Anaemia in chronic kidney disease

What causes anaemia in chronic kidney disease? (Aetiology)^{1 2}

In patients with chronic kidney disease, normochromic normocytic anaemia mainly develops from decreased renal synthesis of erythropoietin. The anaemia becomes more severe as the glomerular filtration rate (GFR) progressively decreases. No reticulocyte response occurs, red blood cell survival is decreased and there is an associated increased bleeding tendency due to uraemia-induced platelet dysfunction.

Iron deficiency is also common in patients with chronic kidney disease (CKD). 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 anaemia.

Other causes for anaemia in chronic kidney disease include the presence of uraemic inhibitors (eg, parathyroid hormone, inflammatory cytokines), reduced half-life of circulating blood cells and deficiencies of folate or vitamin B12.

Anaemia in chronic kidney disease epidemiology

• Anemia is a frequent complication with CKD, and erythropoietin deficiency is its most common factor, together with iron deficiency, folate deficiency, and vitamin B12 deficiency.³

• Anaemia prevalence increases with CKD stage, with comorbidities and with age.⁴

• In patients with CKD, patients with diabetes are at a greater risk of developing anaemia earlier in the course of their disease (associated with inappropriately low levels of erythropoietin). Comparing patients with similar eGFR and erythropoietin levels, those with type 2 diabetes are generally more anaemic.⁵

Anaemia in chronic kidney disease symptoms (presentation)

• It is 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.

Differential diagnosis⁵

The possible causes of anaemia in patients with CKD, 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.

Investigations

Investigate patients with CKD if their haemoglobin falls to 11 g/dL or less, or they get symptoms due to anaemia, such as tiredness or breathlessness.⁵

This will involve ruling out other causes of anaemia, assessment of kidney function, assessment of any cardiovascular and other complications of anaemia or CKD.

• Kidney function, eGFR and electrolytes.

• FBC, blood film, iron studies (ferritin, transferrin saturation, iron), B12 and folate. Where ferritin is <100 μg/L there is iron-deficiency anaemia. If ferritin is above this level, a functional iron deficiency (and hence a requirement for iron supplementation) is defined by the percentage of hypochromic red cells >6% (if test is available) or otherwise a transferrin saturation <20%.^{5 6}

• Other investigations will be determined by likely alternative diagnoses and cardiovascular effects of anaemia - eg, TFTs, renal ultrasound, echocardiography, investigations for gastrointestinal bleeding.

Anaemia in chronic kidney disease treatment and management⁵

• Any patient with CKD presenting with anaemia:
  

  • Should be referred to the local specialist renal department for full assessment and management. Clinical assessment should include an assessment of nutrition, general well-being and other possible causes for anaemia (eg, occult blood loss).

  • Blood pressure should also be checked and any other factor suggesting acute on chronic kidney disease - eg, 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 CKD when the haemoglobin level is less than or equal to 11 g/dL (or 10 g/dL if under 2 years of age).

• In people with anaemia of CKD, treatment should aim to maintain stable haemoglobin levels between 10 and 12 g/dL for adults and children aged over 2 years and between 9.5 and 11.5 g/dL in children aged under 2 years.

• Treatment with erythropoiesis-stimulating agents should be offered to patients with anaemia of CKD who are likely to benefit in terms of quality of life and physical function.⁷ There are few studies comparing the efficacy of the various agents. One study reported that darbepoetin alfa weekly or every two weeks was more efficient in achieving target haemoglobin than those on weekly epoetin alfa, with fewer dose changes and minor vascular access complications.⁸

• ESA (erythropoietic stimulating agent) therapy should not be started in the presence of absolute iron deficiency without also managing the iron deficiency.

• Red blood cell transfusions may be the only available option in some patients in whom erythropoetin treatments are not recommended.⁴

• Blood transfusions should be avoided if possible in people with anaemia of CKD in whom kidney transplant is a treatment option.

• The time taken for erythropoetin treatment to be effective will depend on individual patient factors, such as degree of anaemia, degree of kidney disease and presence of other adverse factors - eg, iron deficiency.

• Contra-indications for erythropoetin treatment include uncontrolled hypertension.⁹

• 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 is given over five minutes), thromboembolic events, pure red cell aplasia, hyperkalaemia and skin reactions.

• Increasing concerns over the risk of cardiovascular events have led to a reduction in the use of erythropoetins as a group in recent years.¹⁰
  

• Iron therapy should be offered if anaemia of CKD and iron deficiency, whether or not on erythropoetin treatment (see NICE guideline for further details).

• Monitoring: in people with anaemia of CKD, 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.

• Other factors which contribute to the anaemia of CKD (eg, 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.⁹

• People receiving erythropoiesis-stimulating agent maintenance therapy should be given iron supplements (often requires intravenous iron) to keep their:
  

  • Percentage of hypochromic red blood cells less than 6% (unless ferritin is greater than 800 µg/litre).

  • Reticulocyte Hb count or equivalent tests above 29 pg (unless serum ferritin is greater than 800 µg/litre).

  • If these tests are not available or the person has thalassaemia or thalassaemia trait, iron therapy should maintain transferrin saturation greater than 20% and serum ferritin level greater than 100 µg/litre.

• In view of the concerns about the adverse effects of erythropoietins, other therapeutic options are being explored. These include hypoxia inducible factor-1 alpha (HIF-1α) stimulators. HIF-1α is known to be associated with oxygenation of the kidney tubule.¹⁰

• Clinically relevant hyperparathyroidism should be treated in order to improve anaemia management in patients with anaemia of CKD.

• Roxadustat is recommended by NICE as an option for treating symptomatic anaemia associated with chronic kidney disease (CKD) in adults only if they have stage 3 to 5 CKD with no iron deficiency, and they are not on dialysis at the start of treatment.¹¹

Prognosis

• Untreated anaemia of CKD is strongly associated with cardiovascular and renal complications, resulting in increased hospitalisations and mortality.Therefore, correcting anaemia is considered an important part of slowing or even stopping the progression of CKD.¹²

• 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.^{13 14}

Prevention

Restricting the progression of CKD - eg, smoking cessation, optimal control of diabetes.¹⁵