Dr Penny Ackland discusses how trial evidence has led NICE to update the intervention and target haemoglobin levels for people with chronic kidney disease-related anaemia

Anaemia in chronic kidney disease (CKD) affects around 100,000 people in the UK,1 and contributes significantly to the heavy symptom burden of CKD. Not only can its presence have a major negative impact on the quality of life and the physical capacity of the person, but it may also increase cardiac output and left ventricular hypertrophy.2 Other possible adverse effects of anaemia are:3

  • increased progression of CKD
  • reduced cognition and concentration
  • reduced libido
  • reduced immune responsiveness.

However, the side-effects of anaemia can be kept at bay if managed properly.

In February 2011, the National Institute for Health and Care Excellence (NICE) updated its clinical guideline on Anaemia management in people with chronic kidney disease as a result of the publication of important evidence regarding target blood haemoglobin levels.1,3 This article summarises the key recommendations from NICE Clinical Guideline 114 (CG114) on managing anaemia in CKD for doctors and nurses in primary care since data from the latest clinical trials have revealed some new safety concerns.

Pathogenesis of anaemia of chronic kidney disease

Anaemia of CKD generally develops when the estimated glomerular filtration rate (eGFR), which measures the rate at which blood is filtered by the kidney, falls below 60 ml/min/1.73m2; the prevalence and severity of the anaemia increases as kidney function declines.4 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.’3

The cause of anaemia in CKD is multifactorial, but the two main contributors are erythropoietin deficiency and iron deficiency. Erythropoietin is a hormone produced by the peritubular cells in the kidney to help make red blood cells.1 Iron deficiency may be functional (this particularly occurs in the presence of inflammation—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).1 The latter condition occurs, in part, because of impaired absorption of iron from the gastrointestinal 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.

Previous management practices

Prior to 1990, severe anaemia of CKD was generally treated with top-up blood transfusions every 2 to 4 weeks. In many cases this led to iron overload, infections, allergic reactions, and increased sensitisation to human leukocyte antigen with consequential difficulties if transplantation was considered. The management of anaemia related to CKD was revolutionised by the introduction of erythropoiesis-stimulating agents (ESAs—similar to the protein, erythropoietin) in the late 1980s.1 Erythropoiesis-stimulating agents allowed earlier and more vigorous treatment of the anaemia.

Subsequent trial data

In order to provide evidence for decisions on the management of anaemia, randomised controlled trials were conducted.5–8 The CREATE (Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin Beta) and CHOIR (Correction of Hemoglobin and Outcomes in Renal Insufficiency) studies,6,7 published in 2006, stirred up some unease about ‘normalising’ the haemoglobin in CKD. However, it was the TREAT (Trial to Reduce Cardiovascular Events with Aranesp Therapy) study,8 published in 2009, which raised serious concerns regarding the safety of ESA therapy.

The TREAT study had two arms:8

  • an ‘active’ arm correcting the haemoglobin to around 13 g/dl with ESA therapy
  • a ‘control’ arm receiving placebo treatment with rescue ESA therapy if the haemoglobin 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 for death, heart failure, or myocardial infarction at the TREAT study endpoint, there were safety concerns regarding:8

  • 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)
  • patients who had experienced a previous malignancy (>10-fold risk of cancer-related mortality).

Post-hoc analysis of the CHOIR and TREAT trials suggests 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 normalise haemoglobin levels.9,10

Updated NICE recommendations

As a consequence of the new data from the trials, which called the safety of ESA therapy into question, NICE decided to update two of its recommendations for Anaemia management in people with chronic kidney disease to reflect this (see Box 1).1,3 The updated recommendations are focused on the:

  • haemoglobin threshold level that helps to determine when to treat anaemia in CKD
  • optimal range within which haemoglobin levels in people with anaemia of CKD should be maintained.
Box 1: Implementing the NICE guideline
  1. Highlight patients with anaemia when setting up the CKD register as part of the QOF11
    • The overall incidence of anaemia in CKD is 12% in stages 3, 4, and 51
  1. Exclude other causes of anaemia. If the patient is iron deficient, ensure that there is no cause for blood loss that is unrelated to the CKD1,3
    • Anaemia of CKD is normochromic and normocytic
    • The prevalence and severity of the anaemia increases as kidney function declines
    • Consider other causes of anaemia if the eGFR ?60 ml/min/1.73m2
  1. Consider investigating and treating anaemia if Hb is <11 g/dl or symptoms attributable to anaemia develop1,3
  1. Determine iron status (functional or absolute deficiency)1,3
    • Absolute iron-deficiency anaemia is diagnosed when serum ferritin is <100 ?g/l in CKD stage 5, and should be considered when serum ferritin is <100 ?g/l in CKD stages 3 and 4
    • Functional iron deficiency is defined by a serum ferritin level >100 ?g/l and either the HRC is >6% or TSAT is <20%
    • Serum ferritin is often raised in CKD; the diagnostic cut-off value should be interpreted differently from that in patients without CKD
  2. Treat iron deficiency and optimise iron status1,3
    • Use intravenous iron to treat both functional iron deficiency and patients who do not respond to (or tolerate) oral iron
    • Iron status should be optimised before deciding whether to use ESAs in non-dialysis patients
  3. Iron correction should maintain serum ferritin >200 ?g/l, TSAT >20%,
    and %HRC <6% (unless ferritin >800 ?g/l)1,3
  1. Review iron dose when ferritin reaches 500 ?g/l (it should not rise above 800 ?g/l)1,3
  1. Consider referral for ESA therapy if:
    • patients are likely to benefit in quality of life and physical function
    • co-morbidities and prognosis are unlikely to negate the benefit of correcting the anaemia with ESAs
    • uncertain regarding the benefit:risk of ESA therapy (a trial of the therapy may be warranted)
Age alone should not be a determinant for treating anaemia of CKD.1,3

CKD=chronic kidney disease; QOF=quality and outcomes framework; eGFR=estimated glomerular filtration rate; Hb=haemoglobin; HRC=hypochromic red cells; TSAT=transferrin saturation; ESA=erythropoiesis-stimulating agent

When to begin treating anaemia of CKD

NICE advises that consideration should be given to investigating and managing anaemia in people with CKD if:1,3

  • their haemoglobin falls to ?11 g/dl (or ?10.5 g/dl if the patient is aged <2 years) or
  • the patient develop symptoms attributable to anaemia (e.g. tiredness, shortness of breath, lethargy, and palpitations).

Aspirational range and action thresholds for haemoglobin

The following factors should be taken into account when determining individual aspirational haemoglobin ranges for people with anaemia of CKD:

  • patient preferences
  • symptoms and co-morbidities
  • the required treatment.

The use of ESAs to correct haemoglobin 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 people with CKD-related anaemia. Typically the aspirational range of ESA-corrected haemoglobin should lie between 10 and 12 g/dl for adults (or between 9.5 and 11.5 g/dl for children younger than 2 years of age). Haemoglobin should be kept within this aspirational range; healthcare professionals should not wait until haemoglobin levels are outside this range before adjusting treatment (for example, action should be taken when haemoglobin levels are within 0.5 g/dl of the range’s limits).2

The role of primary care

Erythropoietin therapy tends not to be managed within the primary care setting. However, in the current climate of cutbacks, provision of care closer to home, and the increasing prevalence of CKD, it is likely that management of patients with anaemia in CKD will be kept increasingly within the domains of general practice. It is to be hoped that the NICE recommendations will allow GPs to improve the identification and care of patients with this condition. Recent trial evidence has led to the recommendation that correction of anaemia with ESAs should not usually occur until the haemoglobin level is likely to fall below 10 g/dl. Hence there is scope for increasing the management of anaemia within primary care, particularly if intravenous iron can be delivered in a primary care setting.

Implementation tools

NICE has developed the following tools to support implementation of Clinical Guideline 114 on Anaemia management in people with chronic kidney disease. The tools are now available to download from the NICE website: www.nice.org.uk/CG114

Baseline assessment tool

The baseline assessment tool is an Excel spreadsheet that can be used by organisations to identify if they are in line with practice recommended in NICE guidance and to help them plan activity that will help them meet the recommendations.

Costing tools

A costing report and local cost templates for the guideline have been produced:

  • Costing reports are estimates of the national cost impact arising from implementation based on assumptions about current practice, and predictions of how it might change following implementation of the guideline
  • Costing templates are spreadsheets that allow individual NHS organisations and local health economies to estimate the costs of implementation taking into account local variation from the national estimates, and they quickly assess the impact the guideline may have on local budgets.

Slide set

The slides provide a framework for discussing the NICE guideline with a variety of audiences and can assist in local dissemination. This information does not supersede or replace the guidance itself.

Implementation advice

This tool aims to provide direction when implementing a specific piece of NICE guidance. It will help implementers identify recommendations in the guideline that are not part of current practice, and suggests actions that could be taken.

Podcast

A member of the Guideline Development Group discusses implementation of the updated recommendations in clinical practice.

Conclusion

Anaemia management in people with CKD has undergone a paradigm shift in the last year or so following the publication of the TREAT study. It is clear that a carefully considered balance is needed between the benefits, such as reduced red cell transfusions and increased quality of life, and potential harm from increased risk of stroke and venous thromboembolism, and possible exacerbation of malignancy.

Both the trigger haemoglobin (the level that will prompt introduction of ESA therapy) and the target haemoglobin (the aspirational range for patients on ESA therapy), are more conservative than previously believed. Individualisation of treatment has become more important than ever, with increased recognition of factors impacting on the benefit:risk ratio of treatment.

For further information and to download copies of NICE Clinical Guideline 114, visit: www.nice.org.uk/CG114. This webpage also includes practical tools to help GPs implement the guideline, as well as information for patients detailing the treatment options that they can expect to receive.

References

  1. National Clinical Guideline Centre. Anaemia management in chronic kidney disease. Rapid update 2011. London: NCGC, 2011. Available at: www.nice.org.uk/CG114 nhs_accreditation
  2. London G. Cardiovascular disease in chronic renal failure: pathophysiologic aspects. Semin Dial 2003; 16 (2): 85–94.
  3. National Institute for Health and Care Excellence. Anaemia mangement in people with chronic kidney disease. Clinical Guideline 114. London: NICE, 2011. Available at: www.nice.org.uk/CG114 nhs_accreditation
  4. Astor B, Muntner P, Levin A et al. Association of kidney function with anaemia: the third National Health and Nutrition Examination Survey (1988–1994). Arch Intern Med 2002; 162 (12): 1401–1408.
  5. Besarab A, Bolton W, Browne J et al. The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. N Engl J Med 1998; 339 (9): 584–590.
  6. Drüeke T, Locatelli F, Clyne N et al; CREATE Investigators. Normalization of haemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med 2006; 355 (20): 2071–2084.
  7. Singh A, Szczech L, Tang K et al; CHOIR Investigators 2006. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med 2006; 355 (20): 2085–2098.
  8. Pfeffer M, Burdmann E, Chen C et al; TREAT Investigators. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med 2009; 361 (21): 2019–2032.
  9. Szczech L, Barnhart H, Inrig J et al. Secondary analysis of the CHOIR trial epoetin-alpha dose and achieved hemoglobin outcomes. Kidney Int 2008; 74 (6): 791–798.
  10. Solomon S, Uno H, Lewis E et al. Erythropoietic response and outcomes in kidney disease and type 2 diabetes. N Engl J Med 2010; 363 (12): 1146–1155.
  11. British Medical Association. Quality and outcomes framework guidance for GMS contract, 2009/10. Delivering investment in general practice. London: BMA, 2009. Available at: www.bma.org.uk/employmentandcontracts/independent_contractors/quality_outcomes_framework/ G