anaemia:
  • Should be referred to the local specialist renal department for full assessment and management. Clinical assessment should include an assessment nutrition, general well-being and other possible causes for anaemia (e.g. occult blood loss).
  • Blood pressure should also be checked and any other factor suggesting acute on chronic renal failure, e.g. infection.
  • The basic blood test investigations as outlined above should be sent (ensuring the results are available at the renal department).
• Management of anaemia should be considered in people with anaemia of chronic kidney disease when the haemoglobin level is less than or equal to 11g/dl (or 10 g/dl if under 2 years of age).
• In people with anaemia of chronic kidney disease, treatment should maintain stable haemoglobin levels between 10.5 and 12.5 g/dl for adults and children aged over 2 years, and between 10 and 12 g/dl in children aged under 2 years.
• Treatment with erythropoiesis stimulating agents should be offered to patients with anaemia of chronic kidney disease who are likely to benefit in terms of quality of life and physical function.
• There is no evidence to distinguish between erythropoiesis stimulating agents in terms of efficacy.
• The time taken for erythropoetin treatment to be effective will depend on individual patient factors such as degree of anaemia, degree of renal failure and presence of other adverse factors, e.g. iron deficiency.
• Contra-indications for erythropoetin treatment include uncontrolled hypertension.²
• Potential side-effects of erythropoetin include increase in blood pressure or aggravation of hypertension, headache, increase in platelet count, influenza-like symptoms (may be reduced if intravenous injection given over 5 minutes), thromboembolic events, pure red cell aplasia, hyperkalaemia, and skin reactions.
  

  There have been very rare reports of pure red cell aplasia in patients treated with epoetin alfa. The Commission on Human Medicines has advised that in patients developing epoetin alfa failure with a diagnosis of pure red cell aplasia, treatment with epoetin alfa must be discontinued and testing for erythropoietin antibodies considered. Patients who develop pure red cell aplasia should not be switched to another erythropoietin.2

• Monitoring: In people with anaemia of chronic kidney disease, haemoglobin should be monitored:
  • Every 2-4 weeks in the induction phase of erythropoiesis-stimulating agent therapy.
  • Every 1-3 months in the maintenance phase of erythropoiesis-stimulating agent therapy.
  • More actively after dose adjustment of the erythropoiesis-stimulating agent.
  • Epoetin alfa
    • Epoetin (recombinant human erythropoietin) is used for the anaemia associated with erythropoietin deficiency in chronic renal failure. The clinical efficacy of epoetin alfa and epoetin beta is similar.
    • It is also used to increase the yield of autologous blood in normal individuals and to shorten the period of anaemia in patients receiving cytotoxic chemotherapy.
    • Epoetin beta is also used for the prevention of anaemia in preterm neonates of low birth-weight.
  • Darbepoetin
    • Is a hyperglycosylated derivative of epoetin which has a longer half-life and may be administered less frequently than epoetin.
• Other factors which contribute to the anaemia of chronic renal failure, e.g. iron or folate deficiency should be corrected before treatment and monitored during therapy.
• Aluminium toxicity, concurrent infection or other inflammatory disease may impair the response to erythropoietin.²
• People receiving erythropoiesis stimulating agents maintenance therapy should be given iron supplements (often requires intravenous iron) to keep their:
  • Serum ferritin between 200 and 500 mcg/l , and either
  • The transferrin saturation level above 20% (unless ferritin >800 ug/l), or
  • Percentage hypochromic red cells less than 6% (unless ferritin >800ug/l)
• Clinically relevant hyperparathyroidism should be treated in order to improve anaemia management in patients with anaemia of chronic kidney disease.
• Where possible, blood transfusions should be avoided in patients in whom kidney transplant is a treatment option.

• Anaemia is an adverse indicator for the progression of chronic renal disease. Therefore correcting anaemia is considered an important part of slowing or even stopping the progression of chronic renal disease.³
• Treatment with recombinant human erythropoietin in pre-dialysis patients corrects anaemia, avoids the requirement for blood transfusions and also improves quality of life and exercise capacity.^{4 5}

Restricting the progression of chronic renal disease, e.g. smoking cessation, optimal control of diabetes.⁶