Nephrology

517 Haemolytic Uraemic Syndrome

  • Haemolytic Uraemic Syndrome (HUS): Management Guideline

     

    Introduction

    HUS comes under the spectrum of thrombotic microangiopathy (TMA), which includes TTP (Thrombotic Thrombocytopaenic Purpura) and other secondary forms of TMA such as post bone-marrow transplant, calcineurin inhibitor-induced and malignant hypertension. These conditions share common haematological findings reflecting intravascular microthrombosis- red cell fragmentation, anaemia, thrombocytopaenia and elevated LDH. However, the end-organ damage effects can vary considerably, characteristically biased towards severe kidney injury in HUS, whereas neurological injury and systemic symptoms characterise TTP. However, an increasing understanding of the molecular basis of these diseases demonstrates the blurring of these clinical distinctions. As there are therapeutic implications, a correct diagnosis is very important.

    This guideline is intended for the management of HUS, likely to have presented with acute kidney injury (AKI). However, it is to be expected that a haematologist will be involved in confirming the fragmentation on blood film and to further advise if there is any possibility of TTP. The child with HUS is characteristically extremely sick and at risk of rapid decompensation with multi-organ involvement including some/ all of:

    1. AKI- oliguric, hyperkalaemic and hypertensive complications common
    2. Neurological- irritability, seizures, decreased conscious state
    3. Bleeding risk with severe thrombocytopaenia and anaemia
    4. Cardiac- hypertensive cardiomyopathy/ myocarditis/ ischaemia
    5. Gastrointestinal- bleeding/ perforation
    6. Pancreatitis
    7. Pulmonary- oedema, haemorrhage

    Nomenclature in HUS has evolved over recent years and the commonest form remains a toxin-induced form which characteristically begins with an infectious colitis (Stx-HUS or STEC-HUS). However, up to 1/3 of cases will have no history of diarrhoea and almost 1/3 of cases due to genetic causes will be triggered by an illness associated with diarrhoea. Therefore the term diarrhoea-associated or D+ HUS should no longer be used. See Table 1 for a contemporary approach to the classification of HUS.

    Notify a case of HUS to Department of health as soon as clinical diagnosis made.

    Table 1 HUS Classification

    Aetiology Advanced

    Aetology Unknown

    1. Infection induced
    1. STX-HUS
    2. Pn-HUS
    1. HIV
    1. Disorders of Complement Reg’n
    1. Genetic
    2. Acquired
    1. Malignancy, Chemotherapy, Radiotherapy
    1. ADAMTS13 deficiency
    1. Genetic
    2. Acquired
    1. CNI, Transplantation
    1. Cobalamin deficiency

     

    1. Pregnancy, HELLP, OCP

     

    1. Quinine-induced

     

    1. SLE, APS

     

     

    1. Unclassified

    Ped Neph 2009, 687-696 (Adapted)

    Diagnostic assessment

    This is a challenging area for HUS. The goals are:

    1.  Confirm a diagnosis of HUS
    2. Identify reversible and life-threatening complications
    3. Identify a cause for the HUS
    4. Typical- may be done with testing at RCH, local laboratories in Melbourne.
    5. Atypical- likely to require sophisticated testing at external centres. These may need to be arranged well after initiation of treatment. It is therefore important to at least obtain stored serum before exposure to blood products.

     

    Practical approach- SUMMARY

    1. For all patients: Send Iist of initial investigations and 10ml serum to store (prior to exposure to blood products). Discuss with haematology regarding citrate adjustment in blue tube prior to collection for coagulation and ADAMTS13 samples.
    2. In selected cases, request form to RCH lab: CD46 by flow cytometry, Factors H & I, ADAMTS13 (Notify immunology lab 55725).
    3. In selected cases, Request form to Paris to be sent later with stored serum and DNA: Factor B, FHAb, gene mutation analysis: see Nephrology protocol 5.4.27.

     

    Initial Investigations for all cases HUS (Minimum volume and tubes)

    1. Haematology (0.25ml red tube; 1.4ml blue tube; 2.7ml red)
      • FBE and film for fragments
      • Coags
      • DAT (Coombs)
      • Grp and hold/ XM if Hb< 70:
    2. Biochemistry (2ml brown tube)
      1. UEC, Ca, P, LFT, CRP
      2. LDH
      3. Haptoglobin
      4. Lipase, Amylase
      5. Acid-base
      6. CK +/- troponin
    3. Microbiology/ virology
      1. Blood culture
      2. Faeces: MCS, Stx toxin, PCR for EHEC (If diarrhoea resolved, may need rectal swab)

    NB. STX tested by PCR at MDU (Tel: 8344-5701) run on Wed, needs to arrive Mon for enrichment. Sample can be tested on faeces or urine. Results within 24hr.

    •  
      • MSU- MCS, Pr:Cr +/- Stx PCR
      • Other focus eg BAL/ VATS for pneumococcus
      • NPA- Influenza A
    • Radiology:
      • CXR
      • Renal U/S +/- Doppler
      • Abdominal U/S if concern of GI Cx/ pancreatitis
    • Other if atypical (2.5ml brown tube, excluding cobalamin metabolism)
      • bHCG
      • Cobalamin metabolism:  Homocysteine/ MMA screen (blood/ urine)
      • HIV, HBV, HCV
      • C3, C4, ANA, lupus anticoagulant, antiphospholipid antibodies
    • Serum! Take 10mls of blood in gel tube for storage before exposure to blood products.

    Arranging molecular and gene mutation analysis for cases of Atypical HUS

    (see appendix 1 for diagnostic sites)

     Complement factor level/ expression

    1. CD46 (MCP)- FACS performed at RCH- notify immunology lab Ext 55725
    2. Factor H, I- performed at SEALS, HAPS, Paris lab
    3. Factor B- performed at Paris lab
    4. FH Ab- performed at performed at Paris lab (ELISA being developed at RCH, expected to be available early 2014)
    5. ADAMTS13 level- performed at MMC

    Gene mutation analysis

    1. CFH, CFI, MCP, ADAMTS13- performed at HAPS
    2. CFH, CFI, MCP, ADAMTS13, CFB, Thrombomodulin, CFHR 1/3- performed at Paris, UK labs.

    Note from Sharon Choo

    “whenever you measure complement components you should measure CH50/AP50 (classical and alternative pathway activity) and C3/C4 at the same time. It is very difficult interpreting factor h, factor i and factor b results without knowing what the CH50/AP50 and C3/C4 results are on the same sample.”

    Treatment

    Children with HUS have a high risk of rapidly developing oliguric AKI with at least half of children requiring dialysis. Additionally, many children will experience extra-renal complications, including up to 30% developing seizures. Once the diagnosis is considered, nephrology and haematology advice should be urgently sought in order to optimise management, especially preparation for dialysis access and blood product administration. The following provides a general outline of management, but this should be individualised by the treating nephrologist.

    1. Anaemia- Aim to avoid excessive to transfusion due to risk of fluid overload and hyperkalaemia. Target Hb 70-100 g/L.
    2. Thrombocytopaenia- Correct to > 50 x109/L for operative procedures or for active bleeding. Consideration for platelet transfusions should be given if platelet count < 10 x109/L.
    3. Hypertension- Children with HUS are critically sensitive to hypertensive complications, especially encephalopathy and seizures. Initiate antihypertensive treatment with nifedipine 0.5mg/kg as needed, but this usually implies a high likelihood of fluid overload- direct therapy at fluid restriction, trial of diuretics and likely need for dialysis. Commence patient on strict fluid balance, weight at least daily and restrict fluid intake to urine output + insensible losses (400ml/m2/ day) with no KCl in fluids.
    4. AKI
      1. Fluid: In some circumstances HUS presents very early and there may be reversible pre-renal AKI. Fluid resuscitation is indicated, but requires close monitoring for evolving fluid overload.
      2. Hypertension and fluid overload (see 3).
      3. Severe biochemical derangements include those of Na, K, Ca, Phosphate and acid-base. If not easily correctable with medical therapy, dialysis is necessary. Notify surgeon early to arrange theatre access for Tenckhoff/ Permacath.
      4. Dialysis options include:
        1. CVVH- performed in PICU and indicated for haemodynamic instability.
        2. Peritoneal dialysis- The preferred option in most cases of HUS due to gentle and continuous dialysis and fluid removal.
        3. Intermittent haemodialysis- preferred in some older children, where abdominal complications preclude PD or if plasma exchange may be required.
    5. Seizures- initiate anti-epileptics according to standard approaches with neurology input. Consider brain imaging to exclude intracranial haemorrhage.
    6. Plasma exchange (TPE)- 1.5 volume exchange (60ml/kg) against all FFP. If access for TPE is likely to be delayed >24hr or TTP is considered an alternative diagnosis, infusion of FFP 10-20ml/kg may be initiated until TPE can be instituted. Frequency of plasma therapy (TPE/ FFP infusion) to be determined according to investigation results and response, but initially daily for the first 5 days. There is no evidence TPE improves outcomes in paediatric Stx-HUS. However, severe Stx-HUS, especially with neurological involvement, is often treated with empiric TPE for the following reasons:
      1. This sub-group with a greater risk of long-term morbidity and mortality is has not been adequately evaluated in randomised studies to exclude a benefit from TPE. TPE is still used in adult HUS, though with little evidence of proven benefit.
      2. During the initial assessment, it may be impossible to exclude the possibility of TTP, for which TPE is a proven therapy. ADAMTS13 <10% supports a diagnosis of TTP and mandates TPE.
      3. During the initial assessment, it may be impossible to exclude the possibility of aHUS, for which TPE is of benefit in some patients.
    7. Eculizumab- This is a humanised monoclonal Ab directed against C5. It has shown efficacy in controlling disease in aHUS and is approved for use in PNH (Proxysmal nocturnal Haemoglobinuria) and aHUS. Once initiated, recommendations advise it is continued indefinitely due to the persistent risk of relapse in aHUS.  Preliminary data suggests a possible role for eculizumab in severe Stx-HUS, but confirmation from larger published studies is awaited. Eculizumab is subsidised for use in Australia for cases meeting the diagnostic criteria and must be made through a specific PBS application and submission of supporting documentation with a cover-letter.  Access to treatment is possible within several hours of making direct contact by phone.  Up-to-date applications are available through the following government website:
                                 
                                             https://www.humanservices.gov.au/health-professionals/enablers/atypical-haemolytic-uraemic-syndrome      

       The decision to initiate therapy must be undertaken by the treating nephrologist (For dosing see Appendix 2)


    1. Specific therapy:
      • There is no benefit of antibiotics for STEC (Shigatoxin- producing enterohaemorrhagic E Coli).
      • Pneumococcus and influenza should be treated with directed antimicrobial therapies. Avoidance of plasma products may reduce the risk of flaring of HUS by T-antibodies
    2. Other:
      • Folate is recommended to facilitate red cell recovery
      • Pancreatitis- generally requires TPN initially, but enteral feeding may be possible- discuss with gastroenterology. Discuss with endocrinology if hyperglycaemic.
      • Myocarditis/ cardiac ischaemia- manage with cardiology advice.
    3. Please enrol in Australian TTP registry (www.torc.org.au) for any case of TMA; contact Dr. Joshua Kausman, Dept Nephrology for further details; Joshua.Kausman@rch.org.au

     


     

    Appendix 1: Laboratories offering specialised investigation/ Complement studies

    Insert web links to each lab for requests and costs.

    Australian- based

    1. HAPS- Hunter Area Pathology Service, Lookout Rd, Lambton, NSW.

    A service which is developing as the reference laboratory for TMA testing in Australia. Currently performs measurement of plasma levels and mutation analysis for: CFH, CFI, MCP and ADAMTS13. Also measure Shigatoxin, Pneumococcal Ag, RBC Ag, ADAMTS13 Antibody and RNAPIII antibodies.

     For advice contact Dr. Theo de malmanche 02 4921 3000; Theo.demalmanche@hnehealth.nsw.gov.au

    1. RCH- Royal Childrens Hospital, Melbourne

    Performs, flow cytometry for expression of CD46 (MCP) on leukocytes. Currently developing ELISA for Factor H Antibody.  Ext 55725.

    For advice contact Dr. Sharon Choo, Dept Allergy and Immunology, RCH; Sharon.Choo@rch.org.au

    1. SEALS- South Eastern Area Laboratory Services, Sydney, NSW

    Performs testing for Factors H and I levels. Send serum to RCH lab with request for these tests from SEALS and laboratory will arrange transfer of samples. Contact: 02 9540 7440

    www.seals.health.nsw.gov.au/home/.aspx

    International sites

     

    1. Service d’Immunologie Biologique, Hopital Europeen Georges Pompidou, 20-40 rue Leblanc, 75908 Paris cedex 15, France.

    An expert complement laboratory that undertakes comprehensive measurement of Factor concentrations in plasma and full mutation analysis as a diagnostic service. Results provided within 3 months. There is a charge for this.

    For advice contact Dr. Veronique Fremeaux-Bacchi: phone 331 56093947; Fax 331 56092080; Veronique.fremeaux-bacchi@egp.aphp.fr

     See Nephrology protocol 5.4.27 for detailed process of sending samples.

     

    1. The Northern Genetic Service, National Health Service, Royal Victoria Infirmary, NE1 4LP, Newcastle upon-Tyne, UK.

    An accredited diagnostic immunology and genetic service that provides serum levels and mutation screening. There is a charge for this service.

    For advice contact Prof Tim Goodship, (44) 191 282 4519, email;  t.h.j.goodship@ncl.ac.uk

    For the service laboratory email; lisa.strain@ncl.ac.uk

     

    1. Mario Negri Institute for Pharmacological Research, Via Gavazzeni 11, 24125 Bergamo, Italy.

    A research active group that undertakes protein and genetic investigation of complement Factors. Results provided within 4 months. There is no charge for these tests. Clinicians must supply full clinical details using the institute’s case questionnaire.

    For advice contact Prof Giuseppe Remuzzi, email;  gremuzzi@marionegri.it and Dr Marina Noris, email: noris@marionegri.it

    1. Dept Biological Infection, Leibniz Institute for Natural Product Research and Infection Biology, Hans Knoell Institute for Natural Product Research, Beutenbergstr. 11a, 07745 Jena, Germany.

    Complement protein analysis and genomic investigation of complement factor H, factor I and MCP (CD46) is available as a service from the research group headed by Professor Peter Zipfel. There is a charge for this service, scientific aspects may have exemption. 

    Contact Professor Peter Zipfel  email peter.zipfel@hki-jena.de

     

     

    Appendix 2 Eculizumab dosing

    Body Weight Group

    Induction Dose

    Maintenance Dose

    ≥ 40 kg

    900 mg Weekly for 4 Weeks

    1200 mg at Week 5 then Every 2 Weeks

    30 – <40 kg

    600 mg Weekly for 2 Weeks

    900 mg at Week 3 then Every 2 Weeks

    20 – <30 kg

    600 mg Weekly for 2 Weeks

    600 mg at Week 3 then Every 2 Weeks

    10 – <20 kg

    600 mg Weekly for 1 Week

    300 mg at Week 2 then Every 2 Weeks

    5 – <10 kg

    300 mg Weekly for 1 Week

    300 mg at Week 2 then Every 3 Weeks

    Note- all children treated with eculizumab should be vaccinated against meningococcus and receive antibiotic prophylaxis with penicillin due to an increased risk of meningococcal disease.

     

    Appendix 3 Key references

    1. 2013 NEJM LEGENDRE 2169
    2. 2009 PED NEPH ARICETA 687
    3. 2013 CJASN LOIRAT 554
    4. 2012 NRN NORIS 622
    5. 2012 NDT BARBOUR 2673
    6. 2012 NDT KARPMAN 3669
    7. 2011 NEJM LAPEYRAQUE 1-3 LETTER RE: 3 CASES DURING OUTBREAK.
    8. 2009 NEJM NORIS REMUZZI 1676 AHUS
    9. 2006 CJASN BRESIN DAINA 88
    10. 2009 JASN SALAND RUGGENENTI 940 Tx guideline
    11. 2006 KI TSAI 16
    12. 2011 NEJM FRANK WERBER 1771
    13. 2004 PED NEPH COCHRAN 317 PN HUS
    14. 2001 NATURE LEVY ADAMTS13 TTP
    15. 2005 LANCET TARR CHANDLER 1073
    16. 2007 PEDIATRICS WATERS KERECUK 140

     

    Dr. Joshua Kausman

    December 2013