BMJ 2015;350:h2258 doi: 10.1136/bmj.h2258 (Published 4 June 2015)
Page 1 of 4
Practice
PRACTICE GUIDELINES
Management of anaemia in chronic kidney disease: summary of updated NICE guidance 1
1
Smita Padhi senior research fellow , Jessica Glen senior research fellow , Ben A J Pordes project 1 2 manager , Mark E Thomas consultant physician and nephrologist , on behalf of the Guideline Development Group National Clinical Guideline Centre, Royal College of Physicians, London NW1 4LE, UK; 2Department of Renal Medicine, Birmingham Heartlands Hospital, Birmingham, UK 1
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.
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) 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 (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.]
For personal use only: See rights and reprints http://www.bmj.com/permissions
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. 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-declaringand-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. 1 2 3 4 5
Coresh J, Astor BC, Greene T, et al. Prevalence of chronic kidney disease and decreased kidney function in the adult US population: third national health and nutrition examination survey. Am J Kidney Dis 2003;41:1-12 De Lusignan S, Chan T, Stevens P, et al. Identifying patients with chronic kidney disease from general practice computer records. Fam Pract 2005;22:234-41. National Institute for Health andCare Excellence. Anaemia management in chronic kidney disease: update 2011. (Clinical guideline 114. ). 2011http://guidance.nice.org.uk/CG114. National Institute for Health and Care Excellence. Chronic kidney disease: early identification and management of chronic kidney disease in adults in primary and secondary care. (Clinical guideline 182. ) 2014http://guidance.nice.org.uk/CG182. National Institute for Health and Care Excellence. Anaemia management in chronic kidney disease: update 2015. (Clinical guideline ng8. ) 2015. http://www.nice.org.uk/guidance/ ng8.
Subscribe: http://www.bmj.com/subscribe
BMJ 2015;350:h2258 doi: 10.1136/bmj.h2258 (Published 4 June 2015)
Page 4 of 4
PRACTICE
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
Page 1 of 4
Practice
PRACTICE GUIDELINES
Management of anaemia in chronic kidney disease: summary of updated NICE guidance 1
1
Smita Padhi senior research fellow , Jessica Glen senior research fellow , Ben A J Pordes project 1 2 manager , Mark E Thomas consultant physician and nephrologist , on behalf of the Guideline Development Group National Clinical Guideline Centre, Royal College of Physicians, London NW1 4LE, UK; 2Department of Renal Medicine, Birmingham Heartlands Hospital, Birmingham, UK 1
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.
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) 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 (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.]
For personal use only: See rights and reprints http://www.bmj.com/permissions
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. 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-declaringand-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. 1 2 3 4 5
Coresh J, Astor BC, Greene T, et al. Prevalence of chronic kidney disease and decreased kidney function in the adult US population: third national health and nutrition examination survey. Am J Kidney Dis 2003;41:1-12 De Lusignan S, Chan T, Stevens P, et al. Identifying patients with chronic kidney disease from general practice computer records. Fam Pract 2005;22:234-41. National Institute for Health andCare Excellence. Anaemia management in chronic kidney disease: update 2011. (Clinical guideline 114. ). 2011http://guidance.nice.org.uk/CG114. National Institute for Health and Care Excellence. Chronic kidney disease: early identification and management of chronic kidney disease in adults in primary and secondary care. (Clinical guideline 182. ) 2014http://guidance.nice.org.uk/CG182. National Institute for Health and Care Excellence. Anaemia management in chronic kidney disease: update 2015. (Clinical guideline ng8. ) 2015. http://www.nice.org.uk/guidance/ ng8.
Subscribe: http://www.bmj.com/subscribe
BMJ 2015;350:h2258 doi: 10.1136/bmj.h2258 (Published 4 June 2015)
Page 4 of 4
PRACTICE
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
