Nephrology

1219 Management of Renal Anaemia

  • Recombinant human erythropoietin is widely used to maintain adequate haemoglobin concentrations and avoid transfusion dependency in patients with renal anaemia.

    Darbepoetin alfa (Aranesp) is a novel erythropoiesis stimulating protein produced by recombinant DNA technology. It is produced in Chinese hamster ovary (CHO) cells by recombinant DNA technology. Aranesp is a 165 amino acid protein containing five N-linked oligosaccharide chains, whereas erythropoietin contains only three. The additional carbohydrate chains increase the molecular weight of the glycoprotein from approximately 30,000 to 37,000 daltons. It has the advantage of less frequent dosing.

    Epoetin Beta (NeoRecormon) is a stable recombinant human erythropoietin concentrate produced from genetically engineered Chinese hamster ovary (CHO) cells containing a cloned human erythropoietin gene.

    The active ingredient, epoetin beta, is a highly purified glycoprotein, identical in amino acid sequence to endogenous erythropoietin, with an apparent molecular weight of 32,000 to 40,000 Daltons. Epoetin beta is greater than or equal to 98% pure, with no detectable cell line residues.

    Indication for use of Darbepoetin Alfa and Epoetin Beta

    The Section 100 listing is for the treatment of anaemia requiring transfusion associated with chronic renal failure (Haemoglobin <100g/L).

    The main cause of anaemia in children with CRI is ineffective erythropoiesis caused by inadequate erythropoietin production.   Other causes include chronic blood loss and increased RBC destruction caused by uraemia toxins and / or dialysis.  It is normocytic, normochromic anaemia.  The aim of management of renal anaemia is for a target Hb of 120g/L in children over 1 year of age and 110g/L in children under 1 year of age.

    Management of Anaemia

    First Evaluate causes of Anaemia:

    • CRF
    • Iron
    • Vit B12
    • Folate Deficiency
    • Blood Loss
    • Haemolysis
    • Infection/Inflammation
    • Aluminium toxicity
    • Hyperparathyroidism

    Ensure Adequate Iron Stores:

    • Ferritin (300-650µg/L)
    • % Saturation (20-50%)
    • Percentage Hypochromic red cells <10%

    Refer patient to Renal Anaemia Co-ordinator (Ext 5721) and commence Epoetin Beta or Darbepoetin alfa if appropriate.

    Correction of Anaemia

    If the increased in Hb is inadequate (less than 10g/L in 4 weeks) and iron stores are adequate, the dose of Epoetin Beta and Darbepoetin Alfa may be increased by 25%.  Further increases may be made at 4 week intervals until the desired response is attained.

    If the rise in Hb is greater than 25g/L in 4 weeks, the dose of Epoetin Beta and Darbepoetin Alfa should be decreased by 25-50%, depending on the rate of increase.  If the Hb exceeds 140g/L, doses should be reinitiated at a dose approximately 25% below the previous dose.

    Administration

    Epoetin Beta

    The cap needs to be removed from the syringe. A needle must then be fixed on the syringe to allow injection. A needle for subcutaneous administration is provided. Only solutions which are clear or slightly opalescent, colourless and practically free of visible particles may be injected. Epoetin Beta prefilled syringes are sterile but do not contain preservatives. Product is for single use in one patient only.

    Dosing with Subcutaneous NeoRecormon
    Sc NeoRecormon
    Correction dose
    Maintenance dose

    Starting dose

    60 IU/kg/week administered Once weekly

     

    Titration

    Increase starting dose every 4 weeks by 60 IU/kg/week if Hb increase is <5g/L

    Adjust dose every 4-8 weeks to suit individual patient

    Maximum dose

    720 IU/kg/week

     

    Dosing with Intravenous NeoRecormon

    IV NeoRecormon

    Correction dose

    Maintenance dose

    Starting dose

    120 IU/kg/week administered in 3 divided doses

     

    Titration

    Increase starting dose every 4 weeks by 240 IU/kg/week if Hb increase is <5g/L

    Adjust dose every 4-8 weeks to suit individual patient

    Maximum dose

    720 IU/kg/week

     

    Darbepoetin alfa

    Darbepoetin Alfa can be administered SC or IV. Chronic Renal Failure Dosage 0.45 mcg/kg SC or IV once weekly; patients not on dialysis: 0.75 mcg/kg SC once every 2 weeks; adjust dose as needed every 4 weeks to achieve rise in Hb of 10 to 25 g/4 wks; maintenance: aim for Hb of 110-140 g/L and adjust dose every 3-4 wks as needed.

    Do not shake Darbepoetin alfa. Prolonged vigorous shaking may denature any protein, rendering it biologically inactive.

    Parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration. Do not use any products exhibiting particulate matter or discolouration.

    Do not dilute or administer Darbepoetin alfa in conjunction with other drug solutions.

    Darbepoetin alfa contains no antimicrobial agent. Darbepoetin alfa is for single use in one patient only. Discard any residue.

    Allow the Darbepoetin alfa prefilled syringe and prefilled pen to reach room temperature before injecting.

    The Darbepoetin alfa prefilled pen (SureClick) delivers the complete dose.

    Both Darbepoetin alfa and Epoetin Beta are stable for up to 2 days at room temperature.

    Contraindications

    Darbepoetin Alfa

    • Uncontrolled hypertension.
    • Known sensitivity to products derived from mammalian cells.

    Epoetin Beta

    • Poorly controlled hypertension and known hypersensitivity to the medication
    • Do not use for   increasing yield of autologous blood in patients who have, in the month preceding treatment, suffered a myocardial infarction or stroke, patients with unstable angina pectoris, or patients who are at risk of deep venous thrombosis.

    Adverse Events

    Darbepoetin Alfa

    Monitoring of Anaemia Indicators

    During correction phase of uraemic anaemia both Hb and Iron studies should be checked monthly.   During maintenance phase (i.e. following attainment of target Hb), Hb should be checked monthly and iron studies checked 3 monthly. 

    In patients with % sat > 50% +/or serum ferritin > 800µg/L, all iron supplements ahould be withheld for up to 3 months at which time the iron studies should be rechecked.

    References

    CARI Guidelines 2003

    DOQI Guidelines 2000

    MIMS Online (RCH)

    NeoRecormon.com.au

    Amgem Australia

     

     

     

     

     

     

     

     

     

     

     

     

     

     

     

     

     

     

     

     

     

     

     

     

     

     

     

     

     

     

     

     

    Iron

     

    Iron is an essential component of many protein molecules.  Most of the body's iron is consumed in the process of erythropoiesis.  Iron bound to the protein, transferrin, circulates in plasma and is taken up by the developing RBC's in the bone marrow, where it forms one of the main components of haemoglobin.

     

    Iron Deficiency

     

     

    Absolute Iron deficiency is when iron stores are inadequate to support bone marrow requirements.  Functional Iron deficiency is when iron stores are adequate, but cannot supply quickly enough to satisfy demand.  The rate of release of iron from iron stores is inadequate.

     

    Measurement of Iron Stores

     

    Measurements of iron stores must be deferred for one week following an IV infusion of <200mg Ferrum H, or for 2 weeks if larger doses are used.

     

    Percentage Hypochromic RBC's

     

    This is a sensitive marker for early iron deficiency.   Hypochromic RBC's result from low iron delivery to the bone marrow, causing some of the RBC's  to contain less than normal amounts of haemoglobin. 

    • Levels should be <10% (target <2.5%).

     

    Percentage Saturation of Transferrin

     

    As iron is circulated on the transferrin molecule, transferrin saturation is a measured of available iron. 

    • Levels should be >20% (target 20-50%)

     

    Serum Ferritin (measure of iron storage)

    Level should be >300µg/L (target 300-650µ/L) in patients on erythropoietin

    Serum Ferritin is not a specific marker of iron status, as it is an acute phase reactant.  As such, it can increase in the setting of inflammation.

     

    Other measurements that can be used are:

     

    a) Serum Fe:               Little use in isolation.

    Diurnal variation in concentration marked (low in early afternoon)

    b) Red Blood Cell:      Volume (<77 fl)

                                         Haemoglobin content (<25 pg)

     

     

     

     

    c) Distribution of RBC width:            >15% variation (elevated by increased reticulocytosis

    due to EPO treatment, older cells get smaller in renal failure)

     

    d) Soluble transferrin receptor increased in iron deficiency normal in chronic disease

     

    Iron Supplementation

     

    Supplementary iron should be administered to prevent iron deficiency and to maintain adequate iron stores, so that the target Hb can be achieved.

    Most children receiving Darbepoetin Alfa or Epoetin Beta will require iron supplementation, as sustained erythropoiesis mobilizes and eventually exhausts iron stores if adequate supplementation is not administered.

    If oral iron is given it should be given as a daily dose of 2-3mg/kg, and is best absorbed without food or other medications.

     

    Intravenous Iron - Dosage

     

    IV iron is more efficacious than oral iron for correction of uraemic anaemia with Darbepoetin Alfa or Epoetin Beta.

     

    IV iron can be given:

    • As an infusion for pre-dialysis children or for children on Peritoneal Dialysis
    • Or as oral incremental low-dose course for children on HD

     

     

    Contraindications for IV Iron

     

    Iron tends to accumulate in inflamed tissues; therefore it should not be given intravenously to patients with severe inflammation or infection of the kidney or liver.

    Ferrum H should not be given to patients presenting with any of the following conditions:

    • Hypersensitivity to iron(III) hydroxide polymatose complex;
    • Anaemia not caused by simple iron deficiency or CRF (e.g. haemolytic anaemia, Megaloblastic anaemia caused by vitamin B12 deficiency, disturbances in erythropoiesis, hypoplasia of the marrow);
    • Iron overload (e.g. haemochromatosis, haemosiderosis);
    • Osler-Rendu-Weber syndrome;
    • Chronic polyarthritis;
    • Bronchial asthma;
    • Infectious renal complaints in acute phase;
    • Uncontrolled hyperparathyroidism;
    • Decompensated hepatic cirrhosis;
    • Infectious hepatitis;
    • During the first trimester of pregnancy.

    As elemental iron tends to accumulate in inflamed tissues, parenteral iron should not be given to patients with severe inflammation or infection of the kidney or liver.

     

    Adverse Reactions to IV Iron

    Adverse reactions to parenteral Ferrum H have only been reported infrequently. However the following reactions are known to have occurred after parenteral iron therapy.

    General. Flushing, sweating, chills and fever; chest and back pain.

    Hypersensitivity. Anaphylaxis.

    Gastrointestinal. Nausea and vomiting.

    Central nervous system. Headache; dizziness.

    Musculoskeletal. Joint and muscle pain; arthralgia; sensation of stiffening of the arms, legs or face.

    Cardiovascular. Faintness; syncope; tachycardia; hypotension; circulatory collapse.

    Respiratory. Bronchospasm with dyspnoea.

    Haematological. Generalised lymphadenopathy.

    Dermatological. Rash; urticaria; angioneurotic oedema.

    Adverse reactions may be delayed by one to two days after treatment with Ferrum H injection.

    IV Iron Infusion low-dose course for children on Haemodialysis

     

    For children undergoing HD, incremental IV iron infusion can be given at a dose of Ferrum H 2mg/kg weekly (up to a maximum of 100mg)

     

    A test dose of IV iron should be given prior to first dose.

     

    Administration of Iron on Haemodialysis

     

    Ferrum H is given diluted into 20mls of Normal Saline over 1 hour during the last hour of dialysis.

     

    Iron levels should be checked one week after iron infusion.  The test should be done after haemodialysis from the venous line.

     

    During low-dose course of Ferrum H, the Hb and iron studies should be rechecked every 8 weeks.

     

    Test Dose of IV Iron

     

    An initial test dose of iron polymaltose should be given prior to the first therapeutic dose of the drug. Adrenaline and facilities for cardiopulmonary resuscitation must be available. In the case of a mild allergic reaction, administer antihistamines.

     

     

    <10kg

    10-20kg

    >20kg

    Dose for test- dose

    0.2ml (10mg)

    0.3ml (15mg)

    0.5ml (25mg)

     

    The test-dose should be given during the day-time and medical staff must be present during administration and for 15 minutes following test-dose. 

    Vital signs should be monitored 15 minutely and observe child closely for 30 minutes for adverse reactions.

     

    The test-dose should be given by slow IV push over 30-60 seconds.  The remainder of the iron dose should not be given until at least 1 hour after test-dose has been given.  If no immediate allergic reactions occur, subsequent routine dosing can be given without a test-dose.

     

    References

     

    CARI Guidelines 2003

    DOQI Guidelines 2000

    MIMS Online (RCH)