Levels of evidence (I–IV) and grading of recommendations (A–D, GPP) are defined at the end of the Major Recommendations field.
Diagnostic Evaluation and Assessment of Anaemia
Diagnostic Role of Haemoglobin (Hb) Levels
D - Management of anaemia should be considered in people with anaemia of chronic kidney disease (CKD) when their haemoglobin level is less than or equal to 11 g/dL (C) (or 10 g/dL if younger than 2 years of age).
See section 3.2.1 in the original full-length guideline document for the associated algorithm.
Diagnostic Role of Glomerular Filtration Rate
D - An estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73m2 should trigger investigation into whether anaemia is due to CKD. When the eGFR is >60 mL/min/1.73m2 the anaemia is more likely to be related to other causes.
See section 3.2.1 in the original full-length guideline document for the associated algorithm.
Diagnostic Tests to Determine Iron Status
A (DS) - Serum ferritin levels may be used to assess iron deficiency in people with CKD. Because 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.
D (GPP) - Iron deficiency anaemia should be:
- Diagnosed in people with stage 5 CKD with a ferritin level of less than 100 micrograms/L
- Considered in people with stage 3 and 4 CKD if the ferritin level is less than 100 micrograms/L
B (DS) - In people with CKD who have serum ferritin levels greater than 100 micrograms/L, functional iron deficiency (and hence those patients who are most likely to benefit from intravenous iron therapy) should be defined by:
- Percentage of hypochromic red cells >6%, where the test is available or
- Transferrin saturation <20%, when the measurement of the percentage of hypochromic red cells is unavailable
Measurement of Erythropoietin
D (GPP) - Measurement of erythropoietin levels for the diagnosis or management of anaemia should not be routinely considered for people with anaemia of CKD.
Management of Anaemia
Initiation of Erythropoiesis Stimulating Agents (ESAs) Therapy in Iron-Deficient Patients
D (GPP) - ESA therapy should not be initiated in the presence of absolute iron deficiency without also managing the iron deficiency.
D (GPP) - In people with functional iron deficiency, iron supplements should be given concurrently when initiating ESA therapy.
Maximum Iron Levels in Patients With Anaemia of CKD
D (GPP) - In people treated with iron, serum ferritin levels should not rise above 800 micrograms/L. In order to prevent this, the dose of iron should be reviewed when serum ferritin levels reach 500 micrograms/L.
Clinical Utility of ESA Therapy in Iron-Replete Patients
D (GPP) - The pros and cons of a trial of anaemia management should be discussed between the clinician, the person with anaemia of CKD, and their families and carers if applicable.
D (GPP) - ESAs need not be administered where the presence of comorbidities, or the prognosis, is likely to negate the benefits of correcting the anaemia.
D (GPP) - A trial of anaemia correction should be initiated when there is uncertainty over whether the presence of comorbidities, or the prognosis, would negate benefit from correcting the anaemia with ESAs.
D (GPP) - Where a trial of ESA therapy has been performed, the effectiveness of the trial should be assessed after an agreed interval. Where appropriate, a mutual decision should be agreed between the clinician, the person with anaemia of CKD, and their families and carers on whether or not to continue ESA therapy.
D (GPP) - All people started on ESA therapy should be reviewed after an agreed interval in order to decide whether or not to continue using ESAs.
Nutritional Supplements
A - Supplements of vitamin C, folic acid, or carnitine should not be prescribed as adjuvants specifically for the treatment of anaemia of CKD.
Androgens
C - In people with anaemia of CKD, androgens should not be used to treat the anaemia.
Hyperparathyroidism
C - In people with anaemia of CKD, clinically relevant hyperparathyroidism should be treated to improve the management of the anaemia.
Patient-Centred Care: ESAs
D - People offered ESA therapy, and their General Practitioners (GPs), should be given information about why ESA therapy is required, how it works, and what benefits and side effects may be experienced.
D (GPP) - When managing the treatment of people with anaemia of CKD, there should be agreed protocols defining roles and responsibilities of healthcare professionals in primary and secondary care.
D - People receiving ESA therapy should be informed about the importance of concordance with therapy and the consequences of poor concordance.
D (GPP) - When prescribing ESA therapy, healthcare professionals should take into account patient preferences about supervised- or self-administration, dose frequency, pain on injection, method of supplying ESA, and storage.
D - In order for people to self-administer their ESA in a way that is clinically effective and safe, arrangements should be made to provide ready, reasonable, and uninterrupted access to supplies.
Patient Education Programmes
D (GPP) - Culturally and age-appropriate patient education programmes should be offered to all people diagnosed with anaemia of CKD and their families and carers. These should be repeated as requested, and according to the changing circumstances of the patient.
They should include the following key areas:
- Practical information about how anaemia of CKD is managed
- Knowledge (e.g., about symptoms, iron management, causes of anaemia, associated medications, phases of treatment)
- Professional support (e.g., contact information, community services, continuity of care, monitoring, feedback on progress of results)
- Lifestyle (e.g., diet, physical exercise, maintaining normality, meeting other patients)
- Adaptation to chronic disease (e.g., previous information and expectations, resolution of symptoms)
Assessment and Optimisation of Erythropoiesis
Benefits of Treatment with ESAS
A - Treatment with ESAs should be offered to people with anaemia of CKD who are likely to benefit in terms of quality of life and physical function.
See section 3.2.2 in the original full-length guideline document for the associated algorithm.
Blood Transfusions
D - In people with anaemia of CKD, in whom kidney transplant is a treatment option, blood transfusions should be avoided where possible.
D (GPP) - In people with anaemia of CKD there may be situations where a transfusion is indicated clinically. In these cases, the relevant haematology guidelines should be followed.
Comparison of ESAs
A - The choice of ESA should be discussed with the person with anaemia of CKD when initiating treatment and at subsequent review, taking into consideration the patient's dialysis status, the route of administration, and the local availability of ESAs. There is no evidence to distinguish between ESAs in terms of efficacy.
Coordinating Care
D (GPP) - People with anaemia of CKD should have access to a designated contact person or persons who have principal responsibility for their anaemia management and who have skills in the following activities:
- Monitoring and managing a caseload of patients in line with locally agreed protocols
- Providing information, education, and support to empower patients and their families and carers to participate in their care
- Coordinating an anaemia service for people with CKD, working between secondary and primary care, and providing a single point of contact, to ensure patients receive a seamless service of the highest standard
- Prescribing medicines related to anaemia management and monitoring their effectiveness
Providing ESAs
D (GPP) - ESA therapy should be clinically effective, consistent, and safe in people with anaemia of CKD. To achieve this, the prescriber and patient should agree a plan that is patient-centred and includes:
- Continuity of drug supply
- Flexibility of where the drug is delivered and administered
- The 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
ESAs: Optimal Route of Administration
C - The patient with anaemia of CKD and the prescriber should agree (and revise as appropriate) the route of administration of ESAs, taking into account the following factors:
- Patient population (e.g., haemodialysis patients)
- Pain of injection
- Frequency of administration
- The lifestyle and preferences of the patient
- Efficacy (e.g., subcutaneous vs intravenous administration, or long-acting vs short-acting preparations)
- Cost of drug supply
A - The prescriber should take into account that when using short-acting ESAs, subcutaneous injection allows the use of lower doses of drugs than intravenous administration.
ESAs: Dose and Frequency
When correcting anaemia of CKD, the dose and frequency of ESAs should be:
- B - Determined by the duration of action and route of administration of the ESA
- D (GPP) - Adjusted to keep the rate of Hb increase between 1 and 2g/dL/month
Optimal Hb Levels
C - In people with anaemia of CKD, treatment should maintain stable Hb levels between 10.5 and 12.5 g/dL for adults and children older than 2 years of age, and between 10 and 12 g/dL in children younger than 2 years of age, reflecting the lower normal range in that age group. This should be achieved by:
- Adjusting treatment, typically when Hb rises above 12.0 or falls below 11.0 g/dL
- Taking patient preferences, symptoms, and comorbidities into account and revising the aspirational range and action thresholds accordingly
D (GPP) - In people who do not achieve a haemoglobin level above 10.5g/dL (or 10.0 g/dL in children younger than 2 years of age) despite correction of iron deficiency and exclusion of the known causes of resistance to ESA therapy (defined as treatment with >300 IU/kg/week of subcutaneous epoetin or >450 IU/kg/week of intravenous epoetin or 1.5 micrograms/kg/week of darbepoetin), lower levels of haemoglobin may have to be accepted.
D (GPP) - Age alone should not be a determinant for treatment of anaemia of CKD.
See section 3.2.3 in the original full-length guideline document for the associated algorithm.
Optimum Haemoglobin Levels In Children with Anaemia of CKD
Recommendations pertaining to children with anaemia of chronic kidney disease are presented in relevant sections throughout the guideline.
Adjusting ESA Therapy
C - Iron status should be optimised before or coincident with the initiation of ESA administration.
D - Use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin-II receptor antagonists is not precluded, but if they are used, an increase in ESA therapy should be considered.
D (GPP) - Haemoglobin measurements should be taken into account when determining the dose and frequency of ESA administration:
- The cause of an unexpected change in Hb level should be investigated (i.e., intercurrent illness, bleeding) to enable intervention.
- ESA dose and/or frequency should be increased or decreased when Hb measurements fall outside action thresholds (usually below 11.0g/dL or above 12.0g/dL), or for example when the rate of change of haemoglobin suggests an established trend (e.g., >1g/dL/month).
See section 3.2.3 in the original full-length guideline document for the associated algorithm.
Treating Iron Deficiency: Correction
D (GPP) - People with anaemia of CKD who are receiving ESAs should be given iron therapy to maintain:
- Serum ferritin >200 micrograms/L
- Transferrin saturation >20% (unless ferritin >800 micrograms/L)
- Hypochromic red blood cells <6% (unless ferritin >800 micrograms/L)
Most patients will require 600–1,000 mg of iron for adults or equivalent doses for children, in a single or divided dose depending on the preparation. Patients with functional iron deficiency should be treated with intravenous iron. Peritoneal dialysis and non-dialysis patients who do not respond to oral iron will require intravenous iron. In appropriate circumstances, iron treatment can also be administered in the community.
D (GPP) - In non-dialysis patients with anaemia of CKD in whom there is evidence of absolute or functional iron deficiency, this should be corrected before deciding whether ESA therapy is necessary.
See section 3.2.2 in the original full-length guideline document for the associated algorithm.
Treating Iron Deficiency: Maintenance
D (GPP) - Once ferritin >200 micrograms/L and hypochromic red cells (HRC) <6% or transferrin saturation (TSAT) >20%, people with anaemia of CKD who are receiving ESAs should be given maintenance iron. The dosing regimen will depend on modality, for example haemodialysis patients will require the equivalent of 50–60 mg intravenous iron per week (or an equivalent dose in children of 1 mg/kg/week). Peritoneal dialysis and non-dialysis patients who do not respond to oral iron will require intravenous iron.
See section 3.2.2 in the original full-length guideline document for the associated algorithm.
ESAs: Monitoring Iron Status During Treatment
Patients receiving ESA maintenance therapy should be given iron supplements to keep their:
- D - Serum ferritin between 200 and 500 micrograms/L in both haemodialysis patients and non-haemodialysis patients, and either
- B - The transferrin saturation level above 20% (unless ferritin >800 micrograms/L) or
- D (GPP) - Percentage hypochromic red cells (%HRC) less than 6% (unless ferritin >800 micrograms/L).
In practice it is likely this will require intravenous iron.
Monitoring Treatment of Anaemia of CKD
Monitoring Iron Status
C - 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 dependant on the product used and the amount of iron given.
D (GPP) - Routine monitoring of iron stores should be at intervals of 4 weeks to 3 months.
Monitoring Haemoglobin Levels
D (GPP) - In people with anaemia of CKD, haemoglobin should be monitored:
- Every 2–4 weeks in the induction phase of ESA therapy
- Every 1–3 months in the maintenance phase of ESA therapy
- More actively after an ESA dose adjustment
- In a clinical setting chosen in discussion with the patient, taking into consideration their convenience and local healthcare systems
Detecting ESA Resistance
D (GPP) - After other causes of anaemia, such as intercurrent illness or chronic blood loss have been excluded, people with anaemia of CKD should be considered resistant to ESAs when:
- An aspirational Hb range is not achieved despite treatment with >300 IU/kg/week of subcutaneous epoetin or >450 IU/kg/week of intravenous epoetin or 1.5 micrograms/kg/week of darbepoetin, or
- There is a continued need for the administration of high doses of ESAs to maintain the aspirational Hb range
D - 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 GDG considered that PRCA should be confirmed when anti-erythropoietin antibodies are present and there is a lack of pro-erythroid progenitor cells in the bone marrow.
C - 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.
See section 3.2.4 in the original full-length guideline document for the associated algorithm.
Managing ESA Resistance
C - 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.
ESA-induced PRCA should be managed in accordance with current best practice. Specialist referral should be considered.
Note: Current best practice for this rare condition is available from the PRCA Global Scientific Advisory Board (GSAB).
See section 3.2.4 of the original full-length guideline document for the associated algorithm.
Definitions:
Levels of Evidence for Studies of Diagnostic Tests
Ia: Systematic review (with homogeneity)* of level-1 studies**
Ib: Level-1 studies**
II: Level-2 studies*** Systematic reviews of level-2 studies
III: Level-3 studies**** Systematic reviews of level-3 studies
IV: Evidence obtained from expert committee reports or opinions and/or clinical experience without explicit critical experience, based on physiology, bench research, or first principles.
*Homogeneity means there are no or minor variations in the directions and degrees of results between individual studies that are included in the systematic review.
**Level-1 studies are studies:
- That use a blind comparison of the test with a validated reference standard (gold standard)
- In a sample of patients that reflects the population to whom the test would apply
***Level-2 studies are studies that have only one of the following:
- Narrow population (the sample does not reflect the population to whom the test would apply)
- Use a poor reference standard (defined as that where the "test" is included in the "reference", or where the "testing" affects the "reference")
- The comparison between the test and reference is not blind
- Case-control studies
****Level-3 studies are studies that have at least two or three of the features listed above.
Levels of Evidence for Studies of Interventions
1++ High quality meta-analyses, systematic review of randomised controlled trials (RCTs), or RCTs with a very low risk of bias
1+ Well conducted meta-analyses, systematic reviews of RCTs, or RCTs with a low risk of bias
1- Meta-analyses, systematic review of RCTs, or RCTs with a high risk of bias
2++ High quality systematic reviews of case-control or cohort studies. High quality case-control or cohort studies with a very low risk of confounding, bias, or chance and a high probability that the relationship is causal
2+ Well conducted case-control or cohort studies with a low risk of confounding, bias, or chance and a moderate probability that the relationship is causal
2- Case-control or cohort studies with a high risk of confounding, bias, or chance and a significant risk that the relationship is not causal
3 Non-analytic studies (for example, case reports, case series)
4 Expert opinion, formal consensus
Grading of Recommendations
Grade A:
- Level 1++, and directly applicable to the target population, or
- Level 1+, directly applicable to the target population, and consistency of results
- Evidence drawn from a National Institute for Health and Clinical Excellence (NICE) technology appraisal
Grade B:
- Level 2++, directly applicable to the target population, and consistency of results, or
- Extrapolated evidence from studies rated as 1++ or 1+
Grade C:
- Level 2+, directly applicable to the target population and demonstrating overall consistency of results, or
- Extrapolated evidence from studies rated as 2++
Grade D:
- Evidence level 3 or 4, or
- Extrapolated from 2+, or
- Formal consensus
D (GPP):
- A good practice point (GPP) is a recommendation for best practice based on the experience of the Guideline Development Group
Grading of Recommendations on Diagnostic Tests
Grade A (DS): Studies with level of evidence Ia or Ib
Grade B (DS): Studies with level of evidence II
Grade C (DS): Studies with level of evidence III
Grade D (DS): Studies with level of evidence IV
(DS = diagnostic studies)
Grading of Recommendations on Interventions
Grade A:
- Level 1++, and directly applicable to the target population, or
- Level 1+, directly applicable to the target population, and consistency of results
- Evidence drawn from a National Institute for Health and Clinical Excellence (NICE) technology appraisal
Grade B:
- Level 2++, directly applicable to the target population, and consistency of results, or
- Extrapolated evidence from studies rated as 1++ or 1+
Grade C:
- Level 2+, directly applicable to the target population and demonstrating overall consistency of results, or
- Extrapolated evidence from studies rated as 2++
Grade D:
- Evidence level 3 or 4, or
- Extrapolated from 2+, or
- Formal consensus
D (GPP):
- A good practice point (GPP) is a recommendation for best practice based on the experience of the Guideline Development Group
