NOTES FOR PRESENTERS You can add your own organisation’s logo alongside the NICE logo. DISCLAIMER This slide set is an implementation tool and should be used alongside the published guidance. This information does not supersede or replace the guidance itself
NOTES FOR PRESENTERS NICE clinical guidelines aim to ensure that promotion of good health and patient care in the NHS are in line with the best available evidence of clinical effectiveness and cost effectiveness. Guidelines help healthcare professionals in their work, but they do not replace their knowledge and skills. Standards for Better Health, issued in July 2004 by the Department of Heath, identifies core and developmental standards for NHS organisations. Core standard C5 states that healthcare organisations should take into account nationally agreed guidance when planning and delivering treatment and care. Implementation of clinical guidelines forms part of developmental standard D2 which states that patients should receive effective treatment and care that conforms to nationally agreed best practice, particularly as defined in NICE guidance. The guideline can be read in conjunction with National Policy National Service Framework for Renal services. Parts 1 and 2 National Service Framework for Children, Young People and Maternity Services Renal services for children and young people - National Service Framework The Department of Health has just (June 2006) published 'The national service framework for renal services: working for children and young people'. This guide is a supplement to The National Service Framework (NSF) for Renal Services. The Renal NSF deals with services for renal patients of all ages: this document focuses specifically on services for children and young people, and describes in greater detail than the Renal NSF how the standards, quality requirements and markers of good practice apply to the care of children and young people with kidney disease and their families . Also, the Renal Association and Royal College of Physicians have produced ‘Treatment of adults and children with renal failure: standards and audit measures’ 3rd edition (2002)
NOTES FOR PRESENTERS The guideline recommendations span primary and secondary care and all age groups including the elderly and children. Consider how these audiences and their relevant carers can be reached when disseminating the guideline and its recommendations.
NOTES FOR PRESENTERS Introduction: Blood haemoglobin concentration serves as the key indicator for anaemia because it can be measured directly, has an international standard and is not influenced by differences in technology Conventionally anaemia is defined as a haemoglobin concentration lower than the established cut off defined by the World Health Organisation in people living at sea level. Different biological groups have different cut off haemoglobin values below which anaemia is said to be present. eg pregnant women
NOTES FOR PRESENTERS In addition to gender, age and pregnancy status, other factors influence the cut-off values for haemoglobin concentration. These include altitude, race and whether the individual smokes. This slide provides an overview of normal values published by the World Health Organisation.
NOTES FOR PRESENTERS There has been much debate over several years about whether the adverse effects listed on the slide translate into adverse outcomes such as impaired quality of life, increased hospitalisation and increased cardiovascular events. Equally, the debate has questioned whether adverse outcomes associated with anaemia are influenced by age, gender and ethnicity. Subgroup analys e s of those over and under 60 years of age by Moreno and colleagues (Moreno et al, American Journal of Kidney Diseases.1996; 27(4):548-556) found a significant increase in quality of life scored associated with higher Hb levels in both age groups. No studies were found during the guideline development process that reviewed gender or ethnicity or health economic evidence.
NOTES FOR PRESENTERS This slide provides an overview of the stages of chronic kidney disease. The Renal National Service Framework has adopted the US National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF-KDOQI) classifications of Chronic Kidney Disease (CKD). This classification divides CKD into 5 stages defined by evidence of kidney damage and level of renal function as measured by GFR - glomerular filtration rate. Stages 1 and 2 are defined by the presence of kidney damage (structural or functional damage) for greater than or equal to 3 months and by level of eGFR. Stages 3-5 are defined by level of eGFR less than60ml/min/1.73m 2 for greater than or equal to 3 months. Stage 5 CKD may be described as established renal failure and is CKD which has progressed so far that renal replacement therapy (regular dialysis treatment or kidney transplantation) will be required to maintain life. It is an irreversible, long-term condition. Kidney disease is diagnosed in clinical practice by estimated glomerular filtration rate (eGFR). This is routinely measured within samples tested for urea and electrolytes.
NOTES FOR PRESENTERS So what is the prevalence of anaemia of CKD? NHANES III (3 rd US National Health and Nutrition Examination Survey) suggests that overall 11% of the population have some degree of kidney disease: 3.3% of the population are in stage 1, 3% in stage 2 , 4.3% are in CKD stage 3, 0.2% in stage 4 and 0.2% in stage 5. Data derived from primary care records in this country indicate a similar population prevalence of stage 3-5 CKD although this is probably an underestimate (for methodological reasons) (Ref; De Lusignan et al Identifying patients with chronic kidney disease from general practice computer records . Family Practice. 2005; 22(3)234-241) The NHANES survey found lower levels of kidney function to be associated with lower haemoglobin levels and a higher prevalence and severity of anaemia (see slide ) Although anaemia in patients with CKD may develop in response to a wide variety of causes, erythropoietin (EPO) deficiency is the primary cause of anaemia in CKD . Predominantly produced by peritubular cells in the kidney, EPO is the hormone responsible for maintaining the proliferation and differentiation of erythroid progenitor cells in the bone marrow. Loss of peritubular cells leads to an inappropriately low level of circulating EPO in the face of anaemia
NOTES FOR PRESENTERS Anaemia is associated with kidney disease because damaged kidneys are unable to produce enough of the hormone erythropoietin, which stimulates the bone marrow to produce red blood cells by a process called erythropoiesis. Within these cells, oxygen is carried round the body by haemoglobin. When haemoglobin cannot be produced in normal amounts, the body does not receive enough oxygen to meet its needs.
NOTES FOR PRESENTERS Not all anaemia in patients with CKD will be ‘renal anaemia’ and causes of anaemia other than CKD should be actively looked for and excluded before a diagnosis of anaemia associated with CKD is made. Iron deficiency anaemia is the most common cause of anaemia worldwide. Although anaemia in patients with CKD may develop in response to a wide variety of causes, erythropoietin deficiency is the primary cause of anaemia associated with CKD . Other factors in the genesis of renal anaemia include functional or absolute iron deficiency, blood loss (either occult or overt), the presence of uraemic inhibitors (for example, parathyroid hormone, inflammatory cytokines), reduced half life of circulating blood cells and deficiencies of folate or vitamin B 12
NOTES FOR PRESENTERS What are we trying to achieve? Not all of these goals may be achievable and there may be certain patients whose physical and mental status renders these goals unachievable from the outset. For many older patients, improvement in quality of life is their paramount need and older people should not be excluded from treatment because of their age. (NICE recommendation 220.127.116.11: Age alone should not be a determinant for treatment of anaemia of CKD)
NOTES FOR PRESENTERS Appropriate diagnosis and assessment of anaemia of CKD will prevent adverse effects of anaemia translating into adverse outcomes. An algorithm is presented in the guideline to inform the diagnosis of anaemia of CKD. Iron management forms an essential part of the treatment of anaemia associated with CKD and availability of iron is key for optimal erythropoiesis and maintenance of a stable haemoglobin. Therefore patients should have their iron status monitored before considering ESA therapy. Erythropoiesis stimulating agents [ESAs] are agents stimulating production of red blood cells through a direct or indirect action on erythropoietin receptors of erythroid progenitor cells in the bone marrow Initiation of ESA therapy is appropriate in iron-replete patients where existing co-morbidities or prognosis do not negate its effect. The potential benefits of ESA therapy are numerous and include avoidance of blood transfusions, improved quality of life and physical functioning. Monitoring is part of care in ESA induction and maintenance, including the rate of haemoglobin change. Monitoring of iron status should aim to ensure that patients undergoing treatment with ESAs maintain optimum levels of iron, i.e. that ensure effective erythropoiesis.
NOTES FOR PRESENTERS The starting point is highlighted in Green. The key pathways will ‘fly in’ following a single click. When there is a pause, click again for the next pathway to ‘fly in’. Question points are highlighted in pink. The end point is highlighted in blue. To minimise the adverse effects of anaemia of CKD early diagnosis is encouraged. This will include measurement of haemoglobin, eGFR, and iron status. It is likely that management of patients with a diagnosis of anaemia of CKD will be shared between specialist nephrology services in secondary care and primary care Using the suggested algorithm for diagnosis of anaemia of CKD in adults will ensure that non-renal causes of anaemia are excluded. (Sections 1.2. and 1.3 of the guideline discuss the management of anaemia and the assessment and optimisation of erythropoiesis) Recommendation 18.104.22.168 Management of anaemia should be considered in people with anaemia of chronic kidney disease (CKD) when their haemoglobin (Hb) level is less than or equal to 11 g/dl (or 10 g/dl if younger than 2 years of age) Recommendation 22.214.171.124 an estimated glomerular filtration rate (eGFR) of < 60ml/min/1.73m 2 should trigger investigation into whether anaemia is due to CKD. When the eGFR is > 60ml/min/1.73m 2 the anaemia is more likely to be related to other causes Recommendation 126.96.36.199 Serum ferritin levels may be used to assess iron deficiency in patients with CKD. As serum ferritin is an acute-phase reactant and frequently raised in CKD, the diagnostic cut off value should be interpreted differently to non-CKD patients Recommendation 188.8.131.52 iron deficiency anaemia should be: diagnosed in patients with stage 5 CKD with a ferritin of less than 100 µg/l considered in stage 3 and 4 CKD if the ferritin is less than 100 µg/l . Recommendation 184.108.40.206 in people with CKD who have serum ferritin levels greater than 100 µg/l , functional iron deficiency ( and hence , those patients who are most likely to benefit from IV iron therapy) should be defined by : % hypochromic red cells > 6% where the test is available. transferrin saturation < 20% when the measurement of % hypochromic red cells is unavailable Recommendation 220.127.116.11 measurement of erythropoetin levels for the diagnosis or management of anaemia should not be routinely considered for patients with anaemia of CKD. (anaemia is associated with increased EPO levels in individuals without evidence of CKD but the anaemia associated with CKD is characterized by a relative lack of EPO response.)
NOTES FOR PRESENTERS The starting point is highlighted in Green. The key pathways will ‘fly in’ following a single click. When there is a pause, click again for the next pathway to ‘fly in’. Action points are highlighted in pink. Treatment points are highlighted in lilac. The end points are highlighted in dark blue In this presentation, the algorithm assumes the patient has anaemia of CKD. Additional iron therapy is not normally recommended if the ferritin is > 500 µg/l, because of the risk of iron overload. ESA therapy should not be offered as a first line treatment. Iron deficiency should be corrected before or when starting ESAs, or before considering them for haemodialysis patients. Once Hb is greater than 11 g/dl, enter the Hb maintenance algorithm and adjust ESA dose according to schedule (in NICE guideline) Recommendation 18.104.22.168 Age alone should not be a determinant for treatment of anaemia of CKD. Recommendation 22.214.171.124 Treatment with ESAs should be offered to patients with anaemia of CKD who are likely to benefit in terms of quality of life and physical function. Recommendation 126.96.36.199 management of anaemia should be considered in people with anaemia of CKD when the haemoglobin is less than or equal to 11 g/dl (or 10 g/dl if under 2 years of age) Recommendation 188.8.131.52 Patients with anaemia of CKD who are receiving ESAs should be given iron therapy to maintain: Serum ferritin level greater than 200 µg/l Transferrin saturation greater than 20% (unless ferritin is greater than 800 µg/l) Percentage hypochromic red blood cells (HRC) less than 6% (unless ferritin is greater than 800 µg/l)
NOTES FOR PRESENTERS A little reminder: Erythropoiesis stimulating agents [ESAs] are agents stimulating production of red blood cells through a direct or indirect action on erythropoietin receptors of erythroid progenitor cells in the bone marrow Evidence statements on efficacy of available ESAs suggest that both darbopoetin and epoetin beta effectively maintain target Hb levels. There was no difference between darbopoetin and epoetin alfa , for the outcomes measured , in a selected group of patients who were stable. Recommendation 184.108.40.206 ESA therapy should be clinically effective, consistent and safe in people with anaemia of CKD. To achieve this, the prescriber should agree a plan that is patient centred and includes: Provision of a secure drug supply Flexibility of where the drug is delivered and administered Lifestyle and preferences of the patient Cost of drug supply Desire for self care where appropriate Regular review of the plan in light of changing needs Recommendation 220.127.116.11 People receiving ESA maintenance therapy should be given iron supplements to keep their: Serum ferritin levels between 200 and 500 µg/l in haemodialysis patients Serum ferritin levels between 200 and 500 µg/l in non-haemodialysis patients, and either Transferrin saturation level above 20% (unless ferritin is > than 800µg/l) or Percentage hypochromic red cells (%HRC) less than 6% (unless ferritin is > than 800µg/l). In practice it is likely this will require intravenous iron.
NOTES FOR PRESENTERS This algorithm assumes that patients are receiving ESA therapy and maintenance i.v. iron. The full algorithm for Hb maintenance can be viewed on page 33 of the NICE guideline. For clarity, part of the algorithm is represented here. When ferritin is ≤ 200 µg/l and the Hb is > 12 g/dl and if there is a ‘no’ response to the TSAT, 20% or HRC > 6% measurement point (refer to previous slide for visual support. In the maintenance algorithm the measurement of Hb is increased from 11 g/dl to 12 g/dl), this algorithm prompts measurement of Hb. The prompt then re-enters the ferritin measurement at the beginning of the cycle of the maintenance algorithm. It is important to take into account patient preferences, symptoms and comorbidity and revise the aspirational range and action thresholds accordingly. The optimal haemoglobin range to be maintained following correction of anaemia associated with CKD is that which confers the most benefit, and least adverse effect in the most cost effective way. Recommendation 18.104.22.168 In people with anaemia of chronic kidney disease, treatment should maintain stable haemoglobin (Hb) levels between 10.5 and 12.5 g/dl for adults and children aged over 2 years and between 10 and 12 g/dl in children aged under 2 years, reflecting the lower normal range in that age group. This should be achieved by: Considering adjustment to treatment, typically when Hb rises above 12.0 g/dL or falls below 11.0 g/dL Taking patient preferences, symptoms and comorbidity into account and revising the aspirational range and action thresholds accordingly The guideline also provides: Suggested ESA adjustment schedules for adults An example iron dosage schedule for adult haemodialysis patients over 50 kg Frequency of haemoglobin monitoring in adults schedule There are no benefits to raising haemoglobin levels above 12 g/dl in terms of outcomes based on current evidence with patients who have anaemia of CKD.
NOTES FOR PRESENTERS Iron Status Monitoring of iron status should be aimed at ensuring that patients undergoing treatment with ESAs maintain levels of iron that ensure maximally effective erythropoiesis Recommendation: 22.214.171.124 people with anaemia of CKD should not have iron levels checked earlier than 1 week after receiving intravenous iron. The length of time to monitoring of iron status is dependent on the product used and the amount of iron given. Recommendation: 126.96.36.199 routine monitoring of iron stores should be at intervals of 4 weeks to 3 months Haemoglobin Recommendation 188.8.131.52 In people with anaemia of CKD, Hb should be monitored: Every 2–4 weeks in the induction phase of ESA treatment Every 1–3 months in the maintenance phase of ESA treatment More actively after a ESA dose adjustment In a clinical setting chosen in discussion with the patient, taking into consideration their convenience and local health care systems Detecting ESA resistance – it is important to distinguish between true resistance (a lack of bone marrow response to ESA therapy) and apparent resistance, where increased red cell destruction or red cell loss offsets ESA stimulated red cell production. This is discussed in the next slide
NOTES FOR PRESENTERS Recommendation 184.108.40.206 details specific indicators of resistance to ESAs. After exclusion of anaemia from other causes such as intercurrent illness or chronic blood loss, these include: Target Hb levels not being reached despite treatment with ≥ 300 IU/kg/week of subcutaneous epoetin or ≥ 450 IU/kg/week of IV epoetin or 1.5 µg/kg/week of darbopoetin or a continuing need for administration of high doses of ESAs to maintain the target Hb level Other possible causes of ESA resistance are detailed in recommendations : 220.127.116.11 In people with CKD, pure red cell aplasia (PRCA) is indicated by a low reticulocyte count, together with anaemia and the presence of neutralising antibodies. The Guidleeine Development Group considered PRCA should be confirmed when anti-erythropoietin antibodies are present and there is a lack of pro-erythroid progenitor cells in the bone marrow. 18.104.22.168 In people with anaemia of CKD, aluminium toxicity should be considered as a potential cause of a reduced response to ESAs after other causes, such as intercurrent illness and chronic blood loss, have been excluded. Managing ESA resistance Recommendation 22.214.171.124 In haemodialysis patients with anaemia of CKD in whom aluminium toxicity is suspected, a desferrioxamine test should be performed and the patient ’s management reviewed accordingly Recommendation 126.96.36.199 In patients with anaemia of CKD, ESA-induced PRCA should be managed in accordance with current best practice. Specialist referral should be considered. ( Current best practice for this rare condition is available from PRCA global scientific advisory board: http://www.prcaforum.com/treatment.php)
NOTES FOR PRESENTERS Suggested actions are not recommendations from NICE. They are advisory for your consideration Work with primary and secondary care services to ensure that all age groups are considered for anaemia management where appropriate Consider how disease registries/chronic conditions registers within primary care may yield patients who would benefit from testing for anaemia of CKD. For example, Anaemia diagnosed in diabetics, heart failure patients and elderly patients currently managed in primary care should be further investigated for renal causes. There are 27 points allocated to CKD in QOF2 Develop local protocols in conjunction with your local renal unit/services which reflect the algorithms presented in the guideline and ensure that these are shared appropriately Management of ESA resistance needs specialist advice so any measures should be in conjunction with the local renal unit. ESA resistance wouldn’t be managed in primary care. It will be important to ensure that practitioners can recognise ESA resistance and know how and who to refer to for advice. Develop consultations between the clinician, patient and their carers if appropriate that can support discussion of the pros and cons of anaemia management Education programmes should cover all aspects of: practical management of anaemia knowledge of symptoms, ESA management and product delivery and storage professional support available and roles and responsibilities patients’ lifestyle [and preferences] adaptation (phases of treatment, expectations, resolution of symptoms)
NOTES FOR PRESENTERS Consider the roles within primary care and secondary care who could assume a coordinating function for this group of patients. This might be the community matron, district nurse and or nurse/pharmacist with responsibility for patients with long term conditions. This role could also assume a coordinating function in relation to treatment with ESAs, maintaining haemoglobin, and monitoring of anaemia of CKD treatment. The skills required for this role might include: monitoring and managing a caseload; providing information, education and support; coordinating an anaemia service and prescribing medicines related to anaemia management. Working with primary care services and people having ESA therapy will ensure that professionals, carer and patients have sufficient information about the condition and treatment to allow people to make informed choices about their treatment. It will also increase concordance with ESA therapy. Develop healthcare professional skills and capacity to support people who choose to have ESA and intravenous iron therapy outside of the acute setting, for example within primary care Build in a review of management of anaemia of CKD after an agreed interval to ensure improved quality of life and physical function. If there is little evidence that ESA therapy is resulting in an increase in quality of life and increased physical function after an agreed interval discuss with the patient the option of discontinuing ESA therapy
NOTES FOR PRESENTERS The NICE document ‘How to put NICE guidance into practice – a guide to implementation for organisations’ is a support tool that provides further information on each of the steps necessary to support implementation. The implementation advice that supports this clinical guideline gives you more information on each of the necessary steps and a suggested action plan for consideration. Both tools can be found on the NICE website.
NOTES FOR PRESENTERS Because of the breadth and complexity of the guideline, this report focuses on the recommendations that are considered to have the greatest impact on resources and will therefore require the most additional resources to implement or that will generate savings. The costing report and the costing template have focussed on detailing the costing issues related to: The cost of ESAs quoted in the costing report is the full BNF cost, the actual cost of ESAs at a local level will vary considerably. Discounts of up to 50% on the BNF price may be achievable for a large renal unit. It is assumed that a large group of people, mostly elderly, with anaemia of CKD are currently unknown to renal services, either due to their anaemia being undetected or untreated. The key recommendation of age not being a determinant for treatment is likely to increase the numbers being referred for treatment. The costing is based on prevalence across the whole age range and will incorporate this increase
NOTES FOR PRESENTERS This guideline is supported by a number of implementation tools, all of which are accessible via the NICE website
NOTES FOR PRESENTERS The guideline is available in a number of formats. You can download them from the NICE website or order hard copies of the quick reference guide or ‘Understanding NICE guidance’ by calling the NHS Response Line on 0870 1555455 and quoting reference number N1115 (for the QRG) or N1116 (for the UNG).
Anaemia management in people with chronic kidney disease September, 2006
a state in which the quality and/or quantity of circulating red blood cells is below normal
haemoglobin cut offs in general population defining anaemia in people living at sea level 13.0 Males > 15 years 12.0 Non-pregnant females > 15 years 12.0 12 to 14 years 11.5 5 to 11 years 11.0 6 months to 5 years Children Haemoglobin below (g/dl) Age or gender group
increased cardiac output and left ventricular hypertrophy
reduced cognition, concentration and libido
reduced immune responsiveness
stages of CKD Established renal failure < 15 5 Severe decrease in eGFR, with or without other evidence of kidney damage 15–29 4 Moderate decrease in eGFR, with or without other evidence of kidney damage 30–59 3 Slight decrease in eGFR, with other evidence of kidney damage 60–89 2 Normal or increased eGFR, with other evidence of kidney damage > 90 1 Description eGFR (ml/min/1.73m 2 ) Stage
how prevalent is anaemia of CKD? NHANES III data 33% 10.3 12.0 15 9% 12.2 13.8 30 1% 13.5 14.9 60 Prevalence of anaemia Median Hb in women (g/dl) Median Hb in men (g/dl) eGFR (ml/min/1.73m 2
diagnosis of anaemia of CKD in adults eGFR < 60ml/min/1.73m 2 AND Hb ≤ 11 g/dl No Consider other causes Yes Non renal and haematinic deficiency excluded? No Treat and repeat Hb Yes Patient on haemodialysis? No See sections 1.2 & 1.3 Yes See initial management algorithm
initial management algorithm Ferritin < 500 µg/l? No Yes Ferritin < 200 µg/l? Yes No TSAT < 20% Or %HRC > 6% No Yes – functional iron deficiency Assess Hb ESA (s.c.or i.v.) Hb > 9 g/dl Hb < 9 g/dl i.v. iron ESA (s.c.or i.v.) and iron Assess Hb at 6 weeks Hb < 11 g/dl Hb > 11 g/dl Continue monitoring Hb and iron status If Hb increase < 1g/dl after 4 weeks, increase ESA using dose schedule
iron supplements should be given to maintain serum ferritin levels
ESA therapy is appropriate in iron-replete patients where existing comorbidities or prognosis do not negate its effect
benefits of ESA therapy include improved quality of life and physical functioning
there is no evidence to distinguish between ESAs in terms of efficacy
Hb maintenance algorithm (assumes ESA therapy and maintenance i.v. iron) Measure Hb Hb < 11 g/dl Hb 11–12 g/dl Hb 12–15 g/dl Hb > 15 g/dl ↑ ESA dose/ frequency as per schedule unless Hb rising by 1/g/dl/month. Check Hb as per Schedule. No change unless Hb rising by 1g/dl/month in which case consider ESA dose adjustment Consider stopping i.v. iron. ↓ ESA dose/frequency as per schedule unless Hb falling by more than 1g/dl/month. Check Hb as per schedule. Stop i.v. iron. Consider stopping ESA or halve dose/frequency. Check Hb in 2 weeks. If Hb is persistently low see poor response algorithm Ferritin < 200 µg/l?