Management of anaemia in chronic kidney disease: summary of updated NICE guidance
BMJ 2015; 350 doi: https://doi.org/10.1136/bmj.h2258 (Published 04 June 2015) Cite this as: BMJ 2015;350:h2258
- Smita Padhi, senior research fellow1,
- Jessica Glen, senior research fellow1,
- Ben A J Pordes, project manager1,
- Mark E Thomas, consultant physician and nephrologist 2
- on behalf of the Guideline Development Group
- 1National Clinical Guideline Centre, Royal College of Physicians, London NW1 4LE, UK
- 2Department of Renal Medicine, Birmingham Heartlands Hospital, Birmingham, UK
- Correspondence to: M E Thomas mark.thomas{at}heartofengland.nhs.uk
The bottom line
Various factors—including deficiency of erythropoietin, iron, folate, or vitamin B12; blood loss; infection; and inflammation—contribute to the development of the anaemia of chronic kidney disease
Recognise anaemia by monitoring the blood count as well as glomerular filtration rate
Consider investigating and managing anaemia when haemoglobin falls to 110 g/L in adults or 105 g/L in children under 2 years
To diagnose iron deficiency, use percentage hypochromic red cells (>6%; only if processing within six hours is possible), reticulocyte haemoglobin content (<29 pg), or reticulocyte haemoglobin equivalent
Do not use ferritin or transferrin saturation alone to monitor for iron deficiency
How patients were involved in the creation of this article
Lay members of the Guideline Development Group involved in this guideline update contributed to the formulation of the recommendations summarised here. Patient organisations were among the registered stakeholders who were consulted at both scoping and development stages.
About 5% of the population of the United States and United Kingdom have stages 3-5 chronic kidney disease (CKD; estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2),1 2 and about 15% of these people have anaemia according to World Health Organization criteria.2 Overall more than 100 000 people in the UK have anaemia of CKD.3 Anaemia of CKD develops as renal disease progresses, and it is mainly caused by erythropoietin deficiency; other contributory factors include deficiency of iron, folate, or vitamin B12; blood loss; and infection or inflammation. This article summarises 2006 and 2011 guidance from the National Institute for Health and Care Excellence (NICE) on the management of anaemia of CKD,3 4 and it also highlights key points of the 2015 update.5
Recommendations
NICE recommendations are based on systematic reviews of best available evidence and explicit consideration of cost effectiveness. When minimal evidence is available, recommendations are based on the Guideline Development Group’s experience and opinion of what constitutes good practice. Evidence levels for the recommendations are given in italic in square brackets.
Diagnostic evaluation and assessment of anaemia
Consider investigating and managing anaemia in people with CKD if:
-Haemoglobin falls to 110 g/L or less (or ≤105 g/L if younger than 2 years) or
-They develop symptoms attributable to anaemia (such as tiredness, shortness of breath, lethargy, and palpitations). (2011 recommendation.) [Based on low to moderate quality evidence from prospective and retrospective cohort studies.]
An eGFR of less than 60 mL/min/1.73 m2 should trigger investigation into whether anaemia is caused by CKD. When the eGFR is 60 mL/min/1.73 m2 or more, anaemia is more likely to be related to other causes. (2006 recommendation.) [Based on low to very low quality evidence from retrospective and cross sectional cohort studies.]
Carry out testing to diagnose iron deficiency and determine potential responsiveness to iron therapy and long term iron requirements every three months (every one to three months in people receiving haemodialysis), as follows:
-Use percentage of hypochromic red blood cells (>6%) only if the blood sample can be processed within six hours
-If it is not possible to use percentage of hypochromic red blood cells, use reticulocyte haemoglobin content (<29 pg) or an equivalent test, such as reticulocyte haemoglobin equivalent
-If these tests are not available or the person has thalassaemia or thalassaemia trait, use a combination of transferrin saturation (<20%) and serum ferritin measurement (<100 µg/L). (New recommendation.) [Based on moderate to low quality evidence from randomised control trials (RCTs), low to very low quality evidence from a meta-analysis of diagnostic accuracy cohort studies, cost effectiveness analysis, and the experience and opinion of the Guideline Development Group (GDG).]
Do not request transferrin saturation or serum ferritin measurement alone to assess iron deficiency status in people with anaemia of CKD. Patients with CKD often experience a complex inflammatory state that makes it difficult to diagnose iron deficiency when using these standard markers alone. (New recommendation.) [Based on very low quality evidence from diagnostic accuracy cohort studies, cost effectiveness analysis, and the experience and opinion of the GDG.]
Managing anaemia
Erythropoietin stimulating agent (ESA) therapy (intravenous or subcutaneous)
Offer treatment with ESAs to people with anaemia of CKD who are likely to benefit in terms of quality of life and physical function. The guidance is to treat any iron deficiency before, or at the latest in parallel with, ESA therapy, and obviously not to start an ESA alone while ignoring iron deficiency. (2006 recommendation.) [Based on high quality evidence from a systematic review and meta-analysis of RCTs.]
Correction to normal levels of haemoglobin with ESAs is not usually recommended in people with anaemia of CKD. Instead, the following are recommended:
-Typically maintain the aspirational haemoglobin range at 100-120 g/L in adults, young people, and children aged 2 years or more, and at 95-115 g/L in children under 2 years of age, reflecting the lower normal range in that age group
-To keep haemoglobin within the aspirational range, do not wait until levels are outside the aspirational range before adjusting treatment (for example, take action when haemoglobin is within 5 g/L of the range’s limits). (2011 recommendation.) [Based on moderate to very low quality evidence from RCTs for adults; based on the experience and opinion of the 2011 GDG with respect to children.]
Iron therapy in people with anaemia of CKD not receiving ESA therapy
Offer iron therapy to people with anaemia of CKD who are iron deficient and who are not receiving ESA therapy. The following are recommended:
-For people who are not receiving haemodialysis, consider a trial of oral iron before offering intravenous iron therapy. If they are intolerant of oral iron or target haemoglobin levels are not reached within three months, offer intravenous iron therapy
-For people who are receiving haemodialysis, offer intravenous iron therapy. (New 2015.) [Based on high to low quality evidence from RCTs, cost analysis, and the experience and opinion of the GDG.]
Iron therapy in people with anaemia of CKD receiving ESA therapy
Offer iron therapy to people with anaemia of CKD who are iron deficient and who are receiving ESA therapy. The following are recommended:
-Discuss the risks and benefits of treatment options.5 Take into account the person’s choice
-For adults and young people, offer intravenous iron therapy. Evidence indicates that oral iron does not supply iron to the bone marrow at a rate sufficient to support ESA stimulated erythropoiesis. Intravenous iron is more effective than oral iron at correcting iron deficiency in adults and young people receiving ESA
-For children who are receiving haemodialysis, offer intravenous iron therapy
-For children who are not receiving haemodialysis, consider oral iron. If the child is intolerant of oral iron or target haemoglobin levels are not reached within three months, offer intravenous iron therapy. (New 2015.) [Based on high to very low quality evidence from RCTs, cost analysis, and the experience and opinion of the GDG.]
Offer oral iron therapy to adults and young people who are receiving ESA therapy only if:
-Intravenous iron therapy is contraindicated, or
-The person chooses not to have intravenous iron therapy after discussing the relative efficacy and side effects of oral and intravenous iron therapy. (New 2015.) [Based on high to very low quality evidence from RCTs, cost analysis, and the experience and opinion of the GDG.]
When offering intravenous iron to adults consider a high dose, low frequency regimen as the treatment of choice for those not having haemodialysis; for all children and for adults having in-centre haemodialysis a low dose, high frequency regimen may be more appropriate. (New 2015.) [Based on high to moderate quality evidence from RCTs, cost analysis, and the experience and opinion of the GDG.]
Monitoring and maintenance of iron status
Offer iron therapy to people receiving ESA maintenance therapy to keep their:
-Percentage of hypochromic red blood cells less than 6% (unless serum ferritin is >800 µg/L)
-Reticulocyte haemoglobin count or equivalent tests above 29 pg (unless serum ferritin is >800 µg/L)
-Transferrin saturation level above 20% and serum ferritin above 100 µg/L (unless serum ferritin is >800 µg/L).
The marker of iron status should be monitored every one to three months in people receiving haemodialysis.
In people who are predialysis or receiving peritoneal dialysis, levels are typically monitored every three months. If these people have a normal full blood count there is little benefit in checking iron status. (New 2015.) [Based on the experience and opinion of the 2015 GDG.]
In people treated with iron, serum ferritin levels should not rise above 800 µg/L. To prevent this occurring, review the dose of iron when serum ferritin reaches 500 µg/L. (2006 recommendation.) [Based on the experience and opinion of the 2006 GDG.]
To prevent iron overload, iron stores should be monitored by measuring serum ferritin every one to three months. (2006 recommendation, amended 2015.) [Based on low quality evidence from one cohort study and the experience and opinion of the 2015 GDG.]
ESA resistance and blood transfusion
In ESA resistance, anaemia consistently fails to respond adequately to ESA treatment. Therefore, these patients often receive large doses of ESA or frequent blood transfusions (or both), with limited benefits and at high cost to the NHS.5
Consider referring people with ESA resistance to a haematology service, particularly if an underlying haematological disorder is suspected. (New 2015.) [Based on the experience and opinion of the 2015 GDG.]
Evaluate and discuss the risks and benefits of red cell transfusion with the person or, where appropriate, with the family or carers.5 (New 2015.) [Based on the experience and opinion of the 2015 GDG.]
Avoid blood transfusions where possible in people with anaemia of CKD in whom kidney transplantation is a treatment option to avoid sensitisation. (2006 recommendation.) [Based on low to very low quality evidence from observational studies.]
When thinking about the need for red cell transfusion, in addition to haemoglobin levels also take into account the person’s symptoms, quality of life, underlying conditions, and the chance of a future successful kidney transplant. (New 2015.) [Based on the experience and opinion of the 2015 GDG.]
Review the rate of red cell transfusion and consider a trial period of stopping ESA in people who have ESA resistance (typically on haemodialysis and on high dose ESA) and are having frequent transfusions when:
-Αll reversible causes of ESA resistance have been taken into account and excluded (for example, inflammatory or other intercurrent illness, such as infection), and
-The person’s condition is otherwise “stable” (without intercurrent illness), and
-The person is receiving adequate dialysis.
Review the rate of red cell transfusion between one and three months after stopping ESA therapy. If the rate of transfusion has increased, consider restarting ESA therapy. (New 2015.) [Based on the experience and opinion of the 2015 GDG.]
Overcoming barriers
The guideline update advises that “traditional” tests familiar to clinicians (ferritin or transferrin saturation alone) should no longer be used to diagnose iron deficiency in anaemia of CKD. About 70% of blood count analysers in the UK can already do one of the suggested red cell tests for the diagnosis and management of iron deficiency. Haematology laboratories should consider the need to do these tests when upgrading or purchasing blood count analysers. Analysis of blood count samples within the six hour time frame may require planning but was thought to be achievable for UK patients. Use of the recommended tests to diagnose and manage iron deficiency in patients with anaemia of CKD should improve diagnostic accuracy, enabling more effective iron prescribing and patient care.
Further information on the guidance
For this 2015 update of the guideline, the Guideline Development Group (GDG) considered evidence in several areas that clinicians who manage anaemia of chronic kidney disease (CKD) find challenging. This included recent evidence on newer markers of iron deficiency and iron preparations, given the difficulties of interpreting standard markers, such as transferrin saturation or ferritin alone, in CKD.
The GDG also considered uncertainties in the management of patients who are “erythropoietin stimulating agent (ESA) resistant” and those with anaemia of CKD receiving ESA therapy and admitted with an intercurrent illness, such as pneumonia (which may temporarily render them acutely hyporesponsive to ESA).
Methods
The updated guideline was developed using current National Institute for Health and Care Excellence (NICE) guideline methodology (www.nice.org.uk/article/PMG20/chapter/1%20Introduction%20and%20overview). The GDG comprised four consultant nephrologists (including the chair), a renal pharmacist, a paediatric anaemia nurse specialist, two patient members, two anaemia nurse specialists, a general practitioner, a paediatric nephrologist, and a haematologist. A consultant geriatrician and diabetologist acted as expert witnesses.
The group developed clinical questions, collected and appraised clinical evidence, and evaluated the cost effectiveness of proposed interventions and management strategies through literature review and economic analysis. The draft guideline went through a rigorous review process, in which stakeholder organisations were invited to comment; the group took all comments into consideration when producing the final version of the guideline. Quality ratings of the evidence were based on GRADE methodology (www.gradeworkinggroup.org). These relate to the quality of the available evidence for assessed outcomes rather than the quality of the clinical study. Where standard methods could not be applied, a customised quality assessment was done. These were either presented as a narrative summary of the evidence or in customised GRADE tables (for example, for observational studies and individual patient data meta-analysis).
NICE has produced three different versions of the guideline: a full version (www.nice.org.uk/guidance/ng8/evidence); a summary version known as the “NICE guideline” (www.nice.org.uk/guidance/ng8); and a version for people who have anaemia of CKD, their families and carers, and the public (www.nice.org.uk/guidance/ng8/informationforpublic). All of these versions, as well as a pathway, are available from the NICE website (http://pathways.nice.org.uk/pathways/anaemia-management-in-people-chronic-kidney-disease). Updates of the guideline will be produced as part of NICE’s guideline development programme.
Diagnostic meta-analysis and review of test accuracy
A diagnostic meta-analysis was conducted on two tests for which sufficient data were available at clinically relevant thresholds (transferrin saturation <20% and serum ferritin <100 µg/L). These results were used to facilitate recommendations by providing pooled summary statistics to feed into a new health economic analysis. The limited sensitivity and specificity of transferrin saturation and serum ferritin observed in the diagnostic meta-analysis contributed to the GDG’s decision to recommend against the use of either of these tests in isolation for the diagnosis of iron deficiency anaemia in people with CKD.
Cost effectiveness analysis of different iron deficiency test and treat strategies
An economic model was developed from an NHS perspective to compare the cost effectiveness of different iron deficiency test and treat strategies.
For patients on haemodialysis, treatment of those with percentage of hypochromic red cells more than 6% dominated all other strategies (lowest cost and highest number of quality adjusted life years (QALYs)). In patients not on haemodialysis, the lowest cost strategy was to treat only those patients with transferrin saturation less than 20% and serum ferritin less than 100 µg/L. However, the most cost effective strategy was to treat those with percentage of hypochromic red cells more than 6% at a threshold of £20 000 (€28 018; $30 480) per QALY, costing £11 300 per additional QALY gained.
Cost analysis for iron therapy
Oral iron
For patients who can tolerate oral iron and whose haemoglobin levels respond adequately, oral iron is the lowest cost intervention.
Intravenous iron
The costs of different intravenous iron therapy regimens for predialysis patients and those on peritoneal dialysis were compared. Although a high dose, low frequency regimen was optimal in the base case analysis and sensitivity analyses, the specific least cost regimen varied in the sensitivity analysis. A simple costing tool was developed to allow providers to work out the lowest cost regimen locally.
The incremental cost of intravenous iron therapy would be much lower for patients receiving haemodialysis in hospital than for patients who have to attend hospital specifically for iron therapy, so low dose, high frequency regimens are much more likely to be cost effective for these patients.
Future research
What is the optimal management (in terms of clinical effectiveness and cost effectiveness) of anaemia of CKD in patients who are receiving ESAs and have a serious concurrent acute infectious illness?
In people with chronic ESA resistant anaemia of CKD, what are the clinical effectiveness and cost effectiveness of treating with high dose ESA compared with blood transfusion?
What is the most effective type of intervention to treat patients on haemodialysis who have ESA resistant anaemia?
What are the clinical effectiveness and cost effectiveness of different iron therapies for people with anaemia of CKD who opt for conservative care (defined in relation to haemodialysis)?
In people with anaemia of CKD who opt for conservative management, what are the clinical effectiveness and cost effectiveness of treating to different target haemoglobin values?
Notes
Cite this as: BMJ 2015;350:h2258
Footnotes
This is one of a series of BMJ summaries of new guidelines based on the best available evidence; they highlight important recommendations for clinical practice, especially where uncertainty or controversy exists.
The members of the Guideline Development Group were Mark Thomas (chair), Christopher Brown, Roy Connell, Belinda Dring, Damian Fogarty, Kathryn Griffith, Nicholas Palmer, Jan Cooper, Ashraf Mikhail, Mark Devonald, Mark Prentice, Laura Ratcliffe, Suzanne Stephens, Wayne Thomas. The technical team at the National Clinical Guideline Centre included Joanna Ashe, Saoussen Ftouh, Jessica Glen, Bethany King, Susan Latchem, Grace Marsden, Smita Padhi, Ben Pordes, and David Wonderling. The co-opted expert advisers were Richard Frearson and Peter Hammond.
Contributors: All authors contributed to the conception and drafting of this article, and to revising it critically. They have all approved this version. MT is guarantor.
Funding: SP, JG, and BAJP are employees of the Royal College of Physicians, National Clinical Guideline Centre, which is funded by the National Institute for Health and Care Excellence to produce clinical guidelines.
Competing interests: We declare the following interests based on the National Institute for Health and Care Excellence’s policy on conflicts of interests (available at http://www.nice.org.uk/Media/Default/About/Who-we-are/Policies-and-procedures/code-of-practice-for-declaring-and-managing-conflicts-of-interest.pdf): MET was a local investigator for an Amgen sponsored trial of fortnightly versus monthly darbepoetin dosing in chronic kidney disease (CKD). This resulted in standard trial fees paid into the departmental research fund for a research nurse, physician, and other costs. The last invoice was paid in May 2012. He was UK chief investigator for this multinational study, a role that is nominal as it has not required any work or resulted in any payment. MET was a local investigator for a Vifor sponsored randomised controlled trial of intravenous Ferinject (ferric carboxymaltose) versus oral iron therapy in treatment of iron deficiency of CKD (the FIND-CKD study). This has resulted in standard trial fees paid into the departmental research fund for a research nurse, physician, and other costs. MET attended a meeting at the Birmingham Nephology Club sponsored by Amgen, which included a meal, on 3 July 2014. MET’s department is involved in the PIVOTAL trial. The authors’ full statements can be viewed at: www.bmj.com/content/bmj/350/bmj.h2258/related#datasupp.
Provenance and peer review: Commissioned; not externally peer reviewed.