Pediatric Nephrology

Clinical Practice Guidelines on Hemolytic Uremic Syndrome in a Developing Country

--Manuscript Draft--

Manuscript Number:

Full Title: Clinical Practice Guidelines on Hemolytic Uremic Syndrome in a Developing Country

Article Type: Consensus Conference

Corresponding Author: Arvind Bagga

All India Institute of Medical Sciences
New Delhi, INDIA

Corresponding Author Secondary

Information:

Corresponding Author's Institution: All India Institute of Medical Sciences

Corresponding Author's Secondary

Institution:

First Author: Arvind Bagga

First Author Secondary Information:

Order of Authors: Arvind Bagga

Priyanka Khandelwal

Kirtisudha Mishra

Ranjeet Thergaonkar

Anil Vasudevan

Jyoti Sharma

Saroj Kumar Patnaik

Sidharth Sethi

Pankaj Hari

Aditi Sinha

Marie-Agnes Dragon-Durey

Order of Authors Secondary Information:

Funding Information: Department of Science and Technology, Dr. Aditi Sinha

Government of India
(EMR12016/002781)
All India Institute of Medical Sciences, Dr. Aditi Sinha
New Delhi
(A-386)
Indian Council of Medical Research Prof. Arvind Bagga
(5/7/1090/2013-RHN)
Indo-French Centre for the Promotion of Prof. Arvind Bagga
Advanced Research
(IFC/A/4703-1/2015/1562; IFC/Network
1/2185)
Department of Biotechnology, Prof. Arvind Bagga
Government of India
(BT/PR14651/MED/30/566/2010)

Abstract: Hemolytic uremic syndrome (HUS) is a leading cause of severe acute kidney injury
requiring dialysis in children. An understanding of its pathogenesis has resulted in
relatively standard classification and approach to management of these patients. The
availability of eculizumab has significantly impacted therapy of HUS in the developed
world. While international guidelines emphasize comprehensive diagnostic evaluation,
and selective treatment with eculizumab, access to diagnostic and therapeutic facilities

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 is limited and expensive in India and most developing countries. In view of limited
facilities for detecting shiga toxin producing microbes, the burden of shiga toxin
associated HUS in India is not clear. Children show high prevalence of anti-factor H
(FH) associated HUS, facilities for genetic diagnosis are limited and therapy with
eculizumab is not available. We propose practice guidelines for patients with HUS in
India, which are perhaps applicable to other developing countries. Priorities for
capacity building in regional and national laboratories are highlighted. The
management of patients with presumed shiga toxin associated HUS is supportive.
Prompt initiation of plasma exchanges is the chief therapy in patients with atypical
HUS; treatment with eculizumab is considered in those who fail to show hematological
remission or following recurrent HUS in the allograft. Patients with anti-FH associated
disease are most appropriately managed with a combination of plasma exchanges and
immunosuppressive medications.

Suggested Reviewers: Chantal Loirat

chantal.loirat@rdb.aphp.fr

Martin Bitzan
martin.bitzan@mcgill.ca

Christoph Licht
christoph.licht@sickkids.ca

Hesham Safouh
heshamsafouh@hotmail.com

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1 1
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5 Clinical Practice Guidelines on Hemolytic Uremic Syndrome in a Developing Country
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11 Arvind Bagga1, Priyanka Khandelwal1, Kirtisudha Mishra2, Ranjeet Thergaonkar1, Anil
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13 Vasudevan3, Jyoti Sharma4, Saroj Kumar Patnaik5, Sidharth Sethi6, Pankaj Hari1, Aditi Sinha1,
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16 Marie-Agnes Dragon-Durey7
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21 1
22 Divison of Nephrology, Department of Pediatrics, All India Institute of Medical Sciences, New
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24 Delhi
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26
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27 Department of Pediatrics, Chacha Nehru Bal Chikitsalya, New Delhi
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29
3
30 Department of Pediatric Nephrology, St. Johns Medical College and Hospital, Bengaluru
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33 Renal Unit, KEM Hospital, Pune
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35
5
36 Department of Pediatrics, Army Hospital Research & Referral, New Delhi
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39 Department of Nephrology, Medanta Hospital, New Delhi
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7
Laboratoired’Immunologie, Hopital Europeen Georges Pompidou, APHP, INSERM UMRS
43
44 1138, Paris, France
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50 Correspondence to: Arvind Bagga, Division of Nephrology, Department of Pediatrics, All India
51
52
53 Institute of Medical Sciences, New Delhi 110029; 91-11-26593472
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56 E-mail: arvindbagga@hotmail.com
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 1 2
2
3
4 Abstract
5
6
7 Hemolytic uremic syndrome (HUS) is a leading cause of severe acute kidney injury requiring
8
9 dialysis in children. An understanding of its pathogenesis has resulted in relatively standard
10
11
12 classification and approach to management of these patients. The availability of eculizumab has
13
14 significantly impacted therapy of HUS in the developed world. While international guidelines
15
16
17 emphasize comprehensive diagnostic evaluation, and selective treatment with eculizumab, access
18
19 to diagnostic and therapeutic facilities is limited and expensive in India and most developing
20
21 countries. In view of limited facilities for detecting shiga toxin producing microbes, the burden
22
23
24 of shiga toxin associated HUS in India is not clear. Children show high prevalence of anti-factor
25
26 H (FH) associated HUS, facilities for genetic diagnosis are limited and therapy with eculizumab
27
28
29 is not available. We propose practice guidelines for patients with HUS in India, which are
30
31 perhaps applicable to other developing countries. Priorities for capacity building in regional and
32
33
34 national laboratories are highlighted. The management of patients with presumed shiga toxin
35
36 associated HUS is supportive. Prompt initiation of plasma exchanges is the chief therapy in
37
38
39
patients with atypical HUS; treatment with eculizumab is considered in those who fail to show
40
41 hematological remission or following recurrent HUS in the allograft. Patients with anti-FH
42
43 associated disease are most appropriately managed with a combination of plasma exchanges and
44
45
46 immunosuppressive medications.
47
48 Key words Anti-factor H antibodies, Complement, Plasma exchange, Thrombotic microangiopathy
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 1 3
2
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4 Hemolytic uremic syndrome (HUS) is an important cause of severe acute kidney injury (AKI) in
5
6
7 childhood. A significant proportion of patients require renal replacement therapy and about one-
8
9 third may show features of chronic kidney disease. Across the world, the majority of HUS
10
11
12 follows gastrointestinal infection with shiga toxin producing organisms, chiefly Escherichia coli.
13
14 HUS might also be associated with systemic illnesses (secondary HUS), and with disorders of
15
16
17 complement regulation (atypical HUS, aHUS, Table 1). Management of the disease is chiefly
18
19 supportive, with attention to AKI and therapy of underlying disorders. The availability of
20
21 eculizumab, a complement inhibitor, has had major impact on treatment of aHUS in the
22
23
24 developed world.
25
26
27 There are differences in the epidemiology and management of HUS in India compared to
28
29 developed countries. Improving standards of hygiene and health care have led to decline in
30
31
32 incidence of shigella associated HUS, the chief form of shiga toxin associated disease in the
33
34 region [1]. There is limited information on the epidemiology of enterohemorrhagic E. coli, with
35
36
37 reports not suggesting a role in etiology of diarrheal or dysenteric illnesses [2-4]. Second, unlike
38
39 European cohorts, aHUS associated with factor H (FH) antibodies is common, accounting for
40
41
~50% of pediatric patients [5]. The capacity for diagnosis of shiga toxin associated HUS and
42
43
44 genetic screening is limited, posing hurdles in etiological classification. Finally, in absence of
45
46 access to eculizumab, plasma therapy forms the basis for managing aHUS in India and most
47
48
49 developing countries, including patients with anti-FH associated disease.
50
51
52 International guidelines on management of HUS [6-13] that emphasize comprehensive
53
54 evaluation and specific therapy with eculizumab for patients with aHUS might not be suitable in
55
56
57 resource constrained settings. Given these challenges, we propose guidelines for evaluation and
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 1 4
2
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4 management of HUS in Indian children. These guidelines are likely to be suitable for developing
5
6
7 countries with less than optimal access to diagnostic and therapeutic facilities.
8
9
10 Consensus Development
11
12
13 The process involved workgroups on key issues in management: (i) Investigations, biopsy,
14
15 genetics and differential diagnosis; (ii) infection associated HUS; (iii) atypical HUS; and (iv)
16
17
18 complement blockade. Prior to the formal meeting on 31 March and 1 April 2017 in New Delhi,
19
20 each workgroup searched databases for research articles, identified the state of knowledge and
21
22
23
formulated questions though emails. At the meeting, the workgroups developed consensus
24
25 statements through alternating breakout and plenary sessions. Research studies were rated from
26
27 A to D using standard criteria [14].
28
29
30 A: Systematic review, well designed randomized controlled trials, or diagnostic studies without
31
32 significant limitations
33
34
35 B: Randomized controlled trials or diagnostic studies with methodological limitations; consistent
36
37 evidence from observational studies
38
39
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C: Small cohorts or case control studies; case series
41
42 D: Expert opinion; case reports
43
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45 Each consensus statement was assigned one of two levels of recommendation, based on
46
47 assessment of relative benefit versus harm, and relevance in context of limited diagnostic
48
49
50 facilities.
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53 Level 1. Recommendation applicable to most subjects, based on consistent information
54
55 confirming benefit over harm or vice versa
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 1 5
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4 Level 2. Suggestion or option based on equivocal or insufficient evidence, with unclear balance
5
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7 of benefit over harm.
8
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10 The final manuscript was circulated to participants for approval.
11
12
13 Guideline 1: Diagnosis of HUS
14
15
16 Rapid diagnosis and prompt management of HUS is essential to limit irreversible renal damage.
17
18 Patients with suspected HUS require urgent evaluation by a specialist to initiate appropriate care.
19
20
21 1.1 We recommend making a diagnosis of HUS in presence of all of the following [1B]
22
23
24 (i) Microangiopathic hemolytic anemia (MAHA), defined by anemia (hemoglobin <10 g/dl,
25
26 hematocrit <30%) and fragmented red cells on peripheral smear (schistocytes ≥2%) with
27
28 either elevated lactate dehydrogenase (LDH >450 IU/l) or undetectable haptoglobin
29
30
31 (ii) Thrombocytopenia (platelet count <150,000/µl) and
32
33 (iii) AKI, defined as increase in serum creatinine by 50% over baseline level [15]
34
35
36 1.2 We recommend evaluation and exclusion of disseminated intravascular coagulation (DIC)
37
38 and thrombotic thrombocytopenic purpura (TTP), when clinically indicated (see below). [1B]
39
40
41 1.3 We suggest exclusion of common infections that mimic or trigger HUS, e.g., malaria,
42
43 leptospirosis and dengue. [2C]
44
45
46 Rationale
47
48
49 The diagnosis of HUS is based on presence of MAHA, thrombocytopenia and AKI [6, 16]. The
50
51 threshold for each of these parameters is not well defined and 15-20% patients may not have
52
53
54 thrombocytopenia [13, 17, 18]. The diagnostic sensitivity of HUS is increased if platelet counts
55
56 are screened at multiple time points [11]. Differentiating DIC from HUS is necessary, especially
57
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59 in the setting of sepsis or malignancy (Fig. 1). DIC is characterized by prolonged prothrombin
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 1 6
2
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4 time or activated partial thromboplastin time, low fibrinogen, elevated D-dimer and soluble
5
6
7 fibrin monomers [19]; haptoglobin levels are normal (30-100 mg/dl) [11]. Online scoring criteria
8
9 for diagnosis of DIC are available [20]:
10
11
12 www.thecalculator.co/health/Disseminated-Intravascular-Coagulation-(DIC)-Score-Calculator-1048.html
13
14 Patients with shigella associated HUS may occasionally show features of DIC [1].
15
16
17 TTP is a rare disorder in children, with inherited and acquired TTP reported in 2.4% and 4.6%
18
19
patients, respectively of a French cohort of thrombotic microangiopathy (TMA) [21].
20
21
22 Confirmation is feasible, but assays for ADAMTS13 (A Disintegrin And Metalloproteinase with
23
24 a ThromboSpondin type 1 motif, member 13) activity are available at limited centers and have a
25
26
27 long turnaround time.
28
29
30 Due to its rarity, a recent meeting of the KDIGO did not advise routine evaluation for
31
32 ADAMTS13 activity prior to complement blockade in children with HUS [22]. TTP should be
33
34
35 suspected in patients with severe, persistent thrombocytopenia (<30,000/µl) [13, 23] and mild or
36
37 no AKI [24, 25]. However, severe AKI is described in 10-12% patients with idiopathic TTP [21,
38
39
40
24]. Congenital TTP (Upshaw Schulman syndrome) has varied phenotype, and may present in
41
42 neonates with MAHA and jaundice, or in children with unexplained thrombocytopenia. It is
43
44 characterized by ADAMTS13 activity <5%, absent antibodies to ADAMTS13 and a
45
46
47 homozygous or compound heterozygous mutation in ADAMTS13 [26].
48
49
50 Due to limited availability of the ADAMTS13 assay, we suggest storing blood samples
51
52 (collected in 3.2% sodium citrate) at -20° to -70° C in patients with suspected HUS. The
53
54
55 possibility of TTP should be revisited if the etiology of TMA is unclear. The diagnosis is
56
57 confirmed by demonstrating ADAMTS13 activity <10% on fluorescence resonance energy
58
59
60
transfer (FRET) based assays and/or presence of anti-ADAMTS13 antibodies.
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 1 7
2
3
4 HUS may at times mimic or occur in association with infections such as malaria [27], dengue
5
6
7 [28] and leptospirosis [29]. These disorders might result in anemia, thrombocytopenia and AKI
8
9 that is not due to renal microangiopathy.
10
11
12 Guideline 2: Infection associated HUS
13
14
15 HUS may be associated with specific infections (Table 1). Shiga toxin associated gut infection is
16
17
18 one of the chief causes and confirmed by stool examination (see below). If indicated, antibodies
19
20 to human immunodeficiency virus; polymerase chain reaction (PCR) for influenza virus (H1N1),
21
22
23
cytomegalovirus and Epstein-Barr virus; peripheral smear and quantitative buffy coat for malaria
24
25 parasite; NS-1 antigen or dengue-IgM antibody; and specific tests for leptospirosis and rickettsia
26
27 are performed.
28
29
30 2.1 We suggest that diagnosis of shiga toxin associated HUS, either due to shiga toxin
31
32
33 producing Escherichia coli (STEC) or S. dysenteriae, be based on the following criteria. [2B]
34
35
36 Confirmed case. HUS associated with infection with shiga toxin producing organisms confirmed
37
38 by positive stool culture, and either of the following:
39
40
41 (i) Detection of virulence genes (by PCR)
42
43
44 (ii) Free fecal shiga toxin or O157 lipopolysaccharide antigen (by ELISA)
45
46 (iii) Serum antibodies to lipopolysaccharide of prevalent serogroups (by ELISA)
47
48
(iv) Elevated serum antibodies to shiga toxin (by ELISA) (Table 2)
49
50
51 Suspected case. HUS occurring within 2-3 weeks of bloody diarrhea, and/or occurring during a
52
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54 known outbreak of STEC-HUS in patients above 6 months of age
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57 2.2 We suggest screening for STEC infection in all suspected cases of STEC-HUS on stool
58
59 samples collected at admission. [2D]
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 1 8
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4 Rationale
5
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7 Guidelines from the Center for Disease Control recommend stool culture and testing for shiga
8
9
10 toxin to detect all serotypes of STEC [30]. While STEC is the leading cause of HUS in
11
12 developed countries [17], fecal isolation is difficult following antibiotic administration [31]. The
13
14
15 presence of shiga toxin in stool, and serum antibodies against lipopolysaccharide or shiga toxin
16
17 are important evidence for STEC infection [16, 31, 32].
18
19
20 While circulation of S. dysenteriae is reported to be extremely low in recent years in India [33],
21
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23
there is limited data regarding the epidemiology of STEC. In a study from north India, STEC
24
25 was isolated in 1.7% stool samples of acute non-bloody diarrhea and 1.6% samples of bloody
26
27 diarrhea [2]. The authors found serogroup diversity of non-O157 STEC; O157 was not isolated,
28
29
30 signifying either its absence or presence in low numbers [2]. Non-O157:H7 STEC was detected
31
32 by PCR for stx and eae in 23% of 198 patients with acute diarrhea in southern India; only three
33
34
35 isolates were identified as STEC by serotyping [3]. In the absence of epidemiological data of
36
37 STEC-HUS in India, we suggest confirming the diagnosis by detection of fecal shiga toxin as
38
39
40
well as by culture. Since excretion of STEC is short-lasting (median 10-14 days; 92% isolation
41
42 rate within 6 days) [34, 35], delayed referral and prior antimicrobial use reduce the likelihood of
43
44 detection. In such patients, serologic evidence might enable retrospective diagnosis [32].
45
46
47 Five-10% patients with sporadic STEC infection and ~20% patients during outbreaks develop
48
49
50 HUS. Risk factors for occurrence of HUS are: young age (<5 years), >3 days of diarrhea, blood
51
52 in stools, and high leukocyte count (>15,000/µl) [36, 37]. While international guidelines state
53
54
55 that patients with HUS should be screened for STEC infection, access to microbiological
56
57 diagnosis is difficult in developing countries. In view of insufficient information on
58
59
60 epidemiology, lack of surveillance of food borne pathogens, and limited facilities for
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 1 9
2
3
4 microbiological confirmation, the diagnosis of STEC-HUS is usually clinical. The present
5
6
7 guidelines therefore suggest suspecting STEC-HUS in patients with prior history of bloody
8
9 diarrhea, or if occurring during an outbreak of STEC infection. It is emphasized that ~30-40%
10
11
12 cases of STEC-HUS may not have dysentery; the condition is also reported in patients without
13
14 diarrhea and infants below 6-months of age [13].
15
16
17 A diagnosis of probable pneumococcal HUS is made in patients, usually younger than 2-years,
18
19
20
with sepsis, pneumonia or meningitis and positive direct Coombs’ test without features of DIC
21
22 [38, 39]. The diagnosis is confirmed by either:(i) S. pneumoniae isolated by bacterial culture,
23
24 PCR or ELISA on appropriate body fluid or, (ii) positive peanut lectin (Arachis hypogaea)
25
26
27 agglutination assay indicating activation of Thomsen Friedenreich antigen [38, 39]. Therapy is
28
29 with parenteral cephalosporins; vancomycin is used if there is high prevalence of multi-drug
30
31
32 resistance [40]. Plasma infusions or plasma exchanges (PEX) are avoided; washed red cells and
33
34 platelets are used, if necessary.
35
36
37 Guideline 3: Cobalamin deficiency associated HUS
38
39
40 3.1 We suggest screening for cobalamin C (cblC) deficiency by total homocysteine levels in
41
42
43
patients with HUS. [2C]
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46
Probable cblC deficiency related HUS HUS and elevated plasma total
47
48 homocysteine level (>50-100 M/L by chromatography or immunoassay) with normal levels of
49
50
51
vitamin B12 and folate.
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53
54
Confirmed cblC deficiency related HUS Homozygous or compound heterozygous mutation
55
56 in the MMACHC gene in a patient with probable cblC deficiency.
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 1 10
2
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4 3.2 We recommend that patients with probable or confirmed cblC deficiency should receive
5
6
7 prompt therapy with parenteral hydroxycobalamin, oral betaine and folic acid. [1B]
8
9
10 Rationale
11
12
13 Cobalamin deficiency accounts for a small (~6-8%) proportion of patients with HUS. At all ages
14
15 patients present with varied features and do not respond to PEX [17]. Features include failure to
16
17
18 thrive, feeding difficulties, seizures, abnormal muscle tone, visual impairment and
19
20 developmental delay. Megaloblastic anemia is present in 10-25%. One-third patients do not have
21
22
23
extrarenal features, although neurological (44%) or cardiopulmonary (39%) disease, and
24
25 pulmonary hypertension (17%) are frequent [41].
26
27
28 Elevated blood levels of total homocysteine are characteristic. Samples may be stored and
29
30 processed later, if the assay is not immediately available. Plasma samples centrifuged within 30
31
32
33 minutes of collection are stored at -20° to -70° C (Fig. 1). Free homocysteine levels are not
34
35 required; vitamin B12 and folate deficiency also result in elevated total homocysteine [42].
36
37
38 Plasma and urine methylmalonic acid levels are high in cblC deficiency, but may be normal in
39
40 cblD (MMADHC) deficiency [42].
41
42
43 The mortality in patients with untreated disease is high [17, 41]; early treatment is thus
44
45
46
recommended [42]. Patients respond to therapy with parenteral hydroxycobalamin (1 mg daily)
47
48 to lower homocysteine levels <40-60 M/L; cyanocobalamin is not effective. Betaine (250
49
50
51
mg/kg/day in three divided doses) helps in methylating homocysteine to methionine. Folate (5-
52
53 30 mg divided in 2-3 doses per week) is used as adjunct therapy [42]. Specific therapy allows
54
55 renal recovery and prevents relapses.
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57
58 Guideline 4: Diagnosis of atypical HUS (aHUS)
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 1 11
2
3
4 4.1 We suggest the diagnosis of aHUS where suspected STEC-HUS and secondary HUS are
5
6
7 excluded based on clinical and laboratory features. [2D]
8
9
10 4.2 We also suggest a diagnosis of aHUS in patients with: (i) negative results for infection by
11
12 shiga toxin producing organism; (ii) positive non-synchronous family history; or (iii) recurrent
13
14
15 disease. [2C]
16
17
18 Rationale
19
20
21 Many algorithms are proposed for evaluation of patients with TMA [7, 8, 11, 13]. In resource
22
23 limited settings, it is important to follow a pragmatic approach without compromising the
24
25
principles of management. We endorse the etiology-based classification of HUS proposed by
26
27
28 international guidelines, emphasizing the importance to differentiate between infection
29
30 associated illness, cblC deficiency, secondary HUS and aHUS (Table 1, Fig. 1) [18, 43, 44].
31
32
33 Since TTP and cblC deficiency are relatively infrequent causes, units lacking facility to screen
34
35 for these disorders might store samples for subsequent analysis. Confirmation of STEC-HUS is
36
37
38 difficult due to limited diagnostic facilities, delayed analysis and prior use of antibiotics. Plasma
39
40 specimens may be stored for later serological investigations.
41
42
43 Guideline 5: Evaluation of atypical HUS (Table 2, Fig. 1)
44
45
46 5.1 We recommend the following evaluation in patients with aHUS: (i) Complement C3; (ii)
47
48
ELISA for anti-factor H (FH) antibodies; (iii) flow cytometry for expression of membrane
49
50
51 cofactor protein (MCP, CD46) on neutrophils; and (iv) sequencing of CFH, CFI, CFB, C3,
52
53 CD46, THBD and DGKE. Blood specimens for C3 and anti-FH antibodies should be drawn prior
54
55
56 to instituting therapy. [1B]
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 1 12
2
3
4 5.2 We recommend the manual ELISA, based on the Paris protocol, to estimate anti-FH
5
6
7 antibodies. Positive threshold should be determined based on data in the local population. [1C]
8
9
10 5.3 We suggest that patients with anti-FH antibody associated HUS do not routinely require
11
12 screening for genetic variants. Genetic screening is advised with: (i) early age of onset, (ii)
13
14
15 relapsing course, (iii) family history of HUS, (iv) illness that is refractory to therapy with PEX,
16
17 and (v) prior to renal transplantation. [2C]
18
19
20 Rationale
21
22
23 Evaluation of patients with aHUS is done in a step-wise manner, adapted to availability of
24
25
resources (Table 2). Blood levels of C3 are reduced in 30-40% patients, but are often normal and
26
27
28 do not correlate with severity of disease. Flow cytometry for surface expression of CD46 is a
29
30 useful screening test; labs are advised to simultaneously run specimens from healthy controls.
31
32
33 Reduced expression that persists following hematological remission helps identify patients with
34
35 possible CD46 mutation. Because these patients are unlikely to benefit from PEX, a precise
36
37
38 diagnosis is important [45, 46].
39
40
41 Anti-FH antibody associated aHUS constitutes ~50% of pediatric patients with aHUS in India,
42
43 chiefly affecting children between the age of 5-15 years [5]. Most patients have high levels of
44
45
46
antibodies (1000 to 20000 AU/ml) [47]. Given the therapeutic implications, it is necessary to
47
48 screen for anti-FH antibodies in all patients with aHUS. Methods for ELISA differ in approach to
49
50 coating, blocking, incubation and color development [48]. Of available assays, the Paris method
51
52
53 is easy to set up, reproducible and cost effective. Sample specific subtraction is done to rule out
54
55 false positives and a reference arbitrary unit (AU/ml) scale, based on standard positive anti-FH
56
57
58 serum, is used for reporting. Using this method, a positive threshold of 150 AU/ml is established
59
60 for Indian controls [5]. This protocol is preferred over commercial kits that might show false
61
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 1 13
2
3
4 positive results and underestimate antibody titers, limiting their role during follow up; a positive
5
6
7 threshold for these kits is also not defined [48].
8
9
10 Variants in six complement genes (CFH, CFI, CD46, CFB, C3, THBD) and rearrangements of
11
12 CFHR1-5 and CFH are found in 19-52% patients with aHUS, including studies from India [17,
13
14
15 49]. Mutations in DGKE are described in 2-3%, chiefly but not limited to patients <2-years-old
16
17 [50]. Genetic sequencing and screening for hybrid genes is recommended in all patients with
18
19
20
aHUS to guide regarding prognosis, risk of relapses, genetic counseling and transplantation.
21
22 Variants found on next-generation platforms should be validated by Sanger sequencing. Expert
23
24 opinion is necessary for ascribing pathogenicity. A database of gene variants is available at:
25
26
27 http://www.complement-db.org/home.php
28
29
30 Anti-FH associated aHUS is strongly associated with the polymorphism, an 84 kb homozygous
31
32 deletion of the CFHR1 gene, present in ~5-10% healthy individuals across the world [47, 51].
33
34
35 MLPA or end-point PCR [52] is useful in confirming the deletion, but not required in clinical
36
37 practice. Detection of deletion helps confirm antibody mediated disease, in patients with (i) low
38
39
40 antibody titers, especially if having received multiple PEX before screening, (ii) onset of illness
41
42 <3-yr of age, and (iii) atypical presentation.
43
44
45 The need for additional genetic screening in patients with anti-FH associated HUS is debated. Of
46
47
48
~300 patients with anti-FH positive illness screened, ~5% show change in complement
49
50 regulatory genes [17, 47, unpublished data], mostly polymorphisms or variants of unknown
51
52 significance. The likelihood of detecting pathogenic mutations in complement genes in patients
53
54
55 with anti-FH associated HUS is low. Evaluation for additional defects is suggested in patients
56
57 with a refractory, relapsing or atypical illness, and before renal transplant.
58
59
60
61
62
63
64
65
 1 14
2
3
4 Immune assays for FH, FI and FB are expensive and require to be performed at specialized
5
6
7 laboratories. Their normal levels do not rule out the possibility of normally expressed, but
8
9 functionally impaired protein [9]. In our experience, measurement of blood levels of FH and FI
10
11
12 has not been useful in screening children with aHUS. Estimation of levels is useful if a variant is
13
14 found in the corresponding gene; if deficient these levels serve as a marker of efficacy of
15
16
17 supplemental therapy. The experts felt that resources should be invested for capabilities, with
18
19 implications for diagnosis and therapy (Table 3).
20
21
22 Guideline 6: Indications for renal biopsy
23
24
25 We recommend that renal biopsy be considered in patients with (i) unclear diagnosis of HUS; (ii)
26
27 unsatisfactory clinical response, to determine extent of renal damage and help in prognosis; and
28
29
30 (iii) distinguish between causes of allograft dysfunction, including recurrent HUS. [1B]
31
32
33 Rationale
34
35
36 The diagnosis of HUS is clinical; renal biopsy is not required to demonstrate TMA and adds little
37
38 to the etiology or prognostic information at onset. Histological diagnosis is required in patients
39
40
41 not manifesting the triad, and where the diagnosis may be doubtful. In patients with
42
43 unsatisfactory clinical response, biopsy provides information regarding the extent and severity of
44
45
46
the illness and potential reversibility of damage. Patients with HUS undergoing transplantation
47
48 may present with features of graft dysfunction. Since these patients are at risk of recurrent HUS,
49
50 an early kidney biopsy enables precise diagnosis and institution of specific therapies. The biopsy
51
52
53 should be interpreted by a renal pathologist; histology findings of TMA have recently been
54
55 reviewed [22].
56
57
58 Guideline 7: Therapy of shiga toxin associated HUS
59
60
61
62
63
64
65
 1 15
2
3
4 7.1 We recommend maintaining hydration by early use of isotonic IV fluids in patients with
5
6
7 dysentery, starting from onset of bloody diarrhea to the day of onset of HUS, and monitoring for
8
9 fluid overload in patients with renal failure. [1B]
10
11
12 7.2 We recommend therapy with appropriate antibiotics for bloody diarrhea. [1A]
13
14
15 7.3 We do not suggest the routine use of PEX and eculizumab in patients with shiga toxin
16
17
18 associated HUS. Therapy may be considered for patients with severe neurological or cardiac
19
20 involvement. [2D]
21
22
23 7.4 We do not recommend the use of plasma infusions, heparin, urokinase, dipyridamole,
24
25
antimotility agents, glucocorticoids and shiga toxin binders. [1B]
26
27
28 Rationale
29
30
31 Patients with HUS due to proven or presumed STEC infection show an association between
32
33
34 dehydration and adverse outcomes [53]. A review of cohort studies (1500 children with
35
36 presumed or proven STEC infection) showed that hematocrit (>23%) at presentation and lack of
37
38
39 fluid administration before onset of HUS was associated with unsatisfactory outcomes including
40
41 oliguric AKI, need for renal replacement therapy and neurological complications [53-58].
42
43
44 Careful management of intravascular volume is therefore necessary. Ringer lactate or dextrose
45
46 saline should be infused during bloody diarrhea and including the day of diagnosis of HUS to
47
48
prevent dehydration. Since fluid overload is an important predictor of mortality in AKI [15], we
49
50
51 recommend judicious monitoring of fluid balance subsequently [7].
52
53
54 Patients with shigellosis require prompt antimicrobial treatment in order to reduce mortality,
55
56 fecal shedding and complications [59]. While there is limited circulation of S. dysenteriae [33],
57
58
59 bacteriological confirmation of infection with STEC and distinction from shigellosis is not
60
61
62
63
64
65
 1 16
2
3
4 feasible. WHO recommends ciprofloxacin as first line therapy for shigellosis; cefixime and
5
6
7 azithromycin are second-line agents [59]. The role of antibiotics in STEC gastroenteritis is
8
9 debated, since these agents might induce expression of shiga toxin [60] and increase the risk of
10
11
12 HUS [61]. Recent reviews and cohort studies do not show an increased risk of HUS with use of
13
14 antibiotics for STEC dysentery [37, 60, 62-66]. We recommend that patients with bloody
15
16
17 diarrhea should receive either oral ciprofloxacin for 3 days or cefixime for 5 days.
18
19
20
The American Society of Apheresis does not recommend PEX for patients with shiga toxin HUS
21
22 [67]. Two multicenter randomized trials did not show benefit of plasma infusions over
23
24 supportive care [68, 69]. Data in adults [64, 70] and children [71] from the German outbreak did
25
26
27 not show benefit of PEX in reducing the need for dialysis, and respiratory or neurological
28
29 complications. While PEX reduced mortality in adults (31% versus 83% with or without PEX,
30
31
32 respectively) [72], it did not improve outcomes of patients with severe neurological involvement
33
34 [73].
35
36
37 Since there is evidence of activation of the complement pathway during acute STEC infection
38
39
40
[74], it has been proposed that complement blockade may have a role in patients with severe
41
42 disease. While there was no benefit with use of eculizumab in the German epidemic [64, 70],
43
44 anecdotal reports suggest that patients with severe neurological and cardiac features might
45
46
47 respond to therapy [75, 76]. A review of interventions in STEC-HUS reported no benefit with
48
49 plasma infusions, heparin, urokinase, dipyridamole, antimotility agents, steroids and shiga toxin
50
51
52 binders [77].
53
54
55 Guideline 8: Atypical HUS without anti-FH antibodies
56
57
58 Inherited defects of the alternative pathway are the chief cause of aHUS in Europe and North
59
60 America. The standard of care for patients is complement blockade with eculizumab, a
61
62
63
64
65
 1 17
2
3
4 humanized anti-C5 antibody [78]. However, eculizumab is expensive and unlikely to be available
5
6
7 soon in India and other developing countries, posing hurdles in management. Thus, PEX or
8
9 plasma infusions are the only option for patients with aHUS, especially those with confirmed
10
11
12 genetic defect in the complement pathway.
13
14
15 8.1 In the absence of eculizumab, we recommend prompt initiation of PEX in patients with
16
17 aHUS. For initial therapy, we recommend that PEX be preferred to plasma infusions. [1C]
18
19
20 8.2 We suggest that PEX be administered daily until hematological remission, and then
21
22
23
tapered over 4-6 weeks (Table 4). [2D]
24
25
8.3 Patients on plasma therapy should be monitored for plasma or filter reactions,
26
27
28 complications of catheter insertion, infection or thrombosis and blood borne infections. [1C]
29
30
31 8.4 We recommend efforts to enable therapy with eculizumab in the following: (i) lack of
32
33 remission despite 5-7 days of PEX; (ii) life-threatening features (seizures, cardiac dysfunction);
34
35
36 (iii) complications due to PEX or vascular access; and (iv) inherited defect in complement
37
38 regulation. [1C]
39
40
41 Rationale
42
43
44 Prior to approval and use of eculizumab, the 2009 European guidelines recommended prompt
45
46
47
therapy of aHUS with PEX within 24-hours of presentation [9]. PEX may be performed by
48
49 membrane filtration or by centrifugation based methods [79] (Table 4). PEX is preferred to
50
51 plasma infusions for initial therapy, since larger volumes of fresh plasma can be infused. PEX
52
53
54 also enables removal of dysfunctional proteins and antibodies, present in significant proportion
55
56 of children with aHUS.
57
58
59
60
61
62
63
64
65
 1 18
2
3
4 An audit on the safety of PEX from centers in Europe and North America showed procedure
5
6
7 related complications and hypersensitivity to plasma in one-third patients [80]. While there are
8
9 risks of securing vascular access in infants, a multicenter study showed that the procedure was
10
11
12 safe [81]. An audit of 2024 PEX sessions (n=109 patients) in New Delhi showed adverse events
13
14 in ~10%, including chills, abdominal pain, hypotension, urticaria, seizures and hypocalcemia
15
16
17 [unpublished data]. Plasma hypersensitivity was rare, and rate of catheter-related infections was
18
19 1.45/1000 catheter-days. Parents should be counseled about the risk of blood-borne infections
20
21 with repeated therapies. While use of Octaplas, a sterile solution of pooled human plasma treated
22
23
24 by a solvent detergent process, reduces the risk of hypersensitivity reactions and blood-borne
25
26 infections [82], the product is not available in most developing countries.
27
28
29 Eculizumab The outcome of aHUS from large cohorts managed with plasma therapy alone is
30
31
32 unsatisfactory; 30-50% patients progress to end-stage renal disease at 1-5 years’ follow up [18,
33
34 83]. The evidence for benefit of eculizumab is derived from prospective single arm industry
35
36
37 sponsored trials in adults and children [78, 84-86]. In a trial on17 adults refractory to plasma
38
39 therapy, hematological remission was achieved by 1-2 weeks and sustained in 88% [78]; renal
40
41
functions improved with 12% patients on chronic dialysis after 2 years’ therapy [85]. Another
42
43
44 trial on 20 plasma-dependent adults with chronic kidney disease showed hematological
45
46 remission in 90% [78] and increase in glomerular filtration rate over next 2-years [85]. Two
47
48
49 subsequent trials underscored the efficacy of eculizumab as first-line treatment prior to initiation
50
51 of aHUS in children [86] and adults [84]. Hematological remission was maintained in 82%
52
53
54 children and 88–90% adults at 1-year and 2-years’therapy, respectively [17, 84, 86]. Progression
55
56 to end-stage renal disease or death occurred in fewer patients (6–15%), compared to controls
57
58
59
managed with plasma therapy [18, 83].
60
61
62
63
64
65
 1 19
2
3
4 Eculizumab is thus the specific therapy for patients with aHUS with inherited defects in
5
6
7 complement regulation. Where possible, we recommend following international guidelines for
8
9 treatment with this agent, including monitoring for complement blockade, dose interval and
10
11
12 duration of therapy (Table 5). Hematological remission is achieved at median of 7-8 days
13
14 following treatment; patients lacking response by 10-14 days of therapy should be reviewed for:
15
16
17 (i) inadequate dose, suggested by trough level <50 µg/ml and CH50 >20%; (ii) losses (nephrotic
18
19 range proteinuria, or PEX); (iii) resistance due to ongoing infection, inflammation or surgery;
20
21 and (iv) C5 variant with impaired binding to eculizumab (seen in patients of Asian origin) [87].
22
23
24 Eculizumab is not indicated for therapy of complement independent disorders, e.g., DGKE or
25
26
27 MMACHC mutations [50]. Information on efficacy of eculizumab for extrarenal manifestations
28
29 of is limited. Therapy was useful in a patient with digital gangrene and another with skin
30
31
32 necrosis and intestinal perforation [88-90]. The medication has variable efficacy in managing
33
34 neurological or myocardial manifestations [91-93]. The duration of therapy with eculizumab is
35
36
37 not clear. Discontinuation of treatment results in relapses in 60-72% patients with CFH
38
39 mutations, 43% with C3 defects, 37-50% with MCP mutations and ~10% with no identified
40
41
defect [87].
42
43
44
Guideline 9: Anti-FH antibody associated HUS (Fig. 2)
45
46
47 9.1 We recommend a combination of prompt PEX (with fresh frozen plasma as replacement
48
49
50 fluid), and immunosuppressive therapy for patients with anti-FH antibodies (Fig. 2). [1B]
51
52
53 9.2 We do not recommend use of immunosuppressive medications without confirming
54
55 presence of anti-FH antibodies. [1D]
56
57
58
59
60
61
62
63
64
65
 1 20
2
3
4 9.3 We suggest administering PEX daily until hematological remission, and then tapered
5
6
7 over 3-6 weeks. We do not recommend plasma infusions as a substitute for PEX. [2D]
8
9
10 9.4 Since high anti-FH levels might predict a relapse, we recommend monitoring antibody
11
12 titers frequently during the first 12-24 months. [1C]
13
14
15 9.5 We suggest efforts for therapy with eculizumab in the following: (i) lack of remission
16
17
18 despite 5-7 PEX; (ii) life-threatening features (seizures, cardiac dysfunction); (iii) complications
19
20 due to PEX or vascular access; and (iv) inherited defect in complement regulation. [2C]
21
22
23 Rationale
24
25
26 The aim of therapy for patients with anti-FH associated HUS is to reduce antibody titers. The
27
28 American Society for Apheresis assigns level I category to anti-FH associated HUS, implying
29
30
31 that PEX is a primary therapeutic intervention [67]. Since the antibodies are chiefly IgG, 5-7
32
33 PEX achieve 80% reduction in antibody titers [94]. Prompt initiation and continued PEX for at
34
35
36 least 3-6 weeks, is advised. While blockade of the terminal complement pathway by eculizumab
37
38 is effective in inducing hematological remission, it has no impact on antibody titers.
39
40
41 We endorse guidelines that emphasize combined therapy with PEX and immunosuppressive
42
43
44 agents for patients with anti-FH antibodies [13, 17]. Immunosuppression inhibits further
45
46 production of antibodies, especially following PEX, with improved medium term outcomes [47].
47
48
High dose induction therapy is required initially. Outcomes were similar for patients managed by
49
50
51 rituximab (n=14) and intravenous cyclophosphamide (n=31) [95]. In a large series, the
52
53 probability of relapse free survival was 92% at 1 year and 87% at follow up in patients receiving
54
55
56 maintenance therapy, compared to 69% and 46%, respectively in those not receiving treatment
57
58 [5].
59
60
61
62
63
64
65
 1 21
2
3
4 Antibody titers are monitored closely, between days 7-28 and then every 3–6 months. Elevated
5
6
7 titer (>1500 AU/ml) during the first 12-24 months suggest an increased risk of relapse [47].
8
9 Relapses follow minor infectious illnesses in the initial 2-years. Immunosuppression with
10
11
12 azathioprine or mycophenolate mofetil and tapering doses of prednisolone is useful in reducing
13
14 the risk of relapses [5].
15
16
17 Eculizumab does not affect generation of antibodies and additional immunosuppression might
18
19
20
still be required. The use of eculizumab has been reported in 18 patients with anti-FH associated
21
22 disease, either after failing PEX or as first line therapy [87]. The efficacy of concomitant
23
24 immunosuppression (in 72% cases) in reducing antibody titers and risk of relapse cannot be
25
26
27 determined, since relapses were uncommon. Prospective studies are required to determine the
28
29 comparative efficacy of eculizumab to PEX and immunosuppression. Therapy with eculizumab
30
31
32 should be considered in patients who are refractory to PEX, show life-threatening features, or
33
34 have concomitant defect(s) in complement regulation [47].
35
36
37 10. Supportive Care and Monitoring
38
39
40 Standard recommendations should be followed for AKI with attention to fluid and electrolytes,
41
42
43 avoiding radiocontrast and nephrotoxic agents, and timely institution of dialysis [96]. The choice
44
45 of dialytic modality is based on feasibility and physician expertise. We suggest avoiding platelet
46
47
transfusions unless count is <10,000/µL, or to enable vascular catheter insertion. Blood
48
49
50 transfusion is recommended for patients with hemoglobin <6 g/dl or hemodynamic instability.
51
52 Standard measures are instituted to retard CKD progression, especially control of hypertension
53
54
55 and proteinuria [97]. Complications such as malignant hypertension, seizures, bowel infarction,
56
57 stenosis or perforation, pancreatitis and cardiomyopathy require appropriate management. All
58
59
60 patients require follow up for at least 5-years for hypertension, proteinuria and estimated GFR.
61
62
63
64
65
 1 22
2
3
4 Patients and their families should be counseled regarding the risk and recognition of relapses,
5
6
7 and complications of the disease.
8
9
10 11. Transplantation
11
12
13 Patients with HUS show variable risk of recurrent disease in the allograft. Donors and recipients
14
15 need careful evaluation and peri-transplant management (Table 6). Screening of recipients for
16
17
18 mutations in relevant genes and for anti-FH antibodies is recommended. While the risk of
19
20 recurrence is high in patients with dysregulation of the alternate pathway, those with variants in
21
22
23 membrane anchored (CD46) or intracellular (DGKE) proteins have low risk [50, 98, 99].
24
25 Families should be counseled about the risk of recurrence, based on presence and type of
26
27 mutations and titer of anti-FH antibodies.
28
29
30 Live related donation should be avoided in patients at high risk of disease recurrence [100]. Such
31
32
33 patients require either combined liver kidney transplantation or therapy with eculizumab (peri-,
34
35 post-transplant) [100]. Patients with high titer anti-FH antibodies and no additional defects are
36
37
38 managed by PEX prior to and following transplantation and use of rituximab. Since CFHR1
39
40 deletion is a risk factor for anti-FH associated aHUS, it is unclear whether healthy live related
41
42
43 donors with the deletion should be accepted as donors, without predisposing them to a risk.
44
45 Patients should be monitored for recurrence following transplantation [47, 101]. If recurrent
46
47
HUS is confirmed, all efforts are made to procure and institute therapy with eculizumab.
48
49
50
Conclusions
51
52
53 While all recent guidelines recommend comprehensive diagnostic assessment of patients with
54
55
56 HUS, especially in those with atypical disease, these facilities are often not available in
57
58 developing countries. Therapy with eculizumab is not feasible given its non-availability and
59
60
61
62
63
64
65
 1 23
2
3
4 exorbitant cost. International guidelines on management of HUS are therefore not likely to be
5
6
7 implemented in India and most developing countries in the near future. This article provides
8
9 clinical practice guidelines for patients with HUS in India, which might also be applicable to
10
11
12 other developing countries. Changing epidemiology of the disease and availability of novel
13
14 agents that block the complement cascade might necessitate revision of these guidelines.
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
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50
51
52
53
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 1 24
2
3
4 Working Group Members
5
6
7
Ranjeet Thergaonkar, Visakhapatnam (Group chair)
8
9 Kirtisudha Mishra, New Delhi (Group chair)
10
11 Sushmita Banerjee, Kolkata
12
13 Kamran Afzal, Aligarh
14
15
Sriram Krishnamurthy, Puducherry
16
17
18 Girish Bhatt, Bhopal
19
20 Manish Kumar, New Delhi
21
22 Mamta Puraswani, New Delhi
23
24 Anil Vasudevan, Bangalore (Group chair)
25
26
27 Jyoti Sharma, Pune (Group chair)
28
29 Indira Agarwal, Vellore
30
31 OP Mishra, Varanasi
32
33 Kara L Tiewsoh, Chandigarh
34
35
36 Aditi Sinha, New Delhi (Group chair)
37
38 Saroj K Patnaik, New Delhi (Group chair)
39
40 Amarjeet Mehta, Jaipur
41
42 Susan Uthup, Thiruvanthapuram
43
44
45
Rajiv Sinha, Kolkata
46
47 Sudha Ekambaram, Chennai
48
49 Pankaj Hari, New Delhi (Group chair)
50
51 Sidharth Sethi, Gurugram (Group chair)
52
53
Abhijeet Saha, New Delhi
54
55
56 Swati Bhardwaj, New Delhi
57
58 Priyanka Khandelwal, New Delhi (Rapporteur)
59
60 Arvind Bagga, New Delhi
61
62
63
64
65
 1 25
2
3
4 Experts
5
6
7
Marie-Agnes Dragon-Durey, Hopital Europeen Georges Pompidou, INSERM UMRS, Paris, France
8
9 Amit K Dinda, All India Institute of Medical Sciences, New Delhi
10
11 Neelam Taneja, Postgraduate Institute of Medical Education and Research, Chandigarh
12
13 Acknowledgments
14
15
Funding support for collaborative research studies and consensus development provided by: Indo-French
16
17
18 Centre for the Promotion of Advanced Research (CEFIPRA) [IFC/A/4703-1/2015/1562; IFC/Network
19
20 1/2185]; Department of Biotechnology, Government of India [BT/PR14651/MED/30/566/2010]; Indian
21
22 Council of Medical Research [Advanced Center for Research in Pediatric Kidney Diseases;
23
24 5/7/1090/2013-RHN]; Department of Science and Technology, Government of India
25
26
27 [EMR12016/002781]; and All India Institute of Medical Sciences, New Delhi [A-386]
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2
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38 Langman C, Licht C, Pecoraro C, Riedl M, Siomou E, van de Kar N, Walle JV, Loirat C, Taylor
39 CM (2014) An audit analysis of a guideline for the investigation and initial therapy of diarrhea
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44 81. Paglialonga F, Schmitt CP, Shroff R, Vondrak K, Aufricht C, Watson AR, Ariceta G, Fischbach
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46 M, Klaus G, Holtta T, Bakkaloglu SA, Zurowska A, Jankauskiene A, Vande Walle J, Schaefer B,
47 Wright E, Connell R, Edefonti A (2015) Indications, technique, and outcome of therapeutic
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49 apheresis in European pediatric nephrology units. Pediatr Nephrol 30:103-111.
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52 82. Davin JC, Groothoff J, Gracchi V, Bouts A (2011) Long-term renal function under plasma
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58 Sorosina A, Piras R, Donadelli R, Maranta R, van der Meer I, Conway EM, Zipfel PF, Goodship
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4 TH, Remuzzi G (2010) Relative role of genetic complement abnormalities in sporadic and
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6 familial aHUS and their impact on clinical phenotype. Clin J Am Soc Nephrol 5:1844-1859.
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9 84. Fakhouri F, Hourmant M, Campistol JM, Cataland SR, Espinosa M, Gaber AO, Menne J, Minetti
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11 EE, Provot F, Rondeau E, Ruggenenti P, Weekers LE, Ogawa M, Bedrosian CL, Legendre CM
12 (2016) Terminal Complement Inhibitor Eculizumab in Adult Patients With Atypical Hemolytic
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14 Uremic Syndrome: A Single-Arm, Open-Label Trial. Am J Kidney Dis 68:84-93.
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17 85. Licht C, Greenbaum LA, Muus P, Babu S, Bedrosian CL, Cohen DJ, Delmas Y, Douglas K,
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Furman RR, Gaber OA, Goodship T, Herthelius M, Hourmant M, Legendre CM, Remuzzi G,
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20 Sheerin N, Trivelli A, Loirat C (2015) Efficacy and safety of eculizumab in atypical hemolytic
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22 uremic syndrome from 2-year extensions of phase 2 studies. Kidney Int 87:1061-1073.
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25 86. Greenbaum LA, Fila M, Ardissino G, Al-Akash SI, Evans J, Henning P, Lieberman KV,
26 Maringhini S, Pape L, Rees L, van de Kar NC, Vande Walle J, Ogawa M, Bedrosian CL, Licht C
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28 (2016) Eculizumab is a safe and effective treatment in pediatric patients with atypical hemolytic
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30 uremic syndrome. Kidney Int 89:701-711.
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33 87. Fakhouri F, Loirat C (2018) Anticomplement Treatment in Atypical and Typical Hemolytic
34 Uremic Syndrome. Semin Hematol 55:150-158.
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37 88. Malina M, Gulati A, Bagga A, Majid MA, Simkova E, Schaefer F (2013) Peripheral gangrene in
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39 children with atypical hemolytic uremic syndrome. Pediatrics 131:e331-335.
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42 89. Ariceta G, Arrizabalaga B, Aguirre M, Morteruel E, Lopez-Trascasa M (2012) Eculizumab in the
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90. Ardissino G, Tel F, Testa S, Marzano AV, Lazzari R, Salardi S, Edefonti A (2014) Skin
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48 involvement in atypical hemolytic uremic syndrome. Am J Kidney Dis 63:652-655.
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51 91. Krishnappa V, Gupta M, Elrifai M, Moftakhar B, Ensley MJ, Vachharajani TJ, Sethi SK, Raina R
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53 (2018) Atypical Hemolytic Uremic Syndrome: A Meta-Analysis of Case Reports Confirms the
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4 92. Gulleroglu K, Fidan K, Hancer VS, Bayrakci U, Baskin E, Soylemezoglu O (2013) Neurologic
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6 involvement in atypical hemolytic uremic syndrome and successful treatment with eculizumab.
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8 Pediatr Nephrol 28:827-830.
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11 93. Hu H, Nagra A, Haq MR, Gilbert RD (2014) Eculizumab in atypical haemolytic uraemic
12 syndrome with severe cardiac and neurological involvement. Pediatr Nephrol 29:1103-1106.
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15 94. Williams ME, Balogun RA (2014) Principles of separation: indications and therapeutic targets for
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17 plasma exchange. Clin J Am Soc Nephrol 9:181-190.
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20 95. Khandelwal P, Gupta A, Sinha A, Saini S, Hari P, Dragon Durey MA, Bagga A (2015) Effect of
21 plasma exchange and immunosuppressive medications on antibody titers and outcome in anti-
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23 complement factor H antibody-associated hemolytic uremic syndrome. Pediatr Nephrol 30:451-
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25 457.
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28 96. Jha V, Arici M, Collins AJ, Garcia-Garcia G, Hemmelgarn BR, Jafar TH, Pecoits-Filho R, Sola
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31 Conference Participants (2016) Understanding kidney care needs and implementation strategies
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33 in low- and middle-income countries: conclusions from a "Kidney Disease: Improving Global
34 Outcomes" (KDIGO) Controversies Conference. Kidney Int 90:1164-1174.
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37 97. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group (2013) KDIGO 2012
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39 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney
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41 Int Suppl 3:1-150.
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98. Bresin E, Rurali E, Caprioli J, Sanchez-Corral P, Fremeaux-Bacchi V, Rodriguez de Cordoba S,
45 Pinto S, Goodship TH, Alberti M, Ribes D, Valoti E, Remuzzi G, Noris M, European Working
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47 Party on Complement Genetics in Renal Diseases (2013) Combined complement gene mutations
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49 in atypical hemolytic uremic syndrome influence clinical phenotype. J Am Soc Nephrol 24:475-
50 486.
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53 99. Le Quintrec M, Zuber J, Moulin B, Kamar N, Jablonski M, Lionet A, Chatelet V, Mousson C,
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55 Mourad G, Bridoux F, Cassuto E, Loirat C, Rondeau E, Delahousse M, Fremeaux-Bacchi V
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(2013) Complement genes strongly predict recurrence and graft outcome in adult renal transplant
58 recipients with atypical hemolytic and uremic syndrome. Am J Transplant 13:663-675.
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4 100. Bacchetta J, Cochat P (2015) Primary disease recurrence-effects on paediatric renal
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6 transplantation outcomes. Nat Rev Nephrol 11:371-384.
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9 101. Khandelwal P, Sinha A, Hari P, Bansal VK, Dinda AK, Bagga A (2014) Outcomes of renal
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11 transplant in patients with anti-complement factor H antibody-associated hemolytic uremic
12 syndrome. Pediatr Transplant 18:E134-139.
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2
3
4 Legends to Figures
5
6
7 Fig. 1 Evaluation of patients with hemolytic uremic syndrome (HUS). Patients with secondary
8
9 and infection triggered HUS should also be screened for abnormalities of the alternate
10
11
12 complement pathway.
13
14 *Consider renal biopsy if triad not present and/or unexplained acute kidney injury
15
16
17 **Also consider atypical HUS if: nonsynchronous family history, recurrent or insidious disease
18
19 CD46 membrane cofactor protein; DIC disseminated intravascular coagulation; LDH lactate dehydrogenase; TTP
20
21 thrombotic thrombocytopenic purpura
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23
24
25
26
27
28 Fig. 2 Management of patients with anti-factor H (FH) associated atypical hemolytic uremic
29
30 syndrome (aHUS). Initial therapy should begin with either plasma exchanges (PEX) or
31
32
33 eculizumab, depending on availability and physician preference. Modification of therapy is
34
35 required in specific instances.
36
37
38 *Prednisolone is given daily for 4-weeks; then 1 mg/kg on alternate days for 4 weeks; tapered by
39
40 0.25 mg/kg every 2 weeks, to 0.2-0.3 mg/kg on alternate days for 1-year
41
42 ELISA enzyme linked immunosorbent assay; IVIG intravenous immunoglobulin; PEX plasma exchange
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 41

1
2
3
4 Table 1 Classification of hemolytic uremic syndrome (HUS)
5
6 Infection associated HUS*
7
Shiga toxin producing Escherichia coli, Shigella dysenteriae type 1, Citrobacter and Campylobacter
8
9 Invasive infection with Streptococcus pneumoniae
10
11 Secondary HUS
12
13
Systemic lupus erythematosus; antiphospholipid antibody syndrome
14 Hematopoietic stem cell or solid organ (including kidney) transplant
15
16 Malignancy
17
18
Malignant hypertension
19 Drugs: Quinine, mitomycin, ticlopidine, clopidogrel, calcineurin inhibitors, sirolimus, oral
20
21 contraceptives, bevacizumab
22
23 Defective cobalamin metabolism
24 Homozygous or compound heterozygous mutation in MMACHC
25
26 Atypical HUS
27
28 Homozygous or heterozygous mutations in CFH,# CFI, CFB, C3, CD46, THBD or DGKE
29 Autoantibodies to factor H
30
31 Unexplained
32
33 *Infections known to trigger HUS include influenza A, human immunodeficiency virus,
34 cytomegalovirus, Epstein Barr virus, parvovirus B19, Coxsackie virus, echovirus, varicella virus,
35
36 hepatitis A, B and C, Salmonella typhi, Bartonella, leptospira, malaria, dengue and rickettsia.
37 #Pregnancy
is a frequent trigger for HUS, usually in patients with CFH mutations
38
39 C3 complement C3; CD46 membrane cofactor protein; CFB factor B; CFH complement factor H; CFI
40
41 factor I; DGKE diacyglycerol kinase ε; MMACHC methylmalonic aciduria and homocystinuria type C;
42 THBD thrombomodulin
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 42

Table 2 Evaluation of patients with hemolytic uremic syndrome (HUS)

1
2 Diagnosis
3
4 Complete blood counts; peripheral smear for schistocytes; reticulocyte counta
5
Lactate dehydrogenase, haptoglobina
6
7 Direct Coombs testb
8
9 Blood: creatinine, complement C3a
10 Rapid test for malaria, dengue; IgM antibodies for dengue, leptospirosis (if suspected)
11
12 Coagulation profilea (suspected systemic sepsis)
13
Defining systemic involvement
14
15 Urinalysis
16
17 Blood: Electrolytes, transaminases, bilirubin
18 Ultrasound abdomen
19
20 Echocardiogram, neuroimaging, amylase, troponin T (if clinical features present)
21
22 Determining cause of HUS
23 Essential
24
25 Investigate for infection associated or secondary HUS, if clinically suspected (see Table 1; below)
26 Anti-factor H antibodiesa; antinuclear antibodies
27
28 CD46 expression on neutrophils (flow cytometry)a
29
30 Store blood for ADAMTS13 activitya,c; total homocysteinea,c
31 Selected patients
32
33 Suspected infection associated HUS
34 Shigatoxin associated: Stool sample for culture (sorbitol MacConkey agar, selective media); real time
35
36 PCR for stx1, stx2, intimin (eae) and enterohemolysin (ehxA) genes; ELISA for free shiga toxin
37
38 ELISA for antibodies to lipopolysaccharide(s) or shiga toxina,c
39 Pneumococcal: Culture, PCR or ELISA for pneumococci; peanut lectin agglutination assay
40
41 Sequencing genes: CFH, CFI, CFB, C3, CD46, DGKE; THBD, MMACHC
42 Multiplex ligation dependent probe amplification: Copy number variations in CFHR1-5 and CFH
43
44
45 ADAMTS13 A disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; C3
46 complement C3; CD46 membrane cofactor protein; CFB complement factor B; CFH factor H; CFHR CFH
47 related; CFI factor I; DGKE diacyglycerol kinase ε; ELISA enzyme linked immunosorbent assay; MMACHC
48 methylmalonic aciduria and homocystinuria type C; PCR polymerase chain reaction; stx shiga toxin; THBD
49 thrombomodulin
50
51 a
Blood samples should be drawn before plasma exchanges or infusion
52 b
May be positive with pneumococcal infection, systemic lupus and prior administration of blood products
53 c
Fresh citrated blood (ADAMTS13) and plasma (homocysteine, antibodies to lipopolysaccharide or shiga
54 toxin) samples to be frozen at -20 to -70○C
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 43

Table 3 Priorities for capacity building in regional and national laboratories

1
2
3
Microbiology
4 Stool culture on sorbitol MacConkey agar or selective media
5
6 Real time polymerase chain reaction (PCR) for stx1 and stx2*1
7
8
ELISA for free shiga toxin or O157 antigen
9 ELISA for antibodies to Escherichia coli lipopolysaccharide(s), antibodies to shiga toxin
10
11 Immunology and biochemistry
12
13 Flow cytometry for CD46 expression*2
14 ELISA for anti–factor H antibodies*2
15
16 Assay for ADAMTS13 activity; anti-ADAMTS13 antibody
17
18 ELISA for complement factors H (FH), FI and FB
19 Genetics*3
20
21 Next generation sequencing for CFH, CFI, CFB, C3, CD46, THBD,DGKE
22
23 Sanger validation of changes on next generation sequencing
24 CFHR1 deletion: Multiplex ligation dependent probe amplification or endpoint PCR
25
26
27 Performed at*1Postgraduate Institute of Medical Education and Research, Chandigarh
28 *2All India Institute of Medical Sciences, New Delhi
29
30 *3Various private and reference laboratories
31
32
33
34
35
36
37
38
39
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42
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 44

Table 4 Protocol for plasma exchanges or infusion

1
2 Method: Membrane filtration or centrifugation
3
4 Replacement fluid: Fresh frozen plasma (preferably irradiated and virus inactivated, Octaplas®)
5 Anticoagulation: Heparin or citrate
6
7 Medications
8
9 Intravenous premedication: Pheniramine and hydrocortisone prior
10 Maintain ionized calcium >1mmol/l; potassium 3.5-5 mEq/l
11
12 Prime circuit if extracorporeal volume >10% of blood volume
13
14 Schedule
15 Daily with 1.5 times plasma volume (60-75 ml/kg) per session for 5 days or until hematological
16
17 remission, whichever is later
18
19 Alternate days at 40 ml/kg for 2 weeks; twice a week for 2-3 weeks
20 Anti-FH positive: Discontinue plasma exchanges after 4-6 weeks
21
22 Anti-FH negative
23
24 Pending genetic screening: Switch to plasma infusions; fresh frozen plasma 10-20 ml/kg once in 7-
25 10 days
26
27 CD46, DGKE variants, no significant genetic variation: Discontinue exchanges or infusions
28
29 CFH, CFI, C3, CFB, THBD variants: Long-term plasma infusions; strongly consider eculizumab
30
31 Definition of response
32 Hematological remission: Platelets >100,000/μl, schistocytes <2% and LDH < upper limit of
33
34 normal on 2 consecutive days
35
36 Relapse: Recurrence of anemia with schistocytes ≥2%, elevated LDH and/or thrombocytopenia
37 (platelets <150,000/µl) with or without AKI, following remission for >2 weeks
38
39 Refractory illness: Platelets <100,000/µl and/or persistent hemolysis (fall in hemoglobin; persisting
40
41 ≥2% schistocytes) despite 5-7 daily adequate volume plasma exchanges
42
43 AKI acute kidney injury; FH factor H; LDH lactate dehydrogenase
44
45
46
47
48
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 45

Table 5 Protocol for Eculizumab

1
2 Dosing regimena
3 Body weight Induction Maintenance
4
5 ≥40 kg 900 mg/wk×4 doses 1,200 mg (week 5), then 1,200 mg q 2 wk
6
7 30 to <40 kg 600 mg/wk×2 doses 900 mg (week 3), then 900 mg q 2 wk
8 20 to <30 kg 600 mg/wk×2 doses 600 mg (week 3), then 600 mg q 2 wk
9
10 10 to <20 kg 600 mg/wk×1 dose 300 mg (week 2), then 300 mg q 2 wk
11
12 5 to <10 kg 300 mg/wk×1 dose 300 mg (week 2), then 300 mg q 3 wk
13 Diluted in 0.9% sodium chloride to achieve concentration of 5 mg/ml; infused over 1-4 hours
14
15 Monitoring of therapy
16
17 CH50 <10% (or AP50 <10%) on day 7
18 Eculizumab trough level >100 µg/ml (if available)
19
20 Meningococcal vaccination
21
22 Mandatory, at least 2-weeks prior to eculizumab, or as soon as possible
23 Quadrivalent conjugate vaccine (anti-A, C, Y, W) [Menactra if age >9 months]
24
25 Antibiotic prophylaxis
26
27 Methylpenicillin (dose for weight and renal function); macrolides
28
Mandatory during the first 2 weeks after vaccination
29
30 Maintained throughout eculizumab treatment (and up to 2 months after discontinuation)
31
32 Adverse effects
33
Headache, nasopharyngitis, back pain, diarrhea, anemia, leukopenia, vomiting
34
35 Refractoriness to therapy
36
37 Lack of hematological remission at 10-14 days (See text)
38
39
Duration of therapy
40 At least for 3-6 months to allow renal recovery
41
42 Duration of therapy not clear; may be discontinued if no known genetic defect
43
44 a
Supplemental dosing required in patients receiving concomitant plasma exchange
45
46
47
48
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15
16
17
18
19
46
20
21
22 Table 6 Risk of recurrent HUS after transplantation
23
24 Risk Type of defect Choice of donora Options to prevent recurrence
25
26 High (% risk) Mutations in CFB, CFH (75-100); C3, CFI Prefer cadaver to live Careful monitoring for recurrence
27
(40-80); THBD (unclear) donation Eculizumab (peri, post-transplantation) or
28
29 Combined liver kidney transplantation
30
31 Less preferred: PEX peri-and post-transplantation
32
33
Moderate Moderate to high titer anti-FH antibodies Live or cadaver donor Plasma exchanges and rituximab peri-transplantation
34 Careful monitoring for recurrence
35
36 Low Mutations in CD46 )MCP( Live or cadaver donor Monitoring for recurrence
37
38
Low titer anti-FH antibodies Consider rituximab peri-transplantation
39 Low or unclear Mutations in DGKE Live or cadaver donor Close monitoring for recurrence
40
41 Shiga toxin associated HUS
42
43 Secondary HUS
44 No identifiable defect
45
46 a
Live related donor must be genetically screened, especially if high risk
47
48
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Figures 1, 2