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Acta Clinica Belgica
International Journal of Clinical and Laboratory Medicine
ISSN: 1784-3286 (Print) 2295-3337 (Online) Journal homepage: http://www.tandfonline.com/loi/yacb20
Belgian consensus statement on the diagnosis and
management of patients with atypical hemolytic
uremic syndrome
Kathleen J Claes, Annick Massart, Laure Collard, Laurent Weekers, Eric
Goffin, Jean-Michel Pochet, Karin Dahan, Johann Morelle, Brigitte Adams,
Nilufer Broeders, Patrick Stordeur, Daniel Abramowicz, Jean-Louis Bosmans,
Koen Van Hoeck, Peter Janssens, Lissa Pipeleers, Patrick Peeters, Steven
Van Laecke, Elena Levtchenko, Ben Sprangers, Lambertus van den Heuvel,
Nathalie Godefroid & Johan Van de Walle
To cite this article: Kathleen J Claes, Annick Massart, Laure Collard, Laurent Weekers, Eric
Goffin, Jean-Michel Pochet, Karin Dahan, Johann Morelle, Brigitte Adams, Nilufer Broeders, Patrick
Stordeur, Daniel Abramowicz, Jean-Louis Bosmans, Koen Van Hoeck, Peter Janssens, Lissa
Pipeleers, Patrick Peeters, Steven Van Laecke, Elena Levtchenko, Ben Sprangers, Lambertus van
den Heuvel, Nathalie Godefroid & Johan Van de Walle (2017): Belgian consensus statement on
the diagnosis and management of patients with atypical hemolytic uremic syndrome, Acta Clinica
Belgica, DOI: 10.1080/17843286.2017.1345185
To link to this article: http://dx.doi.org/10.1080/17843286.2017.1345185
Published online: 23 Oct 2017.
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Date: 25 October 2017, At: 08:47
Acta Clinica Belgica, 2017
https://doi.org/10.1080/17843286.2017.1345185
REVIEW
Belgian consensus statement on the diagnosis and management of patients
with atypical hemolytic uremic syndrome
Kathleen J Claesa,b , Annick Massartc , Laure Collardd , Laurent Weekerse , Eric Goffinf ,
Jean-Michel Pochetf , Karin Dahanf,g , Johann Morellef , Brigitte Adamsh , Nilufer Broedersc ,
Patrick Stordeuri , Daniel Abramowiczj, Jean-Louis Bosmansj , Koen Van Hoeckk, Peter Janssensl ,
Lissa Pipeleersl, Patrick Peetersm , Steven Van Laeckem , Elena Levtchenkon,o , Ben Sprangersa,b ,
Lambertus van den Heuvelo , Nathalie Godefroidp and Johan Van de Walleq Downloaded by [UAE University] at 08:47 25 October 2017
a
Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium; bLaboratory of Nephrology,
Department of Microbiology and Immunology, KU Leuven, University of Leuven, Leuven, Belgium; cDepartment of Nephrology, Erasme
University Hospital, Université Libre de Bruxelles, Brussels, Belgium; dDepartment of Pediatrics, CHU Liège, Liège, Belgium; eDepartment
of Internal Medicine, Division of Nephrology, ULg, CHU Liège, Liège, Belgium; fDepartment of Nephrology, Cliniques Universitaires
Saint-Luc, Université Catholique de Louvain, Brussels, Belgium; gInstitut de Génétique et de Pathologie, IPG, Gosselies, Belgium; hQueen
Fabiola Children’s University Hospital, Brussels, Belgium; iImmunobiology Clinic, Erasme University Hospital, Université Libre de Bruxelles,
Brussels, Belgium; jDepartment of Nephrology, University Hospital Antwerp, Antwerp, Belgium; kDepartment of Pediatrics, University
Hospital Antwerp, Antwerp, Belgium; lDepartment of Nephrology and Hypertension, Universitair Ziekenhuis Brussels, Brussels, Belgium;
m
Department of Nephrology, University Hospital Ghent, Ghent, Belgium; nDepartment of Pediatric Nephrology, University Hospitals
Leuven, Leuven, Belgium; oDepartment of Development and Regeneration, KU Leuven, Leuven, Belgium; pPediatric Department, Cliniques
Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium; qDepartment of Pediatric Nephrology, University Hospital
Ghent, Ghent, Belgium
KEYWORDS aHUS; diagnosis; management
Introduction
In the last decade, significant progress has been made
in the understanding and the treatment of patients with
atypical Hemolytic Uremic Syndrome (aHUS). aHUS
has emerged as a disease largely caused by complement dysregulation. This facilitated the development
of targeted therapy with the approval of a recombinant
humanized IgG2/IgG4 monoclonal anti-C5 antibody
(eculizumab) as major breakthrough. Until recently,
treatment consisted of plasma exchange with variable
and disappointing results. In prospective studies, the use
of eculizumab has shown a fast and sustained control of
the thrombotic microangiopathy (TMA) process.
In January 2017, a protocol with recommendations
for the diagnosis and treatment of patients with a (possible) diagnosis of atypical Hemolytic Uremic Syndrome
was proposed. This protocol was developed by a Belgian
working group consisting of clinicians, both adult and
pediatric nephrologists, biologists and a geneticist working in university hospitals, with a particular interest and
expertise in diagnosis and treatment of aHUS. The recent
breakthroughs in diagnosis and treatment of aHUS
urged us to address some highly relevant questions in the
diagnostic and therapeutic field of aHUS. Therefore, the
following text is a general consensus document on the
diagnosis and the therapeutic approach of this disease.
Since aHUS is an ultra-rare condition and randomized
controlled trials are absent, evidence-based guidelines
CONTACT Kathleen J Claes © Acta Clinica Belgica 2017
kathleen.claes@uzleuven.be
cannot be provided. Consensus was reached on diagnostic approach, treatment duration in native aHUS and
the use and duration of eculizumab as a preventive treatment in renal transplantation. The working group will
have a meeting at least every year in order to update the
diagnostic and treatment recommendations based on the
last available scientific evidence and clinical experience.
Definition and classification
Atypical hemolytic uremic syndrome (aHUS) is an
ultra-rare disease classified in the group of thrombotic
microangiopathies (TMA). aHUS has an estimated prevalence of 2/106 adults and 3.3/106 children [1–3]. These
conditions are characterized by the triad: Coombsnegative microangiopathic hemolytic anemia, thrombocytopenia and organ damage [4]. The pathological
features of the different forms of TMAs are identical:
uncontrolled thrombosis at the arterioles and capillaries
with consumption of thrombocytes, mechanical damage
of erythrocytes and tissue ischemia [5]. However, the
underlying mechanisms starting this cascade differ. In
the working group, we agreed to use the etiology-based
classification of the various forms of TMA and to focus
on diagnosis and treatment of aHUS. In this document, the following definition of aHUS is used: TMA
caused by a dysregulation of the alternative pathway of
the complement system. This definition is based on a
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2 K. J. CLAES ET AL.
Figure 1. Diagnostic and therapeutic approach of TMA (adapted from Campistol JM, Arias M et al) [51].
recent consensus approach of atypical hemolytic uremic
syndrome in children [6]. HUS, triggered by underlying conditions, thrombotic thrombocytopenic purpura
(TTP), and Shiga-like toxin producing Escherichia coli
(STEC)-HUS are briefly discussed in the diagnosis and
therapy section.
Diagnosis of aHUS
Clinical presentation
Even though there is an increase in availability of diagnostic tests, aHUS remains mainly a clinical diagnosis
because of our current inability to diagnose all patients
either biochemically or by genetic testing. Therefore, the
diagnosis is based on the combination of clinical judgment and biochemical testing. Furthermore, results of
genetic testing are not immediately available. Despite
the aforementioned difficulties in diagnosis, our understanding of the clinical characteristics has increased over
the last decades. We are currently aware that aHUS can
present in different ways. However, this further complicates the diagnostic process. The classical presentation with laboratory evidence of the classical triad of
(Coombs-negative) hemolysis (decreased hemoglobin,
elevated LDH, decreased haptoglobin, schistocytes
on blood smear), thrombocytopenia and acute kidney injury is present in the overwhelming majority of
patients. However, a subacute presentation can occur
with proteinuria, acute kidney injury, arterial hypertension with signs of TMA on renal biopsy with or without
thrombocytopenia and hemolysis. Therefore, in every
patient presenting with renal insufficiency and lowgrade hemolysis the differential diagnosis with TMA
needs to be considered. Furthermore, in more than 20%
of patients extra-renal symptoms are present [5,7–9].
Neurological symptoms are the most common [10], but
also cardiac (acute myocardial infarction, cardiomyopathy, heart failure), pulmonary, and gastrointestinal (diarrhea, colitis, abdominal pain, pancreatitis) involvement
has been reported [10–14].
Figure 1 summarizes the diagnostic work-up. These
diagnostic criteria are similar to the criteria defined in
the UK by the aHUS rare disease group [7,15,16]. Firstly,
thrombotic thrombocytopenic purpura (TTP) needs to
be ruled out. TTP results from a severe deficiency in
the metalloproteinase activity of the A Desintegrin and
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ACTA CLINICA BELGICA Metalloproteinase with ThromboSpondin type 1 motif,
member 13 (ADAMTS13). This can be either genetically
or antibody-mediated. The genetic form is rare, constituting less than 5% of all TTP cases. Most adults present
with the acquired form [17,18]. However, among certain
groups such as newborn infants and young children,
hereditary TTP may be more common than acquired
TTP and during pregnancy, hereditary TTP may represent up to one-fourth of TTP cases [19,20]. The
ADAMTS13 activity needs to be assessed. An ADAMTS
13 activity <10% confirms the diagnosis of TTP [21].
Secondly, the majority of HUS cases in children are
caused by a shigatoxin producing Escherichia Coli
(STEC) enteric infection. STEC-HUS must be ruled out
by stool culture, PCR for virulence genes and serologic
studies [4]. Finally, we need to look for environmental
triggers causing TMA or aHUS as they might require
specific management [3,22–29]. A non-exhaustive list of
these conditions are described in the following remarks
on Figure 1.
Remarks on Figure 1:
(1) ADAMTS 13 < 10%: TTP. If ADAMTS-13 < 10%
the diagnosis of thrombotic thrombocytopenic
purpura (TTP) is the most likely and further
analyses are necessary to distinguish between
genetically (rare) or antibody-mediated disease (e.g. primary or secondary, drug-induced
forms for instance after clopidogrel/ticlopidine
intake).
(2) Shigatoxin-associated HUS: STEC/HUS:
(a) Stool culture (rectal swab in the absence of
stools)
(b) PCR for STEC virulence genes in stool
(c) Detection of E. Coli endotoxin serum
antibodies
(3) Underlying conditions triggering aHUS or
causing TMA:
a. Drug-induced TMA (DITMA):
cisplatin; gemcitabine; mitomycin; clopidogrel;
quinine; interferon α, β; anti-vascular endothelial
growth factor therapy; alemtuzumab; calcineurin inhibitors; ciprofloxacin; mTOR inhibitors;
oestrogens, Illicit drugs [e.g. cocaine, heroin, ecstasy, intravenous oxycodone]. www.ouhsc.edu/
platelets/DITMA.htm demonstrates a list with all
published reports on DITMA.
b. Transplantation: bone marrow transplantation and solid organ transplantation
(may be promoted by drugs: Calcineurin
inhibitor, mTOR inhibitors), antibody
mediated rejection, infection (Cytomegalo­
virus infection)
c. HELLP syndrome and pregnancy
3
d. Systemic diseases: systemic lupus erythematosus, antiphospholipid syndrome, scleroderma, vasculitis, malignancies
e. Cobalamin C deficiency
f. DGKE (diacylglycerol kinase epsilon)
mutation
g. Malignant hypertension
h. Infection: HIV, streptococcus pneumoniae, influenza,.. . In case of pneumococcus
infection, Coombs test is generally positive
due to the action of a bacterial neuraminidase on the erythrocyte membrane. This
neuraminidase exposes the erythrocyte
Thomsen–Friedenreich antigen (T antigen,
CD176) to natural antibodies that in turn
activate the classical pathway of the
complement.
i. Rare causes: glomerulonephritis (IgA
nephropathy, C3 glomerulopathy, glomerulopathies associated with monoclonal gammopathies of uncertain significance, …)
As indicated above, many conditions can cause TMA.
However, we need to be aware that these conditions might
be the triggering event for aHUS as well. In women, pregnancy, especially the post-partum period is a triggering
factor for aHUS, as is the use of oral contraceptive agents.
aHUS during pregnancy needs to be differentiated from
HELLP syndrome which is a different condition. In case
of insufficient response to treatment of the underlying
condition or removal of the trigger, the diagnosis of aHUS
and treatment with eculizumab needs to be reconsidered.
Diagnosis of aHUS is challenging and is made by exclusion. Results of genetic testing are not immediately available and the absence of a mutation does not preclude the
diagnosis of aHUS. However, the finding of a mutation
or complement abnormalities are supportive.
Biochemical and genetic analysis.
Currently, complement gene mutations or factor
H antibodies are identified in up to 70% of aHUS
patients. Around 60% of patients are carriers of mutations in complement-regulating genes (CFH, MCP/
CD46, CFI, thrombomodulin) or in the components
of C3-convertase, factor B and C3. Around 5–10% of
patients develop anti-CFH antibodies targeted to the
C-terminal region, mimicking the effect of factor H
mutations. Anti-CFH antibodies are more prevalent in
children. For an overview of the pathophysiology of the
complement system in aHUS, we refer to the thorough
review of Nester in Clinical Immunology [7].
Table 1 summarizes the diagnostic tests recommended for the diagnosis of TMA, including specific
tests for the various etiologies of TMA. Laboratories with
recommendations for sample collection, can be found
4 K. J. CLAES ET AL.
Table 1. Diagnostic tests.
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Biochemical evaluation
Confirm TMA
Hemoglobin, thrombocytes, reticulocytes
LDH-haptoglobin
Blood smear: schistocytes
Indirect Coombs/direct Coombs
PT/aPTT/fibrinogen
Detect shigatoxine producing e Coli (STEC)
Culture of stool or rectal swab
PCR for STEC virulence genes in stool
Serology: serum (E Coli) en Yersinia antibodies (anti-LPS antibodies for
prevalent serotypes)
Detect ADAMTS-13 deficiency
Von Willebrand protease activity
Test underlying causes/triggers depending of the clinical presentation
(1) Plasma homocystein (↑↑), vitamin B12 ± methionine (↓); organic
acid urine (urine methyl malonic acid). Positive result: detect MMACHC
mutation: congenital cobalamin C deficiency
(2) HIV serology, pulmonary cultures, influenza
(3) ANF (ANA)/anti dsDNA (Farr)/anti-centromere Ab /antiphospholipid
antibodies (anticardiolopin IgG and IgM, anti B/lupus anticoagulant
(4) Hemocultures
(5) Pregnancy testing
(6) Chest X-ray
Complement testing
All patients
Antibodies factor H; Factor H; Factor I
CH50
MAC (C5b-9)
C3, C4; index C3d/C3
CD46 expression on leucocytes (poly- or mononuclear leucocytes
using a FACS test)
Spare samples for freezing (cfr infra) for further diagnostics (−80°C)
On indication
Factor B, factor Bb, C3 convertase, Factor H activity, antibodies factor
I,other complement factors, AP50
Extra sampling
Eculizumab dosing and C5-eculizumab binding
Genetic testing
Complement factor H (CFH)
Complement factor I (CFI)
Membrane cofactor protein (MCP)
Complement factor B (CFB)
Complement C3
Complement Factor H related proteins (CFHR)
CFH-CFHR hybrid gen
DGKE mutation: if indicated
Thrombomodulin (THBD)
ADAMTS13-gen: if indicated
MMACHC gen: if indicated to exclude defect in cobalamin deficiency
Other complement genes: if indicated
in Table 2 and on the website of the Belgian Society of
Nephrology (www.bvn-sbn.be).
Firstly, ADAMTS13 activity needs to be assessed
given the therapeutic implications. An ADAMTS 13
activity < 10% confirms the diagnosis of TTP. Secondly,
to exclude STEC-HUS, stool culture, PCR for virulence
genes and antibody detection will be performed. The
laboratory result that must be available before the onset
of treatment with eculizumab is ADAMTS13 activity.
However, blood samples not collected before the onset
of plasmatherapy compromise further test interpretation. Because of lack of reimbursement at this time for
all of the complement testing, we suggest to start with
a limited number of complement testing which can
be expanded to specific complement testing depending on the clinical presentation and the results of the
first analyses. Testing of the complement system, both
biochemically as genetically, is important because of its
role in the evaluation of the prognosis (see therapeutic
section).
Treatment of aHUS
Before the introduction of eculizumab, patients with
aHUS were treated with plasma exchange with variable
outcomes. As stated before, the prognosis is dependent on the genetic mutation found. The complement
abnormality determines the prognosis for both end stage
renal disease (ESRD) and recurrence of the disease after
transplantation. The most important recent advance
in the care of patients with aHUS was the regulatory
approval in 2011 of a ‘first-in-class’ anti-complement
therapeutic named eculizumab (Soliris). Eculizumab
is a recombinant humanized monoclonal antibody
directed against C5 that impedes its cleavage into C5a
and C5b [30]. The current treatment scheme consists of
an induction and maintenance phase. The initial phase
consists of four weekly doses and the maintenance phase
of one dose every two weeks. This dose is depending on
body weight (<40 kg) in children and fixed in patients
weighing more than 40 kg. Treatment with eculizumab
is efficient. However, many questions around the use,
dosage, and duration of therapy with eculizumab remain
unresolved and the cost is very high Data concerning
long-term follow-up, pharmacokinetic variability, individualized treatment regimens, as well as the possibility
to stop treatment (and in which subtypes) are limited.
The recommendations for treatment proposed in this
article are based on current literature (up to date till
December 2016).
Therapeutic approach TTP and other causes
Figure 1 briefly describes the therapeutic approaches
suggested for the diagnosis of TTP and underlying
causes of aHUS.
When ADAMTS13 activity is lower than 10% the
diagnosis of TTP can be made and continuation of
plasma exchange is mandatory with the rapid initiation
of corticosteroids in acquired TTP [31]. In refractory
cases, second-line treatment with immunosuppressive
therapy (intensification of plasma exchange, higher doses
of glucocorticosteroids, rituximab, and bortezomib) or
in the future dedicated monoclonal antibodies can be
considered [32–34]. Further treatment depends on both
the etiology and the response to treatment with plasma
exchange and is beyond the scope of these guidelines.
For the indication for plasma exchange in treatment of
HUS triggered by drugs, we refer to the recommendation text from the American Society of apheresis [35].
In STEC-HUS, early aggressive hydration has a renal
protective role and the benefit of plasma exchange is
uncertain [36,37]. Antibiotic treatment in STEC infections is not recommended since it increases the risk for
ACTA CLINICA BELGICA 5
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Table 2. Sample collection and laboratories.
TEST
Classical pathway (CH 50)
Alternative pathway (AP 50)
Factor H concentration
Factor H function
Anti-factor H antibodya
Factor I concentration
C3Nef
C3
C3d
C4
C5
Factor B
Factor Bb
SC5b-9 complex (MAC)
Paid by the patient or
INAMI/RIZIV
INAMI/RIZIV
Not reimbursed
INAMI/RIZIV
Not reimbursed
Not reimbursed
INAMI/RIZIV
Not reimbursed
INAMI/RIZIV
INAMI/RIZIV
INAMI/RIZIV
Not reimbursed
Not reimbursed
Not reimbursed
Not reimbursed
CD46 (MCP)
INAMI/RIZIV
ADAMTS 13
Not reimbursed
Blood sample
Serum: 5 ml whole blood
From Monday to Friday,
send at room temperature
in the four hours that
follow blood withdrawal,
and in a such way that the
samples arrive in the lab at
the latest at 4 pm
5–10 ml EDTA whole blood
or:
centrifuge, collect and keep
EDTA plasma, citrated
plasma, and/or serum,
each in three aliquots, at
−20 °C for a few days,
5ml citrated whole blood
or at −80 °C for a longer
period, and send while
keeping frozen
5 ml EDTA whole blood
send and keep as such at
room temperature
5 ml citrated whole blood
As LPS antigen E.coli
Enterohemorragis E.coli pcrHUS (faeces)
INAMI/RIZIV
INAMI/RIZIV
5 ml serum whole blood
Faeces
Genetic testing (gene/panel)
INAMI/RIZIV
5–10 ml EDTA or extracted
DNA
Eculizumab
c5-eculizumab complex
Eculizumab inhibiting
capacity
Not reimbursed
Not reimbursed
Not reimbursed
serum (5 ml whole blood)
Laboratory and contact
details
LHUB-ULB Site Anderlecht
(Hopital Erasme); Dr P
Stordeur; Laboratoire
d'Immunologie, 6ème
étage; 808 route de Lennik, 1070 Bruxelles; Tel 02
555 3787/3862 ; e-mail:
ich.labo-iht@erasme.ulb.
ac.be
Available at several laboratories
UZ Brussel; Prof. Dr. D.
Piérard; Microbiologie
en Ziekenhuishygiëne;
Laarbeeklaan 101, 1090
Jette. Tel 02/47750000
IPG, prof. Dr. K Dahan;
avenue Georges Lemaître
25, 6041 Gosselies. Tel
071/473047
centrifuge (2000 g, 10 min at Radboud UMC; Prof dr
4 °C) and freeze at −80 °C
Wevers;Laboratoriumgeneeskunde 830 TML,
Geert Groteplein zuid 10,
6525 GA Nijmegen; Tel
0031243614567; e-mail:
secretariaat-TML.labgk@
radboudumc.nl
a
Anti-Factor H antibody: if requested alone, can be sent at room temperature, and kept for a week at 4 °C, or after separation, serum can be kept at −20 °C
for a longer period.
development of HUS [38]. HUS associated with systemic disease and infections relies on the treatment of
the underlying infection or disease.
In malignant hypertension, aggressive antihypertensive treatment is in order and this usually leads to the
rapid resolution of the TMA with partial or complete
recovery of renal function [39]. We recommend treatment with folinic acid, hydroxycobalamin, betain, and
multidisciplinary follow-up by nephrologist, neurologist, and a metabolic expert for patients with cobalamin
C deficiency. In non-renal transplant recipients, blood
pressure control and adjustment of immunosuppressive treatment is recommended. In renal transplant
recipients, antibody-mediated rejection and infection
(CMV) need to be excluded and if present treated first.
As indicated above, many of these conditions cause
TMA. However, we need to be aware that these conditions might be the triggering events for aHUS. In case of
insufficient response to treatment of the underlying condition or removal of the trigger, the diagnosis of aHUS
needs to be reconsidered.
Therapeutic approach for the first flare of aHUS
Figure 1 demonstrates the consensus on treatment
approach for the first flare of aHUS in adult patients.
For children, earlier start of and first-line treatment with
eculizumab might be indicated, because of the unacceptable high complication rate of plasmapheresis in a
HUS children [6,40].
(1) Collection of blood samples immediately before
plasma exchange.
(2) Start with plasmapheresis 1–1.5 times plasma
volume with substitution of FFP only or
Octaplas®
(3) Start request procedure for Soliris®
(4) Plasma exchange frequency depending on treatment response (start 1 week daily, decrease in
frequency in case of and depending on the
treatment response).
(5) Start Soliris®, after vaccination following the
recommendations below
a. in case of absence of treatment response
after five consecutive days of plasma
exchange. Absence of treatment response is
defined as either the absence of normalization of platelet count or absence of signs of
renal recovery [41], in patients without
severe chronic damage on biopsy or renal
imaging
b. in case of hypersensitivity reactions to
plasma despite pre-treatment with corticosteroids or Octaplas® use
6 K. J. CLAES ET AL.
Table 3. Risk categories.
Underlying abnormalities
MCP/CD46 mutation
Previously positive anti-CFH antibodies
DGKE mutation
Intermediate
No high-risk mutation
No mutation found or auto-antibodies
Variant of unknown functional significance
CFI mutation
Detectable anti-CFH auto-antibodies
High
CFH mutation or gene re-arrangements involving
factor H and factor H related proteins
C3 mutation
CFB mutation
High risk due to recurrence in previous allograft
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Risk classification
Low
c. in case of relapse in situation of reducing
plasmapheresis frequency or in case of
relapse after stopping plasmapheresis
(6) Treatment monitoring: tests are summarized
in Table 1.
(7) After start of Soliris®: re-evaluation after
six months will be done: if no disease activity is
present in adult patients with normalization of
hematological parameters and normalization/
stabilization of renal function, eculizumab will
be stopped with close follow-up. The suggested
follow-up frequency will be discussed in the following section. In case of treatment of aHUS
in a patient with a MCP/CD46 mutation and
complete recovery of renal function, treatment
will be stopped at time of confirmation of this
diagnosis.
(8) In patients in need of renal replacement therapy at time of presentation, treatment with
eculizumab can be started based on duration of ESRD and/or biopsy results. In case
of no signs of recovery of renal function and/
or severe chronic signs on renal biopsy after
four months [42]: treatment with eculizumab
will be stopped.
(9) Treatment of aHUS caused by antibodies
against factor H. In this case, there is need for
immunosuppressive therapy. Eculizumab can
be considered for this indication at the acute
phase of TMA, as well in case of treatment
resistance. We refer to the review of Blanc et al.
on this item [43].
Treatment for recurrent aHUS
Treatment modalities of recurrent aHUS after withdrawal of eculizumab will be decided on a case by case
basis. The decision needs to be based on the complement
abnormalities and clinical response to treatment in the
previous disease episodes.
Prophylactic eculizumab
No
3 months
6 months
Duration decision case by case. Long-term treatment might be
possible with yearly revision by the reimbursement college.
Renal transplantation
After transplantation, the risk of recurrence ranges from
20 to 70% depending on the mutation of the complement pathway. Furthermore, after transplantation, environmental factors such as ischemia/reperfusion injury,
acute rejection, infection, and immunosuppressive drugs
may act as a trigger for disease recurrence. In order to
decrease these triggering factors, the working group proposes the following general recommendations:
(1) Donor criteria:
a. No DCD donor or donor with high risk of
I/R injury. Cold ischemia time as short as
possible
b. Living-related donor:
i. The mutation is known and definitively pathogenic
and is not present in the donor: donation possible
ii. No mutation is found or there is a variant with
unknown functionality: contraindication for
donation
(2) Recipient management [44]:
a. Induction
b. Avoid toxic levels of calcineurin inhibitors
(CNI), avoid mTOR inhibitors
c. Other immunosuppressive scheme: at
center’s discretion
d. Consider statin (protection of the
endothelium)
e. Avoid high blood pressure levels
f. CMV prophylaxis in all risk groups (not if
donor negative/receptor negative)
g. Vaccination has to be completed before
listing
h. No ABO-incompatible renal transplantation
and avoidance of donor-specific antibodies.
The recent reimbursement criteria for prophylactic
treatment of aHUS before renal transplantation allows
the listing of patients with aHUS and high risk for disease recurrence. We will use a standardized protocol to
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ACTA CLINICA BELGICA 7
define the indication and the duration of eculizumab
as prophylactic treatment to prevent recurrence after
transplantation. The risk of recurrence is dependent on
the defect responsible for aHUS. For patients with no
identifiable mutation, the recurrence risk is more difficult to assess. In these recommendations, we stratified
the risk of recurrence in three levels, (based on data by
Zuber and co-workers and the UK guidelines) [15,45].
The risk stratification is based on genetic screening,
presence of auto-antibodies, and previous transplant
history. Recurrence risk is the highest in the immediate post-transplant period and in the first year after
transplantation. This recurrence risk decreases significantly after the second year [46]. Therefore, we propose
to withdraw treatment in patients and chose to limit
the duration of the therapy with close monitoring of
the patients after withdrawal of treatment. In low risk
patients, no prophylaxis will be given, whereas in intermediate and in high-risk patients, prophylactic treatment will be given for, respectively, 3 and 6 months.
In case of recurrence in previous allograft with graft
loss due to the recurrence, duration of treatment will
be decided based on a case by case basis. Long-term
treatment is possible with yearly revision in the reimbursement college (Table 3).
Nimenrix® or Menveo® (ideally, at least two weeks
before treatment and before activation on the transplant waiting list). Booster after 8–12 w. Booster after
three years and subsequent doses every five years.
Bexsero®: a vaccine against serotype B is currently
available in Belgium but not reimbursed. A second vaccine (Trumenba®) is in clinical development and registration at EMA is introduced.
Pneumococcal vaccination: In children >5 years old
and in adults: Prevenar® 13, 2 months later Pneumo 23®.
Pneumo 23® booster after 5 years.
Hemophilus influenzae: children and adults: 1 dose
act-HIB
Antibiotic prophylaxis during treatment in adult
patients:
Antibiotic prophylaxis during treatment in adult
patients: We recommend prophylactic treatment with
azithromycine until 60 days after stop eculizumab in all
patients. We chose treatment with azithromycine over
quinolones because of its narrower spectrum and the
risk of tendon lesions with quinolones in this patient
population.
In children, antibiotic prophylaxis is recommended
as well with antibiotic choice and duration at centers
discretion.
Liver and kidney transplantation
Eculizumab dose
The current treatment scheme consists of an induction and maintenance phase with doses based on body
weight for children (<40 kg). The initial phase consists
of four weekly doses and the maintenance phase of one
dose every two weeks. This dose is depending on body
weight (<40 kg) in children, in the patients weighing
more than 40 kg the dose is fixed to 900 mg in weekly
doses for 4 weeks. A dose of 1200 mg is administered one
week after the final dose of 900 mg and every two weeks
thereafter.
In the future combined liver and kidney transplantation
with prophylactic eculizumab probably will represent a
curative option in selected cases. In this setting, duration
of therapy will be determined by recovery of function
of the liver allograft.
Treatment of patients with eculizumab
Preparation of patients before treatment
All patients should get a vaccination against meningococcal infection given the risk inherent to the treatment
with eculizumab. However, the current vaccination
scheme does not protect against all meningococcal
serotypes and therefore we recommend to give prophylactic antibiotic treatment. Patients should be informed
of the risk and signs of the meningococcal infection and
that they must contact the treating center in any case of
suspicion. The information brochure on meningococcal infection, patient safety card, and the contact details
of the treating physician should be handed over. With
regard to vaccination of the household close contacts:
vaccination with tetravalent conjugated meningococcal
vaccination needs to be considered since it interferes
with carriership and transmission.
The working group recommends the following
scheme:
Vaccination:
Meningococcal vaccination with conjugated tetravalent meningococcal vaccine:
Prophylactic treatment in the setting of renal
transplantation [15]
Adult patients should receive a single dose of 900 mg
eculizumab which is completed prior to the start of surgery. The dose and dosing schedule should be adjusted
for body weight in children as per pediatric dosing
schedule. Adult patients should receive three further
doses of 900 mg eculizumab at weekly intervals. A dose
of 1200 mg is administered one week after the final dose
of 900 mg and every two weeks thereafter. The dose and
dosing schedule should be adjusted for body weight in
children as per pediatric dosing schedule.
Patient monitoring during treatment and after
discontinuation of eculizumab treatment
During the treatment, the monitoring consists of regular
monitoring of CH50. In the future, it might be possible
to monitor treatment by measuring specific complement
activity, eculizumab levels, and binding [47,48]. Table 4
8 K. J. CLAES ET AL.
Table 4. Monitoring after treatment cessation.
Time since last Eculizumab dose
Week 0
Monitoring
Baseline: Hb, thrombocytes, LDH, urea, creatinine and electrolytes,
bilirubin, haptoglobin
Week 2–6
X2/wk Hb, thrombocytes, LDH, urea, creatinine and electrolytes, Weekly:
schistocytes, bilirubin, haptoglobin
Week 6–10
Weekly Hb, thrombocytes, LDH, urea, creatinine and electrolytes, schistocytes, bilirubin, haptoglobin
After week 10
Every 14 days: Hb, thrombocytes, LDH, urea, creatinine and electrolytes,
schistocytes, bilirubin, haptoglobin
Home monitoring and every patient visit
Proteinuria urine: dipstick
Home monitoring and every patient visit
Intensive blood pressure control
In case of trigger (infection, high blood pressure, diarrhea and other intercurrent events) refer patient for monitoring and renal function
recommends the monitoring schedule during and after
stop of treatment, based on the UK guidelines [15].
Downloaded by [UAE University] at 08:47 25 October 2017
Family counseling
Patients should be informed about the possible heritability of the condition and offered genetic counseling
by a geneticist. In case of a known pathogenic mutation, we do recommend routine familial screening in
case of living-related donation. The screening is possible
if the mutation is known pathogenic. If the potential
living donor is not a carrier of the mutation, donation
is possible.
Contraception and pregnancy
Women should be informed about the risk of recurrence
after a pregnancy or following initiation of contraception
containing estrogen.
We recommend the use of contraception with prostagens only. This needs to be discussed with the treating
gynecologist.
As noted above, pregnancy is a triggering event for
recurrence of aHUS. Currently, there are limited data on
the safety of the use of eculizumab during pregnancy in
patients with aHUS [49] but there is growing evidence
of the safety of eculizumab in patients with paroxysmal
nocturnal hemoglobinuria [50]. We recommend that the
patient is referred to a specialized center for counseling
and pregnancy follow-up. We recommend that prophylactic treatment with eculizumab to be considered on a
case by case base.
Conclusion
This text is a general consensus document. aHUS is an
ultra-rare condition and the absence of randomized
controlled trials makes it impossible to establish evidence-based guidelines. This implies that these advices
are dynamic as well. Yearly or sooner in the case of new
evidence, the working group will review the consensus
document. Furthermore, each member of the group has
the right to summon the working group in case he/she
sees a binding reason.
Disclosure statement
Some of the members of the working group have received fees
and support from Alexion Pharmaceuticals (KC, JVDW, AM,
NB, JM, EL, PS, EG, PJ) or OMEROS (AM) either directly or
through their respective employer.
ORCID
Kathleen J Claes http://orcid.org/0000-0001-8510-2345
Annick Massart http://orcid.org/0000-0002-6196-8555
Laure Collard http://orcid.org/0000-0003-3073-8201
Laurent Weekers http://orcid.org/0000-0002-3151-4640
Eric Goffin http://orcid.org/0000-0001-9242-7148
Jean-Michel Pochet http://orcid.org/0000-0001-6564-6740
Karin Dahan http://orcid.org/0000-0003-3036-7981
Johann Morelle http://orcid.org/0000-0002-6925-1989
Brigitte Adams http://orcid.org/0000-0001-9693-2205
Nilufer Broeders http://orcid.org/0000-0001-5377-9335
Patrick Stordeur http://orcid.org/0000-0001-5398-0709
Jean-Louis Bosmans http://orcid.org/0000-0001-7928-5675
Peter Janssens http://orcid.org/0000-0002-0981-8621
Patrick Peeters http://orcid.org/0000-0002-8046-300X
Steven Van Laecke http://orcid.org/0000-0001-9700-5358
Elena Levtchenko http://orcid.org/0000-0002-8352-7312
Ben Sprangers http://orcid.org/0000-0003-1314-9675
Lambertus van den Heuvel http://orcid.org/0000-00033917-6727
Johan Van de Walle http://orcid.org/0000-0001-9700-5358
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