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## Complete Summary

#### GUIDELINE TITLE

Anaemia management in chronic kidney disease. A national clinical
guideline for management in adults and children.

#### BIBLIOGRAPHIC SOURCE(S)

National Collaborating Centre for Chronic Conditions. Anaemia management
in chronic kidney disease. National clinical guideline for management in
adults and children. London (UK): Royal College of Physicians; 2006. 172
p. \[295 references\]

#### GUIDELINE STATUS

This is the current release of the guideline.

### \*\* REGULATORY ALERT \*\*

#### FDA WARNING/REGULATORY ALERT

**Note from the National Guideline Clearinghouse**: This guideline
references a drug(s) for which important revised regulatory and/or
warning information has been released.

-   [July 31, 2008, Erythropoiesis Stimulating Agents
    (ESAs)](http://www.fda.gov/medwatch/safety/2008/safety08.htm#ESA2):
    Amgen and the U.S. Food and Drug Administration (FDA) informed
    healthcare professionals of modifications to certain sections of the
    Boxed Warnings, Indications and Usage, and Dosage and Administration
    sections of prescribing information for Erythropoiesis Stimulating
    Agents (ESAs). The changes clarify the FDA-approved conditions for
    use of ESAs in patients with cancer and revise directions for dosing
    to state the hemoglobin level at which treatment with an ESA should
    be initiated.

-   [November 8, 2007 and January 3, 2008 Update, Erythropoiesis
    Stimulating Agents
    (ESAs)](http://www.fda.gov/medwatch/safety/2007/safety07.htm#ESA2):
    The U.S. Food and Drug Administration (FDA) notified healthcare
    professionals of revised boxed warnings and other safety-related
    product labeling changes for erythropoiesis-stimulating agents
    (ESAs) stating serious adverse events, such as tumor growth and
    shortened survival in patients with advanced cancer and chronic
    kidney failure.

### COMPLETE SUMMARY CONTENT

 \*\* REGULATORY ALERT \*\*\
 SCOPE\
 METHODOLOGY - including Rating Scheme and Cost Analysis\
 RECOMMENDATIONS\
 EVIDENCE SUPPORTING THE RECOMMENDATIONS\
 BENEFITS/HARMS OF IMPLEMENTING THE GUIDELINE RECOMMENDATIONS\
 QUALIFYING STATEMENTS\
 IMPLEMENTATION OF THE GUIDELINE\
 INSTITUTE OF MEDICINE (IOM) NATIONAL HEALTHCARE QUALITY REPORT
CATEGORIES\
 IDENTIFYING INFORMATION AND AVAILABILITY\
 DISCLAIMER

### SCOPE

#### DISEASE/CONDITION(S)

Anaemia of chronic kidney disease

#### GUIDELINE CATEGORY

Assessment of Therapeutic Effectiveness\
Management\
Treatment

#### CLINICAL SPECIALTY

Family Practice\
Geriatrics\
Internal Medicine\
Neurology\
Pharmacology\
Psychiatry

#### INTENDED USERS

Advanced Practice Nurses\
Physician Assistants\
Physicians

#### GUIDELINE OBJECTIVE(S)

To provide a user-friendly, clinical, evidence-based guideline for the
National Health Service (NHS) that:

-   Offers best clinical advice for anaemia management in chronic kidney
    disease (AMCKD)

-   Is based on best published evidence and expert consensus

-   Takes into account patient choice and informed decision-making

-   Defines the major components of NHS care provision for anaemia of
    CKD

-   Indicates areas suitable for clinical audit

-   Details areas of uncertainty or controversy requiring further
    research

-   Provides a choice of guideline versions for differing audiences

#### TARGET POPULATION

Adults and children with anaemia in chronic kidney disease

#### INTERVENTIONS AND PRACTICES CONSIDERED

**Diagnosis/Evaluation**

1.  Haemoglobin levels

2.  Estimated glomerular filtration rate (eGFR)

3.  Serum ferritin levels

**Management**

1.  Erythropoiesis stimulating agents (ESAs), including consideration
    of:

    -   Patient preference

    -   Route of administration

    -   Dose and frequency

    -   Adjusting ESA therapy

2.  Iron supplements (oral and intravenous)

3.  Treatment of clinically relevant hyperparathyroidism

4.  Blood transfusion

5.  Maintenance of stable haemoglobin (Hb) levels

6.  Monitoring

    -   Iron status

    -   Haemoglobin levels

7.  Detecting ESA resistance

8.  Managing ESA resistance

9.  Use of patient-centered care, including

    -   Provision of information to patient and General Practitioner
        (GP)

    -   Establishment of protocols defining roles and responsibilities
        of healthcare professionals in primary and secondary care

    -   Consideration of patient preferences about supervised- or
        self-administration, dose frequency, pain on injection, method
        of supplying ESA, and storage

    -   Provision of culturally and age-appropriate patient education
        programmes

Interventions and practices considered but not recommended include
measurement of erythropoietin levels, supplements of vitamin C, folic
acid or carnitine, and androgens.

#### MAJOR OUTCOMES CONSIDERED

-   Patient satisfaction

-   Quality of life

-   Sensitivity and specificity of diagnostic tests

-   Morbidity and mortality

-   Exercise capacity

-   Blood pressure

-   Haematocrit and haemoglobin levels

-   Erythropoietin dose and plasma levels

-   Parathyroid hormone levels

-   Hospitalisation rate

-   Cost effectiveness

### METHODOLOGY

#### METHODS USED TO COLLECT/SELECT EVIDENCE

Hand-searches of Published Literature (Primary Sources)\
Hand-searches of Published Literature (Secondary Sources)\
Searches of Electronic Databases\
Searches of Unpublished Data

#### DESCRIPTION OF METHODS USED TO COLLECT/SELECT THE EVIDENCE

**Searching for the Evidence**

The information scientist developed a search strategy for each question.
Key words for the search were identified by the Guideline Development
Group (GDG). In addition, the health economist searched for supplemental
papers to inform detailed health economic work (for example modelling).
Papers that were published or accepted for publication in peer-reviewed
journals were considered as evidence by the GDG. Conference paper
abstracts and non-English language papers were excluded from the
searches.

Each clinical question dictated the appropriate study design that was
prioritised in the search strategy but the strategy was not limited
solely to these study types. The research fellow or health economist
identified titles and abstracts from the search results that appeared to
be relevant to the question. Exclusion lists were generated for each
question together with the rationale for the exclusion. The exclusion
lists were presented to the GDG. Full papers were obtained where
relevant. See Appendix A of the original full-length guideline document
for literature search details.

**Appraising the Evidence**

The research fellow or health economist, as appropriate, critically
appraised the full papers. In general, no formal contact was made with
authors; however, there were ad hoc occasions when this was required in
order to clarify specific details. Critical appraisal checklists were
compiled for each full paper. One research fellow undertook the critical
appraisal and data extraction. The evidence was considered carefully by
the GDG for accuracy and completeness.

All procedures are fully compliant with:

-   National Institute for Health and Clinical Excellence (NICE)
    methodology as detailed in the \"Guideline development methods --
    information for National Collaborating Centres and guideline
    developers\" manual.

-   National Collaborating Centre for Chronic Conditions (NCC-CC)
    quality assurance document and systematic review chart, available
    at:
    [www.rcplondon.ac.uk/college/ncc-cc](http://www.rcplondon.ac.uk/college/ncc-cc)

**Updating the Guideline**

Literature searches were repeated for all of the evidence-based
questions at the end of the GDG development process, allowing any
relevant papers published by 28 September 2005 to be considered.

#### NUMBER OF SOURCE DOCUMENTS

Not stated

#### METHODS USED TO ASSESS THE QUALITY AND STRENGTH OF THE EVIDENCE

Expert Consensus

#### RATING SCHEME FOR THE STRENGTH OF THE EVIDENCE

**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

#### METHODS USED TO ANALYZE THE EVIDENCE

Meta-Analysis\
Systematic Review with Evidence Tables

#### DESCRIPTION OF THE METHODS USED TO ANALYZE THE EVIDENCE

**Distilling and Synthesising the Evidence**

The evidence from each full paper was distilled into an evidence table
and synthesised into evidence statements before being presented to the
Guideline Development Group (GDG). This evidence was then reviewed by
the GDG and used as a basis on which to formulate recommendations.

Evidence tables are available online at
[www.rcplondon.ac.uk/college/NCC-CC](http://www.rcplondon.ac.uk/college/NCC-CC).

#### METHODS USED TO FORMULATE THE RECOMMENDATIONS

Expert Consensus

#### DESCRIPTION OF METHODS USED TO FORMULATE THE RECOMMENDATIONS

**Agreeing the Recommendations**

The sign-off workshop employed formal consensus techniques to:

-   Ensure that the recommendations reflected the evidence base

-   Approve recommendations based on lesser evidence or extrapolations
    from other situations

-   Reach consensus recommendations where the evidence was inadequate

-   Debate areas of disagreement and finalise recommendations

The sign-off workshop also reached agreement on the following:

-   Five to ten key priorities for implementation

-   Five key research recommendations

-   Algorithms

In prioritising key recommendations for implementation, the sign-off
workshop also took into account the following criteria:

-   High clinical impact

-   High impact on reducing variation

-   More efficient use of National Health Service (NHS) resources

-   Allowing the patient to reach critical points in the care pathway
    more quickly

**Writing the Guideline**

The first draft version of the guideline was drawn up by the technical
team in accord with the decision of the Guideline Development Group
(GDG). The guideline was then submitted for two formal rounds of public
and stakeholder consultation prior to publication. The registered
stakeholders for this guideline are detailed on the National Institute
for Health and Clinical Excellence (NICE) website, see
[www.nice.org.uk](http://www.nice.org.uk/). Editorial responsibility for
the full guideline rests with the GDG.

#### RATING SCHEME FOR THE STRENGTH OF THE RECOMMENDATIONS

**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

#### COST ANALYSIS

**Health Economic Evidence**

Areas for health economic modelling were agreed by the Guideline
Development Group (GDG) after the formation of the clinical questions.
The health economist reviewed the clinical questions to consider the
potential application of health economic modelling, and these priorities
were agreed with the GDG.

The health economist performed supplemental literature searches to
obtain additional data for modelling. Assumptions and designs of the
models were explained to and agreed by the GDG members during meetings,
and they commented on subsequent revisions.

**Health Economic Model: Target Haemoglobin in Haemodialysis Patients**

The aim of the model was to compare three alternative haemoglobin (Hb)
targets in the anaemia management of haemodialysis patients over a
2-year period. The haemoglobin targets evaluated were: \<11 g/dL, 11--12
g/dL and \>12 g/dL. The cost per quality-adjusted life year gained was
calculated.

**Conclusion**

The results suggest treating anaemia with a target Hb 11--12 g/dL is
cost effective in haemodialysis patients based on a 30,000 pounds
sterling threshold. However, there is uncertainty in the results of the
model from lack of certainty in the input parameters. Nevertheless, the
results are relatively robust based on one-way sensitivity analyses and
threshold analyses. This analysis is a simplified model of the costs and
benefits of treating anaemia in the haemodialysis population and a
variety of assumptions have been used in the baseline analysis.
Therefore, the results should be interpreted correspondingly.

**Health Economic Calculation: Route of Administration of
Erythropoiesis-Stimulating Agents (ESAs)**

A cost-minimisation analysis based on equivalent effectiveness between
intravenous (i.v.) and subcutaneous (s.c.) epoetin was performed. ESAs
are made available to National Health Service (NHS) trusts through a
system of tendering for local supply contracts. Costs therefore vary
between locations and over time, and this should be borne in mind in
applying the findings of this analysis.

**Conclusion**

The subcutaneous route of administration of epoetin vs intravenous route
results in cost savings of approximately 1,100 pounds sterling + 727
pounds sterling per patient per year.

See Appendices C and D in the full length original guideline document
for details on cost-effectiveness models and calculations.

#### METHOD OF GUIDELINE VALIDATION

External Peer Review

#### DESCRIPTION OF METHOD OF GUIDELINE VALIDATION

The guideline was validated through two consultations.

1.  The first draft of the guideline (The full guideline, National
    Institute for Clinical Excellence (NICE) guideline and Quick
    Reference Guide) were consulted with Stakeholders and comments were
    considered by the Guideline Development Group (GDG)

2.  The final consultation draft of the Full guideline, the NICE
    guideline and the Information for the Public were submitted to
    stakeholders for final comments.

The final draft was submitted to the Guideline Review Panel for review
prior to publication.

### RECOMMENDATIONS

#### MAJOR RECOMMENDATIONS

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/1.73m^2^ should trigger investigation into whether anaemia is due
to CKD. When the eGFR is [\>]{.underline}60 mL/min/1.73m^2^ 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 [\>]{.underline}300
IU/kg/week of subcutaneous epoetin or [\>]{.underline}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
    [\>]{.underline}300 IU/kg/week of subcutaneous epoetin or
    [\>]{.underline}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

#### CLINICAL ALGORITHM(S)

Clinical algorithms are provided in the original guideline document for:

-   Diagnosis of anaemia of chronic kidney disease (CKD) in adults

-   Initial management for adult patients (assumes haemoglobin \[Hb\]
    \<11g/dL)

-   Haemoglobin maintenance algorithm (assumes patient is receiving
    erythropoiesis stimulating agents \[ESAs\] and maintenance
    intravenous iron)

-   Algorithm for adult patients with poor response to ESAs

### EVIDENCE SUPPORTING THE RECOMMENDATIONS

#### TYPE OF EVIDENCE SUPPORTING THE RECOMMENDATIONS

The type of supporting evidence is identified and graded for each
recommendation (see \"Major Recommendations\").

### BENEFITS/HARMS OF IMPLEMENTING THE GUIDELINE RECOMMENDATIONS

#### POTENTIAL BENEFITS

Appropriate treatment of anaemia in patients with chronic kidney disease
to improve quality of life and prevent associated complications

#### POTENTIAL HARMS

Side effects of therapy

### QUALIFYING STATEMENTS

#### QUALIFYING STATEMENTS

-   This guidance represents the view of the Institute, which was
    arrived at after careful consideration of the evidence available.
    Healthcare professionals are expected to take it fully into account
    when exercising their clinical judgement. The guidance does not,
    however, override the individual responsibility of healthcare
    professionals to make decisions appropriate to the circumstances of
    the individual patient, in consultation with the patient and/or
    guardian or carer.

-   Healthcare providers need to use clinical judgement, knowledge and
    expertise when deciding whether it is appropriate to apply
    guidelines. The recommendations cited here are a guide and may not
    be appropriate for use in all situations. The decision to adopt any
    of the recommendations cited here must be made by the practitioner
    in light of individual patient circumstances, the wishes of the
    patient, clinical expertise and resources.

-   The National Collaborating Centre for Chronic Conditions (NCC-CC)
    disclaims any responsibility for damages arising out of the use or
    non-use of these guidelines and the literature used in support of
    these guidelines.

-   The purpose of this guideline is to support clinical judgement, not
    to replace it. This means the treating clinician should:

    -   Take into consideration any contraindications in deciding
        whether or not to administer any treatment recommended by this
        guideline.

    -   Consider the appropriateness of any recommended treatment for a
        particular patient in terms of the patient\'s relevant clinical
        and non-clinical characteristics.

-   Wherever possible, before administering any treatment the treating
    clinician should follow good practice in terms of:

    -   Discussing with the patient why the treatment is being offered
        and what health outcomes are anticipated.

    -   Highlighting any possible adverse events or side-effects that
        have been associated with the treatment.

    -   Obtaining explicit consent to administer the treatment.

-   For those recommendations involving pharmacological treatment, the
    most recent Summary of Product Characteristics should be followed
    for the determination of:

    -   Indications

    -   Drug dosage

    -   Method and route of administration

    -   Contraindications

    -   Supervision and monitoring

    -   Product characteristics

    -   Except in those cases where guidance is provided within the
        recommendation itself

### IMPLEMENTATION OF THE GUIDELINE

#### DESCRIPTION OF IMPLEMENTATION STRATEGY

**Implementation in the National Health Service (NHS)**

The Healthcare Commission assesses the performance of NHS organisations
in meeting core and developmental standards set by the Department of
Health in \"Standards for better health\" issued in July 2004.
Implementation of clinical guidelines forms part of the developmental
standard D2. Core standard C5 says that national agreed guidance should
be taken into account when NHS organisations are planning and delivering
care.

The National Institute for Health and Clinical Excellence (NICE) has
developed tools to help organisations implement this guidance (listed
below). These are available on their website
(<http://guidance.nice.org.uk/cg39>) (see also the \"Availability of
Companion Documents\" field).

-   Slides highlighting key messages for local discussion

-   Costing tools

    -   Costing report to estimate the national savings and costs
        associated with implementation.

    -   Costing template to estimate the local costs and savings
        involved.

-   Implementation advice on how to put the guidance into practice and
    national initiatives which support this locally.

Suggested audit criteria based on the key priorities for implementation
are listed in appendix C of the NICE version of the original guideline
document (see \"Availability of Companion Documents\" field), and can be
used to audit practice locally.

**Key Priorities for Implementation**

-   Management of anaemia should be considered in people with anaemia of
    chronic kidney disease (CKD) when the haemoglobin (Hb) level is less
    than or equal to 11 g/dL (or 10 g/dL if under 2 years of age).

-   Treatment with erythropoiesis stimulating agents (ESAs) should be
    offered to patients with anaemia of CKD who are likely to benefit in
    terms of quality of life and physical function.

-   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 which 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

-   In people with anaemia of CKD, treatment should maintain stable 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 adjustments to treatment, typically when Hb rises
        above 12.0 or falls below 11.0 g/dL

    -   Taking patient preferences, symptoms and comorbidity into
        account and revising the aspirational range and action
        thresholds accordingly

-   Age alone should not be a determinant for treatment of anaemia of
    CKD.

-   People receiving ESA maintenance therapy should be given iron
    supplements to keep their:

    -   Serum ferritin between 200 and 500 micrograms/L in both
        haemodialysis patients and nonhaemodialysis patients, and either

        -   The transferrin saturation level above 20% (unless ferritin
            \>800 micrograms/L) or

        -   Percentage hypochromic red cells (%HRC) less than 6% (unless
            ferritin \>800 micrograms/L)

In practice it is likely this will require intravenous iron.

#### IMPLEMENTATION TOOLS

Audit Criteria/Indicators\
Patient Resources\
Quick Reference Guides/Physician Guides\
Resources\
Slide Presentation

For information about
[availability](#identifying-information-and-availability), see the
\"Availability of Companion Documents\" and \"Patient Resources\" fields
below.

### INSTITUTE OF MEDICINE (IOM) NATIONAL HEALTHCARE QUALITY REPORT CATEGORIES

#### IOM CARE NEED

Living with Illness

#### IOM DOMAIN

Effectiveness

### IDENTIFYING INFORMATION AND AVAILABILITY

#### BIBLIOGRAPHIC SOURCE(S)

National Collaborating Centre for Chronic Conditions. Anaemia management
in chronic kidney disease. National clinical guideline for management in
adults and children. London (UK): Royal College of Physicians; 2006. 172
p. \[295 references\]

#### ADAPTATION

Not applicable: The guideline was not adapted from another source.

#### DATE RELEASED

2006

#### GUIDELINE DEVELOPER(S)

National Collaborating Centre for Chronic Conditions - National
Government Agency \[Non-U.S.\]

#### SOURCE(S) OF FUNDING

National Institute for Health and Clinical Excellence (NICE)

#### GUIDELINE COMMITTEE

Guideline Development Group

#### COMPOSITION OF GROUP THAT AUTHORED THE GUIDELINE

*Group Members*: Dr David Halpin (*Chair*) Consultant Thoracic
Physician, Royal Devon and Exeter NHS Foundation Trust; Dr Penny
Ackland, Royal College of General Practitioners, General Practitioner,
London; Dr Samir Agrawal, Royal College of Pathologists, Senior
Lecturer, Queen Mary, University of London, Honorary Consultant in
Haematology, Barts and The London NHS Trust; Ms Carol Anderson, Anaemia
Nurse Specialist Association, Anaemia Nurse Specialist, East Kent
Hospitals NHS Trust; Mr Robert Bradley, UK Renal Pharmacy Group,
Pharmacist, Cardiff and Vale NHS Trust; Mr Robert Dunn, National Kidney
Federation, Patient and Carer Representative, Devon; Dr Jonathan Evans,
British Association for Paediatric Nephrology, Consultant Paediatrician,
Nottingham City Hospital NHS Trust; Mrs Bernadette Ford, NCC-CC,
Information Scientist; Dr Jane Fisher, NCC-CC, Project Manager (until
July 2005); Mr Rob Grant, NCC-CC, Senior Project Manager (from August
2005); Ms Christine Howard, National Kidney Research Fund, Patient and
Carer Representative, Devon; Ms Karen Jenkins, Royal College of Nursing,
Anaemia Nurse Specialist, East Kent Hospitals NHS Trust; Dr Mick
Kumwenda, British Renal Society, Consultant Renal Physician, Conwy and
Denbighshire NHS Trust; Professor Alison MacLeod, Cochrane Renal Group,
Consultant Nephrologist, Aberdeen Royal Infirmary; Professor of
Medicine, University of Aberdeen; Dr Nyokabi Musila, NCC-CC, Health
Services Research Fellow in Guideline Development (until February 2006);
Ms Debbie Nicholl, NCC-CC, Health Economist (until November 2005); Dr
Shelagh O\'Riordan, British Geriatrics Society, Consultant Physician in
Healthcare of Older People, East Kent Hospitals NHS Trust; Mrs Alison
Richards, NCC-CC, Information Scientist; Ms Alison Roche, Anaemia Nurse
Specialist Association, Nurse Consultant, King\'s College Hospital NHS
Trust; Dr Paul Roderick, Faculty of Public Health, Senior Lecturer in
Public Health, University of Southampton and Southampton University
Hospitals NHS Trust; Dr Paul Stevens (*Clinical Adviser*) Consultant
Renal Physician, East Kent Hospitals NHS Trust; Dr Stephen Thomas, Royal
College of Physicians, Consultant in Diabetes Medicine, Guy\'s and St
Thomas\' NHS Foundation Trust; Dr Eric Will, British Renal Society,
Consultant Renal Physician, Leeds Teaching Hospitals NHS Trust; Ms Jane
Alderdice was invited to contribute at a specific meeting as an expert
representing the British Dietetic Association, but was not a full member
of the GDG; Dr Luigi Gnudi acted as a deputy for Dr Stephen Thomas at a
GDG meeting, representing the Royal College of Physicians

#### FINANCIAL DISCLOSURES/CONFLICTS OF INTEREST

All group members made a formal \"declaration of interests\" at the
start of the guideline development and provided updates throughout. The
National Collaborating Centre for Chronic Conditions (NCC-CC) and the
Guideline Development Group (GDG) Chair monitored these.

#### GUIDELINE STATUS

This is the current release of the guideline.

#### GUIDELINE AVAILABILITY

Electronic copies: Available in Portable Document Format (PDF) format
from the [National Institute for Health and Clinical Excellence (NICE)
Web site](http://guidance.nice.org.uk/cg39).

#### AVAILABILITY OF COMPANION DOCUMENTS

The following are available:

-   Anaemia management in people with chronic kidney disease. NICE
    guideline. London (UK): National Institute for Health and Clinical
    Excellence; 2006 Sep. 36 p. (Clinical guideline; no. 39). Electronic
    copies: Available in Portable Document Format (PDF) from the
    [National Institute for Health and Clinical Excellence (NICE) Web
    site](http://guidance.nice.org.uk/cg39/niceguidance/pdf/English).

-   Anaemia management in people with chronic kidney disease. Quick
    reference guide. London (UK): National Institute for Health and
    Clinical Excellence; 2006 Sep. 11 p. (Clinical guideline; no. 39).
    Electronic copies: Available in Portable Document Format (PDF) from
    the [National Institute for Health and Clinical Excellence (NICE)
    Web site](http://www.nice.org.uk/page.aspx?o=CG039Quickrefguide).

-   Anaemia management in people with chronic kidney disease. Costing
    report. Implementing NICE guidance in England. London (UK): National
    Institute for Health and Clinical Excellence; 2006 Sep. 34 p.
    (Clinical guideline; no. 39). Electronic copies: Available in
    Portable Document Format (PDF) from the [National Institute for
    Health and Clinical Excellence (NICE) Web
    site](http://guidance.nice.org.uk/cg39/quickrefguide/pdf/English).

-   Anaemia management in people with chronic kidney disease. Costing
    template. London (UK): National Institute for Health and Clinical
    Excellence; 2006 Sep. various p. (Clinical guideline; no. 39).
    Electronic copies: Available in Portable Document Format (PDF) from
    the [National Institute for Health and Clinical Excellence (NICE)
    Web site](http://www.nice.org.uk/page.aspx?o=367837).

-   Anaemia management in people with chronic kidney disease.
    Implementation advice. London (UK): National Institute for Health
    and Clinical Excellence; 2006 Sep. 17 p. (Clinical guideline; no.
    39). Electronic copies: Available in Portable Document Format (PDF)
    from the [National Institute for Health and Clinical Excellence
    (NICE) Web
    site](http://guidance.nice.org.uk/cg39/implementationadvice/word/English).

-   Anaemia management in people with chronic kidney disease. Slide set.
    London (UK): National Institute for Health and Clinical Excellence;
    2006 Sep. 24 p. (Clinical guideline; no. 39). Electronic copies:
    Available in Portable Document Format (PDF) from the [National
    Institute for Health and Clinical Excellence (NICE) Web
    site](http://guidance.nice.org.uk/cg39/slideset/ppt/English).

Print copies: Available from the National Health Service (NHS) Response
Line 0870 1555 455. ref: N1115. 11 Strand, London, WC2N 5HR.

Additionally, Audit Criteria can be found in section 3.3 of the
[original guideline document](http://guidance.nice.org.uk/cg39).

#### PATIENT RESOURCES

The following is available:

-   Treating anaemia in people with chronic kidney disease.
    Understanding NICE guidance. Information for people who use NHS
    services. London (UK): National Institute for Health and Clinical
    Excellence; 2006 Sep. 12 p. (Clinical guideline; no. 39). Electronic
    copies: Available in Portable Document Format (PDF) from the
    [National Institute for Health and Clinical Excellence (NICE) Web
    site](http://www.nice.org.uk/newsEvents/pressrelease/pdf/English).

Print copies: Available from the National Health Service (NHS) Response
Line 0870 1555 455. ref: N1116. 11 Strand, London, WC2N 5HR.

Please note: This patient information is intended to provide health
professionals with information to share with their patients to help them
better understand their health and their diagnosed disorders. By
providing access to this patient information, it is not the intention of
NGC to provide specific medical advice for particular patients. Rather
we urge patients and their representatives to review this material and
then to consult with a licensed health professional for evaluation of
treatment options suitable for them as well as for diagnosis and answers
to their personal medical questions. This patient information has been
derived and prepared from a guideline for health care professionals
included on NGC by the authors or publishers of that original guideline.
The patient information is not reviewed by NGC to establish whether or
not it accurately reflects the original guideline\'s content.

#### NGC STATUS

This summary was completed by ECRI on February 15, 2007. The information
was verified by the guideline developer on March 9, 2007. This summary
was updated by ECRI Institute on March 21, 2008 following the FDA
advisory on Erythropoiesis Stimulating Agents. This summary was updated
by ECRI Institute on August 15, 2008 following the U.S. Food and Drug
Administration advisory on Erythropoiesis Stimulating Agents (ESAs).

#### COPYRIGHT STATEMENT

This NGC summary is based on the original guideline, which is subject to
the guideline developer\'s copyright restrictions.

### DISCLAIMER

#### NGC DISCLAIMER

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