Guidelines for the Management of Anaemia Secondary to Chronic Kidney Disease (CKD) in Childhood and Adolescence

• Background
• Definitions
• Differential Diagnosis & Investigation
• When to Consider Treating Anaemia Secondary to CKD
• Targets
• Monitoring
• Algorithm for the Management of Anaemia in Children on ESA > or =6 Months of Age
• Prescription of Erythropoiesis-Stimulating Agents (ESAS) & Dose Adjustment of ESAS
• Prescription of Maintenance Intravenous Iron & Correction of Iron Deficiency
• Management of Resistant Anaemia
• Supporting Documentation for Guidelines
• Suggested Audit Points
• Glossary of Terms and Abbreviations

Background

The normal distribution of Haemoglobin concentration (Hb) varies according to age, sex, ethnicity and altitude. There is however considerable variation within the population having normal renal function. A diagnosis of anaemia secondary to chronic kidney disease (CKD) can be made if there is significant renal impairment and no other cause of anaemia can be identified.

There is a large volume of data supporting improved quality of life/well being and decrease in co-morbidity with correction of anaemia in CKD. Erythropoietin deficiency is the primary cause of renal anaemia. Erythropoietin is produced by peritubular cells and maintains normal proliferation and differentiation of erythroid progenitor cells in the bone marrow.

Treatment of anaemia in CKD requires the use of erythropoiesis-stimulating agents (ESAs) and iron supplementation. Patients with CKD have increased iron requirements especially on haemodialysis (HD). This is due to decreased iron absorption and increased losses. Supplementary iron is also required to obtain maximum benefits from ESAs. A small number of pre-dialysis patients may see an improvement in Hb with iron supplementation alone before ESAs are indicated. Intravenous administration is the optimum route for delivery of iron.

Serum ferritin is the standard test used to assess iron stores. Ferritin may also increase during inflammation, malignancy and liver disease. However functional iron deficiency may exist even when ferritin levels are elevated. The availability of iron can be determined by either % hypochromic rbc (% cells with <28g/dL of Hb) or saturation of transferrin receptors (TSAT).

% hypochromic rbc <2.5% = normal
% hypochromic rbc > 6% = definite functional iron deficiency

TSAT is usually expressed as the percentage of total iron binding capacity (TIBC) [serum iron/TIBC x 100%]. TSAT < 20% is indicative of functional iron deficiency. However TSAT is very variable being affected by serum albumin level and cytokine release.

Hb content of reticulocytes, zinc protoporphyrin and circulating transferrin receptors are other possible indicators of iron availability

These Departmental Guidelines are based upon NICE clinical guideline 39, “Anaemia Management in Chronic Kidney Disease: National clinical guideline for management in adults and children.” www.nice.org.uk/CG039

Modifications in target Hb have been made in accordance with latest Summary of Product Characteristics (SPC) for NeoRecormon® (epoetin beta) and Aranesp® (darbepoetin alfa) updated on the electronic Medicines Compendium (eMC). Further information on product information is available from the European Medicines Agency (EMEA). www.emea.europa.eu

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Definitions

Anaemia secondary to CKD
Hb < 11g/dL (or <10g/dL in child < 2 years of age)
In children with eGFR < 60mL/min/1.73m² where non-renal causes and haematinic deficiency have been excluded.

Iron deficiency anaemia in CKD
Serum ferritin < 100micrograms/L
In children with eGFR < 15mL/min/1.73m²
(Plus considered with eGFR < 60mL/min/1.73m²).

Functional iron deficiency anaemia in CKD
Anaemia associated with serum ferritin > 100micrograms/L
in association with either
% hypochromic rbc (HRC) > 6%
or TSAT < 20%  

Children with functional iron deficiency are most likely to benefit from intravenous (IV) iron supplementation.

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Differential Diagnosis & Investigation

Assessment of Anaemia requires:
Hb concentration
Rbc indices (MCV, MCH)
Serum ferritin – to assess iron stores
Percentage hypochromic red blood cells / transferrin saturation – measurement of functional iron availability
CRP – to assess inflammation
B12, folate

Additional tests that maybe indicated:
Hb electrophoresis
Haemolysis(Coomb’s test, haptoglobin, LDH, bilirubin)
Blood film/ bone marrow aspirate
PTH
Thyroid function tests
Absolute reticulocyte count – to assess erythropoietic activity
Serum aluminium 
Erythropoietin antibody titre 

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When to consider treating anaemia secondary to CKD

Treatment should be considered in CKD when Hb ≤ 11g/dL (or ≤ 10g/dL in children < 2 years) in symptomatic patients.

In pre-dialysis patients, absolute or functional iron deficiency should be corrected before deciding whether ESA therapy is necessary.

Dialysis patients will require iron therapy in combination with ESAs.

Peritoneal dialysis and pre-dialysis patients who do not respond to oral iron or have evidence of functional iron deficiency should be given intravenous iron.

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Targets

Haemoglobin:
Hb 10.0 – 12.0 g/dL for adults and children ≥ 6months
Hb 9.5 – 11.5g/dL for children < 6months

Iron stores:
Serum ferritin between 200micrograms/L and 500micrograms/L in both haemodialysis and non-haemodialysis patients

And either
% hypochromic red cells (HRC) < 6% (unless ferritin > 500 microgram/L)
or transferrin saturation (TSAT) > 20% (unless ferritin > 500 microgram/L)

Note:
Ferritin is an acute phase protein which will rise during infection and inflammation and this should be taken into account when interpreting results.

Therefore:
Ferritin levels above 800micrograms/L should be avoided as there is a risk of haemosiderosis.
Ferritin levels between 500 - 800micrograms/L should be repeated after a week interval if there is a possibility of infection before alteration of iron dose.

Refer to Algorithm for the Management of Anaemia in Children on ESA > or =6 Months of Age

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Monitoring

Aim is to keep rate of Hb increase ≥ 1g/dL and ≤ 2g/dL in 4 weeks.

Haemoglobin: 
Every 2-4 weeks in induction phase of ESA therapy
Every 1-3 months in maintenance phase of ESA therapy
More frequently (every 1-2 weeks) after any ESA dose adjustment or change in route of administration or when switching from recombinant human erythropoietin (r-HuEpo) e.g. NeoRecormon® to Aranesp®.

Serum ferritin and %RCH should be assessed:
Monthly on Haemodialysis (HD)
Up to 3 monthly on Peritoneal dialysis (PD)/ pre-dialysis

Algorithm for the Management of Anaemia in Children on ESA > or =6 Months of Age

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Prescription of erythropoiesis-stimulating agents (ESAs) & Dose adjustment of ESAs:

Starting Dose **:

Table 1: NeoRecormon® (Epoetin beta): for all ages

 
Table 2: Aranesp® (Darbepoetin alfa)

** All children < 11years of age should be commenced initially on NeoRecormon® (Epoetin beta). Children <11years on haemodialysis may then be switched to IV Aranesp® (Darbepoetin alfa) once target Hb level has been achieved.
Children ≥ 11 years may be commenced on either NeoRecormon® (Epoetin beta) or Aranesp® (Darbepoetin alfa) according to patient preference.

ESA dose adjustments

Dose adjustments should only occur every 4 weeks unless Hb > 12g/dL

If increase in Hb is inadequate i.e. <1g/dL in four weeks see Table 1 or 2.

If increase in Hb excessive i.e. > 2g/dL in four weeks or Hb >12g/dL then reduce ESA dose by approximately 25%*. Recheck Hb after 2 weeks, if Hb continues to rise reduce ESA dose by a further 25%* and if Hb >13.5g/dL omit ESA until Hb falls and is <12.5g/dL and restart at a dose 25%* less than last administered ESA dose.

* When making ESA dose alterations round dose to the nearest measurable unit dose for NeoRecormon® (see table 4) or 5-10 micrograms Aranesp®

ESA administration:

ESAs are routinely given IV for HD patients and SC for PD and pre-dialysis patients.

NeoRecormon® can be administered up to three times per week in correction phase followed by weekly and up to fortnightly in maintenance phase.

Aranesp® is generally given weekly in correction phase and weekly or every fortnight in maintenance phase. It can be given monthly in pre-dialysis patients once they have attained target Hb.

Conversion from NeoRecormon® to Aranesp®:

NOTE: Intravenous and subcutaneous Aranesp® are dose equivalent, however some studies have shown that NeoRecormon® given intravenously is less potent than when given subcutaneously.  Local practice is not to amend the NeoRecormon® dose when switching the route of administration but to monitor Hb carefully and adjust doses accordingly after 4 weeks.

ESA storage:
Store at 2 to 8 °C, do not freeze, keep the container in the outer carton, in order to protect from light.

Table 3: ESA storage information

Table 4: Available ESA products and suggested uses

Note: NeoRecormon® 10,000 and 20,000 cartridges for Recopen and the 1000 unit pre-filled syringes were discontinued by Roche Ltd in January 2010 for financial reasons.

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Prescription of maintenance intravenous iron & correction of iron deficiency

Preparation concentration & storage
Intravenous iron(III)-hydroxide sucrose complex (Venofer®) 100mg in 5 mL (20mg/mL)

Do not store above 25°C

Maintenance dose

Correction dose

Total iron deficit = [wt (kg) x (target Hb [g/L] – actual Hb [g/L]) x 0.24] + depot iron

Note: Calculation to determine iron deficit must use Hb in g/L i.e. Hb of 10g/dL = 100g/L

Target Hb varies with age

Depot iron

Iron correction should be given in divided doses over 4 to 6 weeks. Each dose administered should not exceed 3mg/kg (up to a maximum of 200mg/dose). No more than 3 doses should be administered each week. If the total necessary dose exceeds the maximum allowed single dose, then administration has to be split.

Administration of intravenous iron sucrose (Venofer®):

Venofer® should be prescribed by a doctor on an infusion chart.

Anaphylactic reactions are rare however the first dose of Venofer® should be administered in a clinical setting with full resuscitation facilities available.

Dilute Venofer® to at least 1mg/mL with normal 0.9% sodium chloride.

A test dose is required at the start of treatment with a doctor present. Test dose is a 25% of total dose (not to exceed 20mg) to be given at HD session/ clinic visit. This should be infused over 15 minutes. If there are no adverse events over a further 15 minutes then the remainder of the dose should be given over 30 - 60minutes. (Infusion rate not to exceed 3mg/kg/hr)

Further doses of Venofer® may be administered over 30 to 60 minutes (infusion rate not to exceed 3mg/kg/hr) in clinic via a peripheral cannula or in the latter half of haemodialysis via the dialysis circuit. Hypotensive episodes may occur if the injection is administered too rapidly.

Pre and post infusion blood pressure (BP) should be checked and the patient observed for 15 minutes following the end of the infusion.

Para-venous leakage (extravasation***) must be avoided because leakage of Venofer® at the injection site may lead to pain, inflammation, tissue necrosis and brown discoloration of the skin.

Note: Intravenous iron may in theory impede neutrophil function and therefore should be omitted when patient shows signs of sepsis ie fever, raised CRP.

***Action to be taken in event of extravasation of Venofer®

1. Remove cannula
2. Apply cold compress
3. Elevate limb
4. Encourage mobilisation
5. Give analgesia appropriate for patient
6. DO NOT massage area as this will distribute the iron
7. Contact duty pharmacist for further advice if required

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Management of resistant anaemia

Loss of Effect (LOE) is defined as a sudden decrease in Hb
(≥ 2g/dL within one month) without any other contributing factor in a patient who has received a therapeutically effective dose of an ESA for at least 3 weeks with a previously stable Hb.

A differential diagnosis and additional investigations should be carried out as per guidelines.

In the absence of an identifiable cause Pure Red Cell Aplasia (PRCA) should be considered.

PRCA is a severe anaemia characterised by the absence of RBC precursors in the bone marrow and reticulocytes < 10,000/mm³.

Causes of PRCA include:
Tumours
Autoimmune disorders
T – cell disorders
Viral infections
Medications

EPO antibody mediated PRCA
EPO antibody testing can be arranged through Ortho-Biotech (A Biopharmaceutical Division of Janssen-Cilag).  ESAs should not be given four days prior to test.

When EPO antibody mediated PRCA is suspected the ESA should be stopped.

Do not switch to another ESA.

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