Atypical Haemolytic Uraemic Syndrome (aHUS) – Clinician Information

  • Diagnosis

    The following diagnostic criteria have been agreed by the aHUS Rare Disease Group:

    Exclusion

    Shiga toxin associated HUS

    Secondary causes – drugs, infection (HIV, Streptococcus pneumonia), transplantation (bone marrow, liver, lung, cardiac but not de-novo renal),  cobalamin deficiency,  SLE, APL Ab syndrome, scleroderma, ADAMTS13 antibodies or deficiency

    Inclusion

    Renal biopsy showing a TMA

    And/or

    The classic triad of  microangiopathic haemolytic anaemia, thrombocytopenia, renal failure.

  • Diagnostic checklist

    A downloadable diagnostic checklist for aHUS can be found here.

  • Initial treatment of patients with a potential diagnosis of aHUS

    We recommend that all patients with a potential new diagnosis of aHUS are offered treatment with eculizumab. The earlier treatment with eculizumab is initiated the greater the chance of recovery of renal function. For this reason we recommend that the only investigation listed on the diagnostic checklist that must be available before the onset of treatment with eculizumab is the ADAMTS13 activity. Until this is available we recommend that plasma therapy is undertaken.

    Provided that the ADAMTS13 activity is greater than 10% we would then recommend that treatment with eculizumab be started.

  • Access to eculizumab in England

    NHS England published a Clinical Commissioning Policy for the use of eculizumab in aHUS in September 2103. This will remain in place until the outcome of the current NICE HST evaluation. This is expected to be issued in July 2014. Until then clinicians in England who wish to treat patients with aHUS should complete the aHUS diagnostic checklist and send it to Professor Tim Goodship (for adults) and Dr Sally Johnson (for children) who are contactable through the switchboard at the Newcastle upon Tyne Hospitals NHS Foundation Trust. A decision as to whether NHS England will fund eculizumab is usually available within 24 hours.

    Most aHUS patients who are on dialysis in England and would benefit from prophylactic treatment with eculizumab to enable a renal transplant have already been identified.  On a named patient basis approval has been given by NHS England for them to receive eculizumab at the time of transplantation according to a standard protocol.

  • Access to eculizumab in Scotland, Northern Ireland and Wales

    In Scotland funding for eculizumab is available through an Individual Patient Treatment Request (IPTR) submitted by the responsible clinician to the appropriate Health Board.

    In Northern Ireland funding for eculizumab is available through an Individual Funding Request submitted by the responsible Trust to the Health and Social Care Board.

    In Wales funding for eculizumab is available through an Individual Funding Patient Request submitted by the responsible clinician to the Welsh Health Specialised Service Committee.

  • Eculizumab dosage

    Adult dosing schedule

    Initial dose: 900 mg via 35 minute IV infusion then every 7 days for the first 4 doses, followed by 1200 mg for the fifth dose 7 days later.

    Maintenance dose: 1200 mg via 35 minute IV infusion every 14 days.

    Paediatric dosing schedule

    • Patient body weight 40 kg or more:

    Initial dose: 900 mg via 35 minute IV infusion then every 7 days for the first 4 doses, followed by 1200 mg for the fifth dose 7 days later.

    Maintenance dose: 1200 mg via 35 minute IV infusion every 14 days.

    • Patient body weight 30 kg to less than 40 kg:

    Initial dose: 600 mg via 35 minute IV infusion repeated after 7 days then followed by 900 mg for the third dose 7 days later.

    Maintenance dose: 900 mg via 35 minute IV infusion every 14 days.

    • Patient body weight 20 kg to less than 30 kg:

    Initial dose: 600 mg via 35 minute IV infusion repeated after 7 days then followed by 600 mg for the third dose 7 days later.

    Maintenance dose: 600 mg via 35 minute IV infusion every 14 days.

    • Patient body weight 10 kg to less than 20 kg:

    Initial dose: 600 mg via 35 minute IV infusion once, followed by 300 mg for the second dose 7 days later.

    Maintenance dose: 300 mg via 35 minute IV infusion every 14 days.

    • Patient body weight 5 kg to less than 10 kg:

    Initial dose: 300 mg via 35 minute IV infusion once, followed by 300 mg for the second dose 7 days later.

    Maintenance dose: 300 mg via 35 minute IV infusion every 21 days.

  • Home administration of eculizumab

    Home administration of eculizumab can be provided by Bupa Home Healthcare. This service is funded by Alexion Pharma UK and is available for both paediatric and adult patients including those with access systems such as a port-a-cath.

    Healthcare professionals who wish to use this service for an aHUS patient should contact either Professor Tim Goodship (for adults) or Dr Sally Johnson (for children) who are contactable through the switchboard at the Newcastle upon Tyne Hospitals NHS Foundation Trust.

  • Monitoring of patients receiving eculizumab

    In addition to routine biochemistry and haematology investigations we would recommend:

    • Pre dose CH50/AH50 –  should be measured at least twice when the patient starts the routine long-term dose of eculizumab (for instance 1200mg every two weeks in adults). Both CH50 and AH50 should show no detectable haemolytic activity. This should then be repeated annually.
    • Platelet count, LDH and haptoglobins – monthly
    • Urinalysis and PCR – monthly
  • Adverse events in patients receiving eculizumab

    All adverse events in patients receiving eculizumab should be reported both through the Yellow Card scheme and to Alexion Pharma UK Ltd.

  • Transplantation of aHUS patients using eculizumab

    For guidelines on using prophylactic Eculizumab for adult aHUS patients undergoing kidney transplantation please click here.

  • Meningococcal guidelines for adults

    For guidelines on the prevention of meningococcal disease in adult aHUS patients receiving eculizumab please click here.

  • Meningococcal guidelines for children

    For guidelines on the prevention of meningococcal disease in paediatric aHUS patients receiving eculizumab please click here.

  • Screening for inherited and acquired complement abnormalities

    Screening for inherited and acquired complement abnormalities is recommended in all patients with a potential diagnosis of aHUS.  We recommend the following:

    • measurement of C3, C4, factor H and factor I levels on a sample taken before the onset of plasma therapy.
    • screening for factor H autoantibodies
    • mutation screening of CFH, CFI, CD46, C3 and CFB
    • mutation screening of DGKE and THBD when recommended by the national aHUS service

    These investigations are available through the Northern Molecular Genetics Service at the Newcastle upon Tyne Hospitals NHS Foundation Trust.

  • Measurement of ADAMTS13 activity

    We recommend that blood is sent for the measurement of  ADAMTS13 activity as soon as possible to exclude a diagnosis of TTP. Assays for ADAMTS13 activity are available locally in some Trusts and nationally at University College London. Please see the request form and handling and shipping information for details. An ADAMTS13 activity of greater than 10% excludes TTP.

  • Withdrawal of eculizumab

    Eculizumab is licenced for the treatment of atypical haemolytic uraemic syndrome (aHUS). The current licence is for continuous use of Eculizumab once treatment is initiated. This recommendation is based on:

    • The known natural history of aHUS
    • Case reports of recurrence of thrombotic microangiopathy after a short course of treatment with Eculizumab
    • Recurrence of disease in patients who did not enter the extension phase of the clinical trials of Eculizumab in aHUS

    However, there has been no systematic assessment of withdrawal of Eculizumab after control of active thrombotic microangiopathy. Therefore the recommendation to continue use is based on limited evidence. There is a need for clinical studies to better inform clinical decisions on the withdrawal of Eculizumab; specifically to define which patients can withdraw from treatment, the optimal timing of withdrawal and how to monitor patients post-withdrawal. Outside the context of a clinical trial the decision to withdraw Eculizumab may be made by the clinical team responsible for the care of the patient. This suggested protocol is designed to support the clinical team after this decision has been made.

    Recommendations:

    1. The decision to stop Eculizumab should be made on an individual patient basis considering factors that will influence the likelihood and consequences of a relapse:

    a. The genetic / autoantibody status of the patient
    b. The severity of the initial presentation
    c. A previous history of relapsing TMA causing organ failure, for example transplant loss

    2.  Eculizumab should be continued for 6 months before withdrawal is considered. There is no evidence to support a recommendation of 6 months treatment. However it is known that there is a high risk of recurrence in patients treated with a short course of Eculizumab, suggesting that the trigger that precipitated the treated TMA may persist. In addition, after transplantation most recurrences of aHUS (>70%) occur within the first 6 months.

    3. Patients should be monitored closely after withdrawal. This should be most intensive immediately after withdrawal as it is not known whether disease is controlled or in remission. However, there is no evidence to inform the frequency of testing, therefore the following is a suggested monitoring regime.  In some patients, particularly after transplant, there is limited systemic evidence of a recurrent renal thrombotic microangiopathy (platelet, LDH, blood film and haptoglobins) and the only indication is a deterioration in renal function.

    Time since last Eculizumab dose

    Suggested monitoring

    Week 0-2

    Baseline assessment: FBC, LDH, U&Es, bilirubin, haptoglobin

    Week 2-4

    X3/wk FBC, LDH, U&Es

    Weekly Blood film, bilirubin, haptoglobin

    Week 4-6

    X2/wk FBC, LDH, U&Es

    Weekly Blood film, Bilirubin, haptoglobin

    Week 6-10

    Weekly FBC, LDH, U&Es, Blood film, Bilirubin, haptoglobin

    After week 10

    Fortnightly FBC, LDH, U&Es, Blood film, Bilirubin, haptoglobin*

    *Replacing fortnightly Eculizumab infusions

    4. Home monitoring with thrice weekly urinalysis is recommended. The patient is advised to return to hospital for evaluation if microscopic haematuria develops.

    5. Patients should be informed about potential symptoms of relapse and advised to seek medical advice if these occur. They should also have the patient alert card (available from aHUS UK) to present to medical staff.

    6. Antibiotic prophylaxis should be continued for 8 weeks after the last dose of Eculizumab.

    7. Eculizumab should be available to treat relapse

  • On-call service

    A 24 hour on-call service for aHUS is available through the switchboard at the Newcastle upon Tyne Hospitals NHS Foundation Trust.

aHUS Clinician Information version 8 updated January 2017
Written by the aHUS Rare Disease Group