Anaemia in CKD affects around 100 000 people in the United Kingdom (NICE 2011) and contributes significantly to the heavy symptom burden of CKD. It becomes more prevalent the more advanced the stage of CKD (1% of people with an eGFR of 60 mL/min, 9% of people with an eGFR of 30 mL/min and 33% of people with an eGFR of 15 mL/min are anaemic). The overall incidence of anaemia in CKD stages 3 to 5 is 12%. Not only can its presence have a major negative impact on the quality of life and physical capacity of the individual, but it may also increase cardiac output and left ventricular hypertrophy (London 2003) Other possible adverse effects of anaemia are (NICE 2011):

• increased bleeding time/impaired platelet function
  
• reduced cognition and concentration
  
• reduced libido
  
• reduced immune responsiveness.

The anaemia of CKD is normochromic and normocytic in nature. The cause is multifactorial, but by far the main contribution is the reduced erythropoietic activity caused by iron deficiency or erythropoietin deficiency, or both. Other minor causes may also contribute to the anaemia of CKD.

Erythropoietin is a hormone produced by the peritubular cells in the kidney, which is critically involved in the manufacture of red blood cells in the bone marrow. Iron is an essential mineral for the production of haem, the oxygen-carrying component of Hb. Iron deficiency may be functional (when body iron stores may be normal or increased but there is a failure of iron delivery to the bone marrow) or absolute (when body iron stores are exhausted) (NICE 2011). The latter condition occurs, in part, because of impaired absorption of iron from the gastrointestinal (GI) tract in uraemia and partly due to increased iron losses as a result of platelet dysfunction associated with, for example, uraemia or aspirin therapy. Furthermore, dialysis may exacerbate increased iron deficiency by the trapping of red cells in the dialyser.

As a result of the inflammation that is associated with CKD (uraemia is now recognized to be a chronic inflammatory state), the serum ferritin is often raised, and diagnostic values need to be interpreted differently from those in patients without this disease: iron-deficiency anaemia is diagnosed when serum ferritin is <100 µg/L in CKD stage 5 and should be considered when serum ferritin is <100 µg/L in CKD stages 3 and 4.

Prior to 1990, severe anaemia of CKD was generally treated with top-up blood transfusions every 2–4 weeks. In many cases, this led to iron overload, infections, allergic reactions and increased sensitization to human leukocyte antigens with consequential difficulties if transplantation was considered. The management of anaemia related to CKD was revolutionized by the introduction of recombinant human erythropoietin in the late 1980s (National Clinical Guideline Centre 2011). Since then, longer-acting erythropoietin analogues have become available, and this class of drugs is known as the erythropoiesis-stimulating agents (ESAs), which have allowed earlier and more sustained treatment of the anaemia.

In order to provide evidence for clinical decision-making on the management of anaemia, several randomized controlled trials have been conducted (Besarab et al. 1998; Drüeke et al. 2006; Singh et al. 2006; Pfeffer et al. 2009). The CREATE (Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin Beta) and the CHOIR (Correction of Hemoglobin and Outcomes in Renal Insufficiency) studies (Drüeke et al. 2006; Singh et al. 2006) stirred up some unease about the safety of ESA therapy. However, it was the TREAT (Trial to Reduce Cardiovascular Events with Aranesp Therapy) study (Pfeffer et al. 2009) that raised more definitive concerns regarding the safety of using ESA therapy to deliberately target Hb concentrations of 13 g/dL or above.

The TREAT study recruited over 4000 patients, who were randomized into one of two arms:

• an ‘active’ arm targeting an Hb of around 13 g/dL with ESA therapy;
  
• a ‘control’ arm receiving placebo treatment with ‘rescue’ ESA therapy if the Hb fell below 9 g/dL (this placebo group started with a level of about 10.5 g/dL and drifted up to around 11 g/dL at the end of the study).

Although there were no significant differences in the overall composite endpoint of death, heart failure, myocardial infarction and stroke, there were a number of pertinent safety outcomes, which caused concern:

• stroke (risk was doubled compared with the control group);
  
• venous thromboembolism (risk was almost doubled compared with the control group);
  
• arterial thromboembolism (slightly higher rate compared with the control group);
  
• >10-fold risk of cancer-related mortality in patients who had experienced a previous malignancy.

Post-hoc analyses of these trials suggest that the risk from ESAs is greatest in patients who are resistant to this particular type of therapy and need larger quantities of ESAs to normalize Hb levels (Szczech et al. 2008; Solomon et al. 2010).

As a consequence, the use of ESAs to correct Hb to normal levels (generally considered to lie between 12 and 14 g/dL in women, and 13 and 16 g/dL in men) is not usually recommended in patients with CKD-related anaemia.

In order to optimize the management of anaemia of CKD, it may be helpful to adopt a step-wise approach.

1. Patients with Anaemia Should be Highlighted

Within general practice this should be done when setting up the CKD register as part of the Quality and Outcomes Framework (QOF) (British Medical Association 2009). The overall incidence of anaemia in CKD stages 3, 4 and 5 is around 12% (National Clinical Guideline Centre 2011).

2. Other Causes of Anaemia Should be Excluded (see Box 5.1)

Anaemia of CKD can start to develop when the eGFR <60 mL/min/1.73 m², and its prevalence and severity increases as kidney function declines. NICE advises that, ‘an estimated glomerular filtration rate of less than 60 mL/min/1.73 m² should trigger investigation into whether anaemia is due to CKD’ (NICE 2011).

If severe iron deficiency is present (e.g. serum ferritin <30 mcg/L), then it is important to consider blood loss as a possible cause of the anaemia.