In this section
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:
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
Ped Neph 2009, 687-696 (Adapted)
This is a challenging area for HUS. The goals are:
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.
(see appendix 1 for diagnostic sites)
“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.”
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.
Appendix 1: Laboratories offering specialised investigation/ Complement studies
Insert web links to each lab for requests and costs.
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.email@example.com
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
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
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.firstname.lastname@example.org
See Nephrology protocol 5.4.27 for detailed process of sending samples.
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; email@example.com
For the service laboratory email; firstname.lastname@example.org
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; email@example.com and Dr Marina Noris, email: firstname.lastname@example.org
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 email@example.com
Appendix 2 Eculizumab dosing
Body Weight Group
≥ 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 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
Dr. Joshua Kausman